EHA Congress 2011

LONDON – The investigational agent blinatumomab could help more patients with relapsed or refractory acute lymphoblastic leukemia achieve remission, compared with conventional treatment strategies, interim findings of an exploratory phase II trial suggest.

Although a small study – just 12 patients were included in the analysis – "we saw a response rate of 75%," principal study investigator Dr. Max S. Topp said in an interview at the annual European Hematology Association congress.

"Obviously it’s a very small number of patients," Dr. Topp, a professor of medicine and consultant in hematology at the University of Wurzburg in Munich, conceded. "Nevertheless it’s basically more than double what you would expect."

The outlook for patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL) is often grim, Dr. Topp noted, with low response rates to intensive chemotherapy (17%-45%), and a high chance of further relapse with a median duration of 4-5 months for complete remission (CR).There is also a high rate of treatment-related mortality, with up to a quarter of patients dying during their treatment.

"Blinatumomab is a new kind of drug. It’s not actually an antibody in the classical sense, which is more passive. This is actually something that is actively looking for the tumor, as it uses the T cells to exert its action," Dr. Topp explained.

According to Micromet, the company developing the novel agent, blinatumomab is the most advanced of a new class of agents called BiTE (bispecific T-cell engager) antibodies. These agents are designed to direct cytotoxic T-cells to CD19-expressing cancer cells (Science 2008;321:974-7).

Data from a phase I study have already shown that blinatumomab is active in the treatment of relapsed or refractory B-cell non-Hodgkin’s lymphoma (American Society of Hematology annual meeting, abstract 2880). Dr. Topp and team have also demonstrated its tolerability and activity in patients with ALL who had minimal residual disease (MRD) (J. Clin. Oncol. 2011;29:2493-8).

"We then asked the question if you can actually treat full-blown relapse, and it looks like we can make a difference here," Dr. Topp observed.

The ongoing, open-label phase II study currently involves seven patients aged a median of 37 years who are being treated with blinatumomab at a dose of 15 mcg/m² per day over three cycles and for maintenance treatment. Another five patients, with a median age of 60 years, are receiving the drug at an initial dose of 5 mcg/m² per day, then at a dose of 15 or 30 mcg/m² per day (cohort 2). Blinatumomab is delivered via continuous intravenous infusion for 2 weeks, with a 2-week treatment-free period.

Although the agent is in its very early days, results show that it has great promise in the treatment of relapsed or refractory ALL. The overall CR rate was 75%, and 71% in patients given the steady 15-mcg dose of blinatumomab and 80% in those whose dose was increased in subsequent cycles.

The increasing dosing regimen appears to be associated with better tolerability. "Adapting the system to have a slow start with 5 mcg and going up to 15 mcg we have had no severe adverse events ... and that is great news," Dr. Topp observed.

Some of the most common side effects seen in the trial to date include raised gamma-glutamyltransferase and C-reactive protein, peripheral edema, fatigue, pyrexia. Blood fibrinogen and fibrin d-dimer have also been increased, suggesting that thrombotic complications could be a future concern.

The bottom line, said Dr. Topp, is that "we have a non-chemotherapy, immunotherapy-based, effective treatment for patients with relapsed ALL, with very good safety profile."

Research is ongoing and a further 10 patients are likely to be included in the current trial. "We’re looking at the safety issues. We have to find the most likely regimen which we would like to use," Dr. Topp said.

The study was funded by Micromet AG. Dr. Topp is the principal investigator for the trial and disclosed acting as a consultant to the company.

LONDON – The investigational agent blinatumomab could help more patients with relapsed or refractory acute lymphoblastic leukemia achieve remission, compared with conventional treatment strategies, interim findings of an exploratory phase II trial suggest.

Although a small study – just 12 patients were included in the analysis – "we saw a response rate of 75%," principal study investigator Dr. Max S. Topp said in an interview at the annual European Hematology Association congress.

"Obviously it’s a very small number of patients," Dr. Topp, a professor of medicine and consultant in hematology at the University of Wurzburg in Munich, conceded. "Nevertheless it’s basically more than double what you would expect."

The outlook for patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL) is often grim, Dr. Topp noted, with low response rates to intensive chemotherapy (17%-45%), and a high chance of further relapse with a median duration of 4-5 months for complete remission (CR).There is also a high rate of treatment-related mortality, with up to a quarter of patients dying during their treatment.

"Blinatumomab is a new kind of drug. It’s not actually an antibody in the classical sense, which is more passive. This is actually something that is actively looking for the tumor, as it uses the T cells to exert its action," Dr. Topp explained.

According to Micromet, the company developing the novel agent, blinatumomab is the most advanced of a new class of agents called BiTE (bispecific T-cell engager) antibodies. These agents are designed to direct cytotoxic T-cells to CD19-expressing cancer cells (Science 2008;321:974-7).

Data from a phase I study have already shown that blinatumomab is active in the treatment of relapsed or refractory B-cell non-Hodgkin’s lymphoma (American Society of Hematology annual meeting, abstract 2880). Dr. Topp and team have also demonstrated its tolerability and activity in patients with ALL who had minimal residual disease (MRD) (J. Clin. Oncol. 2011;29:2493-8).

"We then asked the question if you can actually treat full-blown relapse, and it looks like we can make a difference here," Dr. Topp observed.

The ongoing, open-label phase II study currently involves seven patients aged a median of 37 years who are being treated with blinatumomab at a dose of 15 mcg/m² per day over three cycles and for maintenance treatment. Another five patients, with a median age of 60 years, are receiving the drug at an initial dose of 5 mcg/m² per day, then at a dose of 15 or 30 mcg/m² per day (cohort 2). Blinatumomab is delivered via continuous intravenous infusion for 2 weeks, with a 2-week treatment-free period.

Although the agent is in its very early days, results show that it has great promise in the treatment of relapsed or refractory ALL. The overall CR rate was 75%, and 71% in patients given the steady 15-mcg dose of blinatumomab and 80% in those whose dose was increased in subsequent cycles.

The increasing dosing regimen appears to be associated with better tolerability. "Adapting the system to have a slow start with 5 mcg and going up to 15 mcg we have had no severe adverse events ... and that is great news," Dr. Topp observed.

Some of the most common side effects seen in the trial to date include raised gamma-glutamyltransferase and C-reactive protein, peripheral edema, fatigue, pyrexia. Blood fibrinogen and fibrin d-dimer have also been increased, suggesting that thrombotic complications could be a future concern.

The bottom line, said Dr. Topp, is that "we have a non-chemotherapy, immunotherapy-based, effective treatment for patients with relapsed ALL, with very good safety profile."

Research is ongoing and a further 10 patients are likely to be included in the current trial. "We’re looking at the safety issues. We have to find the most likely regimen which we would like to use," Dr. Topp said.

The study was funded by Micromet AG. Dr. Topp is the principal investigator for the trial and disclosed acting as a consultant to the company.

LONDON – The investigational agent blinatumomab could help more patients with relapsed or refractory acute lymphoblastic leukemia achieve remission, compared with conventional treatment strategies, interim findings of an exploratory phase II trial suggest.

Although a small study – just 12 patients were included in the analysis – "we saw a response rate of 75%," principal study investigator Dr. Max S. Topp said in an interview at the annual European Hematology Association congress.

"Obviously it’s a very small number of patients," Dr. Topp, a professor of medicine and consultant in hematology at the University of Wurzburg in Munich, conceded. "Nevertheless it’s basically more than double what you would expect."

The outlook for patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL) is often grim, Dr. Topp noted, with low response rates to intensive chemotherapy (17%-45%), and a high chance of further relapse with a median duration of 4-5 months for complete remission (CR).There is also a high rate of treatment-related mortality, with up to a quarter of patients dying during their treatment.

"Blinatumomab is a new kind of drug. It’s not actually an antibody in the classical sense, which is more passive. This is actually something that is actively looking for the tumor, as it uses the T cells to exert its action," Dr. Topp explained.

According to Micromet, the company developing the novel agent, blinatumomab is the most advanced of a new class of agents called BiTE (bispecific T-cell engager) antibodies. These agents are designed to direct cytotoxic T-cells to CD19-expressing cancer cells (Science 2008;321:974-7).

Data from a phase I study have already shown that blinatumomab is active in the treatment of relapsed or refractory B-cell non-Hodgkin’s lymphoma (American Society of Hematology annual meeting, abstract 2880). Dr. Topp and team have also demonstrated its tolerability and activity in patients with ALL who had minimal residual disease (MRD) (J. Clin. Oncol. 2011;29:2493-8).

"We then asked the question if you can actually treat full-blown relapse, and it looks like we can make a difference here," Dr. Topp observed.

The ongoing, open-label phase II study currently involves seven patients aged a median of 37 years who are being treated with blinatumomab at a dose of 15 mcg/m² per day over three cycles and for maintenance treatment. Another five patients, with a median age of 60 years, are receiving the drug at an initial dose of 5 mcg/m² per day, then at a dose of 15 or 30 mcg/m² per day (cohort 2). Blinatumomab is delivered via continuous intravenous infusion for 2 weeks, with a 2-week treatment-free period.

Although the agent is in its very early days, results show that it has great promise in the treatment of relapsed or refractory ALL. The overall CR rate was 75%, and 71% in patients given the steady 15-mcg dose of blinatumomab and 80% in those whose dose was increased in subsequent cycles.

The increasing dosing regimen appears to be associated with better tolerability. "Adapting the system to have a slow start with 5 mcg and going up to 15 mcg we have had no severe adverse events ... and that is great news," Dr. Topp observed.

Some of the most common side effects seen in the trial to date include raised gamma-glutamyltransferase and C-reactive protein, peripheral edema, fatigue, pyrexia. Blood fibrinogen and fibrin d-dimer have also been increased, suggesting that thrombotic complications could be a future concern.

