Mantle Cell Lymphoma

First-line combination biologic therapy with lenalidomide plus rituximab produced an 87% overall response rate in stage 3-4 mantle cell lymphoma, in an industry-sponsored, phase II clinical trial reported online Nov. 5 in the New England Journal of Medicine.

Mantle cell lymphoma is generally incurable, and patients have a median survival of 4-5 years. Initial therapy is usually very intensive, involving high-dose chemotherapy and hematopoietic cell transplantation. Since the malignancy primarily affects older adults who aren’t suitable candidates for intensive regimens, treatment “remains a clinical challenge,” said Dr. Jia Ruan of the Meyer Cancer Center and the division of biostatistics and epidemiology, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, and her associates.

Courtesy Wikimedia Commons/Nephron/Creative Commons

Reasoning that biologic therapy might offer effective disease control with fewer and less intense adverse effects, the investigators performed the open-label, single-group trial over a 3-year period. They treated 38 patients whose mean age was 65 years (range, 42-86 years), most of whom were at intermediate or high risk for imminent progression. These participants received a 12-cycle induction phase of lenalidomide plus rituximab, followed by a maintenance phase until disease progressed, unacceptable adverse effects developed, or patients withdrew from the study. The median follow-up was 30 months (range, 10-42 months).

The primary endpoint – overall response rate – was 87% in the intention-to-treat population, and the complete response rate was 61%. The number of complete responses increased over time with continuing treatment: the median time to a partial response was 3 months, and the median time to a complete response was 11 months. Two-year progression-free survival was 85%, and 2-year overall survival was 97%, the investigators said (New Engl. J. Med. 2015 Nov 5. doi: 10.1056/NEJMoa1505237).

Only eight patients showed progression of mantle cell lymphoma while taking lenalidomide plus rituximab, two of whom died from their disease. The other six patients responded to second-line therapy and remain alive, indicating that this first-line combination biologic therapy doesn’t compromise outcomes after subsequent treatments, Dr. Ruan and her associates said.

Almost as important as these favorable survival results were the findings concerning adverse effects. Scores on several quality-of-life measures either remained stable or improved throughout the induction and maintenance phases of treatment. As expected, grade 3 or 4 hematologic adverse effects included neutropenia (50% of patients), thrombocytopenia (13%), and anemia (11%), all of which resolved; grade 3 or 4 nonhematologic adverse effects included rash (29%), tumor flare (11%), serum sickness (8%), and fatigue (8%), all of which also resolved. All the serious infections that developed during the maintenance phase of treatment, which included pneumonia, cholangitis, and West Nile viral encephalitis, also resolved with antibiotics and supportive care.

Secondary cancers that developed during follow-up included two squamous cell skin cancers, one basal cell skin cancer, two cases of melanoma in situ, one Merkel cell carcinoma, and one pancreatic cancer.

“Our data show that a lower-intensity approach for initial therapy than that usually used in the case of patients with this cancer can be highly active, with durable responses observed in most patients,” Dr. Ruan and her associates said.

This study was supported by Celgene, maker of lenalidomide, and a Weill Cornell Medical College Clinical Translational Science Center grant. Dr. Ruan reported ties to Celgene, and her associates reported ties to numerous industry sources.

First-line combination biologic therapy with lenalidomide plus rituximab produced an 87% overall response rate in stage 3-4 mantle cell lymphoma, in an industry-sponsored, phase II clinical trial reported online Nov. 5 in the New England Journal of Medicine.

Mantle cell lymphoma is generally incurable, and patients have a median survival of 4-5 years. Initial therapy is usually very intensive, involving high-dose chemotherapy and hematopoietic cell transplantation. Since the malignancy primarily affects older adults who aren’t suitable candidates for intensive regimens, treatment “remains a clinical challenge,” said Dr. Jia Ruan of the Meyer Cancer Center and the division of biostatistics and epidemiology, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, and her associates.

Courtesy Wikimedia Commons/Nephron/Creative Commons

Reasoning that biologic therapy might offer effective disease control with fewer and less intense adverse effects, the investigators performed the open-label, single-group trial over a 3-year period. They treated 38 patients whose mean age was 65 years (range, 42-86 years), most of whom were at intermediate or high risk for imminent progression. These participants received a 12-cycle induction phase of lenalidomide plus rituximab, followed by a maintenance phase until disease progressed, unacceptable adverse effects developed, or patients withdrew from the study. The median follow-up was 30 months (range, 10-42 months).

The primary endpoint – overall response rate – was 87% in the intention-to-treat population, and the complete response rate was 61%. The number of complete responses increased over time with continuing treatment: the median time to a partial response was 3 months, and the median time to a complete response was 11 months. Two-year progression-free survival was 85%, and 2-year overall survival was 97%, the investigators said (New Engl. J. Med. 2015 Nov 5. doi: 10.1056/NEJMoa1505237).

Only eight patients showed progression of mantle cell lymphoma while taking lenalidomide plus rituximab, two of whom died from their disease. The other six patients responded to second-line therapy and remain alive, indicating that this first-line combination biologic therapy doesn’t compromise outcomes after subsequent treatments, Dr. Ruan and her associates said.

Almost as important as these favorable survival results were the findings concerning adverse effects. Scores on several quality-of-life measures either remained stable or improved throughout the induction and maintenance phases of treatment. As expected, grade 3 or 4 hematologic adverse effects included neutropenia (50% of patients), thrombocytopenia (13%), and anemia (11%), all of which resolved; grade 3 or 4 nonhematologic adverse effects included rash (29%), tumor flare (11%), serum sickness (8%), and fatigue (8%), all of which also resolved. All the serious infections that developed during the maintenance phase of treatment, which included pneumonia, cholangitis, and West Nile viral encephalitis, also resolved with antibiotics and supportive care.

Secondary cancers that developed during follow-up included two squamous cell skin cancers, one basal cell skin cancer, two cases of melanoma in situ, one Merkel cell carcinoma, and one pancreatic cancer.

“Our data show that a lower-intensity approach for initial therapy than that usually used in the case of patients with this cancer can be highly active, with durable responses observed in most patients,” Dr. Ruan and her associates said.

This study was supported by Celgene, maker of lenalidomide, and a Weill Cornell Medical College Clinical Translational Science Center grant. Dr. Ruan reported ties to Celgene, and her associates reported ties to numerous industry sources.

First-line combination biologic therapy with lenalidomide plus rituximab produced an 87% overall response rate in stage 3-4 mantle cell lymphoma, in an industry-sponsored, phase II clinical trial reported online Nov. 5 in the New England Journal of Medicine.

Mantle cell lymphoma is generally incurable, and patients have a median survival of 4-5 years. Initial therapy is usually very intensive, involving high-dose chemotherapy and hematopoietic cell transplantation. Since the malignancy primarily affects older adults who aren’t suitable candidates for intensive regimens, treatment “remains a clinical challenge,” said Dr. Jia Ruan of the Meyer Cancer Center and the division of biostatistics and epidemiology, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, and her associates.

Courtesy Wikimedia Commons/Nephron/Creative Commons

Reasoning that biologic therapy might offer effective disease control with fewer and less intense adverse effects, the investigators performed the open-label, single-group trial over a 3-year period. They treated 38 patients whose mean age was 65 years (range, 42-86 years), most of whom were at intermediate or high risk for imminent progression. These participants received a 12-cycle induction phase of lenalidomide plus rituximab, followed by a maintenance phase until disease progressed, unacceptable adverse effects developed, or patients withdrew from the study. The median follow-up was 30 months (range, 10-42 months).

The primary endpoint – overall response rate – was 87% in the intention-to-treat population, and the complete response rate was 61%. The number of complete responses increased over time with continuing treatment: the median time to a partial response was 3 months, and the median time to a complete response was 11 months. Two-year progression-free survival was 85%, and 2-year overall survival was 97%, the investigators said (New Engl. J. Med. 2015 Nov 5. doi: 10.1056/NEJMoa1505237).

Only eight patients showed progression of mantle cell lymphoma while taking lenalidomide plus rituximab, two of whom died from their disease. The other six patients responded to second-line therapy and remain alive, indicating that this first-line combination biologic therapy doesn’t compromise outcomes after subsequent treatments, Dr. Ruan and her associates said.

Almost as important as these favorable survival results were the findings concerning adverse effects. Scores on several quality-of-life measures either remained stable or improved throughout the induction and maintenance phases of treatment. As expected, grade 3 or 4 hematologic adverse effects included neutropenia (50% of patients), thrombocytopenia (13%), and anemia (11%), all of which resolved; grade 3 or 4 nonhematologic adverse effects included rash (29%), tumor flare (11%), serum sickness (8%), and fatigue (8%), all of which also resolved. All the serious infections that developed during the maintenance phase of treatment, which included pneumonia, cholangitis, and West Nile viral encephalitis, also resolved with antibiotics and supportive care.

Secondary cancers that developed during follow-up included two squamous cell skin cancers, one basal cell skin cancer, two cases of melanoma in situ, one Merkel cell carcinoma, and one pancreatic cancer.

“Our data show that a lower-intensity approach for initial therapy than that usually used in the case of patients with this cancer can be highly active, with durable responses observed in most patients,” Dr. Ruan and her associates said.

This study was supported by Celgene, maker of lenalidomide, and a Weill Cornell Medical College Clinical Translational Science Center grant. Dr. Ruan reported ties to Celgene, and her associates reported ties to numerous industry sources.

Reducing the dose of cytarabine from 800 mg/m² to 500 mg/m² allowed a regimen of rituximab, bendamustine, and cytarabine to be safely administered as first-line therapy to elderly patients who had mantle cell lymphoma and were not candidates for autologous stem cell transplant, according to Dr. Carlo Visco of the San Bortolo Hospital in Vicenza, Italy.

“Hematologic toxicity was substantially reduced, compared to the earlier study, Dr. Visco said, calling the R-BAC500 regimen “a highly effective treatment” for patients with mantle cell lymphoma.

Speaking at the at the International Congress on Malignant Lymphoma in Lugano, Switzerland, Dr. Visco noted the “encouraging results, but high hematologic toxicity” seen in a previous study that employed the higher cytarabine dose. In that previous study, transient grades 3-4 thrombocytopenia occurred in 76% of cycles.

Courtesy Wikimedia Commons/MarinaVladivostok/Creative Commons License

In an attempt to reduce hematologic toxicity, the Fondazione Italiana Linfomi designed a phase II trial in which the cytarabine dose was lowered to 500 mg/m² (R-BAC500). The administration schedule of cytarabine (on days 2-4) and the other components of the original regimen (rituximab, 375 mg/m^2, on day 1 and bendamustine, 70 mg/m^2, on days 2 and 3) remained unchanged.

The 57 study subjects, median age 71, had newly diagnosed mantle cell lymphoma, and were not eligible for autologous transplant as determined by the comprehensive geriatric assessment; 75% of the patients were males and 91% had Ann Arbor stage III/IV disease.

The Mantle Cell International Prognostic Index (MIPI) was low in 15%, intermediate in 40%, and high in 45%; 9% had the blastoid variant of the disease.

The primary endpoints were complete remission rate, as measured by 18-fluorodeoxyglucose–PET, according to Cheson criteria 2007, and safety. Secondary endpoints included molecular response rate, progression-free survival, and overall survival.

The overall response rate was 96%, and the complete remission rate was 93%. The molecular response rate at the end of treatment was 76% on peripheral blood and 55% on bone marrow samples. With a median follow-up of 18 months, the projected 2-year progression-free survival was 83%, and the overall survival was 91% without maintenance therapy.

Nearly all patients, 53 of 57, received at least four cycles of therapy, and 36 had six cycles. Treatment was discontinued because of toxicity (primarily hematologic) in 15 patients. Only one patient discontinued because of progressive disease.

Grade 3 or 4 neutropenia and thrombocytopenia were observed in about half of administered cycles. Febrile neutropenia occurred in 6%. Extrahematologic toxicity was mainly cardiac (5%).

Reducing the dose of cytarabine from 800 mg/m² to 500 mg/m² allowed a regimen of rituximab, bendamustine, and cytarabine to be safely administered as first-line therapy to elderly patients who had mantle cell lymphoma and were not candidates for autologous stem cell transplant, according to Dr. Carlo Visco of the San Bortolo Hospital in Vicenza, Italy.

“Hematologic toxicity was substantially reduced, compared to the earlier study, Dr. Visco said, calling the R-BAC500 regimen “a highly effective treatment” for patients with mantle cell lymphoma.

Speaking at the at the International Congress on Malignant Lymphoma in Lugano, Switzerland, Dr. Visco noted the “encouraging results, but high hematologic toxicity” seen in a previous study that employed the higher cytarabine dose. In that previous study, transient grades 3-4 thrombocytopenia occurred in 76% of cycles.

Courtesy Wikimedia Commons/MarinaVladivostok/Creative Commons License

In an attempt to reduce hematologic toxicity, the Fondazione Italiana Linfomi designed a phase II trial in which the cytarabine dose was lowered to 500 mg/m² (R-BAC500). The administration schedule of cytarabine (on days 2-4) and the other components of the original regimen (rituximab, 375 mg/m^2, on day 1 and bendamustine, 70 mg/m^2, on days 2 and 3) remained unchanged.

The 57 study subjects, median age 71, had newly diagnosed mantle cell lymphoma, and were not eligible for autologous transplant as determined by the comprehensive geriatric assessment; 75% of the patients were males and 91% had Ann Arbor stage III/IV disease.

The Mantle Cell International Prognostic Index (MIPI) was low in 15%, intermediate in 40%, and high in 45%; 9% had the blastoid variant of the disease.

The primary endpoints were complete remission rate, as measured by 18-fluorodeoxyglucose–PET, according to Cheson criteria 2007, and safety. Secondary endpoints included molecular response rate, progression-free survival, and overall survival.

The overall response rate was 96%, and the complete remission rate was 93%. The molecular response rate at the end of treatment was 76% on peripheral blood and 55% on bone marrow samples. With a median follow-up of 18 months, the projected 2-year progression-free survival was 83%, and the overall survival was 91% without maintenance therapy.

