Jen Smith

Hui-Qiang Huang, MD, PhD

Photo by Larry Young

SAN FRANCISCO—A 3-agent chemotherapy regimen can be “highly effective” in patients with extranodal natural killer/T-cell lymphoma (ENKTL), according to researchers.

In a single-center study, this regimen—pegaspargase, gemcitabine, and oxaliplatin (P-GEMOX)—followed by extensive involved-field radiotherapy (EIFRT) produced high rates of long-term overall survival (OS) and progression-free survival (PFS) in newly diagnosed patients with stage I/II ENKTL.

P-GEMOX also proved effective—though to a much lesser degree—in advanced, relapsed, or refractory ENKTL, and these patients appeared to benefit from autologous stem cell transplant (auto-SCT) as consolidation.

Toxicity associated with P-GEMOX was mild to moderate and tolerable, according to Hui-Qiang Huang, MD, PhD, of State Key Laboratory of Oncology in Southern China, Guangzhou, China.

Dr Huang presented these results at the 8th Annual T-cell Lymphoma Forum.

Newly diagnosed patients

Dr Huang and his colleagues studied 56 patients newly diagnosed with stage I/II, nasal-type ENKTL. Most patients were younger than 60 years of age (80.4%, n=45).

About 79% (n=44) had an ECOG status of 0, and 21.4% (n=12) had a status of 1. About 61% (n=34) had stage I disease, and 39.3% (n=22) had stage II.

All patients received P-GEMOX—gemcitabine at 1000 mg/m² on days 1 and 8, oxaliplatin at 150 mg/m² on day 1, and pegaspargase at 2000 U/m² on day 1. Doses could be adjusted in the event of toxicity.

The regimen was repeated every 3 weeks for a maximum of 4 cycles. Patients then underwent EIFRT—56 Gy in 28 fractions over 4 weeks.

The overall response rate (ORR) after P-GEMOX was 89.3% (50/56). Thirty-five patients achieved a complete response (CR), 15 had a partial response (PR), and 4 had stable disease (SD).

After EIFRT, the ORR increased to 94.6% (53/56). Fifty patients had a CR, 3 had a PR, and 1 had SD.

The median follow-up was 35.2 months (range, 10.6-51.4). Six patients relapsed, and the median time to relapse was 6.2 months.

Five patients died of disease progression. The median time to death was 10.9 months after the completion of EIFRT.

The 4-year OS rate was 90.7±4.0%, and the 4-year PFS rate was 89.1±4.2%.

OS and PFS were superior in patients with stage I disease as compared to stage II (P=0.056 and 0.023, respectively). And OS and PFS were superior in patients who responded to P-GEMOX (P=0.004 and 0.001, respectively).

There were no treatment-related deaths. The most common toxicities (occurring in more than 50% of patients) after P-GEMOX were neutropenia (80.3%), thrombocytopenia (55.3%), and hypoproteinemia (75.0%).

The most common grade 3/4 toxicities (occurring in more than 10% of patients) were granulocytosis (23.2%), thrombocytopenia (19.6%), and hypoproteinemia (10.7%).

Advanced & relapsed/refractory patients

Dr Huang and his colleagues also studied 60 patients with newly diagnosed, stage III/IV ENKTL (25%, n=15), relapsed ENKTL (21.7%, n=19), or refractory disease (43.3%, n=26). Seventy percent of these patients (n=42) had nasal-type ENKTL.

Most patients were younger than 60 years of age (91.7%, n=55). About 73% (n=44) had an ECOG status of 0-1, and 26.7% (n=16) had a status of 2. Fifteen percent of patients (n=9) had stage I disease, 16.7% (n=10) had stage II, 35% (n=21) had stage III, and 33.3% (n=20) had stage IV.

The patients received the same P-GEMOX regimen as the newly diagnosed, stage I/II patients, but they did not receive EIFRT, and responders could undergo auto-SCT.

For the whole cohort, the ORR after P-GEMOX was 70% (42/60). Twenty-one patients had a CR, 21 had a PR, and 9 had SD.

In the newly diagnosed patients, the ORR was 80% (12/15). Four patients had a CR, 8 had a PR, and 2 had SD. In the relapsed/refractory patients, the ORR was 66.7% (30/45). Seventeen patients had a CR, 13 had a PR, and 7 had SD.

The 4-year OS was 43.0±7.3%, and the 4-year PFS was 36.5±6.9%.

There was no significant difference in OS or PFS between the newly diagnosed and relapsed/refractory patients (P=0.653 and 0.825, respectively). However, there was a significant difference in PFS and OS between responders and non-responders (P<0.001 for both).

There was a difference in 3-year OS between patients who went on to auto-SCT and those did not, although it did not reach statistical significance (P=0.08). Eleven patients who achieved a CR went on to auto-SCT.

There were no treatment-related deaths. The most common toxicities (occurring in more than 50% of patients) after P-GEMOX were neutropenia (85%), hypoproteinemia (88.3%), anemia (71.6%), fibrinogen decrease (68.3%), and anorexia (53.3%).

The most common grade 3/4 toxicities (occurring in more than 10% of patients) were neutropenia (31.6%), hypoproteinemia (13.3%), and thrombocytopenia (11.7%).

Dr Huang said this research suggests P-GEMOX can be effective for patients with newly diagnosed or previously treated ENKTL. The next step is to investigate which novel agents could be added to the regimen to improve its efficacy.

Hui-Qiang Huang, MD, PhD

Photo by Larry Young

SAN FRANCISCO—A 3-agent chemotherapy regimen can be “highly effective” in patients with extranodal natural killer/T-cell lymphoma (ENKTL), according to researchers.

In a single-center study, this regimen—pegaspargase, gemcitabine, and oxaliplatin (P-GEMOX)—followed by extensive involved-field radiotherapy (EIFRT) produced high rates of long-term overall survival (OS) and progression-free survival (PFS) in newly diagnosed patients with stage I/II ENKTL.

P-GEMOX also proved effective—though to a much lesser degree—in advanced, relapsed, or refractory ENKTL, and these patients appeared to benefit from autologous stem cell transplant (auto-SCT) as consolidation.

Toxicity associated with P-GEMOX was mild to moderate and tolerable, according to Hui-Qiang Huang, MD, PhD, of State Key Laboratory of Oncology in Southern China, Guangzhou, China.

Dr Huang presented these results at the 8th Annual T-cell Lymphoma Forum.

Newly diagnosed patients

Dr Huang and his colleagues studied 56 patients newly diagnosed with stage I/II, nasal-type ENKTL. Most patients were younger than 60 years of age (80.4%, n=45).

About 79% (n=44) had an ECOG status of 0, and 21.4% (n=12) had a status of 1. About 61% (n=34) had stage I disease, and 39.3% (n=22) had stage II.

All patients received P-GEMOX—gemcitabine at 1000 mg/m² on days 1 and 8, oxaliplatin at 150 mg/m² on day 1, and pegaspargase at 2000 U/m² on day 1. Doses could be adjusted in the event of toxicity.

The regimen was repeated every 3 weeks for a maximum of 4 cycles. Patients then underwent EIFRT—56 Gy in 28 fractions over 4 weeks.

The overall response rate (ORR) after P-GEMOX was 89.3% (50/56). Thirty-five patients achieved a complete response (CR), 15 had a partial response (PR), and 4 had stable disease (SD).

After EIFRT, the ORR increased to 94.6% (53/56). Fifty patients had a CR, 3 had a PR, and 1 had SD.

The median follow-up was 35.2 months (range, 10.6-51.4). Six patients relapsed, and the median time to relapse was 6.2 months.

Five patients died of disease progression. The median time to death was 10.9 months after the completion of EIFRT.

The 4-year OS rate was 90.7±4.0%, and the 4-year PFS rate was 89.1±4.2%.

OS and PFS were superior in patients with stage I disease as compared to stage II (P=0.056 and 0.023, respectively). And OS and PFS were superior in patients who responded to P-GEMOX (P=0.004 and 0.001, respectively).

There were no treatment-related deaths. The most common toxicities (occurring in more than 50% of patients) after P-GEMOX were neutropenia (80.3%), thrombocytopenia (55.3%), and hypoproteinemia (75.0%).

The most common grade 3/4 toxicities (occurring in more than 10% of patients) were granulocytosis (23.2%), thrombocytopenia (19.6%), and hypoproteinemia (10.7%).

Advanced & relapsed/refractory patients

Dr Huang and his colleagues also studied 60 patients with newly diagnosed, stage III/IV ENKTL (25%, n=15), relapsed ENKTL (21.7%, n=19), or refractory disease (43.3%, n=26). Seventy percent of these patients (n=42) had nasal-type ENKTL.

Most patients were younger than 60 years of age (91.7%, n=55). About 73% (n=44) had an ECOG status of 0-1, and 26.7% (n=16) had a status of 2. Fifteen percent of patients (n=9) had stage I disease, 16.7% (n=10) had stage II, 35% (n=21) had stage III, and 33.3% (n=20) had stage IV.

The patients received the same P-GEMOX regimen as the newly diagnosed, stage I/II patients, but they did not receive EIFRT, and responders could undergo auto-SCT.

For the whole cohort, the ORR after P-GEMOX was 70% (42/60). Twenty-one patients had a CR, 21 had a PR, and 9 had SD.

In the newly diagnosed patients, the ORR was 80% (12/15). Four patients had a CR, 8 had a PR, and 2 had SD. In the relapsed/refractory patients, the ORR was 66.7% (30/45). Seventeen patients had a CR, 13 had a PR, and 7 had SD.

The 4-year OS was 43.0±7.3%, and the 4-year PFS was 36.5±6.9%.

There was no significant difference in OS or PFS between the newly diagnosed and relapsed/refractory patients (P=0.653 and 0.825, respectively). However, there was a significant difference in PFS and OS between responders and non-responders (P<0.001 for both).

There was a difference in 3-year OS between patients who went on to auto-SCT and those did not, although it did not reach statistical significance (P=0.08). Eleven patients who achieved a CR went on to auto-SCT.

There were no treatment-related deaths. The most common toxicities (occurring in more than 50% of patients) after P-GEMOX were neutropenia (85%), hypoproteinemia (88.3%), anemia (71.6%), fibrinogen decrease (68.3%), and anorexia (53.3%).

The most common grade 3/4 toxicities (occurring in more than 10% of patients) were neutropenia (31.6%), hypoproteinemia (13.3%), and thrombocytopenia (11.7%).

Dr Huang said this research suggests P-GEMOX can be effective for patients with newly diagnosed or previously treated ENKTL. The next step is to investigate which novel agents could be added to the regimen to improve its efficacy.

Hui-Qiang Huang, MD, PhD

Photo by Larry Young

SAN FRANCISCO—A 3-agent chemotherapy regimen can be “highly effective” in patients with extranodal natural killer/T-cell lymphoma (ENKTL), according to researchers.

In a single-center study, this regimen—pegaspargase, gemcitabine, and oxaliplatin (P-GEMOX)—followed by extensive involved-field radiotherapy (EIFRT) produced high rates of long-term overall survival (OS) and progression-free survival (PFS) in newly diagnosed patients with stage I/II ENKTL.

P-GEMOX also proved effective—though to a much lesser degree—in advanced, relapsed, or refractory ENKTL, and these patients appeared to benefit from autologous stem cell transplant (auto-SCT) as consolidation.

Toxicity associated with P-GEMOX was mild to moderate and tolerable, according to Hui-Qiang Huang, MD, PhD, of State Key Laboratory of Oncology in Southern China, Guangzhou, China.

Dr Huang presented these results at the 8th Annual T-cell Lymphoma Forum.

Newly diagnosed patients

Dr Huang and his colleagues studied 56 patients newly diagnosed with stage I/II, nasal-type ENKTL. Most patients were younger than 60 years of age (80.4%, n=45).

About 79% (n=44) had an ECOG status of 0, and 21.4% (n=12) had a status of 1. About 61% (n=34) had stage I disease, and 39.3% (n=22) had stage II.