The bottom line, said Dr. Topp, is that "we have a non-chemotherapy, immunotherapy-based, effective treatment for patients with relapsed ALL, with very good safety profile."

Research is ongoing and a further 10 patients are likely to be included in the current trial. "We’re looking at the safety issues. We have to find the most likely regimen which we would like to use," Dr. Topp said.

The study was funded by Micromet AG. Dr. Topp is the principal investigator for the trial and disclosed acting as a consultant to the company.

LONDON – There is no benefit of performing ¹⁸fluorodeoxyglucose positron emission tomography after the first cycle of treatment in patients with diffuse large B-cell lymphoma or primary mediastinal large B-cell lymphoma, the results of an Italian study suggest.

The imaging technique failed to pick up signs of disease in 10 of 85 (12%) of patients who later relapsed following treatment with R-CHOP (rituximab [Rituxan], cyclophosphamide [Cytoxan], hydroxydaunorubicin [doxorubicin, Adriamycin], Oncovin [vincristine], and prednisolone) in conjunction with radiotherapy.

Interim ¹⁸FDG-PET was associated with a positive predictive value (PPV) of just 58% and a negative predictive value (NPV) of 77%. By comparison, the PPV and NPV of ¹⁸FDG-PET performed after the last treatment cycle were higher, at 70% and 82%, respectively.

"The early identification of nonresponders might be a pivotal step for cure of diffuse large B-cell lymphoma (DLBCL), said study investigator Dr. M. Christina Cox, who presented the findings at the annual congress of the European Hematology Association.

Dr. Cox of the Azienda Ospedaliera Sant’ Andrea in Rome explained that the use of the imaging method early on in the treatment of Hodgkin’s lymphoma had been shown to be a strong predictor of outcome, allowing earlier adjustment of therapy.

"From 2005, several studies showed than in [DLBCL], interim PET might be predictive of event-free survival, progression-free survival, and overall survival," Dr. Cox said. However, "more recent studies have yielded heterogeneous results."

Aiming to clarify the issue, Dr. Cox and colleagues undertook a prospective study of treatment-naive patients with either DLBCL (72 patients) or primary mediastinal large B-cell lymphoma (PMLBCL, 13 patients) enrolled between April 2005 and April 2010. Patients were eligible for the study if they had already undergone a PET or contrast enhancement computed tomography (CECT) scan, had no CNS involvement, were HIV negative, and were not eligible for R-CHOP-like treatments.

After initial staging with ¹⁸FDG-PET and CECT, patients with stage II or higher DLCBL received six cycles of treatment with either R-CHOP-14 if they were younger than 70 years or R-CHOP-21 if they were aged 70 years or older. In both cases, the duration of treatment was reduced to three cycles for patients with stage I disease. Patients with PMLBCL were treated with R-MACOP-14 (rituximab, methotrexate, ara-C [cytarabine], cyclophosphamide, Oncovin [vincristine], and prednisone) for 12 weeks. All patients with PMLBCL and those with stage I DLCBL received radiotherapy.

Interim staging using PET and CECT was performed within 10-20 days of the first cycle of treatment, with the final scans using both imaging techniques taken 6-8 weeks after the last treatment. The recently validated Deauville 5-point scale was used to compare the differences between interim and final PET scans. This scale gauges the uptake of ¹⁸FDG within the tissues.

The minimum observation time was set at 2 years, unless a DLBCL event occurred earlier. Targeted biopsies were performed at the end of treatment if there was a mismatch between PET and CECT results, and at the interim stage if results were conflicting and the site in need of biopsy was easy to reach.

Almost two-thirds (62%) were biopsy negative. Dr. Cox noted that none of the interim PET, biopsy-negative patients relapsed.

At a median follow-up of almost 3 years, 70 (82.3%) patients were still alive, with 65 (76.4%) being disease free after first- or second-line therapy. One-fifth had been refractory to first-line treatment. Of these patients, 78% had a positive interim PET scan.

Looking at factors that might predict the achievement of a complete remission to first-line treatment, only the interim CECT results were statistically significant in a multivariate analysis (P less than .002).

In addition, only the final PET scan was predictive of both overall and progression-free survival, whereas interim and final CECT were both predictive.

"In this series, interim PET proved not to be a robust tool for the early shifting of patients to high-dose therapy," Dr. Cox reported. She added that compared with interim CECT and final PET, "interim PET was not really of adjunctive value." Indeed, most refractory patients (61%) were identified by interim CECT.

"We think that the use of this [interim PET] expensive, radioactive, and emotionally distressing tool is presently not justified outside of clinical trials."

Commenting on the findings in an interview, Dr. Andrew Pettitt, professor of hematological oncology at the University of Liverpool (England), said that although it was a good study, he was not convinced it was adequately powered to draw such a definitive conclusion. "I also have some reservations of the PET-CT reporting and quality control," Dr. Pettitt, who was not involved in the study. "It’s very provocative, but I don’t think it’s definitive."

Dr. Cox and Dr. Pettitt stated that they had no relevant financial disclosures.

LONDON – There is no benefit of performing ¹⁸fluorodeoxyglucose positron emission tomography after the first cycle of treatment in patients with diffuse large B-cell lymphoma or primary mediastinal large B-cell lymphoma, the results of an Italian study suggest.

The imaging technique failed to pick up signs of disease in 10 of 85 (12%) of patients who later relapsed following treatment with R-CHOP (rituximab [Rituxan], cyclophosphamide [Cytoxan], hydroxydaunorubicin [doxorubicin, Adriamycin], Oncovin [vincristine], and prednisolone) in conjunction with radiotherapy.

Interim ¹⁸FDG-PET was associated with a positive predictive value (PPV) of just 58% and a negative predictive value (NPV) of 77%. By comparison, the PPV and NPV of ¹⁸FDG-PET performed after the last treatment cycle were higher, at 70% and 82%, respectively.

"The early identification of nonresponders might be a pivotal step for cure of diffuse large B-cell lymphoma (DLBCL), said study investigator Dr. M. Christina Cox, who presented the findings at the annual congress of the European Hematology Association.

Dr. Cox of the Azienda Ospedaliera Sant’ Andrea in Rome explained that the use of the imaging method early on in the treatment of Hodgkin’s lymphoma had been shown to be a strong predictor of outcome, allowing earlier adjustment of therapy.

"From 2005, several studies showed than in [DLBCL], interim PET might be predictive of event-free survival, progression-free survival, and overall survival," Dr. Cox said. However, "more recent studies have yielded heterogeneous results."

Aiming to clarify the issue, Dr. Cox and colleagues undertook a prospective study of treatment-naive patients with either DLBCL (72 patients) or primary mediastinal large B-cell lymphoma (PMLBCL, 13 patients) enrolled between April 2005 and April 2010. Patients were eligible for the study if they had already undergone a PET or contrast enhancement computed tomography (CECT) scan, had no CNS involvement, were HIV negative, and were not eligible for R-CHOP-like treatments.

After initial staging with ¹⁸FDG-PET and CECT, patients with stage II or higher DLCBL received six cycles of treatment with either R-CHOP-14 if they were younger than 70 years or R-CHOP-21 if they were aged 70 years or older. In both cases, the duration of treatment was reduced to three cycles for patients with stage I disease. Patients with PMLBCL were treated with R-MACOP-14 (rituximab, methotrexate, ara-C [cytarabine], cyclophosphamide, Oncovin [vincristine], and prednisone) for 12 weeks. All patients with PMLBCL and those with stage I DLCBL received radiotherapy.

Interim staging using PET and CECT was performed within 10-20 days of the first cycle of treatment, with the final scans using both imaging techniques taken 6-8 weeks after the last treatment. The recently validated Deauville 5-point scale was used to compare the differences between interim and final PET scans. This scale gauges the uptake of ¹⁸FDG within the tissues.

The minimum observation time was set at 2 years, unless a DLBCL event occurred earlier. Targeted biopsies were performed at the end of treatment if there was a mismatch between PET and CECT results, and at the interim stage if results were conflicting and the site in need of biopsy was easy to reach.

Almost two-thirds (62%) were biopsy negative. Dr. Cox noted that none of the interim PET, biopsy-negative patients relapsed.

At a median follow-up of almost 3 years, 70 (82.3%) patients were still alive, with 65 (76.4%) being disease free after first- or second-line therapy. One-fifth had been refractory to first-line treatment. Of these patients, 78% had a positive interim PET scan.

Looking at factors that might predict the achievement of a complete remission to first-line treatment, only the interim CECT results were statistically significant in a multivariate analysis (P less than .002).

In addition, only the final PET scan was predictive of both overall and progression-free survival, whereas interim and final CECT were both predictive.

"In this series, interim PET proved not to be a robust tool for the early shifting of patients to high-dose therapy," Dr. Cox reported. She added that compared with interim CECT and final PET, "interim PET was not really of adjunctive value." Indeed, most refractory patients (61%) were identified by interim CECT.

"We think that the use of this [interim PET] expensive, radioactive, and emotionally distressing tool is presently not justified outside of clinical trials."

Commenting on the findings in an interview, Dr. Andrew Pettitt, professor of hematological oncology at the University of Liverpool (England), said that although it was a good study, he was not convinced it was adequately powered to draw such a definitive conclusion. "I also have some reservations of the PET-CT reporting and quality control," Dr. Pettitt, who was not involved in the study. "It’s very provocative, but I don’t think it’s definitive."

Dr. Cox and Dr. Pettitt stated that they had no relevant financial disclosures.

LONDON – There is no benefit of performing ¹⁸fluorodeoxyglucose positron emission tomography after the first cycle of treatment in patients with diffuse large B-cell lymphoma or primary mediastinal large B-cell lymphoma, the results of an Italian study suggest.