Nearly all patients, 53 of 57, received at least four cycles of therapy, and 36 had six cycles. Treatment was discontinued because of toxicity (primarily hematologic) in 15 patients. Only one patient discontinued because of progressive disease.

Grade 3 or 4 neutropenia and thrombocytopenia were observed in about half of administered cycles. Febrile neutropenia occurred in 6%. Extrahematologic toxicity was mainly cardiac (5%).

Reducing the dose of cytarabine from 800 mg/m² to 500 mg/m² allowed a regimen of rituximab, bendamustine, and cytarabine to be safely administered as first-line therapy to elderly patients who had mantle cell lymphoma and were not candidates for autologous stem cell transplant, according to Dr. Carlo Visco of the San Bortolo Hospital in Vicenza, Italy.

“Hematologic toxicity was substantially reduced, compared to the earlier study, Dr. Visco said, calling the R-BAC500 regimen “a highly effective treatment” for patients with mantle cell lymphoma.

Speaking at the at the International Congress on Malignant Lymphoma in Lugano, Switzerland, Dr. Visco noted the “encouraging results, but high hematologic toxicity” seen in a previous study that employed the higher cytarabine dose. In that previous study, transient grades 3-4 thrombocytopenia occurred in 76% of cycles.

Courtesy Wikimedia Commons/MarinaVladivostok/Creative Commons License

In an attempt to reduce hematologic toxicity, the Fondazione Italiana Linfomi designed a phase II trial in which the cytarabine dose was lowered to 500 mg/m² (R-BAC500). The administration schedule of cytarabine (on days 2-4) and the other components of the original regimen (rituximab, 375 mg/m^2, on day 1 and bendamustine, 70 mg/m^2, on days 2 and 3) remained unchanged.

The 57 study subjects, median age 71, had newly diagnosed mantle cell lymphoma, and were not eligible for autologous transplant as determined by the comprehensive geriatric assessment; 75% of the patients were males and 91% had Ann Arbor stage III/IV disease.

The Mantle Cell International Prognostic Index (MIPI) was low in 15%, intermediate in 40%, and high in 45%; 9% had the blastoid variant of the disease.

The primary endpoints were complete remission rate, as measured by 18-fluorodeoxyglucose–PET, according to Cheson criteria 2007, and safety. Secondary endpoints included molecular response rate, progression-free survival, and overall survival.

The overall response rate was 96%, and the complete remission rate was 93%. The molecular response rate at the end of treatment was 76% on peripheral blood and 55% on bone marrow samples. With a median follow-up of 18 months, the projected 2-year progression-free survival was 83%, and the overall survival was 91% without maintenance therapy.

Nearly all patients, 53 of 57, received at least four cycles of therapy, and 36 had six cycles. Treatment was discontinued because of toxicity (primarily hematologic) in 15 patients. Only one patient discontinued because of progressive disease.

Grade 3 or 4 neutropenia and thrombocytopenia were observed in about half of administered cycles. Febrile neutropenia occurred in 6%. Extrahematologic toxicity was mainly cardiac (5%).

Rituximab plus bendamustine may prove to be an induction-therapy option for younger patients with mantle cell lymphoma, Dr. Richard Chen and his colleagues in a SWOG (Southwest Oncology Group) trial reported at the International Congress on Malignant Lymphoma in Lugano, Switzerland.

Compared with a more aggressive combination regimen, a rituximab plus bendamustine (Treanda) option is a simple regimen that can be given in an outpatient setting and was associated with fewer adverse events and similar 2-year outcomes, the researchers found. The more aggressive regimen, however, was associated with lower-than-expected stem cell mobilization rates and the trial was prematurely closed, allowing no significant results.

Courtesy Wikimedia Commons/Nephron/Creative Commons

For this study, two induction-therapy regimens were compared in 53 patients with untreated stage III or IV (or bulky stage II) mantle cell lymphoma. All patients were less than age 65 years and received rituximab (R) in combination with one of two regimens: 18 patients received four cycles of R-HyperCVAD + methotrexate + cytarabine (R-HyperCVAD/MTX/ARA-C) and 35 patients received six cycles of R-bendamustine.

The overall response rate was 94% with R-HyperCVAD/MTX/ARA-C and 86% with R-bendamustine; the complete response rates were 31% and 43%, respectively; the partial response rates were 62% and 43%, respectively, Dr. Chen and his associates reported.

The median follow-up for surviving patients is nearly 24 months. The estimated 2-year progression-free survival was 87% for patients in both treatment groups.

Significantly higher rates of bone marrow toxicity occurred in the group receiving the R-HyperCVAD/MTX/ARA-C regimen, compared with the bendamustine regimen. Grade 3 and 4 thrombocytopenia occurred in 69% given R-HyperCVAD/MTX/ARA-C and 17% given R-bendamustine. Anemia affected 56% of those given R-HyperCVAD/MTX/ARA-C and 8.6% given R-bendamustine. Neutropenia was seen in 63% given R-HyperCVAD/MTX/ARA-C and 34% of patients given R-bendamustine. Febrile neutropenia occurred in 31% given R-HyperCVAD/MTX/ARA-C and 14% given R-bendamustine.

The study was discontinued prematurely because of the low mobilization of stem cells at the transplant phase of the study in patients given R-HyperCVAD/MTX/ARA-C. Just 4 of 16 patients on R-HyperCVAD/MTX/ARA-C and 21 of 35 patients given R-bendamustine underwent autologous stem cell transplants.

The R-bendamustine regimen seems less myelosuppressive. Because of the premature closure of the trial, the study did not reach statistical significance for 2-year progression-free survival, the researchers reported. Since bendamustine in combination with rituximab was associated with lower rates of hematologic toxicity, however, it warrants further study as an induction regimen, they concluded.

Rituximab plus bendamustine may prove to be an induction-therapy option for younger patients with mantle cell lymphoma, Dr. Richard Chen and his colleagues in a SWOG (Southwest Oncology Group) trial reported at the International Congress on Malignant Lymphoma in Lugano, Switzerland.

Compared with a more aggressive combination regimen, a rituximab plus bendamustine (Treanda) option is a simple regimen that can be given in an outpatient setting and was associated with fewer adverse events and similar 2-year outcomes, the researchers found. The more aggressive regimen, however, was associated with lower-than-expected stem cell mobilization rates and the trial was prematurely closed, allowing no significant results.

Courtesy Wikimedia Commons/Nephron/Creative Commons

For this study, two induction-therapy regimens were compared in 53 patients with untreated stage III or IV (or bulky stage II) mantle cell lymphoma. All patients were less than age 65 years and received rituximab (R) in combination with one of two regimens: 18 patients received four cycles of R-HyperCVAD + methotrexate + cytarabine (R-HyperCVAD/MTX/ARA-C) and 35 patients received six cycles of R-bendamustine.

The overall response rate was 94% with R-HyperCVAD/MTX/ARA-C and 86% with R-bendamustine; the complete response rates were 31% and 43%, respectively; the partial response rates were 62% and 43%, respectively, Dr. Chen and his associates reported.

The median follow-up for surviving patients is nearly 24 months. The estimated 2-year progression-free survival was 87% for patients in both treatment groups.

Significantly higher rates of bone marrow toxicity occurred in the group receiving the R-HyperCVAD/MTX/ARA-C regimen, compared with the bendamustine regimen. Grade 3 and 4 thrombocytopenia occurred in 69% given R-HyperCVAD/MTX/ARA-C and 17% given R-bendamustine. Anemia affected 56% of those given R-HyperCVAD/MTX/ARA-C and 8.6% given R-bendamustine. Neutropenia was seen in 63% given R-HyperCVAD/MTX/ARA-C and 34% of patients given R-bendamustine. Febrile neutropenia occurred in 31% given R-HyperCVAD/MTX/ARA-C and 14% given R-bendamustine.

The study was discontinued prematurely because of the low mobilization of stem cells at the transplant phase of the study in patients given R-HyperCVAD/MTX/ARA-C. Just 4 of 16 patients on R-HyperCVAD/MTX/ARA-C and 21 of 35 patients given R-bendamustine underwent autologous stem cell transplants.

The R-bendamustine regimen seems less myelosuppressive. Because of the premature closure of the trial, the study did not reach statistical significance for 2-year progression-free survival, the researchers reported. Since bendamustine in combination with rituximab was associated with lower rates of hematologic toxicity, however, it warrants further study as an induction regimen, they concluded.

Rituximab plus bendamustine may prove to be an induction-therapy option for younger patients with mantle cell lymphoma, Dr. Richard Chen and his colleagues in a SWOG (Southwest Oncology Group) trial reported at the International Congress on Malignant Lymphoma in Lugano, Switzerland.

Compared with a more aggressive combination regimen, a rituximab plus bendamustine (Treanda) option is a simple regimen that can be given in an outpatient setting and was associated with fewer adverse events and similar 2-year outcomes, the researchers found. The more aggressive regimen, however, was associated with lower-than-expected stem cell mobilization rates and the trial was prematurely closed, allowing no significant results.

Courtesy Wikimedia Commons/Nephron/Creative Commons

For this study, two induction-therapy regimens were compared in 53 patients with untreated stage III or IV (or bulky stage II) mantle cell lymphoma. All patients were less than age 65 years and received rituximab (R) in combination with one of two regimens: 18 patients received four cycles of R-HyperCVAD + methotrexate + cytarabine (R-HyperCVAD/MTX/ARA-C) and 35 patients received six cycles of R-bendamustine.

The overall response rate was 94% with R-HyperCVAD/MTX/ARA-C and 86% with R-bendamustine; the complete response rates were 31% and 43%, respectively; the partial response rates were 62% and 43%, respectively, Dr. Chen and his associates reported.

The median follow-up for surviving patients is nearly 24 months. The estimated 2-year progression-free survival was 87% for patients in both treatment groups.

Significantly higher rates of bone marrow toxicity occurred in the group receiving the R-HyperCVAD/MTX/ARA-C regimen, compared with the bendamustine regimen. Grade 3 and 4 thrombocytopenia occurred in 69% given R-HyperCVAD/MTX/ARA-C and 17% given R-bendamustine. Anemia affected 56% of those given R-HyperCVAD/MTX/ARA-C and 8.6% given R-bendamustine. Neutropenia was seen in 63% given R-HyperCVAD/MTX/ARA-C and 34% of patients given R-bendamustine. Febrile neutropenia occurred in 31% given R-HyperCVAD/MTX/ARA-C and 14% given R-bendamustine.

The study was discontinued prematurely because of the low mobilization of stem cells at the transplant phase of the study in patients given R-HyperCVAD/MTX/ARA-C. Just 4 of 16 patients on R-HyperCVAD/MTX/ARA-C and 21 of 35 patients given R-bendamustine underwent autologous stem cell transplants.

The R-bendamustine regimen seems less myelosuppressive. Because of the premature closure of the trial, the study did not reach statistical significance for 2-year progression-free survival, the researchers reported. Since bendamustine in combination with rituximab was associated with lower rates of hematologic toxicity, however, it warrants further study as an induction regimen, they concluded.

CHICAGO – Tweaking the R-CHOP recipe to substitute bortezomib for vincristine may bring clinical benefit to patients with newly diagnosed mantle cell lymphoma who are ineligible for bone marrow transplant.

In a randomized phase III trial in patients with MCL who could not undergo bone marrow transplant due to age or comorbidities, those patients who received a combination of rituximab, doxorubicin, bortezomib (Velcade), cyclophosphamide, and prednisone (the VR-CAP regimen) had significantly better progression-free survival than did patients treated with R-CHOP, the same regimen but with vincristine instead of bortezomib.

The VR-CAP regimen "could be considered a new standard of care for newly diagnosed mantle cell lymphoma patients not considered for intensive treatment and bone marrow transplant," Dr. Franco Cavalli reported at the annual meeting of the American Society of Clinical Oncology.

The bortezomib-containing regimen was associated with more grade 3 or 4 toxicities than standard R-CHOP, but adverse events were manageable, and most patients in each study arm were able to stay on chemotherapy for all prescribed cycles, said Dr. Cavalli of the Oncology Institute of Southern Switzerland, Bellinzona.

R-CHOP is a standard frontline therapy for patients with MCL who are deemed to be ineligible for intensive therapy and/or bone marrow transplant. But the regimen offers only limited progression-free survival (PFS) in this population, Dr. Cavalli said.

Because bortezomib is approved for the treatment of relapsed MCL in the United States and 53 other nations, the authors investigated whether it could improve outcomes when given to patients with newly diagnosed disease.

The LYM-3002 trial was a phase III study conducted at 128 centers in 28 countries in Europe, Asia, the Americas, and Africa. Patients with newly diagnosed MCL stage II-IV, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and who were ineligible or not considered for bone marrow transplant, were randomized to receive either R-CHOP or VR-CAP. In R-CHOP, vincristine 1.4 mg/m² was delivered to a maximum of 2 mg intravenously on day 1 of each cycle. In VR-CAP, bortezomib 1.3 mg/m² was delivered via intravenous infusion on days 1, 4, 8, and 11 of each cycle. Patients were assigned to receive at least six cycles of therapy, with an additional two cycles possible if investigator-assessed responses were first documented at the end of cycle 6.

A total of 487 patients (244 assigned to R-CHOP and 243 to VR-CAP) were included in the intention-to-treat analysis.

At a median follow-up of 40 months, median PFS, the primary endpoint, was 24.7 months in the VR-CAP arm, compared with 14.4 months for R-CHOP (hazard ratio, 0.63; P less than .001), as judged by an independent review committee. Investigator-rated PFS was 30.7 months vs. 16.1 months, respectively (HR, 0.51; P less than .001).

Clinical responses according to International Working Group revised response criteria for malignant lymphoma included overall response rates (complete response, complete unconfirmed response, and partial response) of 90% in the R-CHOP–treated patients and 92% in those who received VR-CAP.

However, there was a higher proportion of combined complete response and complete unconfirmed response in the VR-CAP group: 42% for R-CHOP vs. 53% for VR-CAP (odds ratio, 1.69; P = .007).