All patients received P-GEMOX—gemcitabine at 1000 mg/m² on days 1 and 8, oxaliplatin at 150 mg/m² on day 1, and pegaspargase at 2000 U/m² on day 1. Doses could be adjusted in the event of toxicity.

The regimen was repeated every 3 weeks for a maximum of 4 cycles. Patients then underwent EIFRT—56 Gy in 28 fractions over 4 weeks.

The overall response rate (ORR) after P-GEMOX was 89.3% (50/56). Thirty-five patients achieved a complete response (CR), 15 had a partial response (PR), and 4 had stable disease (SD).

After EIFRT, the ORR increased to 94.6% (53/56). Fifty patients had a CR, 3 had a PR, and 1 had SD.

The median follow-up was 35.2 months (range, 10.6-51.4). Six patients relapsed, and the median time to relapse was 6.2 months.

Five patients died of disease progression. The median time to death was 10.9 months after the completion of EIFRT.

The 4-year OS rate was 90.7±4.0%, and the 4-year PFS rate was 89.1±4.2%.

OS and PFS were superior in patients with stage I disease as compared to stage II (P=0.056 and 0.023, respectively). And OS and PFS were superior in patients who responded to P-GEMOX (P=0.004 and 0.001, respectively).

There were no treatment-related deaths. The most common toxicities (occurring in more than 50% of patients) after P-GEMOX were neutropenia (80.3%), thrombocytopenia (55.3%), and hypoproteinemia (75.0%).

The most common grade 3/4 toxicities (occurring in more than 10% of patients) were granulocytosis (23.2%), thrombocytopenia (19.6%), and hypoproteinemia (10.7%).

Advanced & relapsed/refractory patients

Dr Huang and his colleagues also studied 60 patients with newly diagnosed, stage III/IV ENKTL (25%, n=15), relapsed ENKTL (21.7%, n=19), or refractory disease (43.3%, n=26). Seventy percent of these patients (n=42) had nasal-type ENKTL.

Most patients were younger than 60 years of age (91.7%, n=55). About 73% (n=44) had an ECOG status of 0-1, and 26.7% (n=16) had a status of 2. Fifteen percent of patients (n=9) had stage I disease, 16.7% (n=10) had stage II, 35% (n=21) had stage III, and 33.3% (n=20) had stage IV.

The patients received the same P-GEMOX regimen as the newly diagnosed, stage I/II patients, but they did not receive EIFRT, and responders could undergo auto-SCT.

For the whole cohort, the ORR after P-GEMOX was 70% (42/60). Twenty-one patients had a CR, 21 had a PR, and 9 had SD.

In the newly diagnosed patients, the ORR was 80% (12/15). Four patients had a CR, 8 had a PR, and 2 had SD. In the relapsed/refractory patients, the ORR was 66.7% (30/45). Seventeen patients had a CR, 13 had a PR, and 7 had SD.

The 4-year OS was 43.0±7.3%, and the 4-year PFS was 36.5±6.9%.

There was no significant difference in OS or PFS between the newly diagnosed and relapsed/refractory patients (P=0.653 and 0.825, respectively). However, there was a significant difference in PFS and OS between responders and non-responders (P<0.001 for both).

There was a difference in 3-year OS between patients who went on to auto-SCT and those did not, although it did not reach statistical significance (P=0.08). Eleven patients who achieved a CR went on to auto-SCT.

There were no treatment-related deaths. The most common toxicities (occurring in more than 50% of patients) after P-GEMOX were neutropenia (85%), hypoproteinemia (88.3%), anemia (71.6%), fibrinogen decrease (68.3%), and anorexia (53.3%).

The most common grade 3/4 toxicities (occurring in more than 10% of patients) were neutropenia (31.6%), hypoproteinemia (13.3%), and thrombocytopenia (11.7%).

Dr Huang said this research suggests P-GEMOX can be effective for patients with newly diagnosed or previously treated ENKTL. The next step is to investigate which novel agents could be added to the regimen to improve its efficacy.

Maokoto Yamagishi, PhD

Photo by Larry Young

SAN FRANCISCO—Preclinical research suggests a compound that inhibits both EZH1 and EZH2 could be effective against adult T-cell leukemia/lymphoma (ATLL).

The compound, known as OR-S1, has demonstrated activity against ATLL in vitro and in vivo.

Researchers said OR-S1 reversed epigenetic disruption in ATLL cells, selectively eliminated both ATLL cells and cells infected with human T-cell leukemia virus type I (HTLV-1), and inhibited tumor growth in mouse models of ATLL.

Based on these results, the researchers are planning a phase 1 study of the compound.

Makoto Yamagishi, PhD, of The University of Tokyo in Japan, described the preclinical research with OR-S1 and discussed the rationale for developing the compound at the 8th Annual T-cell Lymphoma Forum. The work was carried out in collaboration with Daiichi Sankyo Co., Ltd.

“We do not precisely understand the molecular mechanism of ATLL development, including genetic and epigenetic abnormalities,” Dr Yamagishi noted.

To gain some insight, he and his colleagues performed microRNA profiling, gene expression profiling, and histone methylation/epigenetic factor profiling on cells from ATLL patients and CD4+ T cells from healthy donors.

The team found that PRC2 factors were significantly upregulated in ATLL. EZH2 was the most upregulated histone methyltransferase, but ATLL cells did not have active mutations in the EZH2 gene. Dr Yamagishi said this suggests EZH2 upregulation is critical for the ATLL-specific epigenome.

“At long last, we determined the epigenetic pattern of ATLL,” he said. “ATLL cells showed specific and significant reprogramming of the epigenome, especially H3K27me3 gain. We found abnormal H3K27me3 change in half of genes, and gain was dominant.”

“But, interestingly, the methylated genes are specific in ATLL and do not overlap with other EZH2-dependent cell types, such as embryonic stem cells and diffuse large B-cell lymphoma cells. So ATLL has a very unique epigenome.”

Further investigation revealed that both EZH1 and EZH2 contribute to ATLL-specific epigenetic deregulation. More than 80% of H3K27me3 accumulated genes are occupied by EZH1 and/or EZH2.

So the researchers decided to examine the effects of knocking down EZH1 and EZH2 in ATLL cells.

Compared with knockdown of either gene alone, double knockdown synergistically influenced target gene expression. It led to complete dysfunction of the Polycomb family and had a significant impact on ATLL cell survival.

The researchers also found that EZH1 depletion enhanced ATLL cells’ sensitivity to the EZH2 inhibitor GSK126.

So the team decided to develop a dual EZH1/EZH2 inhibitor. They created OR-S1, which showed “strong activity” against EZH1 and EZH2 but none of the other histone methyltransferases tested.

In in vitro experiments, OR-S1 completely removed H3K27me3 and significantly reduced cell growth in the ATLL-derived cell line TL-Om1.

The drug also reduced cell viability in primary ATLL cells. All 15 samples tested proved sensitive to OR-S1. In addition, OR-S1 treatment selectively removed HTLV-1-infected cells from samples taken from 16 asymptomatic carriers.

Finally, OR-S1 proved active in mice. The drug prevented engraftment of ATLL cells in immunocompromised mice. All 6 OR-S1-treated mice were alive and tumor-free at 49 days, whereas 5 of 6 control mice had died (P=0.0041).

In mice treated after ATLL cell engraftment, OR-S1 reduced tumor growth without causing notable weight loss.

“Synthetic lethality by targeting EZH1 and EZH2 is promising [for ATLL],” Dr Yamagishi said. “Toxicity tests suggest the EZH1/2 dual inhibitor may be sufficient for clinical use, so we are now planning a phase 1 study.”

Maokoto Yamagishi, PhD

Photo by Larry Young

SAN FRANCISCO—Preclinical research suggests a compound that inhibits both EZH1 and EZH2 could be effective against adult T-cell leukemia/lymphoma (ATLL).

The compound, known as OR-S1, has demonstrated activity against ATLL in vitro and in vivo.

Researchers said OR-S1 reversed epigenetic disruption in ATLL cells, selectively eliminated both ATLL cells and cells infected with human T-cell leukemia virus type I (HTLV-1), and inhibited tumor growth in mouse models of ATLL.

Based on these results, the researchers are planning a phase 1 study of the compound.

Makoto Yamagishi, PhD, of The University of Tokyo in Japan, described the preclinical research with OR-S1 and discussed the rationale for developing the compound at the 8th Annual T-cell Lymphoma Forum. The work was carried out in collaboration with Daiichi Sankyo Co., Ltd.

“We do not precisely understand the molecular mechanism of ATLL development, including genetic and epigenetic abnormalities,” Dr Yamagishi noted.

To gain some insight, he and his colleagues performed microRNA profiling, gene expression profiling, and histone methylation/epigenetic factor profiling on cells from ATLL patients and CD4+ T cells from healthy donors.

The team found that PRC2 factors were significantly upregulated in ATLL. EZH2 was the most upregulated histone methyltransferase, but ATLL cells did not have active mutations in the EZH2 gene. Dr Yamagishi said this suggests EZH2 upregulation is critical for the ATLL-specific epigenome.

“At long last, we determined the epigenetic pattern of ATLL,” he said. “ATLL cells showed specific and significant reprogramming of the epigenome, especially H3K27me3 gain. We found abnormal H3K27me3 change in half of genes, and gain was dominant.”

“But, interestingly, the methylated genes are specific in ATLL and do not overlap with other EZH2-dependent cell types, such as embryonic stem cells and diffuse large B-cell lymphoma cells. So ATLL has a very unique epigenome.”

Further investigation revealed that both EZH1 and EZH2 contribute to ATLL-specific epigenetic deregulation. More than 80% of H3K27me3 accumulated genes are occupied by EZH1 and/or EZH2.

So the researchers decided to examine the effects of knocking down EZH1 and EZH2 in ATLL cells.

Compared with knockdown of either gene alone, double knockdown synergistically influenced target gene expression. It led to complete dysfunction of the Polycomb family and had a significant impact on ATLL cell survival.

The researchers also found that EZH1 depletion enhanced ATLL cells’ sensitivity to the EZH2 inhibitor GSK126.

So the team decided to develop a dual EZH1/EZH2 inhibitor. They created OR-S1, which showed “strong activity” against EZH1 and EZH2 but none of the other histone methyltransferases tested.

In in vitro experiments, OR-S1 completely removed H3K27me3 and significantly reduced cell growth in the ATLL-derived cell line TL-Om1.

The drug also reduced cell viability in primary ATLL cells. All 15 samples tested proved sensitive to OR-S1. In addition, OR-S1 treatment selectively removed HTLV-1-infected cells from samples taken from 16 asymptomatic carriers.

Finally, OR-S1 proved active in mice. The drug prevented engraftment of ATLL cells in immunocompromised mice. All 6 OR-S1-treated mice were alive and tumor-free at 49 days, whereas 5 of 6 control mice had died (P=0.0041).

In mice treated after ATLL cell engraftment, OR-S1 reduced tumor growth without causing notable weight loss.

“Synthetic lethality by targeting EZH1 and EZH2 is promising [for ATLL],” Dr Yamagishi said. “Toxicity tests suggest the EZH1/2 dual inhibitor may be sufficient for clinical use, so we are now planning a phase 1 study.”

Maokoto Yamagishi, PhD

Photo by Larry Young

SAN FRANCISCO—Preclinical research suggests a compound that inhibits both EZH1 and EZH2 could be effective against adult T-cell leukemia/lymphoma (ATLL).

The compound, known as OR-S1, has demonstrated activity against ATLL in vitro and in vivo.

Researchers said OR-S1 reversed epigenetic disruption in ATLL cells, selectively eliminated both ATLL cells and cells infected with human T-cell leukemia virus type I (HTLV-1), and inhibited tumor growth in mouse models of ATLL.

Based on these results, the researchers are planning a phase 1 study of the compound.

Makoto Yamagishi, PhD, of The University of Tokyo in Japan, described the preclinical research with OR-S1 and discussed the rationale for developing the compound at the 8th Annual T-cell Lymphoma Forum. The work was carried out in collaboration with Daiichi Sankyo Co., Ltd.