The imaging technique failed to pick up signs of disease in 10 of 85 (12%) of patients who later relapsed following treatment with R-CHOP (rituximab [Rituxan], cyclophosphamide [Cytoxan], hydroxydaunorubicin [doxorubicin, Adriamycin], Oncovin [vincristine], and prednisolone) in conjunction with radiotherapy.

Interim ¹⁸FDG-PET was associated with a positive predictive value (PPV) of just 58% and a negative predictive value (NPV) of 77%. By comparison, the PPV and NPV of ¹⁸FDG-PET performed after the last treatment cycle were higher, at 70% and 82%, respectively.

"The early identification of nonresponders might be a pivotal step for cure of diffuse large B-cell lymphoma (DLBCL), said study investigator Dr. M. Christina Cox, who presented the findings at the annual congress of the European Hematology Association.

Dr. Cox of the Azienda Ospedaliera Sant’ Andrea in Rome explained that the use of the imaging method early on in the treatment of Hodgkin’s lymphoma had been shown to be a strong predictor of outcome, allowing earlier adjustment of therapy.

"From 2005, several studies showed than in [DLBCL], interim PET might be predictive of event-free survival, progression-free survival, and overall survival," Dr. Cox said. However, "more recent studies have yielded heterogeneous results."

Aiming to clarify the issue, Dr. Cox and colleagues undertook a prospective study of treatment-naive patients with either DLBCL (72 patients) or primary mediastinal large B-cell lymphoma (PMLBCL, 13 patients) enrolled between April 2005 and April 2010. Patients were eligible for the study if they had already undergone a PET or contrast enhancement computed tomography (CECT) scan, had no CNS involvement, were HIV negative, and were not eligible for R-CHOP-like treatments.

After initial staging with ¹⁸FDG-PET and CECT, patients with stage II or higher DLCBL received six cycles of treatment with either R-CHOP-14 if they were younger than 70 years or R-CHOP-21 if they were aged 70 years or older. In both cases, the duration of treatment was reduced to three cycles for patients with stage I disease. Patients with PMLBCL were treated with R-MACOP-14 (rituximab, methotrexate, ara-C [cytarabine], cyclophosphamide, Oncovin [vincristine], and prednisone) for 12 weeks. All patients with PMLBCL and those with stage I DLCBL received radiotherapy.

Interim staging using PET and CECT was performed within 10-20 days of the first cycle of treatment, with the final scans using both imaging techniques taken 6-8 weeks after the last treatment. The recently validated Deauville 5-point scale was used to compare the differences between interim and final PET scans. This scale gauges the uptake of ¹⁸FDG within the tissues.

The minimum observation time was set at 2 years, unless a DLBCL event occurred earlier. Targeted biopsies were performed at the end of treatment if there was a mismatch between PET and CECT results, and at the interim stage if results were conflicting and the site in need of biopsy was easy to reach.

Almost two-thirds (62%) were biopsy negative. Dr. Cox noted that none of the interim PET, biopsy-negative patients relapsed.

At a median follow-up of almost 3 years, 70 (82.3%) patients were still alive, with 65 (76.4%) being disease free after first- or second-line therapy. One-fifth had been refractory to first-line treatment. Of these patients, 78% had a positive interim PET scan.

Looking at factors that might predict the achievement of a complete remission to first-line treatment, only the interim CECT results were statistically significant in a multivariate analysis (P less than .002).

In addition, only the final PET scan was predictive of both overall and progression-free survival, whereas interim and final CECT were both predictive.

"In this series, interim PET proved not to be a robust tool for the early shifting of patients to high-dose therapy," Dr. Cox reported. She added that compared with interim CECT and final PET, "interim PET was not really of adjunctive value." Indeed, most refractory patients (61%) were identified by interim CECT.

"We think that the use of this [interim PET] expensive, radioactive, and emotionally distressing tool is presently not justified outside of clinical trials."

Commenting on the findings in an interview, Dr. Andrew Pettitt, professor of hematological oncology at the University of Liverpool (England), said that although it was a good study, he was not convinced it was adequately powered to draw such a definitive conclusion. "I also have some reservations of the PET-CT reporting and quality control," Dr. Pettitt, who was not involved in the study. "It’s very provocative, but I don’t think it’s definitive."

Dr. Cox and Dr. Pettitt stated that they had no relevant financial disclosures.

LONDON – Close relatives of patients with acute myeloid leukemia and myelodysplastic syndromes can be reassured that they are not at increased risk of developing these diseases themselves, according to the findings of a large population-based registry trial.

"Among over 20,000 first-degree relatives of almost 7,000 AML [acute myeloid leukemia] patients, we found no excess risk of developing AML, MDS [myelodysplastic syndromes], or any myeloid neoplasms as a group," said Dr. Magnus Björkholm, a professor of medicine at Karolinska University Hospital, Solna and the Karolinska Institute, both in Stockholm.

Speaking at the annual congress of the European Hematology Association, Dr. Björkholm reported that there was also no strong genetic predisposition for first-degree relatives of patients with MDS to develop myeloid or other hematological neoplasms.

"If you read Wikipedia today, it says that the risk of developing AML is increased threefold in first-degree relatives of patients with AML," Dr. Björkholm observed. "But there is really limited data on the extent of familial aggregation of AML and MDS in the population.

Indeed, the Wikipedia entry cites a paper (J. Natl. Cancer Inst. 1969;42:517-24) from 1969 as the source of this claim, and results of early studies found an increased risk of leukemia among relatives of patients were actually accounted for by cases of chronic lymphocytic leukemia.

"We believe a better understanding on the role for genetic factors in the causation of AML/MDS is of major importance to patients, their families, and healthcare professionals," Dr. Björkholm said, explaining the rationale behind the research.

Using data from the Swedish Cancer Registry, the Swedish Population Registry, and the Swedish Multigenerational Registry, Dr. Björkholm and colleagues identified 6,962 patients diagnosed with AML from Jan. 1, 1958 until Dec. 31, 2004 and 1,388 MDS patients diagnosed from 1993 – the date when MDS was first included in the Swedish Cancer Registry – through Dec. 31, 2004. There were 20,579 first-degree relatives of the AML patients and 3,994 first-degree relatives of the MDS patients.

For each AML and MDS patient, four population-matched control subjects of a similar age, year of birth, and country of residence were randomly selected from the Swedish population, and their first-degree relatives were also identified. In all, there were 27,827 AML controls and 90,406 AML control relatives, and 5,312 MDS controls and 15,818 MDS control relatives.

No excess risk of AML (hazard ratio 0.94) or other myeloid or lymphoid malignancies was statistically significant in relatives of patients with AML with one exception – relatives of patients with AML did have an increased risk of polycythemia vera (HR 2.28, P less than .05). The risks for any hematopoietic or solid malignancies were significantly increased statistically, but only modestly, with risk ratios of 1.16 and 1.09, respectively.

First-degree relatives of AML patients who were diagnosed at a younger age (20 years or less) did, however, have a higher chance of developing AML, myeloid neoplasms, or multiple myeloma, based on small numbers in the sample. Dr. Björkholm suggested that genes predisposing to malignancy in general, environmental factors, or both, might be shared in these families.

No significant excess risks were seen among first-degree relatives of MDS patients.

"The lack of familial aggregation in AML and MDS is rather striking," Dr. Björkholm admitted. It is also "in stark contrast to findings in other myelo- and lymphoproliferative disorders."

In an interview, he emphasized, "The main message is that first-degree relatives of patients with acute myeloid leukemia do not have an increased risk of developing acute myeloid leukemia, which is in contrast to many other solid and hematological malignancies."

Dr. Björkholm also noted that patients are often told by their physicians that there is a two to three times increased risk of their siblings or children developing leukemia. The current findings suggest that this is unlikely, considering the large cohort of subjects that was studied.

"From a global point of view, this [study] is probably the best you can do."

Dr. Björkholm stated he had no conflicts of interest. The study received financial support from the Adolf H. Lundin Charitable Foundation, Karolinska Institute Foundations, Stockholm County Council, Swedish Cancer Society, and the Division of Intramural Research Programs at the National Cancer Institute of the National Institutes of Health.

LONDON – Close relatives of patients with acute myeloid leukemia and myelodysplastic syndromes can be reassured that they are not at increased risk of developing these diseases themselves, according to the findings of a large population-based registry trial.

"Among over 20,000 first-degree relatives of almost 7,000 AML [acute myeloid leukemia] patients, we found no excess risk of developing AML, MDS [myelodysplastic syndromes], or any myeloid neoplasms as a group," said Dr. Magnus Björkholm, a professor of medicine at Karolinska University Hospital, Solna and the Karolinska Institute, both in Stockholm.

Speaking at the annual congress of the European Hematology Association, Dr. Björkholm reported that there was also no strong genetic predisposition for first-degree relatives of patients with MDS to develop myeloid or other hematological neoplasms.

"If you read Wikipedia today, it says that the risk of developing AML is increased threefold in first-degree relatives of patients with AML," Dr. Björkholm observed. "But there is really limited data on the extent of familial aggregation of AML and MDS in the population.

Indeed, the Wikipedia entry cites a paper (J. Natl. Cancer Inst. 1969;42:517-24) from 1969 as the source of this claim, and results of early studies found an increased risk of leukemia among relatives of patients were actually accounted for by cases of chronic lymphocytic leukemia.

"We believe a better understanding on the role for genetic factors in the causation of AML/MDS is of major importance to patients, their families, and healthcare professionals," Dr. Björkholm said, explaining the rationale behind the research.

Using data from the Swedish Cancer Registry, the Swedish Population Registry, and the Swedish Multigenerational Registry, Dr. Björkholm and colleagues identified 6,962 patients diagnosed with AML from Jan. 1, 1958 until Dec. 31, 2004 and 1,388 MDS patients diagnosed from 1993 – the date when MDS was first included in the Swedish Cancer Registry – through Dec. 31, 2004. There were 20,579 first-degree relatives of the AML patients and 3,994 first-degree relatives of the MDS patients.