Median time to response was also shorter with VR-CAP (1.6 vs. 1.4 months; HR, 1.54; P less than .001).

Independent reviewer-rated median time-to-progression was 16.1 months for R-CHOP vs. 30.5 months for VR-CAP (HR, 0.58; P less than .001). Median time to next therapy was 24.8 vs. 44.5 months, respectively (HR, 0.50; P less than .001), and median treatment-free interval was 20.5 vs. 40.6 months (HR, 0.50; P less than .001).

Median overall survival was 56.3 months among R-CHOP–treated patients, vs. not reached among VR-CAP–treated patients.

Grade 3 or higher drug-related adverse events occurred in 85% and 93% of patients, respectively. The events were considered serious in 21% of R-CHOP–treated patients and in 33% of VR-CAP–treated patients. In all, 7% of patients on R-CHOP and 9% of those on VR-CAP discontinued therapy because of adverse events.

Grade 3 adverse events were more frequent with VR-CAP and included neutropenia, leukopenia, lymphopenia, and thrombocytopenia, the last of which occurred in 6% of patients on R-CHOP, compared with 57% for VR-CAP. Despite this difference, however, rates of grade 3 or higher bleeding were similar between the groups, occurring in 1.2% and 1.7%, respectively.

The invited discussant, Dr. Michael E. Williams, chief of hematology/oncology at the University of Virginia Cancer Center, Charlottesville, commented that the study provides proof of principle "that if you add an active single agent and substitute bortezomib for vincristine, which would appear to be a less active agent, that you can certainly improve PFS significantly."

Dr. Williams said that it remains to be seen, however, whether, as Dr. Cavalli suggested, certain treatment strategies could be used to lower the incidence of drug-related adverse events and improve PFS rates further, such as the use of subcutaneous rather than intravenous bortezomib, different dosing schedules, or rituximab in the maintenance phase.

The study was supported by Janssen Global Services and Millennium. Dr. Cavalli disclosed receiving travel support for attending the ASCO annual meeting, but reported having no other conflicts of interest. Dr. Williams disclosed consulting/advising for Millennium and receiving research funding from Janssen and Millennium.

CHICAGO – Tweaking the R-CHOP recipe to substitute bortezomib for vincristine may bring clinical benefit to patients with newly diagnosed mantle cell lymphoma who are ineligible for bone marrow transplant.

In a randomized phase III trial in patients with MCL who could not undergo bone marrow transplant due to age or comorbidities, those patients who received a combination of rituximab, doxorubicin, bortezomib (Velcade), cyclophosphamide, and prednisone (the VR-CAP regimen) had significantly better progression-free survival than did patients treated with R-CHOP, the same regimen but with vincristine instead of bortezomib.

The VR-CAP regimen "could be considered a new standard of care for newly diagnosed mantle cell lymphoma patients not considered for intensive treatment and bone marrow transplant," Dr. Franco Cavalli reported at the annual meeting of the American Society of Clinical Oncology.

The bortezomib-containing regimen was associated with more grade 3 or 4 toxicities than standard R-CHOP, but adverse events were manageable, and most patients in each study arm were able to stay on chemotherapy for all prescribed cycles, said Dr. Cavalli of the Oncology Institute of Southern Switzerland, Bellinzona.

R-CHOP is a standard frontline therapy for patients with MCL who are deemed to be ineligible for intensive therapy and/or bone marrow transplant. But the regimen offers only limited progression-free survival (PFS) in this population, Dr. Cavalli said.

Because bortezomib is approved for the treatment of relapsed MCL in the United States and 53 other nations, the authors investigated whether it could improve outcomes when given to patients with newly diagnosed disease.

The LYM-3002 trial was a phase III study conducted at 128 centers in 28 countries in Europe, Asia, the Americas, and Africa. Patients with newly diagnosed MCL stage II-IV, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and who were ineligible or not considered for bone marrow transplant, were randomized to receive either R-CHOP or VR-CAP. In R-CHOP, vincristine 1.4 mg/m² was delivered to a maximum of 2 mg intravenously on day 1 of each cycle. In VR-CAP, bortezomib 1.3 mg/m² was delivered via intravenous infusion on days 1, 4, 8, and 11 of each cycle. Patients were assigned to receive at least six cycles of therapy, with an additional two cycles possible if investigator-assessed responses were first documented at the end of cycle 6.

A total of 487 patients (244 assigned to R-CHOP and 243 to VR-CAP) were included in the intention-to-treat analysis.

At a median follow-up of 40 months, median PFS, the primary endpoint, was 24.7 months in the VR-CAP arm, compared with 14.4 months for R-CHOP (hazard ratio, 0.63; P less than .001), as judged by an independent review committee. Investigator-rated PFS was 30.7 months vs. 16.1 months, respectively (HR, 0.51; P less than .001).

Clinical responses according to International Working Group revised response criteria for malignant lymphoma included overall response rates (complete response, complete unconfirmed response, and partial response) of 90% in the R-CHOP–treated patients and 92% in those who received VR-CAP.

However, there was a higher proportion of combined complete response and complete unconfirmed response in the VR-CAP group: 42% for R-CHOP vs. 53% for VR-CAP (odds ratio, 1.69; P = .007).

Median time to response was also shorter with VR-CAP (1.6 vs. 1.4 months; HR, 1.54; P less than .001).

Independent reviewer-rated median time-to-progression was 16.1 months for R-CHOP vs. 30.5 months for VR-CAP (HR, 0.58; P less than .001). Median time to next therapy was 24.8 vs. 44.5 months, respectively (HR, 0.50; P less than .001), and median treatment-free interval was 20.5 vs. 40.6 months (HR, 0.50; P less than .001).

Median overall survival was 56.3 months among R-CHOP–treated patients, vs. not reached among VR-CAP–treated patients.

Grade 3 or higher drug-related adverse events occurred in 85% and 93% of patients, respectively. The events were considered serious in 21% of R-CHOP–treated patients and in 33% of VR-CAP–treated patients. In all, 7% of patients on R-CHOP and 9% of those on VR-CAP discontinued therapy because of adverse events.

Grade 3 adverse events were more frequent with VR-CAP and included neutropenia, leukopenia, lymphopenia, and thrombocytopenia, the last of which occurred in 6% of patients on R-CHOP, compared with 57% for VR-CAP. Despite this difference, however, rates of grade 3 or higher bleeding were similar between the groups, occurring in 1.2% and 1.7%, respectively.

The invited discussant, Dr. Michael E. Williams, chief of hematology/oncology at the University of Virginia Cancer Center, Charlottesville, commented that the study provides proof of principle "that if you add an active single agent and substitute bortezomib for vincristine, which would appear to be a less active agent, that you can certainly improve PFS significantly."

Dr. Williams said that it remains to be seen, however, whether, as Dr. Cavalli suggested, certain treatment strategies could be used to lower the incidence of drug-related adverse events and improve PFS rates further, such as the use of subcutaneous rather than intravenous bortezomib, different dosing schedules, or rituximab in the maintenance phase.

The study was supported by Janssen Global Services and Millennium. Dr. Cavalli disclosed receiving travel support for attending the ASCO annual meeting, but reported having no other conflicts of interest. Dr. Williams disclosed consulting/advising for Millennium and receiving research funding from Janssen and Millennium.

CHICAGO – Tweaking the R-CHOP recipe to substitute bortezomib for vincristine may bring clinical benefit to patients with newly diagnosed mantle cell lymphoma who are ineligible for bone marrow transplant.

In a randomized phase III trial in patients with MCL who could not undergo bone marrow transplant due to age or comorbidities, those patients who received a combination of rituximab, doxorubicin, bortezomib (Velcade), cyclophosphamide, and prednisone (the VR-CAP regimen) had significantly better progression-free survival than did patients treated with R-CHOP, the same regimen but with vincristine instead of bortezomib.

The VR-CAP regimen "could be considered a new standard of care for newly diagnosed mantle cell lymphoma patients not considered for intensive treatment and bone marrow transplant," Dr. Franco Cavalli reported at the annual meeting of the American Society of Clinical Oncology.

The bortezomib-containing regimen was associated with more grade 3 or 4 toxicities than standard R-CHOP, but adverse events were manageable, and most patients in each study arm were able to stay on chemotherapy for all prescribed cycles, said Dr. Cavalli of the Oncology Institute of Southern Switzerland, Bellinzona.

R-CHOP is a standard frontline therapy for patients with MCL who are deemed to be ineligible for intensive therapy and/or bone marrow transplant. But the regimen offers only limited progression-free survival (PFS) in this population, Dr. Cavalli said.

Because bortezomib is approved for the treatment of relapsed MCL in the United States and 53 other nations, the authors investigated whether it could improve outcomes when given to patients with newly diagnosed disease.

The LYM-3002 trial was a phase III study conducted at 128 centers in 28 countries in Europe, Asia, the Americas, and Africa. Patients with newly diagnosed MCL stage II-IV, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and who were ineligible or not considered for bone marrow transplant, were randomized to receive either R-CHOP or VR-CAP. In R-CHOP, vincristine 1.4 mg/m² was delivered to a maximum of 2 mg intravenously on day 1 of each cycle. In VR-CAP, bortezomib 1.3 mg/m² was delivered via intravenous infusion on days 1, 4, 8, and 11 of each cycle. Patients were assigned to receive at least six cycles of therapy, with an additional two cycles possible if investigator-assessed responses were first documented at the end of cycle 6.

A total of 487 patients (244 assigned to R-CHOP and 243 to VR-CAP) were included in the intention-to-treat analysis.

At a median follow-up of 40 months, median PFS, the primary endpoint, was 24.7 months in the VR-CAP arm, compared with 14.4 months for R-CHOP (hazard ratio, 0.63; P less than .001), as judged by an independent review committee. Investigator-rated PFS was 30.7 months vs. 16.1 months, respectively (HR, 0.51; P less than .001).

Clinical responses according to International Working Group revised response criteria for malignant lymphoma included overall response rates (complete response, complete unconfirmed response, and partial response) of 90% in the R-CHOP–treated patients and 92% in those who received VR-CAP.

However, there was a higher proportion of combined complete response and complete unconfirmed response in the VR-CAP group: 42% for R-CHOP vs. 53% for VR-CAP (odds ratio, 1.69; P = .007).

Median time to response was also shorter with VR-CAP (1.6 vs. 1.4 months; HR, 1.54; P less than .001).

Independent reviewer-rated median time-to-progression was 16.1 months for R-CHOP vs. 30.5 months for VR-CAP (HR, 0.58; P less than .001). Median time to next therapy was 24.8 vs. 44.5 months, respectively (HR, 0.50; P less than .001), and median treatment-free interval was 20.5 vs. 40.6 months (HR, 0.50; P less than .001).

Median overall survival was 56.3 months among R-CHOP–treated patients, vs. not reached among VR-CAP–treated patients.

Grade 3 or higher drug-related adverse events occurred in 85% and 93% of patients, respectively. The events were considered serious in 21% of R-CHOP–treated patients and in 33% of VR-CAP–treated patients. In all, 7% of patients on R-CHOP and 9% of those on VR-CAP discontinued therapy because of adverse events.

Grade 3 adverse events were more frequent with VR-CAP and included neutropenia, leukopenia, lymphopenia, and thrombocytopenia, the last of which occurred in 6% of patients on R-CHOP, compared with 57% for VR-CAP. Despite this difference, however, rates of grade 3 or higher bleeding were similar between the groups, occurring in 1.2% and 1.7%, respectively.

The invited discussant, Dr. Michael E. Williams, chief of hematology/oncology at the University of Virginia Cancer Center, Charlottesville, commented that the study provides proof of principle "that if you add an active single agent and substitute bortezomib for vincristine, which would appear to be a less active agent, that you can certainly improve PFS significantly."

Dr. Williams said that it remains to be seen, however, whether, as Dr. Cavalli suggested, certain treatment strategies could be used to lower the incidence of drug-related adverse events and improve PFS rates further, such as the use of subcutaneous rather than intravenous bortezomib, different dosing schedules, or rituximab in the maintenance phase.

The study was supported by Janssen Global Services and Millennium. Dr. Cavalli disclosed receiving travel support for attending the ASCO annual meeting, but reported having no other conflicts of interest. Dr. Williams disclosed consulting/advising for Millennium and receiving research funding from Janssen and Millennium.

In 2013, the Food and Drug Administration approved 27 new molecular entities (i.e., drugs) for human use. Because of their indications, it is unlikely that four will be used in pregnancy or lactation, so they are not discussed here. The four agents are ospemifene (Osphena), an estrogen agonist/antagonist used for severe dyspareunia; [²²³Ra]radium dichloride (Xofigo), for late-stage metastatic prostate cancer; conjugated estrogens/bazedoxifene (Duavee) for hot flashes associated with menopause and to prevent osteoporosis; and flutemetamol F-18 injection (Vizamyl), a radioactive diagnostic agent to aid in the evaluation of Alzheimer’s disease and dementia.

There are two other drugs that are unlikely to be used in pregnancy: macitentan (Opsumit) and riociguat (Adempas). These drugs are oral vasodilators indicated for the treatment of pulmonary hypertension. Both are teratogenic in rats and rabbits, but there are no reports of their use in human pregnancy. For female patients of reproductive potential, they are only available through restricted programs. Pregnancy must be excluded before starting therapy, monthly during treatment, and for 1 month after treatment is stopped.

The remaining 21 agents can be classified into the following categories: anticonvulsant (1), antidepressant (1), antidiabetics (2), antineoplastics (7), antihyperlipidemic (1), anti-infectives (4), diagnostics (2), immunologic (1), and respiratory (2). It is important to note that, except for two drugs (fluticasone in a combination product and dimethyl fumarate), there is no reported human pregnancy experience for these agents. Moreover, all probably cross the placenta to the embryo and/or the fetus, at least in some part of pregnancy.

Eslicarbazepine (Aptiom) is indicated as adjunctive treatment of partial-onset seizures. Developmental toxicity was observed in three animals: teratogenicity (mice), embryolethality (rats), and fetal growth restriction (rabbits). The no-effect dose was not found in two species, and was less than the human dose based on body surface area in the third. If a pregnant woman is taking this drug, she should be encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 888-233-2334.