“We do not precisely understand the molecular mechanism of ATLL development, including genetic and epigenetic abnormalities,” Dr Yamagishi noted.

To gain some insight, he and his colleagues performed microRNA profiling, gene expression profiling, and histone methylation/epigenetic factor profiling on cells from ATLL patients and CD4+ T cells from healthy donors.

The team found that PRC2 factors were significantly upregulated in ATLL. EZH2 was the most upregulated histone methyltransferase, but ATLL cells did not have active mutations in the EZH2 gene. Dr Yamagishi said this suggests EZH2 upregulation is critical for the ATLL-specific epigenome.

“At long last, we determined the epigenetic pattern of ATLL,” he said. “ATLL cells showed specific and significant reprogramming of the epigenome, especially H3K27me3 gain. We found abnormal H3K27me3 change in half of genes, and gain was dominant.”

“But, interestingly, the methylated genes are specific in ATLL and do not overlap with other EZH2-dependent cell types, such as embryonic stem cells and diffuse large B-cell lymphoma cells. So ATLL has a very unique epigenome.”

Further investigation revealed that both EZH1 and EZH2 contribute to ATLL-specific epigenetic deregulation. More than 80% of H3K27me3 accumulated genes are occupied by EZH1 and/or EZH2.

So the researchers decided to examine the effects of knocking down EZH1 and EZH2 in ATLL cells.

Compared with knockdown of either gene alone, double knockdown synergistically influenced target gene expression. It led to complete dysfunction of the Polycomb family and had a significant impact on ATLL cell survival.

The researchers also found that EZH1 depletion enhanced ATLL cells’ sensitivity to the EZH2 inhibitor GSK126.

So the team decided to develop a dual EZH1/EZH2 inhibitor. They created OR-S1, which showed “strong activity” against EZH1 and EZH2 but none of the other histone methyltransferases tested.

In in vitro experiments, OR-S1 completely removed H3K27me3 and significantly reduced cell growth in the ATLL-derived cell line TL-Om1.

The drug also reduced cell viability in primary ATLL cells. All 15 samples tested proved sensitive to OR-S1. In addition, OR-S1 treatment selectively removed HTLV-1-infected cells from samples taken from 16 asymptomatic carriers.

Finally, OR-S1 proved active in mice. The drug prevented engraftment of ATLL cells in immunocompromised mice. All 6 OR-S1-treated mice were alive and tumor-free at 49 days, whereas 5 of 6 control mice had died (P=0.0041).

In mice treated after ATLL cell engraftment, OR-S1 reduced tumor growth without causing notable weight loss.

“Synthetic lethality by targeting EZH1 and EZH2 is promising [for ATLL],” Dr Yamagishi said. “Toxicity tests suggest the EZH1/2 dual inhibitor may be sufficient for clinical use, so we are now planning a phase 1 study.”

Youn Kim, MD

Photo by Larry Young

SAN FRANCISCO—The PD-1-blocking antibody pembrolizumab can produce “significant objective clinical responses” in patients with relapsed or refractory cutaneous T-cell lymphoma, according to researchers.

The drug elicited partial responses in 33% of patients enrolled in a phase 2 study. Half of the responders had mycosis fungoides (MF), and half had Sézary syndrome (SS).

All responses are ongoing, and a few patients with stable disease remain on treatment, so they may convert to partial responses, according to Youn Kim, MD, of Stanford University School of Medicine in California.

Dr Kim presented this research at the 8th Annual T-cell Lymphoma Forum.

The study was conducted by the Cancer Immunotherapy Trials Network (CITN) and supported by the National Cancer Institute and Merck, the company developing pembrolizumab.

“There’s good rationale for immune checkpoint blockade in [MF and SS],” Dr Kim said. “There’s systemic and local immune impairment in MF and Sézary, and there’s mounting evidence that T-cell immunity is critical for meaningful antitumor response.”

“[T]umor-infiltrating CD8+ T cells [have been] associated with improved survival, and therapies which augment T-cell function are effective in [MF and SS]. PD-1 and PD-L1 are very well expressed in the tissue and blood, [and] there’s good genomic evidence of immune evasion in [MF and SS].”

With all this in mind, Dr Kim and her colleagues conducted their phase 2 trial of pembrolizumab in 24 patients with relapsed or refractory MF/SS. Patients were excluded if they had central nervous system disease, autoimmune disease, immunodeficiency, or had received immunosuppressive therapy within 7 days.

The patients’ median age was 67 (range, 44-85), and most were male (75%). Thirty-eight percent of patients (n=9) had MF, and 62% (n=15) had SS. Twelve percent (n=3) had large-cell transformation.

Most patients had Stage IVA disease (62%, n=15), followed by IIIB (13%, n=3), IIIA (13%, n=3), IIB (8%, n=2), and IB (4%, n=1). The median number of prior systemic therapies was 4 (range, 1-10).

Treatment and response

Patients received pembrolizumab at 2 mg/kg intravenously every 3 weeks and were allowed to continue therapy for up to 2 years. Dr Kim noted that patients could continue treatment even after the initial documentation of progressive disease (PD) due to the possibility of immune-mediated flare reactions.

“So it’s the investigator’s decision to allow treatment beyond the initial PD,” she said. “However, if there’s confirmation of PD, those people will be removed.”

The median follow-up was 21 weeks (range, 7-39). Eight patients responded to treatment (according to global response criteria), all of which were partial responses. Four of the responders had MF, and 4 had SS. Responses occurred across all disease stages except IB.

“The range of prior therapies varied in the responders,” Dr Kim noted. “People think [patients tend to respond to] immunotherapy [if they are only] mildly [pre-]treated, but that was not the case. Heavily treated patients had great responses to pembrolizumab.”

All responses are ongoing, with a median duration of 13+ weeks (range, 3+ to 30+). The median time to response was 11 weeks (range, 8-22).

Dr Kim noted that 1 responder discontinued treatment because of a severe adverse event, but this patient remains in response without having received subsequent treatment.

The median best mSWAT (modified Skin Weighted Assessment Tool) reduction was 16%. Two patients had near-complete responses in the skin, and 2 patients with stable disease in the skin continue to improve.

Eleven of the 15 SS patients had measurable Sézary burden pre-treatment. And 3 of these patients had a greater than 50% reduction in Sézary count after treatment.

Four patients with stable disease are still on treatment. And at 20 weeks, 75% of patients are progression-free, according to Kaplan-Meier estimates.

Adverse events

Drug-related adverse events occurring at least twice included skin eruptions (21%, n=5), anemia (13%, n=3), decrease in white blood cell count (8%, n=2), elevated liver tests (8%, n=2), diarrhea (8%, n=2), fever (8%, n=2), and face edema (8%, n=2).

Grade 3/4 adverse events included skin eruptions (8%, n=2), anemia (8%, n=2), elevated liver tests (4%, n=1), and face edema (4%, n=1). Skin eruptions (of all grades) included exfoliative dermatitis (n=2), immune-mediated skin flare (n=2), and excessive peeling/edema (n=1).

There were no drug-related serious adverse events. The cause of the aforementioned serious adverse event (which prompted the responding patient to discontinue treatment) could not be determined.

There were 4 patients who did not report any adverse events, regardless of attribution.

In closing, Dr Kim said it is important to conduct biomarker correlative studies to understand the tumor escape mechanisms and enrich the response population.

She and her colleagues at CITN are now exploring the use of pembrolizumab in combination therapy. They are considering combining the drug with interferon-gamma, interleukin-12, low-dose total skin radiation, intratumoral ipilimumab, or Toll-like receptor agonists.

Youn Kim, MD

Photo by Larry Young

SAN FRANCISCO—The PD-1-blocking antibody pembrolizumab can produce “significant objective clinical responses” in patients with relapsed or refractory cutaneous T-cell lymphoma, according to researchers.

The drug elicited partial responses in 33% of patients enrolled in a phase 2 study. Half of the responders had mycosis fungoides (MF), and half had Sézary syndrome (SS).

All responses are ongoing, and a few patients with stable disease remain on treatment, so they may convert to partial responses, according to Youn Kim, MD, of Stanford University School of Medicine in California.

Dr Kim presented this research at the 8th Annual T-cell Lymphoma Forum.

The study was conducted by the Cancer Immunotherapy Trials Network (CITN) and supported by the National Cancer Institute and Merck, the company developing pembrolizumab.

“There’s good rationale for immune checkpoint blockade in [MF and SS],” Dr Kim said. “There’s systemic and local immune impairment in MF and Sézary, and there’s mounting evidence that T-cell immunity is critical for meaningful antitumor response.”

“[T]umor-infiltrating CD8+ T cells [have been] associated with improved survival, and therapies which augment T-cell function are effective in [MF and SS]. PD-1 and PD-L1 are very well expressed in the tissue and blood, [and] there’s good genomic evidence of immune evasion in [MF and SS].”

With all this in mind, Dr Kim and her colleagues conducted their phase 2 trial of pembrolizumab in 24 patients with relapsed or refractory MF/SS. Patients were excluded if they had central nervous system disease, autoimmune disease, immunodeficiency, or had received immunosuppressive therapy within 7 days.

The patients’ median age was 67 (range, 44-85), and most were male (75%). Thirty-eight percent of patients (n=9) had MF, and 62% (n=15) had SS. Twelve percent (n=3) had large-cell transformation.

Most patients had Stage IVA disease (62%, n=15), followed by IIIB (13%, n=3), IIIA (13%, n=3), IIB (8%, n=2), and IB (4%, n=1). The median number of prior systemic therapies was 4 (range, 1-10).

Treatment and response

Patients received pembrolizumab at 2 mg/kg intravenously every 3 weeks and were allowed to continue therapy for up to 2 years. Dr Kim noted that patients could continue treatment even after the initial documentation of progressive disease (PD) due to the possibility of immune-mediated flare reactions.

“So it’s the investigator’s decision to allow treatment beyond the initial PD,” she said. “However, if there’s confirmation of PD, those people will be removed.”

The median follow-up was 21 weeks (range, 7-39). Eight patients responded to treatment (according to global response criteria), all of which were partial responses. Four of the responders had MF, and 4 had SS. Responses occurred across all disease stages except IB.

“The range of prior therapies varied in the responders,” Dr Kim noted. “People think [patients tend to respond to] immunotherapy [if they are only] mildly [pre-]treated, but that was not the case. Heavily treated patients had great responses to pembrolizumab.”

All responses are ongoing, with a median duration of 13+ weeks (range, 3+ to 30+). The median time to response was 11 weeks (range, 8-22).

Dr Kim noted that 1 responder discontinued treatment because of a severe adverse event, but this patient remains in response without having received subsequent treatment.

The median best mSWAT (modified Skin Weighted Assessment Tool) reduction was 16%. Two patients had near-complete responses in the skin, and 2 patients with stable disease in the skin continue to improve.

Eleven of the 15 SS patients had measurable Sézary burden pre-treatment. And 3 of these patients had a greater than 50% reduction in Sézary count after treatment.

Four patients with stable disease are still on treatment. And at 20 weeks, 75% of patients are progression-free, according to Kaplan-Meier estimates.

Adverse events

Drug-related adverse events occurring at least twice included skin eruptions (21%, n=5), anemia (13%, n=3), decrease in white blood cell count (8%, n=2), elevated liver tests (8%, n=2), diarrhea (8%, n=2), fever (8%, n=2), and face edema (8%, n=2).

Grade 3/4 adverse events included skin eruptions (8%, n=2), anemia (8%, n=2), elevated liver tests (4%, n=1), and face edema (4%, n=1). Skin eruptions (of all grades) included exfoliative dermatitis (n=2), immune-mediated skin flare (n=2), and excessive peeling/edema (n=1).

There were no drug-related serious adverse events. The cause of the aforementioned serious adverse event (which prompted the responding patient to discontinue treatment) could not be determined.

There were 4 patients who did not report any adverse events, regardless of attribution.

In closing, Dr Kim said it is important to conduct biomarker correlative studies to understand the tumor escape mechanisms and enrich the response population.