For each AML and MDS patient, four population-matched control subjects of a similar age, year of birth, and country of residence were randomly selected from the Swedish population, and their first-degree relatives were also identified. In all, there were 27,827 AML controls and 90,406 AML control relatives, and 5,312 MDS controls and 15,818 MDS control relatives.

No excess risk of AML (hazard ratio 0.94) or other myeloid or lymphoid malignancies was statistically significant in relatives of patients with AML with one exception – relatives of patients with AML did have an increased risk of polycythemia vera (HR 2.28, P less than .05). The risks for any hematopoietic or solid malignancies were significantly increased statistically, but only modestly, with risk ratios of 1.16 and 1.09, respectively.

First-degree relatives of AML patients who were diagnosed at a younger age (20 years or less) did, however, have a higher chance of developing AML, myeloid neoplasms, or multiple myeloma, based on small numbers in the sample. Dr. Björkholm suggested that genes predisposing to malignancy in general, environmental factors, or both, might be shared in these families.

No significant excess risks were seen among first-degree relatives of MDS patients.

"The lack of familial aggregation in AML and MDS is rather striking," Dr. Björkholm admitted. It is also "in stark contrast to findings in other myelo- and lymphoproliferative disorders."

In an interview, he emphasized, "The main message is that first-degree relatives of patients with acute myeloid leukemia do not have an increased risk of developing acute myeloid leukemia, which is in contrast to many other solid and hematological malignancies."

Dr. Björkholm also noted that patients are often told by their physicians that there is a two to three times increased risk of their siblings or children developing leukemia. The current findings suggest that this is unlikely, considering the large cohort of subjects that was studied.

"From a global point of view, this [study] is probably the best you can do."

Dr. Björkholm stated he had no conflicts of interest. The study received financial support from the Adolf H. Lundin Charitable Foundation, Karolinska Institute Foundations, Stockholm County Council, Swedish Cancer Society, and the Division of Intramural Research Programs at the National Cancer Institute of the National Institutes of Health.

LONDON – Close relatives of patients with acute myeloid leukemia and myelodysplastic syndromes can be reassured that they are not at increased risk of developing these diseases themselves, according to the findings of a large population-based registry trial.

"Among over 20,000 first-degree relatives of almost 7,000 AML [acute myeloid leukemia] patients, we found no excess risk of developing AML, MDS [myelodysplastic syndromes], or any myeloid neoplasms as a group," said Dr. Magnus Björkholm, a professor of medicine at Karolinska University Hospital, Solna and the Karolinska Institute, both in Stockholm.

Speaking at the annual congress of the European Hematology Association, Dr. Björkholm reported that there was also no strong genetic predisposition for first-degree relatives of patients with MDS to develop myeloid or other hematological neoplasms.

"If you read Wikipedia today, it says that the risk of developing AML is increased threefold in first-degree relatives of patients with AML," Dr. Björkholm observed. "But there is really limited data on the extent of familial aggregation of AML and MDS in the population.

Indeed, the Wikipedia entry cites a paper (J. Natl. Cancer Inst. 1969;42:517-24) from 1969 as the source of this claim, and results of early studies found an increased risk of leukemia among relatives of patients were actually accounted for by cases of chronic lymphocytic leukemia.

"We believe a better understanding on the role for genetic factors in the causation of AML/MDS is of major importance to patients, their families, and healthcare professionals," Dr. Björkholm said, explaining the rationale behind the research.

Using data from the Swedish Cancer Registry, the Swedish Population Registry, and the Swedish Multigenerational Registry, Dr. Björkholm and colleagues identified 6,962 patients diagnosed with AML from Jan. 1, 1958 until Dec. 31, 2004 and 1,388 MDS patients diagnosed from 1993 – the date when MDS was first included in the Swedish Cancer Registry – through Dec. 31, 2004. There were 20,579 first-degree relatives of the AML patients and 3,994 first-degree relatives of the MDS patients.

For each AML and MDS patient, four population-matched control subjects of a similar age, year of birth, and country of residence were randomly selected from the Swedish population, and their first-degree relatives were also identified. In all, there were 27,827 AML controls and 90,406 AML control relatives, and 5,312 MDS controls and 15,818 MDS control relatives.

No excess risk of AML (hazard ratio 0.94) or other myeloid or lymphoid malignancies was statistically significant in relatives of patients with AML with one exception – relatives of patients with AML did have an increased risk of polycythemia vera (HR 2.28, P less than .05). The risks for any hematopoietic or solid malignancies were significantly increased statistically, but only modestly, with risk ratios of 1.16 and 1.09, respectively.

First-degree relatives of AML patients who were diagnosed at a younger age (20 years or less) did, however, have a higher chance of developing AML, myeloid neoplasms, or multiple myeloma, based on small numbers in the sample. Dr. Björkholm suggested that genes predisposing to malignancy in general, environmental factors, or both, might be shared in these families.

No significant excess risks were seen among first-degree relatives of MDS patients.

"The lack of familial aggregation in AML and MDS is rather striking," Dr. Björkholm admitted. It is also "in stark contrast to findings in other myelo- and lymphoproliferative disorders."

In an interview, he emphasized, "The main message is that first-degree relatives of patients with acute myeloid leukemia do not have an increased risk of developing acute myeloid leukemia, which is in contrast to many other solid and hematological malignancies."

Dr. Björkholm also noted that patients are often told by their physicians that there is a two to three times increased risk of their siblings or children developing leukemia. The current findings suggest that this is unlikely, considering the large cohort of subjects that was studied.

"From a global point of view, this [study] is probably the best you can do."

Dr. Björkholm stated he had no conflicts of interest. The study received financial support from the Adolf H. Lundin Charitable Foundation, Karolinska Institute Foundations, Stockholm County Council, Swedish Cancer Society, and the Division of Intramural Research Programs at the National Cancer Institute of the National Institutes of Health.

LONDON – Measuring levels of a newly described protein at diagnosis could help identify patients that are going to fare worse than others with chronic myeloid leukemia, data from a small study suggest.

Cancerous inhibitor of protein phosphatase 2A (CIP2A) levels were found to be significantly higher in patients with chronic myeloid leukemia (CML) who later went into blast crisis, reported researchers from the University of Liverpool (England). CIP2A could, therefore, represent a novel drug target as well as a biomarker for the disease.

"Prospective identification of patients whose CML will progress despite treatment is not currently possible and the work we have been doing is with PP2A, a tumor suppressor gene," explained Claire M. Lucas, a specialist health care scientist in the department of hematology at the university. Ms. Lucas presented the findings at the annual European Hematology Congress.

PP2A is a serine/threonine phosphatase that down-regulates cell-signaling pathways that lead to tumor cell proliferation, differentiation, and survival. The protein is key target of BCR-ABL1 signaling, and inhibition of the latter via imatinib (Gleevec) is known to increase levels of PP2A, to kick start apoptosis, and to suppress further tumor growth.

Ms. Lucas was part of a team led by Dr. Richard E. Clark that investigated whether the expression of PP2A or its inhibitory proteins SET and CIP2A differed in patients with CML before diagnosis and at disease progression.

The study included 31 patients with CML who were diagnosed in a chronic phase and who were being treated with imatinib within 4 weeks of their presentation. Patients were stratified into three groups based on their clinical response to treatment after 12 months: complete cytogenic response (CCR; n = 14), no CCR (n = 11), and blast crisis (n = 6).

Patients’ peripheral blood was collected before and after treatment for analysis, and evaluated according to their eventual clinical outcome. PP2A protein expression and phosphorylation were found to be increased in cells that had been taken from patients who were seen in blast crisis, Ms. Lucas reported.

CIP2A protein levels at diagnosis were also predictive of patients’ eventual outcome and were found to play a key role in regulating PP2A in CML cells. Chronic-phase patients who had high CIP2A levels at diagnosis had a 100% probability of progressing to blast crisis. Furthermore, CIPA siRNA was found to restore PP2A function and to decrease BCR-ABL tyrosine kinase activity.

Taken together, these data show that CIP2A is not only biologically but also clinically important in CML, Ms. Lucas said.

This is the first time an association between CIP2A and patient outcome has been shown in any hematologic malignancy, the research team believes. CIP2A levels have previously been linked to the aggressiveness of breast and gastric cancers (Clin. Cancer Res. 2009;15:5092-100; Clin. Cancer Res. 2008;14:3722-8; J. Natl. Cancer Inst. 2009;101:793-805).

The study findings have recently been published online (Blood 2011 April 13 [doi:10.1182/blood-2010-08-304477]). Ms. Lucas had no financial disclosures.

LONDON – Measuring levels of a newly described protein at diagnosis could help identify patients that are going to fare worse than others with chronic myeloid leukemia, data from a small study suggest.

Cancerous inhibitor of protein phosphatase 2A (CIP2A) levels were found to be significantly higher in patients with chronic myeloid leukemia (CML) who later went into blast crisis, reported researchers from the University of Liverpool (England). CIP2A could, therefore, represent a novel drug target as well as a biomarker for the disease.

"Prospective identification of patients whose CML will progress despite treatment is not currently possible and the work we have been doing is with PP2A, a tumor suppressor gene," explained Claire M. Lucas, a specialist health care scientist in the department of hematology at the university. Ms. Lucas presented the findings at the annual European Hematology Congress.

PP2A is a serine/threonine phosphatase that down-regulates cell-signaling pathways that lead to tumor cell proliferation, differentiation, and survival. The protein is key target of BCR-ABL1 signaling, and inhibition of the latter via imatinib (Gleevec) is known to increase levels of PP2A, to kick start apoptosis, and to suppress further tumor growth.

Ms. Lucas was part of a team led by Dr. Richard E. Clark that investigated whether the expression of PP2A or its inhibitory proteins SET and CIP2A differed in patients with CML before diagnosis and at disease progression.