Vortioxetine (Brintellix) is indicated for the treatment of major depressive disorder. The drug was not teratogenic in animals but did cause developmental delays in one species. Although the antidepressant mechanism is not fully understood, it appears to be related to the inhibition of the reuptake of serotonin (5-hydroxytryptamine). If so, vortioxetine would be closely related to the drugs in the selective serotonin reuptake inhibitor (SSRI) class: citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), and vilazodone (Viibryd). The relationship could be important because the use of SSRIs or serotonin norepinephrine reuptake inhibitors (SNRIs) close to birth is related to significant toxicity in the newborn.

There are two new antidiabetic agents for the treatment of type 2 diabetes. Alogliptin (Nesina), a dipeptidyl peptidase–4 inhibitor, is in the same pharmacologic class as linagliptin (Tradjenta), saxagliptin (Onglyza), and sitagliptin (Januvia). Canagliflozin (Invokana) is a sodium-glucose cotransporter 2 inhibitor, the first drug in this class to be approved. The animal data for alogliptin suggest low risk, whereas canagliflozin caused renal toxicity in rats at exposures corresponding to the late second and third trimester in humans. Insulin remains the treatment of choice for pregnant diabetics because tight control of glucose levels is beneficial for the mother, embryo-fetus, and newborn.

The seven new antineoplastic agents are ado-trastuzumab emtansine (Kadcyla) for HER2-positive breast cancer; afatinib (Gilotrif) for non–small cell lung cancer; dabrafenib (Tafinlar) for unresectable or metastatic melanoma; ibrutinib (Imbruvica) for mantle cell lymphoma or chronic lymphocytic leukemia; obinutuzumab (Gazyva) for chronic lymphocytic leukemia; pomalidomide (Pomalyst) for multiple myeloma; and trametinib (Mekinist) for unresectable or metastatic melanoma. Only pomalidomide is contraindicated in pregnancy. Although obinutuzumab did not cause teratogenicity in monkeys, its use in the latter portion of pregnancy resulted in newborn depletion of B cells that took up to 6 months after birth to restore. Moreover, it is used in combination with chlorambucil, a known teratogen. The animal data suggest risk in the other five agents. Nevertheless, the maternal condition should determine whether any of these antineoplastics are used in a pregnant woman.

Mipomersen sodium (Kynamro) is given subcutaneously once a week as an adjunct to lipid-lowering medications. The drug caused embryo toxicity in one of three animal species.

Among the four anti-infectives are two oral agents for the treatment of chronic hepatitis C virus infection: simeprevir (Olysio) and sofosbuvir (Sovaldi). Because both agents are recommended to be combined with peginterferon alfa and ribavirin, they are classified as contraindicated in pregnancy. However, when used alone, the animal data suggest that sofosbuvir was low risk, whereas simeprevir might have higher risk.

Luliconazole (Luzu), an azole antifungal, is a cream used for the treatment of tinea pedis, tinea cruris, and tinea corporis. Systemic absorption is minimal. The animal data suggest low risk, but there are no human pregnancy reports. Nevertheless, topical use is probably compatible in pregnancy, as are the other topical azole antifungals in this pharmacologic class: clotrimazole (Lotrimin), econazole (Spectazole), ketoconazole (Kuric), miconazole (Micatin), oxiconazole (Oxistat), sertaconazole (Ertaczo), and sulconazole (Exelderm).

Dolutegravir (Tivicay) is an HIV-1 integrase strand transfer inhibitor given in combination with other antiretroviral drugs. The animal data suggest low risk. If indicated, the drug should not be withheld because of pregnancy.

Gadoterate meglumine (Dotarem), a gadolinium-based contrast agent, is indicated to detect and visualize areas with disruption of the blood brain barrier and/or abnormal vascularity. No developmental toxicity was observed in pregnant animals. Closely related diagnostic agents are gadobenate dimeglumine (MultiHance), gadodiamide (Omniscan), gadofosveset (Ablavar), gadopentetate dimeglumine (Magnevist), gadoteridol (Prohance), and gadoversetamide (OptiMARK). Although the animal data for these agents show risk, no harm has been reported in human pregnancies. However, the available human data are very limited, and the risk magnitude for embryo-fetal harm remains unknown.

Technetium (^99mTc) tilmanocept (Lymphoseek) is a radioactive diagnostic agent used in patients with breast cancer or melanoma. The active ingredient is technetium (^99mTc). Animal reproduction studies have not been conducted. ^99mTc is probably compatible in pregnancy (see Drugs in Pregnancy and Lactation, 10th ed.; Philadelphia: Lippincott, Williams and Wilkins, 2014:1317-8; to be released in August), but the risk of the tilmanocept moiety is unknown.

The immunologic agent dimethyl fumarate (Tecfidera) is indicated for the treatment of patients with relapsing forms of multiple sclerosis. The drug caused developmental toxicity (embryolethality, impaired growth, and birth defects) in animals during all portions of pregnancy. In clinical trials, there were 38 exposed pregnancies with the following outcomes: 22 live births, 3 spontaneous abortions, 9 elective abortions, 3 ongoing pregnancies, and 1 lost to follow-up (CNS Drugs 2014;28:89-94). A pregnancy registry has been established, and patients should be encouraged to enroll by calling 800-456-2255.

Two new respiratory combination products were approved in 2013, both for chronic obstructive pulmonary disease: fluticasone/vilanterol (Breo Ellipta) and umeclidinium/vilanterol (Anoro Ellipta). Inhaled fluticasone, a corticosteroid, is compatible in pregnancy (see Drugs in Pregnancy and Lactation, 9th ed.; Philadelphia: Lippincott, Williams and Wilkins; 2011:599-601). Vilanterol is a long-acting beta₂-adrenergic agonist that is probably compatible in pregnancy. The absolute bioavailability of inhaled fluticasone and vilanterol in nonpregnant adults was about 15% and 27%, respectively. The animal data for the combination or when given individually suggest low risk in pregnancy. Umeclidinium is a long-acting anticholinergic. It also is absorbed from the lung, but the amount was not specified by the manufacturer. The animal data for umeclidinium suggest low risk.

There are no reports of the above drugs being used during breastfeeding, but excretion into breast milk should be expected. The effect of these exposures on a nursing infant is unknown. However, if a mother is taking one of these drugs and breastfeeding, her infant should be monitored for adverse effects, especially those that are the most common (typically listed on the first page of the package insert) in patients taking the drug. Close monitoring is particularly important during the first 2 postpartum months. A 2003 study found that most adverse reactions in nursing infants occurred within that time period (Clin. Pediatr. 2003;42:325-40).

Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He had no other relevant financial disclosures. Contact him at obnews@frontlinemedcom.com.

In 2013, the Food and Drug Administration approved 27 new molecular entities (i.e., drugs) for human use. Because of their indications, it is unlikely that four will be used in pregnancy or lactation, so they are not discussed here. The four agents are ospemifene (Osphena), an estrogen agonist/antagonist used for severe dyspareunia; [²²³Ra]radium dichloride (Xofigo), for late-stage metastatic prostate cancer; conjugated estrogens/bazedoxifene (Duavee) for hot flashes associated with menopause and to prevent osteoporosis; and flutemetamol F-18 injection (Vizamyl), a radioactive diagnostic agent to aid in the evaluation of Alzheimer’s disease and dementia.

There are two other drugs that are unlikely to be used in pregnancy: macitentan (Opsumit) and riociguat (Adempas). These drugs are oral vasodilators indicated for the treatment of pulmonary hypertension. Both are teratogenic in rats and rabbits, but there are no reports of their use in human pregnancy. For female patients of reproductive potential, they are only available through restricted programs. Pregnancy must be excluded before starting therapy, monthly during treatment, and for 1 month after treatment is stopped.

The remaining 21 agents can be classified into the following categories: anticonvulsant (1), antidepressant (1), antidiabetics (2), antineoplastics (7), antihyperlipidemic (1), anti-infectives (4), diagnostics (2), immunologic (1), and respiratory (2). It is important to note that, except for two drugs (fluticasone in a combination product and dimethyl fumarate), there is no reported human pregnancy experience for these agents. Moreover, all probably cross the placenta to the embryo and/or the fetus, at least in some part of pregnancy.

Eslicarbazepine (Aptiom) is indicated as adjunctive treatment of partial-onset seizures. Developmental toxicity was observed in three animals: teratogenicity (mice), embryolethality (rats), and fetal growth restriction (rabbits). The no-effect dose was not found in two species, and was less than the human dose based on body surface area in the third. If a pregnant woman is taking this drug, she should be encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 888-233-2334.

Vortioxetine (Brintellix) is indicated for the treatment of major depressive disorder. The drug was not teratogenic in animals but did cause developmental delays in one species. Although the antidepressant mechanism is not fully understood, it appears to be related to the inhibition of the reuptake of serotonin (5-hydroxytryptamine). If so, vortioxetine would be closely related to the drugs in the selective serotonin reuptake inhibitor (SSRI) class: citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), and vilazodone (Viibryd). The relationship could be important because the use of SSRIs or serotonin norepinephrine reuptake inhibitors (SNRIs) close to birth is related to significant toxicity in the newborn.

There are two new antidiabetic agents for the treatment of type 2 diabetes. Alogliptin (Nesina), a dipeptidyl peptidase–4 inhibitor, is in the same pharmacologic class as linagliptin (Tradjenta), saxagliptin (Onglyza), and sitagliptin (Januvia). Canagliflozin (Invokana) is a sodium-glucose cotransporter 2 inhibitor, the first drug in this class to be approved. The animal data for alogliptin suggest low risk, whereas canagliflozin caused renal toxicity in rats at exposures corresponding to the late second and third trimester in humans. Insulin remains the treatment of choice for pregnant diabetics because tight control of glucose levels is beneficial for the mother, embryo-fetus, and newborn.

The seven new antineoplastic agents are ado-trastuzumab emtansine (Kadcyla) for HER2-positive breast cancer; afatinib (Gilotrif) for non–small cell lung cancer; dabrafenib (Tafinlar) for unresectable or metastatic melanoma; ibrutinib (Imbruvica) for mantle cell lymphoma or chronic lymphocytic leukemia; obinutuzumab (Gazyva) for chronic lymphocytic leukemia; pomalidomide (Pomalyst) for multiple myeloma; and trametinib (Mekinist) for unresectable or metastatic melanoma. Only pomalidomide is contraindicated in pregnancy. Although obinutuzumab did not cause teratogenicity in monkeys, its use in the latter portion of pregnancy resulted in newborn depletion of B cells that took up to 6 months after birth to restore. Moreover, it is used in combination with chlorambucil, a known teratogen. The animal data suggest risk in the other five agents. Nevertheless, the maternal condition should determine whether any of these antineoplastics are used in a pregnant woman.

Mipomersen sodium (Kynamro) is given subcutaneously once a week as an adjunct to lipid-lowering medications. The drug caused embryo toxicity in one of three animal species.

Among the four anti-infectives are two oral agents for the treatment of chronic hepatitis C virus infection: simeprevir (Olysio) and sofosbuvir (Sovaldi). Because both agents are recommended to be combined with peginterferon alfa and ribavirin, they are classified as contraindicated in pregnancy. However, when used alone, the animal data suggest that sofosbuvir was low risk, whereas simeprevir might have higher risk.

Luliconazole (Luzu), an azole antifungal, is a cream used for the treatment of tinea pedis, tinea cruris, and tinea corporis. Systemic absorption is minimal. The animal data suggest low risk, but there are no human pregnancy reports. Nevertheless, topical use is probably compatible in pregnancy, as are the other topical azole antifungals in this pharmacologic class: clotrimazole (Lotrimin), econazole (Spectazole), ketoconazole (Kuric), miconazole (Micatin), oxiconazole (Oxistat), sertaconazole (Ertaczo), and sulconazole (Exelderm).

Dolutegravir (Tivicay) is an HIV-1 integrase strand transfer inhibitor given in combination with other antiretroviral drugs. The animal data suggest low risk. If indicated, the drug should not be withheld because of pregnancy.

Gadoterate meglumine (Dotarem), a gadolinium-based contrast agent, is indicated to detect and visualize areas with disruption of the blood brain barrier and/or abnormal vascularity. No developmental toxicity was observed in pregnant animals. Closely related diagnostic agents are gadobenate dimeglumine (MultiHance), gadodiamide (Omniscan), gadofosveset (Ablavar), gadopentetate dimeglumine (Magnevist), gadoteridol (Prohance), and gadoversetamide (OptiMARK). Although the animal data for these agents show risk, no harm has been reported in human pregnancies. However, the available human data are very limited, and the risk magnitude for embryo-fetal harm remains unknown.

Technetium (^99mTc) tilmanocept (Lymphoseek) is a radioactive diagnostic agent used in patients with breast cancer or melanoma. The active ingredient is technetium (^99mTc). Animal reproduction studies have not been conducted. ^99mTc is probably compatible in pregnancy (see Drugs in Pregnancy and Lactation, 10th ed.; Philadelphia: Lippincott, Williams and Wilkins, 2014:1317-8; to be released in August), but the risk of the tilmanocept moiety is unknown.

The immunologic agent dimethyl fumarate (Tecfidera) is indicated for the treatment of patients with relapsing forms of multiple sclerosis. The drug caused developmental toxicity (embryolethality, impaired growth, and birth defects) in animals during all portions of pregnancy. In clinical trials, there were 38 exposed pregnancies with the following outcomes: 22 live births, 3 spontaneous abortions, 9 elective abortions, 3 ongoing pregnancies, and 1 lost to follow-up (CNS Drugs 2014;28:89-94). A pregnancy registry has been established, and patients should be encouraged to enroll by calling 800-456-2255.