She and her colleagues at CITN are now exploring the use of pembrolizumab in combination therapy. They are considering combining the drug with interferon-gamma, interleukin-12, low-dose total skin radiation, intratumoral ipilimumab, or Toll-like receptor agonists.

Youn Kim, MD

Photo by Larry Young

SAN FRANCISCO—The PD-1-blocking antibody pembrolizumab can produce “significant objective clinical responses” in patients with relapsed or refractory cutaneous T-cell lymphoma, according to researchers.

The drug elicited partial responses in 33% of patients enrolled in a phase 2 study. Half of the responders had mycosis fungoides (MF), and half had Sézary syndrome (SS).

All responses are ongoing, and a few patients with stable disease remain on treatment, so they may convert to partial responses, according to Youn Kim, MD, of Stanford University School of Medicine in California.

Dr Kim presented this research at the 8th Annual T-cell Lymphoma Forum.

The study was conducted by the Cancer Immunotherapy Trials Network (CITN) and supported by the National Cancer Institute and Merck, the company developing pembrolizumab.

“There’s good rationale for immune checkpoint blockade in [MF and SS],” Dr Kim said. “There’s systemic and local immune impairment in MF and Sézary, and there’s mounting evidence that T-cell immunity is critical for meaningful antitumor response.”

“[T]umor-infiltrating CD8+ T cells [have been] associated with improved survival, and therapies which augment T-cell function are effective in [MF and SS]. PD-1 and PD-L1 are very well expressed in the tissue and blood, [and] there’s good genomic evidence of immune evasion in [MF and SS].”

With all this in mind, Dr Kim and her colleagues conducted their phase 2 trial of pembrolizumab in 24 patients with relapsed or refractory MF/SS. Patients were excluded if they had central nervous system disease, autoimmune disease, immunodeficiency, or had received immunosuppressive therapy within 7 days.

The patients’ median age was 67 (range, 44-85), and most were male (75%). Thirty-eight percent of patients (n=9) had MF, and 62% (n=15) had SS. Twelve percent (n=3) had large-cell transformation.

Most patients had Stage IVA disease (62%, n=15), followed by IIIB (13%, n=3), IIIA (13%, n=3), IIB (8%, n=2), and IB (4%, n=1). The median number of prior systemic therapies was 4 (range, 1-10).

Treatment and response

Patients received pembrolizumab at 2 mg/kg intravenously every 3 weeks and were allowed to continue therapy for up to 2 years. Dr Kim noted that patients could continue treatment even after the initial documentation of progressive disease (PD) due to the possibility of immune-mediated flare reactions.

“So it’s the investigator’s decision to allow treatment beyond the initial PD,” she said. “However, if there’s confirmation of PD, those people will be removed.”

The median follow-up was 21 weeks (range, 7-39). Eight patients responded to treatment (according to global response criteria), all of which were partial responses. Four of the responders had MF, and 4 had SS. Responses occurred across all disease stages except IB.

“The range of prior therapies varied in the responders,” Dr Kim noted. “People think [patients tend to respond to] immunotherapy [if they are only] mildly [pre-]treated, but that was not the case. Heavily treated patients had great responses to pembrolizumab.”

All responses are ongoing, with a median duration of 13+ weeks (range, 3+ to 30+). The median time to response was 11 weeks (range, 8-22).

Dr Kim noted that 1 responder discontinued treatment because of a severe adverse event, but this patient remains in response without having received subsequent treatment.

The median best mSWAT (modified Skin Weighted Assessment Tool) reduction was 16%. Two patients had near-complete responses in the skin, and 2 patients with stable disease in the skin continue to improve.

Eleven of the 15 SS patients had measurable Sézary burden pre-treatment. And 3 of these patients had a greater than 50% reduction in Sézary count after treatment.

Four patients with stable disease are still on treatment. And at 20 weeks, 75% of patients are progression-free, according to Kaplan-Meier estimates.

Adverse events

Drug-related adverse events occurring at least twice included skin eruptions (21%, n=5), anemia (13%, n=3), decrease in white blood cell count (8%, n=2), elevated liver tests (8%, n=2), diarrhea (8%, n=2), fever (8%, n=2), and face edema (8%, n=2).

Grade 3/4 adverse events included skin eruptions (8%, n=2), anemia (8%, n=2), elevated liver tests (4%, n=1), and face edema (4%, n=1). Skin eruptions (of all grades) included exfoliative dermatitis (n=2), immune-mediated skin flare (n=2), and excessive peeling/edema (n=1).

There were no drug-related serious adverse events. The cause of the aforementioned serious adverse event (which prompted the responding patient to discontinue treatment) could not be determined.

There were 4 patients who did not report any adverse events, regardless of attribution.

In closing, Dr Kim said it is important to conduct biomarker correlative studies to understand the tumor escape mechanisms and enrich the response population.

She and her colleagues at CITN are now exploring the use of pembrolizumab in combination therapy. They are considering combining the drug with interferon-gamma, interleukin-12, low-dose total skin radiation, intratumoral ipilimumab, or Toll-like receptor agonists.

Meng-Meng Ji, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Preclinical research has revealed mutations that may affect the performance of histone deacetylase inhibitors (HDACis) in patients with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS).

The researchers identified histone-modifying gene mutations in patients with PTCL-NOS and found evidence to suggest these mutations confer shorter survival.

The team also conducted experiments in Jurkat cells showing that certain HDACis could counteract loss-of-function mutations, while others could not.

Meng-Meng Ji, MD, PhD, of the Shanghai Institute of Hematology in China, presented this research at the 8th Annual T-cell Lymphoma Forum.

Dr Ji and her colleagues first performed targeted sequencing in tumor samples from 105 patients newly diagnosed with PTCL-NOS.

The team discovered 62 mutations of “important” lymphoma-associated histone-modifying genes in 31 patients. They found mutations in MLL2 (n=21), TET2 (n=17), EP300 (n=8), CREBBP (n=8), and SETD2 (n=6).

Clinical data revealed a significant difference in overall survival between patients who had these mutations and those who did not (P=0.0038).

Because most of the mutations they identified are loss-of-function mutations, Dr Ji and her colleagues wanted to determine whether HDACis could restore the expression of the mutated genes. So they tested 4 HDACis—valproic acid, vorinostat, romidepsin, and chidamide—in Jurkat cells.

All 4 HDACis upregulated expression of EP300 and CREBBP. However, only romidepsin and chidamide upregulated MLL2, and only valproic acid and vorinostat upregulated SETD2. Dr Ji said there was no obvious change in TET2 expression with any of the HDACis.

The researchers then took a closer look at the EP300, MLL2, and SETD2 mutations. They found that most EP300 mutations were located on the HAT domain. MLL2 mutations could be found in a variety of locations, but some were located on the SET domain. And most SETD2 mutations were located on the SET domain.

Based on the crystal structure of each gene, the team found that EP300 mutations on the HAT domain and both MLL2 mutations and SETD2 mutations located on the SET domain induce loss of function.

So the researchers constructed a mutant for EP300 (p.H1377R), MLL2 (p.V5389M), and SETD2 (p.R1598_) and transfected Jurkat cells with each mutant.

The mutants reduced gene expression significantly when compared to wild-type cells.

Like in the previous experiments, all 4 HDACis could restore the expression of EP300. But only romidepsin and chidamide could restore MLL2 expression, and only valproic acid and vorinostat could restore SETD2 expression.

In addition, all 4 HDACis restored H3K18 hypoacetylation, which was inhibited in Jurkat cells transfected with the EP300 mutant.

Romidepsin and chidamide restored H3K4me3 expression, which was inhibited by the MLL2 mutant. And valproic acid and vorinostat restored H3K36me3 expression, which was inhibited by the SETD2 mutant.

“HDACis targeted differently histone H3 acetylation or methylation modulated by the mutations, suggesting their distinct therapeutic efficiency in PTCL-NOS,” Dr Ji noted.

She said she and her colleagues are continuing this research in samples from patients with PTCL-NOS.

Meng-Meng Ji, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Preclinical research has revealed mutations that may affect the performance of histone deacetylase inhibitors (HDACis) in patients with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS).

The researchers identified histone-modifying gene mutations in patients with PTCL-NOS and found evidence to suggest these mutations confer shorter survival.

The team also conducted experiments in Jurkat cells showing that certain HDACis could counteract loss-of-function mutations, while others could not.

Meng-Meng Ji, MD, PhD, of the Shanghai Institute of Hematology in China, presented this research at the 8th Annual T-cell Lymphoma Forum.

Dr Ji and her colleagues first performed targeted sequencing in tumor samples from 105 patients newly diagnosed with PTCL-NOS.

The team discovered 62 mutations of “important” lymphoma-associated histone-modifying genes in 31 patients. They found mutations in MLL2 (n=21), TET2 (n=17), EP300 (n=8), CREBBP (n=8), and SETD2 (n=6).

Clinical data revealed a significant difference in overall survival between patients who had these mutations and those who did not (P=0.0038).

Because most of the mutations they identified are loss-of-function mutations, Dr Ji and her colleagues wanted to determine whether HDACis could restore the expression of the mutated genes. So they tested 4 HDACis—valproic acid, vorinostat, romidepsin, and chidamide—in Jurkat cells.

All 4 HDACis upregulated expression of EP300 and CREBBP. However, only romidepsin and chidamide upregulated MLL2, and only valproic acid and vorinostat upregulated SETD2. Dr Ji said there was no obvious change in TET2 expression with any of the HDACis.

The researchers then took a closer look at the EP300, MLL2, and SETD2 mutations. They found that most EP300 mutations were located on the HAT domain. MLL2 mutations could be found in a variety of locations, but some were located on the SET domain. And most SETD2 mutations were located on the SET domain.

Based on the crystal structure of each gene, the team found that EP300 mutations on the HAT domain and both MLL2 mutations and SETD2 mutations located on the SET domain induce loss of function.

So the researchers constructed a mutant for EP300 (p.H1377R), MLL2 (p.V5389M), and SETD2 (p.R1598_) and transfected Jurkat cells with each mutant.

The mutants reduced gene expression significantly when compared to wild-type cells.

Like in the previous experiments, all 4 HDACis could restore the expression of EP300. But only romidepsin and chidamide could restore MLL2 expression, and only valproic acid and vorinostat could restore SETD2 expression.

In addition, all 4 HDACis restored H3K18 hypoacetylation, which was inhibited in Jurkat cells transfected with the EP300 mutant.

Romidepsin and chidamide restored H3K4me3 expression, which was inhibited by the MLL2 mutant. And valproic acid and vorinostat restored H3K36me3 expression, which was inhibited by the SETD2 mutant.

“HDACis targeted differently histone H3 acetylation or methylation modulated by the mutations, suggesting their distinct therapeutic efficiency in PTCL-NOS,” Dr Ji noted.

She said she and her colleagues are continuing this research in samples from patients with PTCL-NOS.

Meng-Meng Ji, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Preclinical research has revealed mutations that may affect the performance of histone deacetylase inhibitors (HDACis) in patients with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS).

The researchers identified histone-modifying gene mutations in patients with PTCL-NOS and found evidence to suggest these mutations confer shorter survival.

The team also conducted experiments in Jurkat cells showing that certain HDACis could counteract loss-of-function mutations, while others could not.

Meng-Meng Ji, MD, PhD, of the Shanghai Institute of Hematology in China, presented this research at the 8th Annual T-cell Lymphoma Forum.

Dr Ji and her colleagues first performed targeted sequencing in tumor samples from 105 patients newly diagnosed with PTCL-NOS.

The team discovered 62 mutations of “important” lymphoma-associated histone-modifying genes in 31 patients. They found mutations in MLL2 (n=21), TET2 (n=17), EP300 (n=8), CREBBP (n=8), and SETD2 (n=6).

Clinical data revealed a significant difference in overall survival between patients who had these mutations and those who did not (P=0.0038).

Because most of the mutations they identified are loss-of-function mutations, Dr Ji and her colleagues wanted to determine whether HDACis could restore the expression of the mutated genes. So they tested 4 HDACis—valproic acid, vorinostat, romidepsin, and chidamide—in Jurkat cells.