The study included 31 patients with CML who were diagnosed in a chronic phase and who were being treated with imatinib within 4 weeks of their presentation. Patients were stratified into three groups based on their clinical response to treatment after 12 months: complete cytogenic response (CCR; n = 14), no CCR (n = 11), and blast crisis (n = 6).

Patients’ peripheral blood was collected before and after treatment for analysis, and evaluated according to their eventual clinical outcome. PP2A protein expression and phosphorylation were found to be increased in cells that had been taken from patients who were seen in blast crisis, Ms. Lucas reported.

CIP2A protein levels at diagnosis were also predictive of patients’ eventual outcome and were found to play a key role in regulating PP2A in CML cells. Chronic-phase patients who had high CIP2A levels at diagnosis had a 100% probability of progressing to blast crisis. Furthermore, CIPA siRNA was found to restore PP2A function and to decrease BCR-ABL tyrosine kinase activity.

Taken together, these data show that CIP2A is not only biologically but also clinically important in CML, Ms. Lucas said.

This is the first time an association between CIP2A and patient outcome has been shown in any hematologic malignancy, the research team believes. CIP2A levels have previously been linked to the aggressiveness of breast and gastric cancers (Clin. Cancer Res. 2009;15:5092-100; Clin. Cancer Res. 2008;14:3722-8; J. Natl. Cancer Inst. 2009;101:793-805).

The study findings have recently been published online (Blood 2011 April 13 [doi:10.1182/blood-2010-08-304477]). Ms. Lucas had no financial disclosures.

LONDON – Measuring levels of a newly described protein at diagnosis could help identify patients that are going to fare worse than others with chronic myeloid leukemia, data from a small study suggest.

Cancerous inhibitor of protein phosphatase 2A (CIP2A) levels were found to be significantly higher in patients with chronic myeloid leukemia (CML) who later went into blast crisis, reported researchers from the University of Liverpool (England). CIP2A could, therefore, represent a novel drug target as well as a biomarker for the disease.

"Prospective identification of patients whose CML will progress despite treatment is not currently possible and the work we have been doing is with PP2A, a tumor suppressor gene," explained Claire M. Lucas, a specialist health care scientist in the department of hematology at the university. Ms. Lucas presented the findings at the annual European Hematology Congress.

PP2A is a serine/threonine phosphatase that down-regulates cell-signaling pathways that lead to tumor cell proliferation, differentiation, and survival. The protein is key target of BCR-ABL1 signaling, and inhibition of the latter via imatinib (Gleevec) is known to increase levels of PP2A, to kick start apoptosis, and to suppress further tumor growth.

Ms. Lucas was part of a team led by Dr. Richard E. Clark that investigated whether the expression of PP2A or its inhibitory proteins SET and CIP2A differed in patients with CML before diagnosis and at disease progression.

The study included 31 patients with CML who were diagnosed in a chronic phase and who were being treated with imatinib within 4 weeks of their presentation. Patients were stratified into three groups based on their clinical response to treatment after 12 months: complete cytogenic response (CCR; n = 14), no CCR (n = 11), and blast crisis (n = 6).

Patients’ peripheral blood was collected before and after treatment for analysis, and evaluated according to their eventual clinical outcome. PP2A protein expression and phosphorylation were found to be increased in cells that had been taken from patients who were seen in blast crisis, Ms. Lucas reported.

CIP2A protein levels at diagnosis were also predictive of patients’ eventual outcome and were found to play a key role in regulating PP2A in CML cells. Chronic-phase patients who had high CIP2A levels at diagnosis had a 100% probability of progressing to blast crisis. Furthermore, CIPA siRNA was found to restore PP2A function and to decrease BCR-ABL tyrosine kinase activity.

Taken together, these data show that CIP2A is not only biologically but also clinically important in CML, Ms. Lucas said.

This is the first time an association between CIP2A and patient outcome has been shown in any hematologic malignancy, the research team believes. CIP2A levels have previously been linked to the aggressiveness of breast and gastric cancers (Clin. Cancer Res. 2009;15:5092-100; Clin. Cancer Res. 2008;14:3722-8; J. Natl. Cancer Inst. 2009;101:793-805).

The study findings have recently been published online (Blood 2011 April 13 [doi:10.1182/blood-2010-08-304477]). Ms. Lucas had no financial disclosures.

LONDON – The investigational agent brentuximab vedotin appears to have a beneficial effect in patients with refractory or relapsed Hodgkin’s lymphoma who are ineligible for or have refused to have an autologous stem cell transplant.

A retrospective analysis of two phase I studies performed with the drug used as a single agent have shown that almost one-third of these heavily pretreated patients are able to achieve an objective response to treatment.

Indeed, 6 of 20 patients (30%) aged a median of 32 years achieved an objective response (two complete and four partial remissions). The response can last longer than 6 months, with one patient achieving a durable remission for more than 2 years that later allowed for transplantation.

"These are very encouraging results in patients with [an] unmet need, and additional studies are ongoing," Dr. Ranjana Advani of Stanford University Medical Center in Palo Alto, Calif., said at the annual congress of the European Hematology Association.

"Patients who have primary refractory disease or fail to achieve a remission at relapse have a dismal outcome," Dr. Advani observed. She added that long-term survival prospects for such patients "were pretty bleak, with median overall survival in a small series as low as 4 months."

Brentuximab vedotin is a novel antibody-drug conjugate that comprises an anti-CD30 monoclonal antibody and a synthetic antimicrotubule agent, monomethyl auristatin E (MMAE). After binding to CD30 on the surface of T and B cells, the antibody-drug conjugate is internalized, the link between antibody and drug is severed, and MMAE is released – thus targeting malignant cells while, in theory, leaving normal cells unscathed.

MMAE is a potent antimicrotubule agent, and as with the taxanes, one of the expected side effects of the drug could be peripheral neuropathy. Although this was not seen in the small number of patients discussed by Dr. Advani, she said that peripheral neuropathy, mostly sensory, had been observed in about 15% of patients treated in the clinical trials program to date.

"Adverse events were seen in over 25% of patients, and these were not necessarily drug related; they could have been even disease related," Dr. Advani reported. Common side effects included fatigue (45%); nausea (40%); pyrexia (35%); decreased weight and diarrhea (30% each); vomiting, back pain, decreased appetite, anemia, and night sweats (25% each).

There were no deaths within 30 days of receiving the last dose of the novel agent.

The current findings add to data released separately from a pivotal phase II trial, recently updated and presented at this year’s American Society of Clinical Oncology meeting in Chicago. In that trial (J. Clin. Oncol. 2011 29[suppl.]: abstract 8031), brentuximab vedotin (SGN-35) induced objective responses in 75% of patients with relapsed or refractory Hodgkin’s disease; 34% achieved a durable complete remission, with two-thirds of patients remaining in complete remission.

Brentuximab has also recently been linked to durable remissions in patients with relapsed or refractory systemic anaplastic large-cell lymphoma (sALCL), an aggressive subtype of peripheral T-cell lymphoma.

The Food and Drug Administration has granted brentuximab vedotin orphan drug status for the treatment of Hodgkin’s lymphoma and sALCL.

Further studies are underway, and include the phase III AETHERA trial – which is comparing brentuximab vedotin to placebo in high-risk patients with Hodgkin’s lymphoma after autologous stem cell transplantation. Another phase I trial is also looking at the combination of brentuximab vedotin and the ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) regimen as de novo treatment in Hodgkin’s lymphoma.

Seattle Genetics and Millennium: the Takeda Oncology Co. funded the research. Dr. Advani disclosed acting as a principal investigator and receiving research support and advisory board fees from the company.

LONDON – The investigational agent brentuximab vedotin appears to have a beneficial effect in patients with refractory or relapsed Hodgkin’s lymphoma who are ineligible for or have refused to have an autologous stem cell transplant.

A retrospective analysis of two phase I studies performed with the drug used as a single agent have shown that almost one-third of these heavily pretreated patients are able to achieve an objective response to treatment.

Indeed, 6 of 20 patients (30%) aged a median of 32 years achieved an objective response (two complete and four partial remissions). The response can last longer than 6 months, with one patient achieving a durable remission for more than 2 years that later allowed for transplantation.

"These are very encouraging results in patients with [an] unmet need, and additional studies are ongoing," Dr. Ranjana Advani of Stanford University Medical Center in Palo Alto, Calif., said at the annual congress of the European Hematology Association.

"Patients who have primary refractory disease or fail to achieve a remission at relapse have a dismal outcome," Dr. Advani observed. She added that long-term survival prospects for such patients "were pretty bleak, with median overall survival in a small series as low as 4 months."

Brentuximab vedotin is a novel antibody-drug conjugate that comprises an anti-CD30 monoclonal antibody and a synthetic antimicrotubule agent, monomethyl auristatin E (MMAE). After binding to CD30 on the surface of T and B cells, the antibody-drug conjugate is internalized, the link between antibody and drug is severed, and MMAE is released – thus targeting malignant cells while, in theory, leaving normal cells unscathed.

MMAE is a potent antimicrotubule agent, and as with the taxanes, one of the expected side effects of the drug could be peripheral neuropathy. Although this was not seen in the small number of patients discussed by Dr. Advani, she said that peripheral neuropathy, mostly sensory, had been observed in about 15% of patients treated in the clinical trials program to date.

"Adverse events were seen in over 25% of patients, and these were not necessarily drug related; they could have been even disease related," Dr. Advani reported. Common side effects included fatigue (45%); nausea (40%); pyrexia (35%); decreased weight and diarrhea (30% each); vomiting, back pain, decreased appetite, anemia, and night sweats (25% each).

There were no deaths within 30 days of receiving the last dose of the novel agent.