Two new respiratory combination products were approved in 2013, both for chronic obstructive pulmonary disease: fluticasone/vilanterol (Breo Ellipta) and umeclidinium/vilanterol (Anoro Ellipta). Inhaled fluticasone, a corticosteroid, is compatible in pregnancy (see Drugs in Pregnancy and Lactation, 9th ed.; Philadelphia: Lippincott, Williams and Wilkins; 2011:599-601). Vilanterol is a long-acting beta₂-adrenergic agonist that is probably compatible in pregnancy. The absolute bioavailability of inhaled fluticasone and vilanterol in nonpregnant adults was about 15% and 27%, respectively. The animal data for the combination or when given individually suggest low risk in pregnancy. Umeclidinium is a long-acting anticholinergic. It also is absorbed from the lung, but the amount was not specified by the manufacturer. The animal data for umeclidinium suggest low risk.

There are no reports of the above drugs being used during breastfeeding, but excretion into breast milk should be expected. The effect of these exposures on a nursing infant is unknown. However, if a mother is taking one of these drugs and breastfeeding, her infant should be monitored for adverse effects, especially those that are the most common (typically listed on the first page of the package insert) in patients taking the drug. Close monitoring is particularly important during the first 2 postpartum months. A 2003 study found that most adverse reactions in nursing infants occurred within that time period (Clin. Pediatr. 2003;42:325-40).

Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He had no other relevant financial disclosures. Contact him at obnews@frontlinemedcom.com.

In 2013, the Food and Drug Administration approved 27 new molecular entities (i.e., drugs) for human use. Because of their indications, it is unlikely that four will be used in pregnancy or lactation, so they are not discussed here. The four agents are ospemifene (Osphena), an estrogen agonist/antagonist used for severe dyspareunia; [²²³Ra]radium dichloride (Xofigo), for late-stage metastatic prostate cancer; conjugated estrogens/bazedoxifene (Duavee) for hot flashes associated with menopause and to prevent osteoporosis; and flutemetamol F-18 injection (Vizamyl), a radioactive diagnostic agent to aid in the evaluation of Alzheimer’s disease and dementia.

There are two other drugs that are unlikely to be used in pregnancy: macitentan (Opsumit) and riociguat (Adempas). These drugs are oral vasodilators indicated for the treatment of pulmonary hypertension. Both are teratogenic in rats and rabbits, but there are no reports of their use in human pregnancy. For female patients of reproductive potential, they are only available through restricted programs. Pregnancy must be excluded before starting therapy, monthly during treatment, and for 1 month after treatment is stopped.

The remaining 21 agents can be classified into the following categories: anticonvulsant (1), antidepressant (1), antidiabetics (2), antineoplastics (7), antihyperlipidemic (1), anti-infectives (4), diagnostics (2), immunologic (1), and respiratory (2). It is important to note that, except for two drugs (fluticasone in a combination product and dimethyl fumarate), there is no reported human pregnancy experience for these agents. Moreover, all probably cross the placenta to the embryo and/or the fetus, at least in some part of pregnancy.

Eslicarbazepine (Aptiom) is indicated as adjunctive treatment of partial-onset seizures. Developmental toxicity was observed in three animals: teratogenicity (mice), embryolethality (rats), and fetal growth restriction (rabbits). The no-effect dose was not found in two species, and was less than the human dose based on body surface area in the third. If a pregnant woman is taking this drug, she should be encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 888-233-2334.

Vortioxetine (Brintellix) is indicated for the treatment of major depressive disorder. The drug was not teratogenic in animals but did cause developmental delays in one species. Although the antidepressant mechanism is not fully understood, it appears to be related to the inhibition of the reuptake of serotonin (5-hydroxytryptamine). If so, vortioxetine would be closely related to the drugs in the selective serotonin reuptake inhibitor (SSRI) class: citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), and vilazodone (Viibryd). The relationship could be important because the use of SSRIs or serotonin norepinephrine reuptake inhibitors (SNRIs) close to birth is related to significant toxicity in the newborn.

There are two new antidiabetic agents for the treatment of type 2 diabetes. Alogliptin (Nesina), a dipeptidyl peptidase–4 inhibitor, is in the same pharmacologic class as linagliptin (Tradjenta), saxagliptin (Onglyza), and sitagliptin (Januvia). Canagliflozin (Invokana) is a sodium-glucose cotransporter 2 inhibitor, the first drug in this class to be approved. The animal data for alogliptin suggest low risk, whereas canagliflozin caused renal toxicity in rats at exposures corresponding to the late second and third trimester in humans. Insulin remains the treatment of choice for pregnant diabetics because tight control of glucose levels is beneficial for the mother, embryo-fetus, and newborn.

The seven new antineoplastic agents are ado-trastuzumab emtansine (Kadcyla) for HER2-positive breast cancer; afatinib (Gilotrif) for non–small cell lung cancer; dabrafenib (Tafinlar) for unresectable or metastatic melanoma; ibrutinib (Imbruvica) for mantle cell lymphoma or chronic lymphocytic leukemia; obinutuzumab (Gazyva) for chronic lymphocytic leukemia; pomalidomide (Pomalyst) for multiple myeloma; and trametinib (Mekinist) for unresectable or metastatic melanoma. Only pomalidomide is contraindicated in pregnancy. Although obinutuzumab did not cause teratogenicity in monkeys, its use in the latter portion of pregnancy resulted in newborn depletion of B cells that took up to 6 months after birth to restore. Moreover, it is used in combination with chlorambucil, a known teratogen. The animal data suggest risk in the other five agents. Nevertheless, the maternal condition should determine whether any of these antineoplastics are used in a pregnant woman.

Mipomersen sodium (Kynamro) is given subcutaneously once a week as an adjunct to lipid-lowering medications. The drug caused embryo toxicity in one of three animal species.

Among the four anti-infectives are two oral agents for the treatment of chronic hepatitis C virus infection: simeprevir (Olysio) and sofosbuvir (Sovaldi). Because both agents are recommended to be combined with peginterferon alfa and ribavirin, they are classified as contraindicated in pregnancy. However, when used alone, the animal data suggest that sofosbuvir was low risk, whereas simeprevir might have higher risk.

Luliconazole (Luzu), an azole antifungal, is a cream used for the treatment of tinea pedis, tinea cruris, and tinea corporis. Systemic absorption is minimal. The animal data suggest low risk, but there are no human pregnancy reports. Nevertheless, topical use is probably compatible in pregnancy, as are the other topical azole antifungals in this pharmacologic class: clotrimazole (Lotrimin), econazole (Spectazole), ketoconazole (Kuric), miconazole (Micatin), oxiconazole (Oxistat), sertaconazole (Ertaczo), and sulconazole (Exelderm).

Dolutegravir (Tivicay) is an HIV-1 integrase strand transfer inhibitor given in combination with other antiretroviral drugs. The animal data suggest low risk. If indicated, the drug should not be withheld because of pregnancy.

Gadoterate meglumine (Dotarem), a gadolinium-based contrast agent, is indicated to detect and visualize areas with disruption of the blood brain barrier and/or abnormal vascularity. No developmental toxicity was observed in pregnant animals. Closely related diagnostic agents are gadobenate dimeglumine (MultiHance), gadodiamide (Omniscan), gadofosveset (Ablavar), gadopentetate dimeglumine (Magnevist), gadoteridol (Prohance), and gadoversetamide (OptiMARK). Although the animal data for these agents show risk, no harm has been reported in human pregnancies. However, the available human data are very limited, and the risk magnitude for embryo-fetal harm remains unknown.

Technetium (^99mTc) tilmanocept (Lymphoseek) is a radioactive diagnostic agent used in patients with breast cancer or melanoma. The active ingredient is technetium (^99mTc). Animal reproduction studies have not been conducted. ^99mTc is probably compatible in pregnancy (see Drugs in Pregnancy and Lactation, 10th ed.; Philadelphia: Lippincott, Williams and Wilkins, 2014:1317-8; to be released in August), but the risk of the tilmanocept moiety is unknown.

The immunologic agent dimethyl fumarate (Tecfidera) is indicated for the treatment of patients with relapsing forms of multiple sclerosis. The drug caused developmental toxicity (embryolethality, impaired growth, and birth defects) in animals during all portions of pregnancy. In clinical trials, there were 38 exposed pregnancies with the following outcomes: 22 live births, 3 spontaneous abortions, 9 elective abortions, 3 ongoing pregnancies, and 1 lost to follow-up (CNS Drugs 2014;28:89-94). A pregnancy registry has been established, and patients should be encouraged to enroll by calling 800-456-2255.

Two new respiratory combination products were approved in 2013, both for chronic obstructive pulmonary disease: fluticasone/vilanterol (Breo Ellipta) and umeclidinium/vilanterol (Anoro Ellipta). Inhaled fluticasone, a corticosteroid, is compatible in pregnancy (see Drugs in Pregnancy and Lactation, 9th ed.; Philadelphia: Lippincott, Williams and Wilkins; 2011:599-601). Vilanterol is a long-acting beta₂-adrenergic agonist that is probably compatible in pregnancy. The absolute bioavailability of inhaled fluticasone and vilanterol in nonpregnant adults was about 15% and 27%, respectively. The animal data for the combination or when given individually suggest low risk in pregnancy. Umeclidinium is a long-acting anticholinergic. It also is absorbed from the lung, but the amount was not specified by the manufacturer. The animal data for umeclidinium suggest low risk.

There are no reports of the above drugs being used during breastfeeding, but excretion into breast milk should be expected. The effect of these exposures on a nursing infant is unknown. However, if a mother is taking one of these drugs and breastfeeding, her infant should be monitored for adverse effects, especially those that are the most common (typically listed on the first page of the package insert) in patients taking the drug. Close monitoring is particularly important during the first 2 postpartum months. A 2003 study found that most adverse reactions in nursing infants occurred within that time period (Clin. Pediatr. 2003;42:325-40).

Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He had no other relevant financial disclosures. Contact him at obnews@frontlinemedcom.com.

NEW ORLEANS – Early data suggest that the second-generation oral BTK inhibitor ONO-4059 may give ibrutinib a run for its money in chronic lymphocytic leukemia.

The response rate to ONO-4059 monotherapy was 89% overall and 71% in those with the deleterious 17p deletion among 18 heavily pretreated patients with relapsed/refractory or high-risk CLL in a phase I, dose-escalation study.

Courtesy Guillaume Cartron

Patients had already received a median of three prior therapies, including rituximab (84%) and fludarabine (95%), and had no higher priority therapy available to them, said Dr. Gilles Salles of Hospices Civils de Lyon (France), Universite Claude Bernard Lyon.

All patients had improved hemoglobin and platelet counts after 3 months on treatment and rapid reductions in lymph node size within the first 28-day cycle. Tumor burden was reduced by 50% for most patients, and all but one patient experienced a response that was detectable on a CT scan.

"This was true whatever their FISH status or 17p or 11q deletion status," Dr. Salles said at the annual meeting of the American Society of Hematology.

ONO-4059 is a highly selective Bruton’s tyrosine kinase (BTK) inhibitor with antitumor activity in several preclinical models.

No patients had received prior treatment with a P13 kinase or a BTK inhibitor, including ibrutinib (Imbruvica), which recently gained accelerated approval for previously treated mantle cell lymphoma.

ONO-4059 was given at daily doses ranging from 20 mg to 320 mg for up to 6 months, with the option of additional dosing up to 2 years. Sustained BTK inhibition was established at doses of 40 mg and higher.

Overall, the best response was a partial response in 14 patients, as well as two partial responses with lymphocytosis and one stable disease, he said. No complete responses occurred.

One patient progressed roughly 1 month after showing an initial response and complete disappearance of all palpable disease on physical exam. Richter’s syndrome was suspected.

Courtesy Guillaume Cartron

"It’s very promising efficacy in this highly pretreated population," Dr. Salles said.

Patients with relapsed/refractory mantle cell lymphoma and diffuse large B-cell lymphoma, especially the ABC subtype, also appear sensitive to ONO-4059. Overall response rates were 43% and 75%, respectively, including three complete responses reported from the phase I study in a separate poster presentation at the meeting.

ONO-4059 had a favorable safety profile with a single dose-limiting toxicity observed in a patient who had Waldenstrom’s macroglobulinemia, was on the 320-mg dose, and was intolerant to all prior therapies. The maximum tolerated dose has not yet been reached.

The majority of adverse events in the CLL patients were grades 1 and 2. There were no clinically significant bleeding events or bruising, and there was a low incidence of diarrhea and rash, Dr. Salles said.

ONO-4059–related grade 3-4 events were independent of dose and included one grade 3 neutropenia at 20 mg and two grade 4 events at 20 mg and 320 mg. Four serious adverse events (febrile neutropenia, pyrexia, rash, and neutropenia) occurred in three patients, all of whom are still in the study and showing good clinical response, Dr. Salles said. Of the 30 patients dosed to date, 22 remain in the study.

No other trials are firmly planned, and pharmacokinetics/pharmacodynamics data continue to be explored in order to assess a phase II dosage, he said in an interview.

Dr. Salles reported consulting for and receiving honoraria from Roche. Several coauthors have financial ties, including employment with the study sponsor, Ono Pharmaceutical, which is developing ONO-4059.

pwendling@frontlinemedcom.com

NEW ORLEANS – Early data suggest that the second-generation oral BTK inhibitor ONO-4059 may give ibrutinib a run for its money in chronic lymphocytic leukemia.

The response rate to ONO-4059 monotherapy was 89% overall and 71% in those with the deleterious 17p deletion among 18 heavily pretreated patients with relapsed/refractory or high-risk CLL in a phase I, dose-escalation study.

Courtesy Guillaume Cartron

Patients had already received a median of three prior therapies, including rituximab (84%) and fludarabine (95%), and had no higher priority therapy available to them, said Dr. Gilles Salles of Hospices Civils de Lyon (France), Universite Claude Bernard Lyon.

All patients had improved hemoglobin and platelet counts after 3 months on treatment and rapid reductions in lymph node size within the first 28-day cycle. Tumor burden was reduced by 50% for most patients, and all but one patient experienced a response that was detectable on a CT scan.

"This was true whatever their FISH status or 17p or 11q deletion status," Dr. Salles said at the annual meeting of the American Society of Hematology.

ONO-4059 is a highly selective Bruton’s tyrosine kinase (BTK) inhibitor with antitumor activity in several preclinical models.