All 4 HDACis upregulated expression of EP300 and CREBBP. However, only romidepsin and chidamide upregulated MLL2, and only valproic acid and vorinostat upregulated SETD2. Dr Ji said there was no obvious change in TET2 expression with any of the HDACis.

The researchers then took a closer look at the EP300, MLL2, and SETD2 mutations. They found that most EP300 mutations were located on the HAT domain. MLL2 mutations could be found in a variety of locations, but some were located on the SET domain. And most SETD2 mutations were located on the SET domain.

Based on the crystal structure of each gene, the team found that EP300 mutations on the HAT domain and both MLL2 mutations and SETD2 mutations located on the SET domain induce loss of function.

So the researchers constructed a mutant for EP300 (p.H1377R), MLL2 (p.V5389M), and SETD2 (p.R1598_) and transfected Jurkat cells with each mutant.

The mutants reduced gene expression significantly when compared to wild-type cells.

Like in the previous experiments, all 4 HDACis could restore the expression of EP300. But only romidepsin and chidamide could restore MLL2 expression, and only valproic acid and vorinostat could restore SETD2 expression.

In addition, all 4 HDACis restored H3K18 hypoacetylation, which was inhibited in Jurkat cells transfected with the EP300 mutant.

Romidepsin and chidamide restored H3K4me3 expression, which was inhibited by the MLL2 mutant. And valproic acid and vorinostat restored H3K36me3 expression, which was inhibited by the SETD2 mutant.

“HDACis targeted differently histone H3 acetylation or methylation modulated by the mutations, suggesting their distinct therapeutic efficiency in PTCL-NOS,” Dr Ji noted.

She said she and her colleagues are continuing this research in samples from patients with PTCL-NOS.

Kisato Nosaka, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Results of a phase 2 trial suggest lenalidomide may be a treatment option for patients with relapsed adult T-cell leukemia-lymphoma (ATLL).

Lenalidomide produced a 42% overall response rate (ORR) in this trial, and patients had a “favorable” median overall survival, according to Kisato Nosaka, MD, PhD, of the National Center for Global Health and Medicine in Tokyo, Japan.

He noted, however, that the survival data are still immature and may have been confounded by subsequent therapies.

Dr Nosaka presented these results at the 8th Annual T-cell Lymphoma Forum. The study was sponsored by Celgene K.K.

The trial included 26 Japanese patients with relapsed ATLL. Fifty-eight percent of patients had the acute subtype, 27% had the lymphoma subtype, and 15% had the unfavorable chronic subtype.

The patients’ median age was 68.5 (range, 53-81), and 65% of patients were 65 or older. Fifty percent of patients had an ECOG performance status of 0, 35% had a status of 1, and 15% had a status of 2.

Most patients had a low-risk simplified ATL-PI score (65%), but 35% had an intermediate-risk score. Fifteen percent had bone marrow involvement.

The median number of prior treatment regimens was 2 (range, 1-4). Forty-two percent of patients had prior mogamulizumab, and 35% had received LSG15 or modified LSG15.

Patients received lenalidomide at 25 mg per day, given continuously until disease progression or intolerability.

Safety

The median duration of treatment was 3.7 months (range, 0.4 to 18.3 months). There were no deaths during treatment or for 28 days after.

Nine patients (35%) experienced serious adverse events (AEs), but only 1 serious AE occurred in more than 1 patient. Two patients had serious thrombocytopenia.

The most frequent AEs were thrombocytopenia (77%), neutropenia (73%), lymphopenia (69%), and increased C-reactive protein (42%). The most frequent grade 3 or higher AEs were neutropenia (65%), leukopenia (38%), and lymphopenia (38%).

Response and survival

The median follow-up was 3.9 months. The ORR was 42%, including 5 complete responses/unconfirmed complete responses and 6 partial responses. Eight patients (31%) had stable disease, and 7 (27%) progressed.

Dr Nosaka noted that responses occurred in all disease subtypes and at all disease sites. The ORR was 33% (5/15) for the acute subtype, 50% (2/4) for the unfavorable chronic subtype, and 57% (4/7) for the lymphoma subtype.

The ORR was 31% (5/16) at the target lesion, 60% (6/10) in the peripheral blood, and 75% (6/8) for PGA (Physician’s Global Assessment of Clinical Condition, used to assess skin lesions).

Dr Nosaka also pointed out that the ORR was higher in patients who did not receive prior mogamulizumab (60%) than in patients who did (18%). However, he said the number of patients was too small for a definitive conclusion to be reached.

Similarly, the ORR was higher for patients in the low-risk simplified ATL-PI risk group than for those in the intermediate-risk group—53% and 22%, respectively.

Among the 11 responders, the median duration of response was not reached (range, 0.5 months to not reached). The mean duration of response was 5.2 months (range, 0 to 16.6 months).

The median progression-free survival was 3.8 months (range, 1.9 months to not reached). The median overall survival was 20.3 months (range, 9.1 months to not reached).

The overall survival was longer for patients in the low-risk ATL-PI group than the intermediate-risk group—not reached and 10.1 months, respectively (P=0.03).

In closing, Dr Nosaka said these results support lenalidomide as a possible treatment option for patients with relapsed/recurrent ATLL.

Kisato Nosaka, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Results of a phase 2 trial suggest lenalidomide may be a treatment option for patients with relapsed adult T-cell leukemia-lymphoma (ATLL).

Lenalidomide produced a 42% overall response rate (ORR) in this trial, and patients had a “favorable” median overall survival, according to Kisato Nosaka, MD, PhD, of the National Center for Global Health and Medicine in Tokyo, Japan.

He noted, however, that the survival data are still immature and may have been confounded by subsequent therapies.

Dr Nosaka presented these results at the 8th Annual T-cell Lymphoma Forum. The study was sponsored by Celgene K.K.

The trial included 26 Japanese patients with relapsed ATLL. Fifty-eight percent of patients had the acute subtype, 27% had the lymphoma subtype, and 15% had the unfavorable chronic subtype.

The patients’ median age was 68.5 (range, 53-81), and 65% of patients were 65 or older. Fifty percent of patients had an ECOG performance status of 0, 35% had a status of 1, and 15% had a status of 2.

Most patients had a low-risk simplified ATL-PI score (65%), but 35% had an intermediate-risk score. Fifteen percent had bone marrow involvement.

The median number of prior treatment regimens was 2 (range, 1-4). Forty-two percent of patients had prior mogamulizumab, and 35% had received LSG15 or modified LSG15.

Patients received lenalidomide at 25 mg per day, given continuously until disease progression or intolerability.

Safety

The median duration of treatment was 3.7 months (range, 0.4 to 18.3 months). There were no deaths during treatment or for 28 days after.

Nine patients (35%) experienced serious adverse events (AEs), but only 1 serious AE occurred in more than 1 patient. Two patients had serious thrombocytopenia.

The most frequent AEs were thrombocytopenia (77%), neutropenia (73%), lymphopenia (69%), and increased C-reactive protein (42%). The most frequent grade 3 or higher AEs were neutropenia (65%), leukopenia (38%), and lymphopenia (38%).

Response and survival

The median follow-up was 3.9 months. The ORR was 42%, including 5 complete responses/unconfirmed complete responses and 6 partial responses. Eight patients (31%) had stable disease, and 7 (27%) progressed.

Dr Nosaka noted that responses occurred in all disease subtypes and at all disease sites. The ORR was 33% (5/15) for the acute subtype, 50% (2/4) for the unfavorable chronic subtype, and 57% (4/7) for the lymphoma subtype.

The ORR was 31% (5/16) at the target lesion, 60% (6/10) in the peripheral blood, and 75% (6/8) for PGA (Physician’s Global Assessment of Clinical Condition, used to assess skin lesions).

Dr Nosaka also pointed out that the ORR was higher in patients who did not receive prior mogamulizumab (60%) than in patients who did (18%). However, he said the number of patients was too small for a definitive conclusion to be reached.

Similarly, the ORR was higher for patients in the low-risk simplified ATL-PI risk group than for those in the intermediate-risk group—53% and 22%, respectively.

Among the 11 responders, the median duration of response was not reached (range, 0.5 months to not reached). The mean duration of response was 5.2 months (range, 0 to 16.6 months).

The median progression-free survival was 3.8 months (range, 1.9 months to not reached). The median overall survival was 20.3 months (range, 9.1 months to not reached).

The overall survival was longer for patients in the low-risk ATL-PI group than the intermediate-risk group—not reached and 10.1 months, respectively (P=0.03).

In closing, Dr Nosaka said these results support lenalidomide as a possible treatment option for patients with relapsed/recurrent ATLL.

Kisato Nosaka, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Results of a phase 2 trial suggest lenalidomide may be a treatment option for patients with relapsed adult T-cell leukemia-lymphoma (ATLL).

Lenalidomide produced a 42% overall response rate (ORR) in this trial, and patients had a “favorable” median overall survival, according to Kisato Nosaka, MD, PhD, of the National Center for Global Health and Medicine in Tokyo, Japan.

He noted, however, that the survival data are still immature and may have been confounded by subsequent therapies.

Dr Nosaka presented these results at the 8th Annual T-cell Lymphoma Forum. The study was sponsored by Celgene K.K.

The trial included 26 Japanese patients with relapsed ATLL. Fifty-eight percent of patients had the acute subtype, 27% had the lymphoma subtype, and 15% had the unfavorable chronic subtype.

The patients’ median age was 68.5 (range, 53-81), and 65% of patients were 65 or older. Fifty percent of patients had an ECOG performance status of 0, 35% had a status of 1, and 15% had a status of 2.

Most patients had a low-risk simplified ATL-PI score (65%), but 35% had an intermediate-risk score. Fifteen percent had bone marrow involvement.

The median number of prior treatment regimens was 2 (range, 1-4). Forty-two percent of patients had prior mogamulizumab, and 35% had received LSG15 or modified LSG15.

Patients received lenalidomide at 25 mg per day, given continuously until disease progression or intolerability.

Safety

The median duration of treatment was 3.7 months (range, 0.4 to 18.3 months). There were no deaths during treatment or for 28 days after.

Nine patients (35%) experienced serious adverse events (AEs), but only 1 serious AE occurred in more than 1 patient. Two patients had serious thrombocytopenia.

The most frequent AEs were thrombocytopenia (77%), neutropenia (73%), lymphopenia (69%), and increased C-reactive protein (42%). The most frequent grade 3 or higher AEs were neutropenia (65%), leukopenia (38%), and lymphopenia (38%).

Response and survival

The median follow-up was 3.9 months. The ORR was 42%, including 5 complete responses/unconfirmed complete responses and 6 partial responses. Eight patients (31%) had stable disease, and 7 (27%) progressed.

Dr Nosaka noted that responses occurred in all disease subtypes and at all disease sites. The ORR was 33% (5/15) for the acute subtype, 50% (2/4) for the unfavorable chronic subtype, and 57% (4/7) for the lymphoma subtype.

The ORR was 31% (5/16) at the target lesion, 60% (6/10) in the peripheral blood, and 75% (6/8) for PGA (Physician’s Global Assessment of Clinical Condition, used to assess skin lesions).

Dr Nosaka also pointed out that the ORR was higher in patients who did not receive prior mogamulizumab (60%) than in patients who did (18%). However, he said the number of patients was too small for a definitive conclusion to be reached.

Similarly, the ORR was higher for patients in the low-risk simplified ATL-PI risk group than for those in the intermediate-risk group—53% and 22%, respectively.

Among the 11 responders, the median duration of response was not reached (range, 0.5 months to not reached). The mean duration of response was 5.2 months (range, 0 to 16.6 months).

The median progression-free survival was 3.8 months (range, 1.9 months to not reached). The median overall survival was 20.3 months (range, 9.1 months to not reached).

The overall survival was longer for patients in the low-risk ATL-PI group than the intermediate-risk group—not reached and 10.1 months, respectively (P=0.03).