The current findings add to data released separately from a pivotal phase II trial, recently updated and presented at this year’s American Society of Clinical Oncology meeting in Chicago. In that trial (J. Clin. Oncol. 2011 29[suppl.]: abstract 8031), brentuximab vedotin (SGN-35) induced objective responses in 75% of patients with relapsed or refractory Hodgkin’s disease; 34% achieved a durable complete remission, with two-thirds of patients remaining in complete remission.

Brentuximab has also recently been linked to durable remissions in patients with relapsed or refractory systemic anaplastic large-cell lymphoma (sALCL), an aggressive subtype of peripheral T-cell lymphoma.

The Food and Drug Administration has granted brentuximab vedotin orphan drug status for the treatment of Hodgkin’s lymphoma and sALCL.

Further studies are underway, and include the phase III AETHERA trial – which is comparing brentuximab vedotin to placebo in high-risk patients with Hodgkin’s lymphoma after autologous stem cell transplantation. Another phase I trial is also looking at the combination of brentuximab vedotin and the ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) regimen as de novo treatment in Hodgkin’s lymphoma.

Seattle Genetics and Millennium: the Takeda Oncology Co. funded the research. Dr. Advani disclosed acting as a principal investigator and receiving research support and advisory board fees from the company.

LONDON – The investigational agent brentuximab vedotin appears to have a beneficial effect in patients with refractory or relapsed Hodgkin’s lymphoma who are ineligible for or have refused to have an autologous stem cell transplant.

A retrospective analysis of two phase I studies performed with the drug used as a single agent have shown that almost one-third of these heavily pretreated patients are able to achieve an objective response to treatment.

Indeed, 6 of 20 patients (30%) aged a median of 32 years achieved an objective response (two complete and four partial remissions). The response can last longer than 6 months, with one patient achieving a durable remission for more than 2 years that later allowed for transplantation.

"These are very encouraging results in patients with [an] unmet need, and additional studies are ongoing," Dr. Ranjana Advani of Stanford University Medical Center in Palo Alto, Calif., said at the annual congress of the European Hematology Association.

"Patients who have primary refractory disease or fail to achieve a remission at relapse have a dismal outcome," Dr. Advani observed. She added that long-term survival prospects for such patients "were pretty bleak, with median overall survival in a small series as low as 4 months."

Brentuximab vedotin is a novel antibody-drug conjugate that comprises an anti-CD30 monoclonal antibody and a synthetic antimicrotubule agent, monomethyl auristatin E (MMAE). After binding to CD30 on the surface of T and B cells, the antibody-drug conjugate is internalized, the link between antibody and drug is severed, and MMAE is released – thus targeting malignant cells while, in theory, leaving normal cells unscathed.

MMAE is a potent antimicrotubule agent, and as with the taxanes, one of the expected side effects of the drug could be peripheral neuropathy. Although this was not seen in the small number of patients discussed by Dr. Advani, she said that peripheral neuropathy, mostly sensory, had been observed in about 15% of patients treated in the clinical trials program to date.

"Adverse events were seen in over 25% of patients, and these were not necessarily drug related; they could have been even disease related," Dr. Advani reported. Common side effects included fatigue (45%); nausea (40%); pyrexia (35%); decreased weight and diarrhea (30% each); vomiting, back pain, decreased appetite, anemia, and night sweats (25% each).

There were no deaths within 30 days of receiving the last dose of the novel agent.

The current findings add to data released separately from a pivotal phase II trial, recently updated and presented at this year’s American Society of Clinical Oncology meeting in Chicago. In that trial (J. Clin. Oncol. 2011 29[suppl.]: abstract 8031), brentuximab vedotin (SGN-35) induced objective responses in 75% of patients with relapsed or refractory Hodgkin’s disease; 34% achieved a durable complete remission, with two-thirds of patients remaining in complete remission.

Brentuximab has also recently been linked to durable remissions in patients with relapsed or refractory systemic anaplastic large-cell lymphoma (sALCL), an aggressive subtype of peripheral T-cell lymphoma.

The Food and Drug Administration has granted brentuximab vedotin orphan drug status for the treatment of Hodgkin’s lymphoma and sALCL.

Further studies are underway, and include the phase III AETHERA trial – which is comparing brentuximab vedotin to placebo in high-risk patients with Hodgkin’s lymphoma after autologous stem cell transplantation. Another phase I trial is also looking at the combination of brentuximab vedotin and the ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) regimen as de novo treatment in Hodgkin’s lymphoma.

Seattle Genetics and Millennium: the Takeda Oncology Co. funded the research. Dr. Advani disclosed acting as a principal investigator and receiving research support and advisory board fees from the company.

LONDON – HIV-infected patients with Hodgkin’s lymphoma can be treated more or less the same as any other Hodgkin’s patient, according to new data from the German HIV-related Lymphoma Study Group.

In a prospective, multicenter study of 108 patients with Hodgkin’s lymphoma (HL), all of whom were HIV positive, a risk-adapted treatment strategy was found to be feasible while patients were being treated with HAART (highly active antiretroviral therapy).

"I think the main message is that the prognosis [of patients with HIV-related HL] has dramatically improved with the [use of] HAART and with the stage- and risk-adapted treatment approach," study investigator Dr. Marcus Hentrich said in a June 11 interview at the annual congress of the European Hematology Association, where he presented the study.

"The results are approaching those we have obtained in the HIV-negative population," added Dr. Hentrich of Harlaching Hospital Munich. The findings show that "not every patient needs to be treated with full intensity" for six to eight courses of chemotherapy; rather, "we can distinguish [treatment] depending on the Hodgkin’s stage."

HL is one of the most common non–AIDS-defining cancers that often presents at an advanced stage. To date, there have been few prospective studies looking at how best to treat patients who are both HIV positive and have the hematologic malignancy; indeed, patients with HIV-related HL are often excluded from HL clinical trials. As a consequence, how best to manage such patients remains unknown (Adv. Hematol. 2011 [doi:10.1155/2011/402682]).

Combination therapy regimens have largely been used to treat HL in HIV-infected patients because of the generally late presentation of the disease, and controlling HIV infection via HAART has also been shown to improve the outcome of HL (Ann. Oncol. 2006;17:914-9).

The current study presented by Dr. Hentrich was conducted between March 2004 and October 2010. It included 100 male and 8 female patients with HL who were HIV positive, and its aim was to see whether a risk-adapted treatment strategy that was used in HIV-negative patients with HL could be applied to those infected with HIV.

Treatment for HL was determined by the stage of disease, with two to four cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) used with involved-field radiotherapy (30 Gy) in early-stage patients (that is, those with stage I-II HL and no additional risk factors).

In intermediate-stage patients (that is, those with stage I-II disease plus additional risk factors, such as large mediastinal tumor, extranodal involvement, and three or more lymph node regions involved), treatment consisted of four cycles of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) plus the same radiotherapy regimen.

More advanced HL (stage III-IV) was treated with six to eight cycles of BEACOPP plus facultative radiotherapy (30 Gy initial bulk or rest).

In patients with very advanced HIV infection and a poor performance status, the BEACOPP regimen could be replaced by ABVD, and the dose of ABVD reduced according to individual circumstances.

The median age of recruited patients was 43.9 years (range, 27-70 years). The majority (65%) had advanced disease, with 14% identified as having intermediate-stage HL, and 21% with early-stage disease. Extranodal involvement was observed in about half of patients (54%), and almost two-thirds (65%) had B-symptoms (which includes systemic symptoms such as fever, night sweats, and weight loss; B-symptoms can occur in both HL and non-HL).

Most (77%) patients had received HAART, and the median time from HIV to HL diagnosis was 5.9 years (range, 0-26 years).

After 26 months’ follow-up, 96%, 100%, and 84% of patients with early-, intermediate-, and advanced-stage HL, respectively, were in complete remission.

Perhaps not surprisingly, some advanced-stage patients fared worse, with four (6%) toxic and one (1.4%) unknown cause of death, five (7%) cases of early progression, and one (1.4%) partial remission in this group. One (4%) patient in the early-stage group also died because of toxicity.

Dr. Hentrich pointed out that treatment relapses and failures mainly occurred in patients with advanced disease.

Grade 3/4 toxicity was common and tended to occur in more patients who were treated with BEACOPP than AVBD, but the differences were statistically significantly only in the early-stage patients. The major hematologic toxicity was severe neutropenia.

At 2-years, progression-free and overall survival were 91.7% and 90.2%, respectively, for the whole population, and did not differ greatly between early-, intermediate-, and advanced-stage disease. However, patients with advanced disease and advanced HIV infection were more likely to have a reduced overall survival, compared with the other two groups of patients.

"The next strategy is to focus the amount of intensity to special patients, so we want to incorporate early PET scans after two cycles [of chemotherapy] and then de-escalate therapy or even escalate therapy," Dr. Hentrich said.

Dr. Hentrich had no financial disclosures or conflicts of interest.

LONDON – HIV-infected patients with Hodgkin’s lymphoma can be treated more or less the same as any other Hodgkin’s patient, according to new data from the German HIV-related Lymphoma Study Group.

In a prospective, multicenter study of 108 patients with Hodgkin’s lymphoma (HL), all of whom were HIV positive, a risk-adapted treatment strategy was found to be feasible while patients were being treated with HAART (highly active antiretroviral therapy).

"I think the main message is that the prognosis [of patients with HIV-related HL] has dramatically improved with the [use of] HAART and with the stage- and risk-adapted treatment approach," study investigator Dr. Marcus Hentrich said in a June 11 interview at the annual congress of the European Hematology Association, where he presented the study.

"The results are approaching those we have obtained in the HIV-negative population," added Dr. Hentrich of Harlaching Hospital Munich. The findings show that "not every patient needs to be treated with full intensity" for six to eight courses of chemotherapy; rather, "we can distinguish [treatment] depending on the Hodgkin’s stage."