No patients had received prior treatment with a P13 kinase or a BTK inhibitor, including ibrutinib (Imbruvica), which recently gained accelerated approval for previously treated mantle cell lymphoma.

ONO-4059 was given at daily doses ranging from 20 mg to 320 mg for up to 6 months, with the option of additional dosing up to 2 years. Sustained BTK inhibition was established at doses of 40 mg and higher.

Overall, the best response was a partial response in 14 patients, as well as two partial responses with lymphocytosis and one stable disease, he said. No complete responses occurred.

One patient progressed roughly 1 month after showing an initial response and complete disappearance of all palpable disease on physical exam. Richter’s syndrome was suspected.

Courtesy Guillaume Cartron

"It’s very promising efficacy in this highly pretreated population," Dr. Salles said.

Patients with relapsed/refractory mantle cell lymphoma and diffuse large B-cell lymphoma, especially the ABC subtype, also appear sensitive to ONO-4059. Overall response rates were 43% and 75%, respectively, including three complete responses reported from the phase I study in a separate poster presentation at the meeting.

ONO-4059 had a favorable safety profile with a single dose-limiting toxicity observed in a patient who had Waldenstrom’s macroglobulinemia, was on the 320-mg dose, and was intolerant to all prior therapies. The maximum tolerated dose has not yet been reached.

The majority of adverse events in the CLL patients were grades 1 and 2. There were no clinically significant bleeding events or bruising, and there was a low incidence of diarrhea and rash, Dr. Salles said.

ONO-4059–related grade 3-4 events were independent of dose and included one grade 3 neutropenia at 20 mg and two grade 4 events at 20 mg and 320 mg. Four serious adverse events (febrile neutropenia, pyrexia, rash, and neutropenia) occurred in three patients, all of whom are still in the study and showing good clinical response, Dr. Salles said. Of the 30 patients dosed to date, 22 remain in the study.

No other trials are firmly planned, and pharmacokinetics/pharmacodynamics data continue to be explored in order to assess a phase II dosage, he said in an interview.

Dr. Salles reported consulting for and receiving honoraria from Roche. Several coauthors have financial ties, including employment with the study sponsor, Ono Pharmaceutical, which is developing ONO-4059.

pwendling@frontlinemedcom.com

NEW ORLEANS – Early data suggest that the second-generation oral BTK inhibitor ONO-4059 may give ibrutinib a run for its money in chronic lymphocytic leukemia.

The response rate to ONO-4059 monotherapy was 89% overall and 71% in those with the deleterious 17p deletion among 18 heavily pretreated patients with relapsed/refractory or high-risk CLL in a phase I, dose-escalation study.

Courtesy Guillaume Cartron

Patients had already received a median of three prior therapies, including rituximab (84%) and fludarabine (95%), and had no higher priority therapy available to them, said Dr. Gilles Salles of Hospices Civils de Lyon (France), Universite Claude Bernard Lyon.

All patients had improved hemoglobin and platelet counts after 3 months on treatment and rapid reductions in lymph node size within the first 28-day cycle. Tumor burden was reduced by 50% for most patients, and all but one patient experienced a response that was detectable on a CT scan.

"This was true whatever their FISH status or 17p or 11q deletion status," Dr. Salles said at the annual meeting of the American Society of Hematology.

ONO-4059 is a highly selective Bruton’s tyrosine kinase (BTK) inhibitor with antitumor activity in several preclinical models.

No patients had received prior treatment with a P13 kinase or a BTK inhibitor, including ibrutinib (Imbruvica), which recently gained accelerated approval for previously treated mantle cell lymphoma.

ONO-4059 was given at daily doses ranging from 20 mg to 320 mg for up to 6 months, with the option of additional dosing up to 2 years. Sustained BTK inhibition was established at doses of 40 mg and higher.

Overall, the best response was a partial response in 14 patients, as well as two partial responses with lymphocytosis and one stable disease, he said. No complete responses occurred.

One patient progressed roughly 1 month after showing an initial response and complete disappearance of all palpable disease on physical exam. Richter’s syndrome was suspected.

Courtesy Guillaume Cartron

"It’s very promising efficacy in this highly pretreated population," Dr. Salles said.

Patients with relapsed/refractory mantle cell lymphoma and diffuse large B-cell lymphoma, especially the ABC subtype, also appear sensitive to ONO-4059. Overall response rates were 43% and 75%, respectively, including three complete responses reported from the phase I study in a separate poster presentation at the meeting.

ONO-4059 had a favorable safety profile with a single dose-limiting toxicity observed in a patient who had Waldenstrom’s macroglobulinemia, was on the 320-mg dose, and was intolerant to all prior therapies. The maximum tolerated dose has not yet been reached.

The majority of adverse events in the CLL patients were grades 1 and 2. There were no clinically significant bleeding events or bruising, and there was a low incidence of diarrhea and rash, Dr. Salles said.

ONO-4059–related grade 3-4 events were independent of dose and included one grade 3 neutropenia at 20 mg and two grade 4 events at 20 mg and 320 mg. Four serious adverse events (febrile neutropenia, pyrexia, rash, and neutropenia) occurred in three patients, all of whom are still in the study and showing good clinical response, Dr. Salles said. Of the 30 patients dosed to date, 22 remain in the study.

No other trials are firmly planned, and pharmacokinetics/pharmacodynamics data continue to be explored in order to assess a phase II dosage, he said in an interview.

Dr. Salles reported consulting for and receiving honoraria from Roche. Several coauthors have financial ties, including employment with the study sponsor, Ono Pharmaceutical, which is developing ONO-4059.

pwendling@frontlinemedcom.com

Ibrutinib is now approved for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy, the Food and Drug Administration announced Nov. 13.

The once-daily, oral therapy, marketed as Imbruvica, is the second drug to receive FDA approval under the breakthrough therapy designation established to speed the development and review of treatments for serious or life-threatening diseases.

"Imbruvica’s approval demonstrates the FDA’s commitment to making treatments available to patients with rare diseases," Dr. Richard Pazdur, director of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research, said in a statement.

Mantle cell lymphoma is an orphan disease, with only about 2,900 new cases of MCL diagnosed each year. MCL comprises only about 6% of all non-Hodgkin’s lymphoma cases in the United States.

Ibrutinib’s approval comes a little more than 4 months after the new drug application was filed in June 2013 and is based on a phase II study reporting an investigator-assessed overall response rate of 66% at a daily dose of 560 mg ibrutinib in 111 patients with relapsed or refractory MCL after a median of three prior therapies. The median duration of response was 17.5 months. An improvement in survival and disease-related symptoms has not been established.

Ibrutinib works by blocking Bruton’s tyrosine kinase, a mediator of the B-cell receptor signaling pathway that has been shown in nonclinical studies to inhibit malignant B-cell survival.

The FDA also granted ibrutinib priority review and orphan-product designation, because the drug demonstrated "the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition and is intended to treat a rare disease," according to the FDA statement.

Ibrutinib is the third drug approved to treat MCL. In June 2013, the FDA approved the oral thalidomide analogue lenalidomide (Revlimid) for the treatment of MCL that had relapsed or progressed after two prior therapies including bortezomib (Velcade), a subcutaneous therapy that has been available for MCL since 2006.

"It is gratifying to see an early example of the new breakthrough therapy designation pathway meeting its intention – getting promising treatments to patients who are waiting for new options," Dr. Ellen V. Sigal, chairperson and founder of the Washington-based Friends of Cancer Research advocacy organization, said in a statement issued by Janssen Biotech, which is comarketing the drug with Pharmacyclics.

The two companies are expected to continue with phase III studies of ibrutinib and have also submitted the drug to the FDA for the treatment of previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma.

In the pivotal MCL trial, the most common treatment-related adverse events with single-agent ibrutinib were mild or moderate diarrhea, fatigue, and nausea (N. Engl. J. Med. 2013;369:507-16). Grade 3 or higher hematologic events were neutropenia (16%), thrombocytopenia (11%), and anemia (10%).

pwendling@frontlinemedcom.com

Ibrutinib is now approved for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy, the Food and Drug Administration announced Nov. 13.

The once-daily, oral therapy, marketed as Imbruvica, is the second drug to receive FDA approval under the breakthrough therapy designation established to speed the development and review of treatments for serious or life-threatening diseases.

"Imbruvica’s approval demonstrates the FDA’s commitment to making treatments available to patients with rare diseases," Dr. Richard Pazdur, director of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research, said in a statement.

Mantle cell lymphoma is an orphan disease, with only about 2,900 new cases of MCL diagnosed each year. MCL comprises only about 6% of all non-Hodgkin’s lymphoma cases in the United States.

Ibrutinib’s approval comes a little more than 4 months after the new drug application was filed in June 2013 and is based on a phase II study reporting an investigator-assessed overall response rate of 66% at a daily dose of 560 mg ibrutinib in 111 patients with relapsed or refractory MCL after a median of three prior therapies. The median duration of response was 17.5 months. An improvement in survival and disease-related symptoms has not been established.

Ibrutinib works by blocking Bruton’s tyrosine kinase, a mediator of the B-cell receptor signaling pathway that has been shown in nonclinical studies to inhibit malignant B-cell survival.

The FDA also granted ibrutinib priority review and orphan-product designation, because the drug demonstrated "the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition and is intended to treat a rare disease," according to the FDA statement.

Ibrutinib is the third drug approved to treat MCL. In June 2013, the FDA approved the oral thalidomide analogue lenalidomide (Revlimid) for the treatment of MCL that had relapsed or progressed after two prior therapies including bortezomib (Velcade), a subcutaneous therapy that has been available for MCL since 2006.

"It is gratifying to see an early example of the new breakthrough therapy designation pathway meeting its intention – getting promising treatments to patients who are waiting for new options," Dr. Ellen V. Sigal, chairperson and founder of the Washington-based Friends of Cancer Research advocacy organization, said in a statement issued by Janssen Biotech, which is comarketing the drug with Pharmacyclics.

The two companies are expected to continue with phase III studies of ibrutinib and have also submitted the drug to the FDA for the treatment of previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma.

In the pivotal MCL trial, the most common treatment-related adverse events with single-agent ibrutinib were mild or moderate diarrhea, fatigue, and nausea (N. Engl. J. Med. 2013;369:507-16). Grade 3 or higher hematologic events were neutropenia (16%), thrombocytopenia (11%), and anemia (10%).

pwendling@frontlinemedcom.com

Ibrutinib is now approved for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy, the Food and Drug Administration announced Nov. 13.

The once-daily, oral therapy, marketed as Imbruvica, is the second drug to receive FDA approval under the breakthrough therapy designation established to speed the development and review of treatments for serious or life-threatening diseases.

"Imbruvica’s approval demonstrates the FDA’s commitment to making treatments available to patients with rare diseases," Dr. Richard Pazdur, director of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research, said in a statement.

Mantle cell lymphoma is an orphan disease, with only about 2,900 new cases of MCL diagnosed each year. MCL comprises only about 6% of all non-Hodgkin’s lymphoma cases in the United States.

Ibrutinib’s approval comes a little more than 4 months after the new drug application was filed in June 2013 and is based on a phase II study reporting an investigator-assessed overall response rate of 66% at a daily dose of 560 mg ibrutinib in 111 patients with relapsed or refractory MCL after a median of three prior therapies. The median duration of response was 17.5 months. An improvement in survival and disease-related symptoms has not been established.

Ibrutinib works by blocking Bruton’s tyrosine kinase, a mediator of the B-cell receptor signaling pathway that has been shown in nonclinical studies to inhibit malignant B-cell survival.

The FDA also granted ibrutinib priority review and orphan-product designation, because the drug demonstrated "the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition and is intended to treat a rare disease," according to the FDA statement.

Ibrutinib is the third drug approved to treat MCL. In June 2013, the FDA approved the oral thalidomide analogue lenalidomide (Revlimid) for the treatment of MCL that had relapsed or progressed after two prior therapies including bortezomib (Velcade), a subcutaneous therapy that has been available for MCL since 2006.

"It is gratifying to see an early example of the new breakthrough therapy designation pathway meeting its intention – getting promising treatments to patients who are waiting for new options," Dr. Ellen V. Sigal, chairperson and founder of the Washington-based Friends of Cancer Research advocacy organization, said in a statement issued by Janssen Biotech, which is comarketing the drug with Pharmacyclics.

The two companies are expected to continue with phase III studies of ibrutinib and have also submitted the drug to the FDA for the treatment of previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma.

In the pivotal MCL trial, the most common treatment-related adverse events with single-agent ibrutinib were mild or moderate diarrhea, fatigue, and nausea (N. Engl. J. Med. 2013;369:507-16). Grade 3 or higher hematologic events were neutropenia (16%), thrombocytopenia (11%), and anemia (10%).

pwendling@frontlinemedcom.com

The Food and Drug Administration has approved lenalidomide for the treatment of patients whose mantle cell lymphoma has relapsed or progressed after two prior therapies, one of which included bortezomib.

Lenalidomide, a thalidomide analogue, is already approved for use in combination with dexamethasone for multiple myeloma in patients who have received at least one prior therapy. Lenalidomide also is approved for transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities.

"There remains a tremendous unmet need for [therapies for] patients with previously treated mantle cell lymphoma," said Dr. Andre Goy, chairman and director, and chief of the division of lymphoma at the John Theurer Cancer Center at Hackensack (N.J.) University Medical Center, in a statement issued by lenalidomide maker Celgene. "The approval of lenalidomide delivers a new option and the first oral therapy in this area of lymphoma."

Mantle cell lymphoma is fairly rare, accounting for about 6% of the 66,360 new cases of non-Hodgkin’s lymphoma diagnosed in the United States each year, according to the Leukemia and Lymphoma Society.

The Food and Drug Administration (FDA) said it based its approval on a single-arm, multicenter study with 134 patients who had relapsed after or were refractory to bortezomib or a bortezomib-containing regimen. In the 133 patients who were evaluable for efficacy, the overall lenalidomide response rate was 26%. Nine patients (7%) had a complete response or unconfirmed complete response, and 25 (19%) had a partial response. In the 34 responders, the median duration of response was 16.6 months.