In closing, Dr Nosaka said these results support lenalidomide as a possible treatment option for patients with relapsed/recurrent ATLL.

Yuankai Shi, MD, PhD

Photo by Larry Young

SAN FRANCISCO—The oral histone deacetylase inhibitor chidamide can elicit responses in patients with relapsed or refractory cutaneous T-cell Lymphoma (CTCL), a new study suggests.

Chidamide has already demonstrated efficacy against relapsed or refractory peripheral T-cell lymphoma and has been approved for this indication in China.

Now, results of a phase 2 trial suggest chidamide might be a feasible treatment option for relapsed or refractory CTCL as well.

Yuankai Shi, MD, PhD, of the Chinese Academy of Medical Science & Peking Union Medical College in Beijing, China, discussed this trial at the 8th Annual T-cell Lymphoma Forum. The trial is sponsored by Chipscreen Biosciences Ltd.

He presented results observed in 50 patients with relapsed/refractory CTCL. They had a median age of 47 (range, 26-75), and half were male. Most patients had stage II disease (44%), 20% percent had stage III, and 18% each had stage I and IV. The median time from diagnosis was 2 years.

Patients were randomized to receive chidamide at 30 mg twice a week for 2 weeks out of a 3-week cycle (n=12), 4 weeks out of a 6-week cycle (n=13), or 30 mg twice a week without a drug-free holiday (n=25).

The objective response rate was 32% for the entire cohort, 33% for the 3-week cycle arm, 23% for the 6-week cycle arm, and 36% for the successive dosing arm.

There was 1 complete response, and it occurred in the successive dosing arm. There were 15 partial responses—4 in the 3-week arm, 3 in the 6-week arm, and 9 in the successive dosing arm.

The median duration of response was 92 days overall (range, 78-106), 50 days in the 3-week arm (range, 26-130), 92 days in the 6-week arm (range, 84-99), and 169 days in the successive dosing arm (range, 58-279).

The median progression-free survival was 85 days overall (range, 78-92), 84 days in the 3-week arm (range, 43-126), 81 days in the 6-week arm (range, 39-222), and 88 days in the successive dosing arm (range, 58-261).

Dr Shi noted that the major toxicities associated with chidamide were hematologic and gastrointestinal in nature, and they were controllable.

The incidence of adverse events (AEs) was 83% overall, 92% in the 3-week arm, 85% in the 6-week arm, and 77% in the successive dosing arm. The incidence of grade 3 or higher AEs was 23%, 23%, 38%, and 15%, respectively.

The most common AEs were thrombocytopenia (33%, 39%, 23%, and 35%, respectively), leucopenia (29%, 54%, 31%, and 15%, respectively), fatigue (17%, 23%, 23%, and 12%, respectively), nausea (13%, 23%, 8%, and 12%, respectively), diarrhea (10%, 8%, 8%, and 12%, respectively), fever (8%, 0%, 15%, and 8%, respectively), and anemia (8%, 8%, 15%, and 4%, respectively).

There were 2 serious AEs. One patient in the 3-week arm was hospitalized for fever and lung infection, and 1 patient in the successive dosing arm was hospitalized for hyperglycemia.

Dr Shi said these results suggest chidamide is effective and tolerable for patients with relapsed/refractory CTCL. And, based on the overall profiles of the 3 dosing regimens, successive dosing of chidamide at 30 mg twice a week is recommended.

Yuankai Shi, MD, PhD

Photo by Larry Young

SAN FRANCISCO—The oral histone deacetylase inhibitor chidamide can elicit responses in patients with relapsed or refractory cutaneous T-cell Lymphoma (CTCL), a new study suggests.

Chidamide has already demonstrated efficacy against relapsed or refractory peripheral T-cell lymphoma and has been approved for this indication in China.

Now, results of a phase 2 trial suggest chidamide might be a feasible treatment option for relapsed or refractory CTCL as well.

Yuankai Shi, MD, PhD, of the Chinese Academy of Medical Science & Peking Union Medical College in Beijing, China, discussed this trial at the 8th Annual T-cell Lymphoma Forum. The trial is sponsored by Chipscreen Biosciences Ltd.

He presented results observed in 50 patients with relapsed/refractory CTCL. They had a median age of 47 (range, 26-75), and half were male. Most patients had stage II disease (44%), 20% percent had stage III, and 18% each had stage I and IV. The median time from diagnosis was 2 years.

Patients were randomized to receive chidamide at 30 mg twice a week for 2 weeks out of a 3-week cycle (n=12), 4 weeks out of a 6-week cycle (n=13), or 30 mg twice a week without a drug-free holiday (n=25).

The objective response rate was 32% for the entire cohort, 33% for the 3-week cycle arm, 23% for the 6-week cycle arm, and 36% for the successive dosing arm.

There was 1 complete response, and it occurred in the successive dosing arm. There were 15 partial responses—4 in the 3-week arm, 3 in the 6-week arm, and 9 in the successive dosing arm.

The median duration of response was 92 days overall (range, 78-106), 50 days in the 3-week arm (range, 26-130), 92 days in the 6-week arm (range, 84-99), and 169 days in the successive dosing arm (range, 58-279).

The median progression-free survival was 85 days overall (range, 78-92), 84 days in the 3-week arm (range, 43-126), 81 days in the 6-week arm (range, 39-222), and 88 days in the successive dosing arm (range, 58-261).

Dr Shi noted that the major toxicities associated with chidamide were hematologic and gastrointestinal in nature, and they were controllable.

The incidence of adverse events (AEs) was 83% overall, 92% in the 3-week arm, 85% in the 6-week arm, and 77% in the successive dosing arm. The incidence of grade 3 or higher AEs was 23%, 23%, 38%, and 15%, respectively.

The most common AEs were thrombocytopenia (33%, 39%, 23%, and 35%, respectively), leucopenia (29%, 54%, 31%, and 15%, respectively), fatigue (17%, 23%, 23%, and 12%, respectively), nausea (13%, 23%, 8%, and 12%, respectively), diarrhea (10%, 8%, 8%, and 12%, respectively), fever (8%, 0%, 15%, and 8%, respectively), and anemia (8%, 8%, 15%, and 4%, respectively).

There were 2 serious AEs. One patient in the 3-week arm was hospitalized for fever and lung infection, and 1 patient in the successive dosing arm was hospitalized for hyperglycemia.

Dr Shi said these results suggest chidamide is effective and tolerable for patients with relapsed/refractory CTCL. And, based on the overall profiles of the 3 dosing regimens, successive dosing of chidamide at 30 mg twice a week is recommended.

Yuankai Shi, MD, PhD

Photo by Larry Young

SAN FRANCISCO—The oral histone deacetylase inhibitor chidamide can elicit responses in patients with relapsed or refractory cutaneous T-cell Lymphoma (CTCL), a new study suggests.

Chidamide has already demonstrated efficacy against relapsed or refractory peripheral T-cell lymphoma and has been approved for this indication in China.

Now, results of a phase 2 trial suggest chidamide might be a feasible treatment option for relapsed or refractory CTCL as well.

Yuankai Shi, MD, PhD, of the Chinese Academy of Medical Science & Peking Union Medical College in Beijing, China, discussed this trial at the 8th Annual T-cell Lymphoma Forum. The trial is sponsored by Chipscreen Biosciences Ltd.

He presented results observed in 50 patients with relapsed/refractory CTCL. They had a median age of 47 (range, 26-75), and half were male. Most patients had stage II disease (44%), 20% percent had stage III, and 18% each had stage I and IV. The median time from diagnosis was 2 years.

Patients were randomized to receive chidamide at 30 mg twice a week for 2 weeks out of a 3-week cycle (n=12), 4 weeks out of a 6-week cycle (n=13), or 30 mg twice a week without a drug-free holiday (n=25).

The objective response rate was 32% for the entire cohort, 33% for the 3-week cycle arm, 23% for the 6-week cycle arm, and 36% for the successive dosing arm.

There was 1 complete response, and it occurred in the successive dosing arm. There were 15 partial responses—4 in the 3-week arm, 3 in the 6-week arm, and 9 in the successive dosing arm.

The median duration of response was 92 days overall (range, 78-106), 50 days in the 3-week arm (range, 26-130), 92 days in the 6-week arm (range, 84-99), and 169 days in the successive dosing arm (range, 58-279).

The median progression-free survival was 85 days overall (range, 78-92), 84 days in the 3-week arm (range, 43-126), 81 days in the 6-week arm (range, 39-222), and 88 days in the successive dosing arm (range, 58-261).

Dr Shi noted that the major toxicities associated with chidamide were hematologic and gastrointestinal in nature, and they were controllable.

The incidence of adverse events (AEs) was 83% overall, 92% in the 3-week arm, 85% in the 6-week arm, and 77% in the successive dosing arm. The incidence of grade 3 or higher AEs was 23%, 23%, 38%, and 15%, respectively.

The most common AEs were thrombocytopenia (33%, 39%, 23%, and 35%, respectively), leucopenia (29%, 54%, 31%, and 15%, respectively), fatigue (17%, 23%, 23%, and 12%, respectively), nausea (13%, 23%, 8%, and 12%, respectively), diarrhea (10%, 8%, 8%, and 12%, respectively), fever (8%, 0%, 15%, and 8%, respectively), and anemia (8%, 8%, 15%, and 4%, respectively).

There were 2 serious AEs. One patient in the 3-week arm was hospitalized for fever and lung infection, and 1 patient in the successive dosing arm was hospitalized for hyperglycemia.

Dr Shi said these results suggest chidamide is effective and tolerable for patients with relapsed/refractory CTCL. And, based on the overall profiles of the 3 dosing regimens, successive dosing of chidamide at 30 mg twice a week is recommended.

Philippe Moreau, MD

Photo courtesy of ASH

ORLANDO, FL—Adding the oral proteasome inhibitor ixazomib to treatment with lenalidomide and dexamethasone can prolong progression-free survival (PFS) in patients with relapsed and/or refractory multiple myeloma (MM), according to interim results of the phase 3 TOURMALINE-MM1 trial.

It is not yet clear if the 3-drug combination can prolong overall survival when compared to treatment with lenalidomide and dexamethasone.

However, researchers believe the triplet shows promise and could become a new standard of care for relapsed/refractory MM.

Philippe Moreau, MD, of the University of Nantes in France, discussed this possibility while presenting results from TOURMALINE-MM1 at the 2015 ASH Annual Meeting (abstract 727*). The study was sponsored by Millennium Pharmaceuticals, Inc.

The trial included 722 MM patients enrolled at 147 centers in 26 countries. Patients were randomized to receive ixazomib, lenalidomide, and dexamethasone (IRd, n=360) or placebo, lenalidomide, and dexamethasone (Rd, n=362).

Baseline patient characteristics were similar between the arms. The median age was 66 in both arms (overall range, 30-91), and nearly 60% of patients in both arms were male.

Fifty percent of patients in the IRd arm and 47% in the Rd arm had an ECOG performance status of 0. Forty-three percent and 45%, respectively, had a status of 1, and 5% and 7%, respectively, had a status of 2.

Eighty-seven percent and 88%, respectively, had an ISS stage of I or II. Fifty-five percent of patients in the IRd arm had standard-risk cytogenetics, as did 60% in the Rd arm.

Fifty-nine percent of patients in both arms had received 1 prior line of therapy, and 41% in both arms had 2 or 3 prior lines.

Response and survival

“Ixazomib, when combined with len-dex . . . , was associated with a significant and meaningful improvement in progression-free survival, improved time to progression, and [higher] response rate as well,” Dr Moreau said.

At a median follow-up of about 15 months, the median PFS was 20.6 months in the IRd arm and 14.7 months in the Rd arm. The hazard ratio was 0.742 (P=0.012).

Dr Moreau said the PFS benefit was consistent across pre-specified subgroups. So the benefit was present regardless of age, ISS stage, cytogenetic risk, number of prior therapies, prior exposure to a proteasome inhibitor, prior immunomodulatory therapy, whether the patient was refractory to his last therapy, and whether the patient had relapsed or refractory disease.