HL is one of the most common non–AIDS-defining cancers that often presents at an advanced stage. To date, there have been few prospective studies looking at how best to treat patients who are both HIV positive and have the hematologic malignancy; indeed, patients with HIV-related HL are often excluded from HL clinical trials. As a consequence, how best to manage such patients remains unknown (Adv. Hematol. 2011 [doi:10.1155/2011/402682]).

Combination therapy regimens have largely been used to treat HL in HIV-infected patients because of the generally late presentation of the disease, and controlling HIV infection via HAART has also been shown to improve the outcome of HL (Ann. Oncol. 2006;17:914-9).

The current study presented by Dr. Hentrich was conducted between March 2004 and October 2010. It included 100 male and 8 female patients with HL who were HIV positive, and its aim was to see whether a risk-adapted treatment strategy that was used in HIV-negative patients with HL could be applied to those infected with HIV.

Treatment for HL was determined by the stage of disease, with two to four cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) used with involved-field radiotherapy (30 Gy) in early-stage patients (that is, those with stage I-II HL and no additional risk factors).

In intermediate-stage patients (that is, those with stage I-II disease plus additional risk factors, such as large mediastinal tumor, extranodal involvement, and three or more lymph node regions involved), treatment consisted of four cycles of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) plus the same radiotherapy regimen.

More advanced HL (stage III-IV) was treated with six to eight cycles of BEACOPP plus facultative radiotherapy (30 Gy initial bulk or rest).

In patients with very advanced HIV infection and a poor performance status, the BEACOPP regimen could be replaced by ABVD, and the dose of ABVD reduced according to individual circumstances.

The median age of recruited patients was 43.9 years (range, 27-70 years). The majority (65%) had advanced disease, with 14% identified as having intermediate-stage HL, and 21% with early-stage disease. Extranodal involvement was observed in about half of patients (54%), and almost two-thirds (65%) had B-symptoms (which includes systemic symptoms such as fever, night sweats, and weight loss; B-symptoms can occur in both HL and non-HL).

Most (77%) patients had received HAART, and the median time from HIV to HL diagnosis was 5.9 years (range, 0-26 years).

After 26 months’ follow-up, 96%, 100%, and 84% of patients with early-, intermediate-, and advanced-stage HL, respectively, were in complete remission.

Perhaps not surprisingly, some advanced-stage patients fared worse, with four (6%) toxic and one (1.4%) unknown cause of death, five (7%) cases of early progression, and one (1.4%) partial remission in this group. One (4%) patient in the early-stage group also died because of toxicity.

Dr. Hentrich pointed out that treatment relapses and failures mainly occurred in patients with advanced disease.

Grade 3/4 toxicity was common and tended to occur in more patients who were treated with BEACOPP than AVBD, but the differences were statistically significantly only in the early-stage patients. The major hematologic toxicity was severe neutropenia.

At 2-years, progression-free and overall survival were 91.7% and 90.2%, respectively, for the whole population, and did not differ greatly between early-, intermediate-, and advanced-stage disease. However, patients with advanced disease and advanced HIV infection were more likely to have a reduced overall survival, compared with the other two groups of patients.

"The next strategy is to focus the amount of intensity to special patients, so we want to incorporate early PET scans after two cycles [of chemotherapy] and then de-escalate therapy or even escalate therapy," Dr. Hentrich said.

Dr. Hentrich had no financial disclosures or conflicts of interest.

LONDON – HIV-infected patients with Hodgkin’s lymphoma can be treated more or less the same as any other Hodgkin’s patient, according to new data from the German HIV-related Lymphoma Study Group.

In a prospective, multicenter study of 108 patients with Hodgkin’s lymphoma (HL), all of whom were HIV positive, a risk-adapted treatment strategy was found to be feasible while patients were being treated with HAART (highly active antiretroviral therapy).

"I think the main message is that the prognosis [of patients with HIV-related HL] has dramatically improved with the [use of] HAART and with the stage- and risk-adapted treatment approach," study investigator Dr. Marcus Hentrich said in a June 11 interview at the annual congress of the European Hematology Association, where he presented the study.

"The results are approaching those we have obtained in the HIV-negative population," added Dr. Hentrich of Harlaching Hospital Munich. The findings show that "not every patient needs to be treated with full intensity" for six to eight courses of chemotherapy; rather, "we can distinguish [treatment] depending on the Hodgkin’s stage."

HL is one of the most common non–AIDS-defining cancers that often presents at an advanced stage. To date, there have been few prospective studies looking at how best to treat patients who are both HIV positive and have the hematologic malignancy; indeed, patients with HIV-related HL are often excluded from HL clinical trials. As a consequence, how best to manage such patients remains unknown (Adv. Hematol. 2011 [doi:10.1155/2011/402682]).

Combination therapy regimens have largely been used to treat HL in HIV-infected patients because of the generally late presentation of the disease, and controlling HIV infection via HAART has also been shown to improve the outcome of HL (Ann. Oncol. 2006;17:914-9).

The current study presented by Dr. Hentrich was conducted between March 2004 and October 2010. It included 100 male and 8 female patients with HL who were HIV positive, and its aim was to see whether a risk-adapted treatment strategy that was used in HIV-negative patients with HL could be applied to those infected with HIV.

Treatment for HL was determined by the stage of disease, with two to four cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) used with involved-field radiotherapy (30 Gy) in early-stage patients (that is, those with stage I-II HL and no additional risk factors).

In intermediate-stage patients (that is, those with stage I-II disease plus additional risk factors, such as large mediastinal tumor, extranodal involvement, and three or more lymph node regions involved), treatment consisted of four cycles of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) plus the same radiotherapy regimen.

More advanced HL (stage III-IV) was treated with six to eight cycles of BEACOPP plus facultative radiotherapy (30 Gy initial bulk or rest).

In patients with very advanced HIV infection and a poor performance status, the BEACOPP regimen could be replaced by ABVD, and the dose of ABVD reduced according to individual circumstances.

The median age of recruited patients was 43.9 years (range, 27-70 years). The majority (65%) had advanced disease, with 14% identified as having intermediate-stage HL, and 21% with early-stage disease. Extranodal involvement was observed in about half of patients (54%), and almost two-thirds (65%) had B-symptoms (which includes systemic symptoms such as fever, night sweats, and weight loss; B-symptoms can occur in both HL and non-HL).

Most (77%) patients had received HAART, and the median time from HIV to HL diagnosis was 5.9 years (range, 0-26 years).

After 26 months’ follow-up, 96%, 100%, and 84% of patients with early-, intermediate-, and advanced-stage HL, respectively, were in complete remission.

Perhaps not surprisingly, some advanced-stage patients fared worse, with four (6%) toxic and one (1.4%) unknown cause of death, five (7%) cases of early progression, and one (1.4%) partial remission in this group. One (4%) patient in the early-stage group also died because of toxicity.

Dr. Hentrich pointed out that treatment relapses and failures mainly occurred in patients with advanced disease.

Grade 3/4 toxicity was common and tended to occur in more patients who were treated with BEACOPP than AVBD, but the differences were statistically significantly only in the early-stage patients. The major hematologic toxicity was severe neutropenia.

At 2-years, progression-free and overall survival were 91.7% and 90.2%, respectively, for the whole population, and did not differ greatly between early-, intermediate-, and advanced-stage disease. However, patients with advanced disease and advanced HIV infection were more likely to have a reduced overall survival, compared with the other two groups of patients.

"The next strategy is to focus the amount of intensity to special patients, so we want to incorporate early PET scans after two cycles [of chemotherapy] and then de-escalate therapy or even escalate therapy," Dr. Hentrich said.

Dr. Hentrich had no financial disclosures or conflicts of interest.

LONDON – Stopping treatment with dasatinib and nilotinib might be safe in chronic myeloid leukemia patients who have achieved sustained and complete molecular responses, early data from a pilot study have shown.

The STOP 2GTKI study is a successor to the STop IMatinib (STIM) trial, which showed that stopping treatment with imatinib – the first-generation tyrosine kinase inhibitor (TKI) of BCR-ABL – could be feasible in patients who achieve long-lasting complete molecular responses (Lancet Oncol.2010;11:1029-35).

Although still preliminary, the new data suggest that it could be possible to do the same with these second-generation TKIs in patients who were previously intolerant or resistant to treatment with imatinib, Dr. Delphine Réa said at the annual Congress of the European Hematology Association.

"There are different kinds of reasons why we should aim at stopping tyrosine kinase inhibitors in chronic myeloid leukemia patients," said Dr. Réa of Hôpital Saint-Louis in Paris.

"The first one relates to patients. From the patients’ perspective it’s very important to have the hope of feeling cured," said Dr. Réa, a member of the French team that performed both the STIM and the STOP 2G-TKI studies.

Other reasons given include avoiding the adverse effects of prolonged therapy on quality of life, and reducing health care costs by steering clear of unnecessary long-term treatment for what becomes a chronic disease. It’s also important for clinicians to be able to show that a treatment really does cure a disease, she said, and the only way to do that is to stop the treatment.

Dr. Réa presented early data on 14 patients who had been enrolled in the STOP 2G-TKI pilot study until May 2011 and for whom there was at least 6 months’ follow-up. The median age of patients was 59 years.

"I think it’s very important to have 6 months’ follow-up at least because in the STop IMatinib trial, most of the relapses occurred within the first 6 months," Dr. Réa explained in an interview after her presentation.

"Here we didn’t have any relapses after 6 months," Dr. Réa added. "For the nine patients who didn’t relapse, the median follow-up is 10 months." The duration of time that these patients remained treatment free was between 6 months and 19 months.

For inclusion in the study, patients had to be aged 18 years or older with chronic or acute phase chronic myeloid leukemia at diagnosis, and be receiving ongoing dasatinib or nilotinib treatment after intolerance or resistance to imatinib therapy. TKI treatment had to have been administered for at least 3 years, and patients needed to have undetectable levels of BCR-ABL with at least 20,000 copies of ABL.