Due to adverse events, a little more than half of the patients had to interrupt therapy; 38% had a dose reduction and 19% discontinued therapy. The most common reactions included neutropenia, thrombocytopenia, fatigue, anemia, diarrhea, nausea, cough, pyrexia, rash, dyspnea, pruritus, constipation, peripheral edema, and leukopenia, according to the FDA.

In May 2012, the agency also determined that patients taking the drug for newly diagnosed multiple myeloma are at increased risk for secondary cancers.

Lenalidomide was approved at a recommended dose and schedule of 25 mg orally once daily on days 1-21 of repeated 28-day cycles. Celgene also received approval for a new 20-mg strength of lenalidomide.

aault@frontlinemedcom.com

On Twitter @aliciaault

The Food and Drug Administration has approved lenalidomide for the treatment of patients whose mantle cell lymphoma has relapsed or progressed after two prior therapies, one of which included bortezomib.

Lenalidomide, a thalidomide analogue, is already approved for use in combination with dexamethasone for multiple myeloma in patients who have received at least one prior therapy. Lenalidomide also is approved for transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities.

"There remains a tremendous unmet need for [therapies for] patients with previously treated mantle cell lymphoma," said Dr. Andre Goy, chairman and director, and chief of the division of lymphoma at the John Theurer Cancer Center at Hackensack (N.J.) University Medical Center, in a statement issued by lenalidomide maker Celgene. "The approval of lenalidomide delivers a new option and the first oral therapy in this area of lymphoma."

Mantle cell lymphoma is fairly rare, accounting for about 6% of the 66,360 new cases of non-Hodgkin’s lymphoma diagnosed in the United States each year, according to the Leukemia and Lymphoma Society.

The Food and Drug Administration (FDA) said it based its approval on a single-arm, multicenter study with 134 patients who had relapsed after or were refractory to bortezomib or a bortezomib-containing regimen. In the 133 patients who were evaluable for efficacy, the overall lenalidomide response rate was 26%. Nine patients (7%) had a complete response or unconfirmed complete response, and 25 (19%) had a partial response. In the 34 responders, the median duration of response was 16.6 months.

Due to adverse events, a little more than half of the patients had to interrupt therapy; 38% had a dose reduction and 19% discontinued therapy. The most common reactions included neutropenia, thrombocytopenia, fatigue, anemia, diarrhea, nausea, cough, pyrexia, rash, dyspnea, pruritus, constipation, peripheral edema, and leukopenia, according to the FDA.

In May 2012, the agency also determined that patients taking the drug for newly diagnosed multiple myeloma are at increased risk for secondary cancers.

Lenalidomide was approved at a recommended dose and schedule of 25 mg orally once daily on days 1-21 of repeated 28-day cycles. Celgene also received approval for a new 20-mg strength of lenalidomide.

aault@frontlinemedcom.com

On Twitter @aliciaault

The Food and Drug Administration has approved lenalidomide for the treatment of patients whose mantle cell lymphoma has relapsed or progressed after two prior therapies, one of which included bortezomib.

Lenalidomide, a thalidomide analogue, is already approved for use in combination with dexamethasone for multiple myeloma in patients who have received at least one prior therapy. Lenalidomide also is approved for transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities.

"There remains a tremendous unmet need for [therapies for] patients with previously treated mantle cell lymphoma," said Dr. Andre Goy, chairman and director, and chief of the division of lymphoma at the John Theurer Cancer Center at Hackensack (N.J.) University Medical Center, in a statement issued by lenalidomide maker Celgene. "The approval of lenalidomide delivers a new option and the first oral therapy in this area of lymphoma."

Mantle cell lymphoma is fairly rare, accounting for about 6% of the 66,360 new cases of non-Hodgkin’s lymphoma diagnosed in the United States each year, according to the Leukemia and Lymphoma Society.

The Food and Drug Administration (FDA) said it based its approval on a single-arm, multicenter study with 134 patients who had relapsed after or were refractory to bortezomib or a bortezomib-containing regimen. In the 133 patients who were evaluable for efficacy, the overall lenalidomide response rate was 26%. Nine patients (7%) had a complete response or unconfirmed complete response, and 25 (19%) had a partial response. In the 34 responders, the median duration of response was 16.6 months.

Due to adverse events, a little more than half of the patients had to interrupt therapy; 38% had a dose reduction and 19% discontinued therapy. The most common reactions included neutropenia, thrombocytopenia, fatigue, anemia, diarrhea, nausea, cough, pyrexia, rash, dyspnea, pruritus, constipation, peripheral edema, and leukopenia, according to the FDA.

In May 2012, the agency also determined that patients taking the drug for newly diagnosed multiple myeloma are at increased risk for secondary cancers.

Lenalidomide was approved at a recommended dose and schedule of 25 mg orally once daily on days 1-21 of repeated 28-day cycles. Celgene also received approval for a new 20-mg strength of lenalidomide.

aault@frontlinemedcom.com

On Twitter @aliciaault

ATLANTA – More than one-fifth of patients with relapsed or refractory mantle cell lymphoma had a complete response to single-agent therapy with experimental ibrutinib, and another two-fifths had a partial response, investigators reported.

"Colleagues, this is the highest response rate ever reported, ever achieved by one single drug in the history of relapsed mantle cell lymphoma," Dr. Michael Wang told attendees at the annual meeting of the American Society of Hematology.

Dr. Wang’s evident excitement about the data came exactly 1 year to the day after he announced preliminary results of the phase II trial at ASH 2011. At that time, the drug was known only as PCI-32765.

Those early data showed that ibrutinib, an oral inhibitor of Bruton’s tyrosine kinase (BTK) expressed in several hematologic malignancies, induced complete response in 16% and partial response in 53% of patients evaluated at that time for a combined overall response rate of 69%.

The drug demonstrated efficacy against bulky disease, and its effects in early studies appeared to be independent of the MCL [Mantle Cell Lymphoma] International Prognostic Index (MIPI) score.

At this year’s meeting, Dr. Wang of the University of Texas M.D. Anderson Cancer Center, Houston, reported that in an efficacy cohort of 110 patients, 22% had a complete response and 46% a partial response. Among patients who had previously been treated with bortezomib (Velcade), 23% had a complete response, and 49% had a partial response. In bortezomib-naive patients the response rates were 21% and 44%, respectively.

At 9.2 months of follow-up (data cutoff Sept. 21, 2012), the median duration of response had not been reached. Median progression-free survival was 13.9 months.

Ibrutinib was well tolerated

BTK, an essential element of the B-cell antigen receptor–signaling pathway, is expressed in several hematologic malignancies, including lymphoma and chronic lymphocytic leukemia, for which positive clinical trial data were also presented at the meeting. Ibrutinib blocks receptor signaling and induces apoptosis, as well as mantle cell migration and adhesion. It has been shown in in vitro studies to block pERK, pJNK, and NF-KappaB pathways in MCL cell lines.

Dr. Wang and colleagues at 18 U.S. and European centers enrolled patients with confirmed overexpression of cyclin D1 or the 11;14 translocation and measurable disease. The patients had not been able to achieve at least a partial response to prior therapy, or had disease progression following their most recent treatment regimen. All had at least one, but not more than five prior lines of therapy, and adequate end-organ function, and Eastern Cooperative Oncology Group performance status of 2 or lower.

The drug was generally well tolerated, he said, with neutropenia, thrombocytopenia, and anemia being the most frequent hematologic toxicities, and diarrhea, fatigue, nausea, and respiratory tract infections being the most common nonhematologic adverse events.

Dr. Wang noted that longer follow-up of data on 51 patients in the cohort that he presented at ASH 2011 show improvement in complete response rates. The initial rates among bortezomib-naive, bortezomib experienced, and all patients were 16%, 15%, and 16%, respectively, at a median of 3.7 months. In the current follow-up of these patients, however (median 14.7 months), the complete response rates had improved to 40%, 38%, and 39%, respectively, with respective overall response rates of 77%, 71%, and 75%. He called the gradual increase in complete response rates the "phenomenon of incremental response."

Phenomenon of incremental response

Dr. Andrew D. Zelenetz of Memorial Sloan-Kettering Cancer Center, New York, said after Dr. Wang’s presentation that the "phenomenon of incremental response" Dr. Wang described is not really a phenomenon at all.

"The reason you’re giving the drug continuously is that you expect to see a better response," he said. "It’s not unique to this drug, but in rituximab it’s seen when you stop the drug, in lenalidomide it’s seen when you stop the drug, and in radioimmunotherapy it’s seen when you stop the drug. So incremental response is a well described phenomenon in lymphomas," Dr. Zelenetz said.

"This has been just an interim analysis our data. We look forward to updating you with the final results of this clinical trial with excitement, caution, and confidence," Dr.Wang said.

The study was supported by Pharmacyclics. Dr. Wang is on the scientific advisory board of the company. Dr. Zelenetz had no relevant disclosures.

ATLANTA – More than one-fifth of patients with relapsed or refractory mantle cell lymphoma had a complete response to single-agent therapy with experimental ibrutinib, and another two-fifths had a partial response, investigators reported.

"Colleagues, this is the highest response rate ever reported, ever achieved by one single drug in the history of relapsed mantle cell lymphoma," Dr. Michael Wang told attendees at the annual meeting of the American Society of Hematology.

Dr. Wang’s evident excitement about the data came exactly 1 year to the day after he announced preliminary results of the phase II trial at ASH 2011. At that time, the drug was known only as PCI-32765.

Those early data showed that ibrutinib, an oral inhibitor of Bruton’s tyrosine kinase (BTK) expressed in several hematologic malignancies, induced complete response in 16% and partial response in 53% of patients evaluated at that time for a combined overall response rate of 69%.

The drug demonstrated efficacy against bulky disease, and its effects in early studies appeared to be independent of the MCL [Mantle Cell Lymphoma] International Prognostic Index (MIPI) score.

At this year’s meeting, Dr. Wang of the University of Texas M.D. Anderson Cancer Center, Houston, reported that in an efficacy cohort of 110 patients, 22% had a complete response and 46% a partial response. Among patients who had previously been treated with bortezomib (Velcade), 23% had a complete response, and 49% had a partial response. In bortezomib-naive patients the response rates were 21% and 44%, respectively.

At 9.2 months of follow-up (data cutoff Sept. 21, 2012), the median duration of response had not been reached. Median progression-free survival was 13.9 months.

Ibrutinib was well tolerated

BTK, an essential element of the B-cell antigen receptor–signaling pathway, is expressed in several hematologic malignancies, including lymphoma and chronic lymphocytic leukemia, for which positive clinical trial data were also presented at the meeting. Ibrutinib blocks receptor signaling and induces apoptosis, as well as mantle cell migration and adhesion. It has been shown in in vitro studies to block pERK, pJNK, and NF-KappaB pathways in MCL cell lines.

Dr. Wang and colleagues at 18 U.S. and European centers enrolled patients with confirmed overexpression of cyclin D1 or the 11;14 translocation and measurable disease. The patients had not been able to achieve at least a partial response to prior therapy, or had disease progression following their most recent treatment regimen. All had at least one, but not more than five prior lines of therapy, and adequate end-organ function, and Eastern Cooperative Oncology Group performance status of 2 or lower.

The drug was generally well tolerated, he said, with neutropenia, thrombocytopenia, and anemia being the most frequent hematologic toxicities, and diarrhea, fatigue, nausea, and respiratory tract infections being the most common nonhematologic adverse events.

Dr. Wang noted that longer follow-up of data on 51 patients in the cohort that he presented at ASH 2011 show improvement in complete response rates. The initial rates among bortezomib-naive, bortezomib experienced, and all patients were 16%, 15%, and 16%, respectively, at a median of 3.7 months. In the current follow-up of these patients, however (median 14.7 months), the complete response rates had improved to 40%, 38%, and 39%, respectively, with respective overall response rates of 77%, 71%, and 75%. He called the gradual increase in complete response rates the "phenomenon of incremental response."

Phenomenon of incremental response

Dr. Andrew D. Zelenetz of Memorial Sloan-Kettering Cancer Center, New York, said after Dr. Wang’s presentation that the "phenomenon of incremental response" Dr. Wang described is not really a phenomenon at all.

"The reason you’re giving the drug continuously is that you expect to see a better response," he said. "It’s not unique to this drug, but in rituximab it’s seen when you stop the drug, in lenalidomide it’s seen when you stop the drug, and in radioimmunotherapy it’s seen when you stop the drug. So incremental response is a well described phenomenon in lymphomas," Dr. Zelenetz said.

"This has been just an interim analysis our data. We look forward to updating you with the final results of this clinical trial with excitement, caution, and confidence," Dr.Wang said.

The study was supported by Pharmacyclics. Dr. Wang is on the scientific advisory board of the company. Dr. Zelenetz had no relevant disclosures.

ATLANTA – More than one-fifth of patients with relapsed or refractory mantle cell lymphoma had a complete response to single-agent therapy with experimental ibrutinib, and another two-fifths had a partial response, investigators reported.

"Colleagues, this is the highest response rate ever reported, ever achieved by one single drug in the history of relapsed mantle cell lymphoma," Dr. Michael Wang told attendees at the annual meeting of the American Society of Hematology.

Dr. Wang’s evident excitement about the data came exactly 1 year to the day after he announced preliminary results of the phase II trial at ASH 2011. At that time, the drug was known only as PCI-32765.

Those early data showed that ibrutinib, an oral inhibitor of Bruton’s tyrosine kinase (BTK) expressed in several hematologic malignancies, induced complete response in 16% and partial response in 53% of patients evaluated at that time for a combined overall response rate of 69%.

The drug demonstrated efficacy against bulky disease, and its effects in early studies appeared to be independent of the MCL [Mantle Cell Lymphoma] International Prognostic Index (MIPI) score.

At this year’s meeting, Dr. Wang of the University of Texas M.D. Anderson Cancer Center, Houston, reported that in an efficacy cohort of 110 patients, 22% had a complete response and 46% a partial response. Among patients who had previously been treated with bortezomib (Velcade), 23% had a complete response, and 49% had a partial response. In bortezomib-naive patients the response rates were 21% and 44%, respectively.