Dr Moreau also pointed out that, in the IRd arm, the median PFS in high-risk patients was similar to that in the overall patient population and in patients with standard-risk cytogenetics. This suggests ixazomib may overcome the negative impact of cytogenetic alterations.

Whether IRd confers an overall survival benefit is not clear, as those data are not yet mature. At a median follow-up of about 23 months, the median overall survival was not reached in either treatment arm.

The researchers conducted a non-inferential PFS analysis at the same time point (23 months) and found the median PFS was 20 months in the IRd arm and 15.9 months in the Rd arm. The hazard ratio was 0.82.

As for other efficacy endpoints, the overall response rate was 78.3% in the IRd arm and 71.5% in the Rd arm (P=0.035). The rates of complete response were 11.7% and 6.6%, respectively (P=0.019). And the rates of very good partial response or greater were 48.1% and 39%, respectively (P=0.014).

The median time to response was 1.1 months in the IRd arm and 1.9 months in the Rd arm. The median duration of response was 20.5 months and 15 months, respectively. And the median time to progression was 21.4 months and 15.7 months, respectively.

Adverse events

At a median follow-up of about 23 months, patients had received a median of 17 cycles of IRd and a median of 15 cycles of Rd.

The incidence of any adverse event (AE) was 98% in the IRd arm and 99% in the Rd arm. The incidence of grade 3 or higher AEs was 74% and 69%, respectively. The incidence of serious AEs was 47% and 49%, respectively.

The incidence of AEs resulting in discontinuation was 17% and 14%, respectively. And the incidence of on-study deaths (occurring within 30 days of the last dose) was 4% and 6%, respectively.

Common AEs in the IRd and Rd arms, respectively, were diarrhea (45% vs 39%), constipation (35% vs 26%), nausea (29% vs 22%), vomiting (23% vs 12%), rash (36% vs 23%), back pain (24% vs 17%), upper respiratory tract infection (23% vs 19%), thrombocytopenia (31% vs 16%), peripheral neuropathy (27% vs 22%), peripheral edema (28% vs 20%), thromboembolism (8% vs 11%), and neutropenia (33% vs 31%).

“Ixazomib is adding limited toxicity to lenalidomide and dex, with a very low rate of peripheral neuropathy and no cardiovascular or renal adverse signals,” Dr Moreau said.

“This all-oral triplet regimen may become one of the new standards of care in the relapsed setting. [It has] a very safe profile, [is] a very effective combination, [and is] simple and convenient.”

*Data in the abstract differ from the presentation.

Philippe Moreau, MD

Photo courtesy of ASH

ORLANDO, FL—Adding the oral proteasome inhibitor ixazomib to treatment with lenalidomide and dexamethasone can prolong progression-free survival (PFS) in patients with relapsed and/or refractory multiple myeloma (MM), according to interim results of the phase 3 TOURMALINE-MM1 trial.

It is not yet clear if the 3-drug combination can prolong overall survival when compared to treatment with lenalidomide and dexamethasone.

However, researchers believe the triplet shows promise and could become a new standard of care for relapsed/refractory MM.

Philippe Moreau, MD, of the University of Nantes in France, discussed this possibility while presenting results from TOURMALINE-MM1 at the 2015 ASH Annual Meeting (abstract 727*). The study was sponsored by Millennium Pharmaceuticals, Inc.

The trial included 722 MM patients enrolled at 147 centers in 26 countries. Patients were randomized to receive ixazomib, lenalidomide, and dexamethasone (IRd, n=360) or placebo, lenalidomide, and dexamethasone (Rd, n=362).

Baseline patient characteristics were similar between the arms. The median age was 66 in both arms (overall range, 30-91), and nearly 60% of patients in both arms were male.

Fifty percent of patients in the IRd arm and 47% in the Rd arm had an ECOG performance status of 0. Forty-three percent and 45%, respectively, had a status of 1, and 5% and 7%, respectively, had a status of 2.

Eighty-seven percent and 88%, respectively, had an ISS stage of I or II. Fifty-five percent of patients in the IRd arm had standard-risk cytogenetics, as did 60% in the Rd arm.

Fifty-nine percent of patients in both arms had received 1 prior line of therapy, and 41% in both arms had 2 or 3 prior lines.

Response and survival

“Ixazomib, when combined with len-dex . . . , was associated with a significant and meaningful improvement in progression-free survival, improved time to progression, and [higher] response rate as well,” Dr Moreau said.

At a median follow-up of about 15 months, the median PFS was 20.6 months in the IRd arm and 14.7 months in the Rd arm. The hazard ratio was 0.742 (P=0.012).

Dr Moreau said the PFS benefit was consistent across pre-specified subgroups. So the benefit was present regardless of age, ISS stage, cytogenetic risk, number of prior therapies, prior exposure to a proteasome inhibitor, prior immunomodulatory therapy, whether the patient was refractory to his last therapy, and whether the patient had relapsed or refractory disease.

Dr Moreau also pointed out that, in the IRd arm, the median PFS in high-risk patients was similar to that in the overall patient population and in patients with standard-risk cytogenetics. This suggests ixazomib may overcome the negative impact of cytogenetic alterations.

Whether IRd confers an overall survival benefit is not clear, as those data are not yet mature. At a median follow-up of about 23 months, the median overall survival was not reached in either treatment arm.

The researchers conducted a non-inferential PFS analysis at the same time point (23 months) and found the median PFS was 20 months in the IRd arm and 15.9 months in the Rd arm. The hazard ratio was 0.82.

As for other efficacy endpoints, the overall response rate was 78.3% in the IRd arm and 71.5% in the Rd arm (P=0.035). The rates of complete response were 11.7% and 6.6%, respectively (P=0.019). And the rates of very good partial response or greater were 48.1% and 39%, respectively (P=0.014).

The median time to response was 1.1 months in the IRd arm and 1.9 months in the Rd arm. The median duration of response was 20.5 months and 15 months, respectively. And the median time to progression was 21.4 months and 15.7 months, respectively.

Adverse events

At a median follow-up of about 23 months, patients had received a median of 17 cycles of IRd and a median of 15 cycles of Rd.

The incidence of any adverse event (AE) was 98% in the IRd arm and 99% in the Rd arm. The incidence of grade 3 or higher AEs was 74% and 69%, respectively. The incidence of serious AEs was 47% and 49%, respectively.

The incidence of AEs resulting in discontinuation was 17% and 14%, respectively. And the incidence of on-study deaths (occurring within 30 days of the last dose) was 4% and 6%, respectively.

Common AEs in the IRd and Rd arms, respectively, were diarrhea (45% vs 39%), constipation (35% vs 26%), nausea (29% vs 22%), vomiting (23% vs 12%), rash (36% vs 23%), back pain (24% vs 17%), upper respiratory tract infection (23% vs 19%), thrombocytopenia (31% vs 16%), peripheral neuropathy (27% vs 22%), peripheral edema (28% vs 20%), thromboembolism (8% vs 11%), and neutropenia (33% vs 31%).

“Ixazomib is adding limited toxicity to lenalidomide and dex, with a very low rate of peripheral neuropathy and no cardiovascular or renal adverse signals,” Dr Moreau said.

“This all-oral triplet regimen may become one of the new standards of care in the relapsed setting. [It has] a very safe profile, [is] a very effective combination, [and is] simple and convenient.”

*Data in the abstract differ from the presentation.

Philippe Moreau, MD

Photo courtesy of ASH

ORLANDO, FL—Adding the oral proteasome inhibitor ixazomib to treatment with lenalidomide and dexamethasone can prolong progression-free survival (PFS) in patients with relapsed and/or refractory multiple myeloma (MM), according to interim results of the phase 3 TOURMALINE-MM1 trial.

It is not yet clear if the 3-drug combination can prolong overall survival when compared to treatment with lenalidomide and dexamethasone.

However, researchers believe the triplet shows promise and could become a new standard of care for relapsed/refractory MM.

Philippe Moreau, MD, of the University of Nantes in France, discussed this possibility while presenting results from TOURMALINE-MM1 at the 2015 ASH Annual Meeting (abstract 727*). The study was sponsored by Millennium Pharmaceuticals, Inc.

The trial included 722 MM patients enrolled at 147 centers in 26 countries. Patients were randomized to receive ixazomib, lenalidomide, and dexamethasone (IRd, n=360) or placebo, lenalidomide, and dexamethasone (Rd, n=362).

Baseline patient characteristics were similar between the arms. The median age was 66 in both arms (overall range, 30-91), and nearly 60% of patients in both arms were male.

Fifty percent of patients in the IRd arm and 47% in the Rd arm had an ECOG performance status of 0. Forty-three percent and 45%, respectively, had a status of 1, and 5% and 7%, respectively, had a status of 2.

Eighty-seven percent and 88%, respectively, had an ISS stage of I or II. Fifty-five percent of patients in the IRd arm had standard-risk cytogenetics, as did 60% in the Rd arm.

Fifty-nine percent of patients in both arms had received 1 prior line of therapy, and 41% in both arms had 2 or 3 prior lines.

Response and survival

“Ixazomib, when combined with len-dex . . . , was associated with a significant and meaningful improvement in progression-free survival, improved time to progression, and [higher] response rate as well,” Dr Moreau said.

At a median follow-up of about 15 months, the median PFS was 20.6 months in the IRd arm and 14.7 months in the Rd arm. The hazard ratio was 0.742 (P=0.012).

Dr Moreau said the PFS benefit was consistent across pre-specified subgroups. So the benefit was present regardless of age, ISS stage, cytogenetic risk, number of prior therapies, prior exposure to a proteasome inhibitor, prior immunomodulatory therapy, whether the patient was refractory to his last therapy, and whether the patient had relapsed or refractory disease.

Dr Moreau also pointed out that, in the IRd arm, the median PFS in high-risk patients was similar to that in the overall patient population and in patients with standard-risk cytogenetics. This suggests ixazomib may overcome the negative impact of cytogenetic alterations.

Whether IRd confers an overall survival benefit is not clear, as those data are not yet mature. At a median follow-up of about 23 months, the median overall survival was not reached in either treatment arm.

The researchers conducted a non-inferential PFS analysis at the same time point (23 months) and found the median PFS was 20 months in the IRd arm and 15.9 months in the Rd arm. The hazard ratio was 0.82.

As for other efficacy endpoints, the overall response rate was 78.3% in the IRd arm and 71.5% in the Rd arm (P=0.035). The rates of complete response were 11.7% and 6.6%, respectively (P=0.019). And the rates of very good partial response or greater were 48.1% and 39%, respectively (P=0.014).

The median time to response was 1.1 months in the IRd arm and 1.9 months in the Rd arm. The median duration of response was 20.5 months and 15 months, respectively. And the median time to progression was 21.4 months and 15.7 months, respectively.

Adverse events

At a median follow-up of about 23 months, patients had received a median of 17 cycles of IRd and a median of 15 cycles of Rd.

The incidence of any adverse event (AE) was 98% in the IRd arm and 99% in the Rd arm. The incidence of grade 3 or higher AEs was 74% and 69%, respectively. The incidence of serious AEs was 47% and 49%, respectively.

The incidence of AEs resulting in discontinuation was 17% and 14%, respectively. And the incidence of on-study deaths (occurring within 30 days of the last dose) was 4% and 6%, respectively.

Common AEs in the IRd and Rd arms, respectively, were diarrhea (45% vs 39%), constipation (35% vs 26%), nausea (29% vs 22%), vomiting (23% vs 12%), rash (36% vs 23%), back pain (24% vs 17%), upper respiratory tract infection (23% vs 19%), thrombocytopenia (31% vs 16%), peripheral neuropathy (27% vs 22%), peripheral edema (28% vs 20%), thromboembolism (8% vs 11%), and neutropenia (33% vs 31%).

“Ixazomib is adding limited toxicity to lenalidomide and dex, with a very low rate of peripheral neuropathy and no cardiovascular or renal adverse signals,” Dr Moreau said.

“This all-oral triplet regimen may become one of the new standards of care in the relapsed setting. [It has] a very safe profile, [is] a very effective combination, [and is] simple and convenient.”