The primary end point was the achievement of a stable major molecular response (MMR) at 6 months, determined by monthly blood counts and real-time quantitative polymerase chain reaction for the first year of discontinuation, then every 2-3 months thereafter. Bone marrow smears and cytogenic and mutational analysis are undertaken if there is a rise in BCR-ABL above an internationally standardized (IS) ratio of 1%. Patients are re-treated with dasatinib or nilotinib if there is a loss of MMR of more than 0.1% IS.

Results showed that at 6 months’ follow-up, 71% of patients had a persistent MMR, and 64% remained treatment free. Five patients restarted TKI treatment at a median of 5 months, and four patients lost MMR after a median of 3 months. However, the patients who lost major molecular response retained their sensitivity to TKIs, and BCR-ABL was undetectable in all five patients who restarted therapy.

Asked what these results could mean for clinical practice, Dr. Réa noted that they are an early indicator that stopping treatment with second-generation TKIs will probably be an option for some patients who achieve good responses. Careful (at least monthly) follow-up of patients who cease treatment would be required, at least in the research setting.

"We don’t know, but we hope the relapse rate will be lower than we have seen with imatinib [discontinuation]," Dr. Réa said. She added, however, that there is an indication that the relapse rate could actually be higher than that seen in the STIM trial.

As yet, the optimal duration of treatment with a second-generation TKI before discontinuation can be attempted is unknown. "In the STop IMatinib trial, it seems to be between 4 and 5 years," Dr. Réa observed. "So I don’t think it will be reasonable to stop treatment before that period of time."

Further results from the trial can be expected later in the year, Dr. Réa noted. To date, 23 patients have been recruited and 8 more are to be included in the trial.

Dr. Réa disclosed serving on advisory boards of Bristol-Myers Squibb and Novartis.

LONDON – Stopping treatment with dasatinib and nilotinib might be safe in chronic myeloid leukemia patients who have achieved sustained and complete molecular responses, early data from a pilot study have shown.

The STOP 2GTKI study is a successor to the STop IMatinib (STIM) trial, which showed that stopping treatment with imatinib – the first-generation tyrosine kinase inhibitor (TKI) of BCR-ABL – could be feasible in patients who achieve long-lasting complete molecular responses (Lancet Oncol.2010;11:1029-35).

Although still preliminary, the new data suggest that it could be possible to do the same with these second-generation TKIs in patients who were previously intolerant or resistant to treatment with imatinib, Dr. Delphine Réa said at the annual Congress of the European Hematology Association.

"There are different kinds of reasons why we should aim at stopping tyrosine kinase inhibitors in chronic myeloid leukemia patients," said Dr. Réa of Hôpital Saint-Louis in Paris.

"The first one relates to patients. From the patients’ perspective it’s very important to have the hope of feeling cured," said Dr. Réa, a member of the French team that performed both the STIM and the STOP 2G-TKI studies.

Other reasons given include avoiding the adverse effects of prolonged therapy on quality of life, and reducing health care costs by steering clear of unnecessary long-term treatment for what becomes a chronic disease. It’s also important for clinicians to be able to show that a treatment really does cure a disease, she said, and the only way to do that is to stop the treatment.

Dr. Réa presented early data on 14 patients who had been enrolled in the STOP 2G-TKI pilot study until May 2011 and for whom there was at least 6 months’ follow-up. The median age of patients was 59 years.

"I think it’s very important to have 6 months’ follow-up at least because in the STop IMatinib trial, most of the relapses occurred within the first 6 months," Dr. Réa explained in an interview after her presentation.

"Here we didn’t have any relapses after 6 months," Dr. Réa added. "For the nine patients who didn’t relapse, the median follow-up is 10 months." The duration of time that these patients remained treatment free was between 6 months and 19 months.

For inclusion in the study, patients had to be aged 18 years or older with chronic or acute phase chronic myeloid leukemia at diagnosis, and be receiving ongoing dasatinib or nilotinib treatment after intolerance or resistance to imatinib therapy. TKI treatment had to have been administered for at least 3 years, and patients needed to have undetectable levels of BCR-ABL with at least 20,000 copies of ABL.

The primary end point was the achievement of a stable major molecular response (MMR) at 6 months, determined by monthly blood counts and real-time quantitative polymerase chain reaction for the first year of discontinuation, then every 2-3 months thereafter. Bone marrow smears and cytogenic and mutational analysis are undertaken if there is a rise in BCR-ABL above an internationally standardized (IS) ratio of 1%. Patients are re-treated with dasatinib or nilotinib if there is a loss of MMR of more than 0.1% IS.

Results showed that at 6 months’ follow-up, 71% of patients had a persistent MMR, and 64% remained treatment free. Five patients restarted TKI treatment at a median of 5 months, and four patients lost MMR after a median of 3 months. However, the patients who lost major molecular response retained their sensitivity to TKIs, and BCR-ABL was undetectable in all five patients who restarted therapy.

Asked what these results could mean for clinical practice, Dr. Réa noted that they are an early indicator that stopping treatment with second-generation TKIs will probably be an option for some patients who achieve good responses. Careful (at least monthly) follow-up of patients who cease treatment would be required, at least in the research setting.

"We don’t know, but we hope the relapse rate will be lower than we have seen with imatinib [discontinuation]," Dr. Réa said. She added, however, that there is an indication that the relapse rate could actually be higher than that seen in the STIM trial.

As yet, the optimal duration of treatment with a second-generation TKI before discontinuation can be attempted is unknown. "In the STop IMatinib trial, it seems to be between 4 and 5 years," Dr. Réa observed. "So I don’t think it will be reasonable to stop treatment before that period of time."

Further results from the trial can be expected later in the year, Dr. Réa noted. To date, 23 patients have been recruited and 8 more are to be included in the trial.

Dr. Réa disclosed serving on advisory boards of Bristol-Myers Squibb and Novartis.

LONDON – Stopping treatment with dasatinib and nilotinib might be safe in chronic myeloid leukemia patients who have achieved sustained and complete molecular responses, early data from a pilot study have shown.

The STOP 2GTKI study is a successor to the STop IMatinib (STIM) trial, which showed that stopping treatment with imatinib – the first-generation tyrosine kinase inhibitor (TKI) of BCR-ABL – could be feasible in patients who achieve long-lasting complete molecular responses (Lancet Oncol.2010;11:1029-35).

Although still preliminary, the new data suggest that it could be possible to do the same with these second-generation TKIs in patients who were previously intolerant or resistant to treatment with imatinib, Dr. Delphine Réa said at the annual Congress of the European Hematology Association.

"There are different kinds of reasons why we should aim at stopping tyrosine kinase inhibitors in chronic myeloid leukemia patients," said Dr. Réa of Hôpital Saint-Louis in Paris.

"The first one relates to patients. From the patients’ perspective it’s very important to have the hope of feeling cured," said Dr. Réa, a member of the French team that performed both the STIM and the STOP 2G-TKI studies.

Other reasons given include avoiding the adverse effects of prolonged therapy on quality of life, and reducing health care costs by steering clear of unnecessary long-term treatment for what becomes a chronic disease. It’s also important for clinicians to be able to show that a treatment really does cure a disease, she said, and the only way to do that is to stop the treatment.

Dr. Réa presented early data on 14 patients who had been enrolled in the STOP 2G-TKI pilot study until May 2011 and for whom there was at least 6 months’ follow-up. The median age of patients was 59 years.

"I think it’s very important to have 6 months’ follow-up at least because in the STop IMatinib trial, most of the relapses occurred within the first 6 months," Dr. Réa explained in an interview after her presentation.

"Here we didn’t have any relapses after 6 months," Dr. Réa added. "For the nine patients who didn’t relapse, the median follow-up is 10 months." The duration of time that these patients remained treatment free was between 6 months and 19 months.

For inclusion in the study, patients had to be aged 18 years or older with chronic or acute phase chronic myeloid leukemia at diagnosis, and be receiving ongoing dasatinib or nilotinib treatment after intolerance or resistance to imatinib therapy. TKI treatment had to have been administered for at least 3 years, and patients needed to have undetectable levels of BCR-ABL with at least 20,000 copies of ABL.

The primary end point was the achievement of a stable major molecular response (MMR) at 6 months, determined by monthly blood counts and real-time quantitative polymerase chain reaction for the first year of discontinuation, then every 2-3 months thereafter. Bone marrow smears and cytogenic and mutational analysis are undertaken if there is a rise in BCR-ABL above an internationally standardized (IS) ratio of 1%. Patients are re-treated with dasatinib or nilotinib if there is a loss of MMR of more than 0.1% IS.

Results showed that at 6 months’ follow-up, 71% of patients had a persistent MMR, and 64% remained treatment free. Five patients restarted TKI treatment at a median of 5 months, and four patients lost MMR after a median of 3 months. However, the patients who lost major molecular response retained their sensitivity to TKIs, and BCR-ABL was undetectable in all five patients who restarted therapy.

Asked what these results could mean for clinical practice, Dr. Réa noted that they are an early indicator that stopping treatment with second-generation TKIs will probably be an option for some patients who achieve good responses. Careful (at least monthly) follow-up of patients who cease treatment would be required, at least in the research setting.

"We don’t know, but we hope the relapse rate will be lower than we have seen with imatinib [discontinuation]," Dr. Réa said. She added, however, that there is an indication that the relapse rate could actually be higher than that seen in the STIM trial.

As yet, the optimal duration of treatment with a second-generation TKI before discontinuation can be attempted is unknown. "In the STop IMatinib trial, it seems to be between 4 and 5 years," Dr. Réa observed. "So I don’t think it will be reasonable to stop treatment before that period of time."

Further results from the trial can be expected later in the year, Dr. Réa noted. To date, 23 patients have been recruited and 8 more are to be included in the trial.

Dr. Réa disclosed serving on advisory boards of Bristol-Myers Squibb and Novartis.