At 9.2 months of follow-up (data cutoff Sept. 21, 2012), the median duration of response had not been reached. Median progression-free survival was 13.9 months.

Ibrutinib was well tolerated

BTK, an essential element of the B-cell antigen receptor–signaling pathway, is expressed in several hematologic malignancies, including lymphoma and chronic lymphocytic leukemia, for which positive clinical trial data were also presented at the meeting. Ibrutinib blocks receptor signaling and induces apoptosis, as well as mantle cell migration and adhesion. It has been shown in in vitro studies to block pERK, pJNK, and NF-KappaB pathways in MCL cell lines.

Dr. Wang and colleagues at 18 U.S. and European centers enrolled patients with confirmed overexpression of cyclin D1 or the 11;14 translocation and measurable disease. The patients had not been able to achieve at least a partial response to prior therapy, or had disease progression following their most recent treatment regimen. All had at least one, but not more than five prior lines of therapy, and adequate end-organ function, and Eastern Cooperative Oncology Group performance status of 2 or lower.

The drug was generally well tolerated, he said, with neutropenia, thrombocytopenia, and anemia being the most frequent hematologic toxicities, and diarrhea, fatigue, nausea, and respiratory tract infections being the most common nonhematologic adverse events.

Dr. Wang noted that longer follow-up of data on 51 patients in the cohort that he presented at ASH 2011 show improvement in complete response rates. The initial rates among bortezomib-naive, bortezomib experienced, and all patients were 16%, 15%, and 16%, respectively, at a median of 3.7 months. In the current follow-up of these patients, however (median 14.7 months), the complete response rates had improved to 40%, 38%, and 39%, respectively, with respective overall response rates of 77%, 71%, and 75%. He called the gradual increase in complete response rates the "phenomenon of incremental response."

Phenomenon of incremental response

Dr. Andrew D. Zelenetz of Memorial Sloan-Kettering Cancer Center, New York, said after Dr. Wang’s presentation that the "phenomenon of incremental response" Dr. Wang described is not really a phenomenon at all.

"The reason you’re giving the drug continuously is that you expect to see a better response," he said. "It’s not unique to this drug, but in rituximab it’s seen when you stop the drug, in lenalidomide it’s seen when you stop the drug, and in radioimmunotherapy it’s seen when you stop the drug. So incremental response is a well described phenomenon in lymphomas," Dr. Zelenetz said.

"This has been just an interim analysis our data. We look forward to updating you with the final results of this clinical trial with excitement, caution, and confidence," Dr.Wang said.

The study was supported by Pharmacyclics. Dr. Wang is on the scientific advisory board of the company. Dr. Zelenetz had no relevant disclosures.

AMSTERDAM – Although it is rare and the prognosis for patients is often poor, the presence of central nervous system involvement at the time of diagnosis of mantle cell lymphoma is not always immediately fatal, according to findings from an international study.

According to the European Mantle Cell Lymphoma Network (EMCLN) findings, the crude prevalence of CNS events was 0.9% at the time of diagnosis and 4.1% at any time. The multicenter, retrospective study found that the median time to a CNS event’s occurring was 15.2 months, with an overall survival of 3.9 months after the event was identified, but some patients were still alive 2 years later.

"We now have some better descriptors about what the expectations and outcome of patients with central nervous system involvement are," Dr. John Seymour said in an interview at the annual congress of the European Hematology Association.

Dr. Seymour, professor and chair of the hematology service at Australia’s Peter MacCallum Cancer Centre in East Melbourne, Victoria, added that even though the overall prognosis of patients who develop CNS involvement is very poor, there are some patients who do better than others.

There is "a subgroup [of patients] who are able to receive high-dose ara-c [cytarabine] or high-dose methotrexate treatment, who are young and fit enough, who do somewhat better," Dr. Seymour said. "A proportion will be alive at 2 years, so it’s not an inevitably, rapidly fatal, and ... futile situation."

Mantle cell lymphomas are a rare type of non-Hodgkin’s lymphoma (NHL), accounting for just less than 3% of all NHL cases in the United States and affecting primarily more elderly patients (Cancer 2008;113:791-8).CNS involvement is also a rare and often devastating event, but it has not previously been very well characterized. As a result, it’s not known whether CNS prophylaxis is of benefit to patients.

The aim of the EMCLN study, therefore, was to look at the problem in more detail, to determine the prevalence of CNS involvement, and to look for any clinically defining features, effect of treatment, and patient outcomes.

A retrospective database review by EMCLN members in 12 centers identified 1,396 patients with mantle cell lymphoma, of whom 1,339 had no CNS involvement. Of the 57 patients with CNS involvement, most (44) developed it at some point during the course of their follow-up.

At diagnosis of mantle cell lymphoma, the patients who developed CNS involvement had a median age of 61 years, but this ranged from 38 years to 82 years; patients were predominantly men (70%), with stage IV (91%) disease, and 28% had blastoid histology. Isolated CNS involvement occurred in 15 cases.

Prominent features were a high MIPI (Mantle Cell Lymphoma International Prognostic Index) score (61% of cases), a Ki-67 greater than 30% in 69% of patients, and increased beta₂-microglobulin and lactate dehydrogenase in 77% and 75% of cases, respectively. The bone marrow and the peripheral blood were the most common extranodal sites involved, affecting two or more sites in 61% of patients.

At diagnosis of CNS involvement, patients’ neurologic symptoms included weakness, altered mental state, headache, and ocular problems such as double vision. Other symptoms – such as sensory disturbances, pain, sciatica, dizziness, vertigo, ataxia, seizure, and dysphagia – occurred but were less frequent.

CSF cytology and flow cytometry showed a high sensitivity for identifying CNS involvement, with 85% having positive cytology and 91% a positive flow cytometry result.

"Patients had a range of chemotherapies prior to developing central nervous system involvement, but receipt of these regimens was not totally protective," Dr. Seymour said. Data were not collected to enable the relative risk of CNS development with the regimens received.

Chemotherapy was the most frequent treatment strategy to allay CNS disease (67%), and some patients did appear to achieve a complete remission of the CNS disease as a result. In an exploratory analysis, these patients also tended to have improved overall survival, as did those with lower white cell counts (less than 10.9 x 10⁹/L), and who received treatment with high-dose antimetabolites.

"In the longer term, these data will provide a foundation for us to identify predictive factors, to identify – ahead of the event – those people at increased risk," Dr. Seymour said, adding his hope that this will allow preventive steps to be taken.

Dr. Seymour had no conflicts of interest.

AMSTERDAM – Although it is rare and the prognosis for patients is often poor, the presence of central nervous system involvement at the time of diagnosis of mantle cell lymphoma is not always immediately fatal, according to findings from an international study.

According to the European Mantle Cell Lymphoma Network (EMCLN) findings, the crude prevalence of CNS events was 0.9% at the time of diagnosis and 4.1% at any time. The multicenter, retrospective study found that the median time to a CNS event’s occurring was 15.2 months, with an overall survival of 3.9 months after the event was identified, but some patients were still alive 2 years later.

"We now have some better descriptors about what the expectations and outcome of patients with central nervous system involvement are," Dr. John Seymour said in an interview at the annual congress of the European Hematology Association.

Dr. Seymour, professor and chair of the hematology service at Australia’s Peter MacCallum Cancer Centre in East Melbourne, Victoria, added that even though the overall prognosis of patients who develop CNS involvement is very poor, there are some patients who do better than others.

There is "a subgroup [of patients] who are able to receive high-dose ara-c [cytarabine] or high-dose methotrexate treatment, who are young and fit enough, who do somewhat better," Dr. Seymour said. "A proportion will be alive at 2 years, so it’s not an inevitably, rapidly fatal, and ... futile situation."

Mantle cell lymphomas are a rare type of non-Hodgkin’s lymphoma (NHL), accounting for just less than 3% of all NHL cases in the United States and affecting primarily more elderly patients (Cancer 2008;113:791-8).CNS involvement is also a rare and often devastating event, but it has not previously been very well characterized. As a result, it’s not known whether CNS prophylaxis is of benefit to patients.

The aim of the EMCLN study, therefore, was to look at the problem in more detail, to determine the prevalence of CNS involvement, and to look for any clinically defining features, effect of treatment, and patient outcomes.

A retrospective database review by EMCLN members in 12 centers identified 1,396 patients with mantle cell lymphoma, of whom 1,339 had no CNS involvement. Of the 57 patients with CNS involvement, most (44) developed it at some point during the course of their follow-up.

At diagnosis of mantle cell lymphoma, the patients who developed CNS involvement had a median age of 61 years, but this ranged from 38 years to 82 years; patients were predominantly men (70%), with stage IV (91%) disease, and 28% had blastoid histology. Isolated CNS involvement occurred in 15 cases.

Prominent features were a high MIPI (Mantle Cell Lymphoma International Prognostic Index) score (61% of cases), a Ki-67 greater than 30% in 69% of patients, and increased beta₂-microglobulin and lactate dehydrogenase in 77% and 75% of cases, respectively. The bone marrow and the peripheral blood were the most common extranodal sites involved, affecting two or more sites in 61% of patients.

At diagnosis of CNS involvement, patients’ neurologic symptoms included weakness, altered mental state, headache, and ocular problems such as double vision. Other symptoms – such as sensory disturbances, pain, sciatica, dizziness, vertigo, ataxia, seizure, and dysphagia – occurred but were less frequent.

CSF cytology and flow cytometry showed a high sensitivity for identifying CNS involvement, with 85% having positive cytology and 91% a positive flow cytometry result.

"Patients had a range of chemotherapies prior to developing central nervous system involvement, but receipt of these regimens was not totally protective," Dr. Seymour said. Data were not collected to enable the relative risk of CNS development with the regimens received.

Chemotherapy was the most frequent treatment strategy to allay CNS disease (67%), and some patients did appear to achieve a complete remission of the CNS disease as a result. In an exploratory analysis, these patients also tended to have improved overall survival, as did those with lower white cell counts (less than 10.9 x 10⁹/L), and who received treatment with high-dose antimetabolites.

"In the longer term, these data will provide a foundation for us to identify predictive factors, to identify – ahead of the event – those people at increased risk," Dr. Seymour said, adding his hope that this will allow preventive steps to be taken.

Dr. Seymour had no conflicts of interest.

AMSTERDAM – Although it is rare and the prognosis for patients is often poor, the presence of central nervous system involvement at the time of diagnosis of mantle cell lymphoma is not always immediately fatal, according to findings from an international study.

According to the European Mantle Cell Lymphoma Network (EMCLN) findings, the crude prevalence of CNS events was 0.9% at the time of diagnosis and 4.1% at any time. The multicenter, retrospective study found that the median time to a CNS event’s occurring was 15.2 months, with an overall survival of 3.9 months after the event was identified, but some patients were still alive 2 years later.

"We now have some better descriptors about what the expectations and outcome of patients with central nervous system involvement are," Dr. John Seymour said in an interview at the annual congress of the European Hematology Association.

Dr. Seymour, professor and chair of the hematology service at Australia’s Peter MacCallum Cancer Centre in East Melbourne, Victoria, added that even though the overall prognosis of patients who develop CNS involvement is very poor, there are some patients who do better than others.

There is "a subgroup [of patients] who are able to receive high-dose ara-c [cytarabine] or high-dose methotrexate treatment, who are young and fit enough, who do somewhat better," Dr. Seymour said. "A proportion will be alive at 2 years, so it’s not an inevitably, rapidly fatal, and ... futile situation."

Mantle cell lymphomas are a rare type of non-Hodgkin’s lymphoma (NHL), accounting for just less than 3% of all NHL cases in the United States and affecting primarily more elderly patients (Cancer 2008;113:791-8).CNS involvement is also a rare and often devastating event, but it has not previously been very well characterized. As a result, it’s not known whether CNS prophylaxis is of benefit to patients.

The aim of the EMCLN study, therefore, was to look at the problem in more detail, to determine the prevalence of CNS involvement, and to look for any clinically defining features, effect of treatment, and patient outcomes.

A retrospective database review by EMCLN members in 12 centers identified 1,396 patients with mantle cell lymphoma, of whom 1,339 had no CNS involvement. Of the 57 patients with CNS involvement, most (44) developed it at some point during the course of their follow-up.

At diagnosis of mantle cell lymphoma, the patients who developed CNS involvement had a median age of 61 years, but this ranged from 38 years to 82 years; patients were predominantly men (70%), with stage IV (91%) disease, and 28% had blastoid histology. Isolated CNS involvement occurred in 15 cases.

Prominent features were a high MIPI (Mantle Cell Lymphoma International Prognostic Index) score (61% of cases), a Ki-67 greater than 30% in 69% of patients, and increased beta₂-microglobulin and lactate dehydrogenase in 77% and 75% of cases, respectively. The bone marrow and the peripheral blood were the most common extranodal sites involved, affecting two or more sites in 61% of patients.

At diagnosis of CNS involvement, patients’ neurologic symptoms included weakness, altered mental state, headache, and ocular problems such as double vision. Other symptoms – such as sensory disturbances, pain, sciatica, dizziness, vertigo, ataxia, seizure, and dysphagia – occurred but were less frequent.

CSF cytology and flow cytometry showed a high sensitivity for identifying CNS involvement, with 85% having positive cytology and 91% a positive flow cytometry result.

"Patients had a range of chemotherapies prior to developing central nervous system involvement, but receipt of these regimens was not totally protective," Dr. Seymour said. Data were not collected to enable the relative risk of CNS development with the regimens received.

Chemotherapy was the most frequent treatment strategy to allay CNS disease (67%), and some patients did appear to achieve a complete remission of the CNS disease as a result. In an exploratory analysis, these patients also tended to have improved overall survival, as did those with lower white cell counts (less than 10.9 x 10⁹/L), and who received treatment with high-dose antimetabolites.

"In the longer term, these data will provide a foundation for us to identify predictive factors, to identify – ahead of the event – those people at increased risk," Dr. Seymour said, adding his hope that this will allow preventive steps to be taken.

Dr. Seymour had no conflicts of interest.