*Data in the abstract differ from the presentation.

Elizabeth Raetz, MD

Photo courtesy of ASH

ORLANDO, FL—A subgroup of young patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL) can have “outstanding outcomes” with contemporary therapy, according to researchers.

Results of a large study suggested that patients ages 1 to 30 who have high-risk B-ALL according to National Cancer Institute (NCI) classification can have high rates of event-free survival (EFS) and overall survival (OS) if they have favorable cytogenetic features, have no evidence of CNS disease, and have rapid minimal residual disease (MRD) responses.

The research suggested these patients will not benefit from further chemotherapy intensification.

Elizabeth Raetz, MD, of the University of Utah in Salt Lake City, presented these results at the 2015 ASH Annual Meeting (abstract 807).

She and her colleagues analyzed patients enrolled on the Children’s Oncology Group (COG) AALL03B1 classification study at the time of B-ALL diagnosis. From December 2003 to September 2011, there were 11,144 eligible patients enrolled on this trial.

Eighty-nine percent of these patients were also enrolled on a frontline ALL therapeutic trial, and 96% of these patients were evaluable for post-induction treatment assignment. Sixty-five percent of these patients were treated on a trial for NCI standard-risk B-ALL (COG-AALL0331), and 35% were treated on a trial for high-risk B-ALL (COG-AALL0232).

At the end of induction therapy, patients were classified into low-risk (29%), standard-risk (33%), high-risk (34%), and very-high-risk (4%) groups for further treatment allocation. The variables used for risk classification were age, initial white blood cell count, extramedullary disease status, blast cytogenetics, and early treatment response based on bone marrow morphology and day 29 MRD.

Patients with very-high-risk features (BCR-ABL1, hypodiploidy, induction failure, or poor response at day 43) did not continue on AALL0232/AALL0331 post-induction but did have outcome data captured for analysis.

Response and survival

Rapid early response was defined as M1 (<5% blasts) bone marrow by day 15 plus flow cytometry-based MRD <0.1% on day 29 of induction. Patients with either M2/M3 (≥5% blasts) day 15 marrow or MRD ≥0.1% at day 29 were deemed slow early responders.

Eighty-four percent of patients had a rapid early response to induction, and 16% had a slow early response.

For rapid early responders, the 5-year EFS was 89.3%, and the 5-year OS was 95.2%. For slow early responders, the EFS and OS rates were 67.9% and 84.3%, respectively (P<0.0001 for both EFS and OS comparisons).

Survival according to cytogenetics

Having favorable cytogenetic abnormalities (triple trisomies of chromosomes 4, 10, and 17 or ETV6-RUNX1 fusion) was associated with significantly better EFS and OS than having unfavorable cytogenetics (hypodiploidy [DNA index <0.81 or chromosomes < 44], MLL rearrangements, BCR-ABL1, or iAMP21).

And Dr Raetz pointed out that the 5-year OS exceeded 98% for patients with either standard- or high-risk disease who had favorable cytogenetics.

For patients who were ETV6-RUNX1-positive, the EFS was 93.2% and the OS was 98.3%. For patients who were ETV6-RUNX1 negative, the rates were 83.5% and 92%, respectively (P<0.0001).

For patients with triple trisomy, EFS was 94.7% and OS was 98.7%. For those without triple trisomy, the rates were 83.6% and 92.2%, respectively (P<0.0001).

For patients with MLL rearrangement, the EFS was 73.9% and the OS was 83.1%. For patients without MLL rearrangement, the rates were 85.9% and 93.6%, respectively (P<0.0001).

For patients who were positive for iAMP21, the EFS was 69.5% and the OS was 90.1%. For iAMP21-negative patients, the rates were 86.1% and 93.4%, respectively (P<0.0001 for PFS comparison and P=0.0026 for OS comparison).

Survival according to risk group and MRD

The researchers also assessed EFS and OS among patients with favorable cytogenetics according to NCI risk group and MRD at days 8 and 29.

“One thing to point out is that, regardless of having favorable cytogenetics, those individuals who had end-induction MRD values of greater than 0.01% had inferior outcomes, so that was still a prognostic marker,” Dr Raetz said.

“And one thing that we were pleasantly surprised to see was that, among the NCI high-risk patients, those who had very rapid MRD responses—so less than 1% at day 8 in the blood and less than 0.01% in the marrow on day 29—had a 94.9% 5-year event-free survival and 98.1% overall survival.”

The researchers also divided this group according to age—patients younger than 10 and those 10 years or older. There was no significant difference in EFS or OS between the age groups (P=0.126 and P=0.411).

Standard-risk group

Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 95.7% and the OS was 99.1%.

Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 91.7% and the OS was 99.4%.

Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 88.1% and the OS was 96.8%.

High-risk group

Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 94.9% and the OS was 98.1%.

Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 93.6% and the OS was 95.5%.

Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 75.4% and the OS was 90.4%.

In closing, Dr Raetz said this study showed that real‐time classification incorporating clinical features, blast cytogenetics, and early response was feasible in a large group of patients enrolled on COG ALL trials and identified patients with varying outcomes for risk‐based treatment allocation.

She noted that early response by marrow morphology was not prognostic when MRD response was used and is therefore no longer used in COG studies.

And although favorable cytogenetic features were not prognostic in NCI high-risk B‐ALL patients in prior COG studies, the current study indicates that these patients can have “excellent outcomes” if they have no evidence of CNS leukemia and are rapid MRD responders. So these patients will not benefit from further chemotherapy intensification.

Elizabeth Raetz, MD

Photo courtesy of ASH

ORLANDO, FL—A subgroup of young patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL) can have “outstanding outcomes” with contemporary therapy, according to researchers.

Results of a large study suggested that patients ages 1 to 30 who have high-risk B-ALL according to National Cancer Institute (NCI) classification can have high rates of event-free survival (EFS) and overall survival (OS) if they have favorable cytogenetic features, have no evidence of CNS disease, and have rapid minimal residual disease (MRD) responses.

The research suggested these patients will not benefit from further chemotherapy intensification.

Elizabeth Raetz, MD, of the University of Utah in Salt Lake City, presented these results at the 2015 ASH Annual Meeting (abstract 807).

She and her colleagues analyzed patients enrolled on the Children’s Oncology Group (COG) AALL03B1 classification study at the time of B-ALL diagnosis. From December 2003 to September 2011, there were 11,144 eligible patients enrolled on this trial.

Eighty-nine percent of these patients were also enrolled on a frontline ALL therapeutic trial, and 96% of these patients were evaluable for post-induction treatment assignment. Sixty-five percent of these patients were treated on a trial for NCI standard-risk B-ALL (COG-AALL0331), and 35% were treated on a trial for high-risk B-ALL (COG-AALL0232).

At the end of induction therapy, patients were classified into low-risk (29%), standard-risk (33%), high-risk (34%), and very-high-risk (4%) groups for further treatment allocation. The variables used for risk classification were age, initial white blood cell count, extramedullary disease status, blast cytogenetics, and early treatment response based on bone marrow morphology and day 29 MRD.

Patients with very-high-risk features (BCR-ABL1, hypodiploidy, induction failure, or poor response at day 43) did not continue on AALL0232/AALL0331 post-induction but did have outcome data captured for analysis.

Response and survival

Rapid early response was defined as M1 (<5% blasts) bone marrow by day 15 plus flow cytometry-based MRD <0.1% on day 29 of induction. Patients with either M2/M3 (≥5% blasts) day 15 marrow or MRD ≥0.1% at day 29 were deemed slow early responders.

Eighty-four percent of patients had a rapid early response to induction, and 16% had a slow early response.

For rapid early responders, the 5-year EFS was 89.3%, and the 5-year OS was 95.2%. For slow early responders, the EFS and OS rates were 67.9% and 84.3%, respectively (P<0.0001 for both EFS and OS comparisons).

Survival according to cytogenetics

Having favorable cytogenetic abnormalities (triple trisomies of chromosomes 4, 10, and 17 or ETV6-RUNX1 fusion) was associated with significantly better EFS and OS than having unfavorable cytogenetics (hypodiploidy [DNA index <0.81 or chromosomes < 44], MLL rearrangements, BCR-ABL1, or iAMP21).

And Dr Raetz pointed out that the 5-year OS exceeded 98% for patients with either standard- or high-risk disease who had favorable cytogenetics.

For patients who were ETV6-RUNX1-positive, the EFS was 93.2% and the OS was 98.3%. For patients who were ETV6-RUNX1 negative, the rates were 83.5% and 92%, respectively (P<0.0001).

For patients with triple trisomy, EFS was 94.7% and OS was 98.7%. For those without triple trisomy, the rates were 83.6% and 92.2%, respectively (P<0.0001).

For patients with MLL rearrangement, the EFS was 73.9% and the OS was 83.1%. For patients without MLL rearrangement, the rates were 85.9% and 93.6%, respectively (P<0.0001).

For patients who were positive for iAMP21, the EFS was 69.5% and the OS was 90.1%. For iAMP21-negative patients, the rates were 86.1% and 93.4%, respectively (P<0.0001 for PFS comparison and P=0.0026 for OS comparison).

Survival according to risk group and MRD

The researchers also assessed EFS and OS among patients with favorable cytogenetics according to NCI risk group and MRD at days 8 and 29.

“One thing to point out is that, regardless of having favorable cytogenetics, those individuals who had end-induction MRD values of greater than 0.01% had inferior outcomes, so that was still a prognostic marker,” Dr Raetz said.

“And one thing that we were pleasantly surprised to see was that, among the NCI high-risk patients, those who had very rapid MRD responses—so less than 1% at day 8 in the blood and less than 0.01% in the marrow on day 29—had a 94.9% 5-year event-free survival and 98.1% overall survival.”

The researchers also divided this group according to age—patients younger than 10 and those 10 years or older. There was no significant difference in EFS or OS between the age groups (P=0.126 and P=0.411).

Standard-risk group

Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 95.7% and the OS was 99.1%.

Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 91.7% and the OS was 99.4%.

Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 88.1% and the OS was 96.8%.

High-risk group

Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 94.9% and the OS was 98.1%.

Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 93.6% and the OS was 95.5%.

Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 75.4% and the OS was 90.4%.

In closing, Dr Raetz said this study showed that real‐time classification incorporating clinical features, blast cytogenetics, and early response was feasible in a large group of patients enrolled on COG ALL trials and identified patients with varying outcomes for risk‐based treatment allocation.

She noted that early response by marrow morphology was not prognostic when MRD response was used and is therefore no longer used in COG studies.

And although favorable cytogenetic features were not prognostic in NCI high-risk B‐ALL patients in prior COG studies, the current study indicates that these patients can have “excellent outcomes” if they have no evidence of CNS leukemia and are rapid MRD responders. So these patients will not benefit from further chemotherapy intensification.

Elizabeth Raetz, MD

Photo courtesy of ASH

ORLANDO, FL—A subgroup of young patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL) can have “outstanding outcomes” with contemporary therapy, according to researchers.

Results of a large study suggested that patients ages 1 to 30 who have high-risk B-ALL according to National Cancer Institute (NCI) classification can have high rates of event-free survival (EFS) and overall survival (OS) if they have favorable cytogenetic features, have no evidence of CNS disease, and have rapid minimal residual disease (MRD) responses.

The research suggested these patients will not benefit from further chemotherapy intensification.

Elizabeth Raetz, MD, of the University of Utah in Salt Lake City, presented these results at the 2015 ASH Annual Meeting (abstract 807).

She and her colleagues analyzed patients enrolled on the Children’s Oncology Group (COG) AALL03B1 classification study at the time of B-ALL diagnosis. From December 2003 to September 2011, there were 11,144 eligible patients enrolled on this trial.

Eighty-nine percent of these patients were also enrolled on a frontline ALL therapeutic trial, and 96% of these patients were evaluable for post-induction treatment assignment. Sixty-five percent of these patients were treated on a trial for NCI standard-risk B-ALL (COG-AALL0331), and 35% were treated on a trial for high-risk B-ALL (COG-AALL0232).

At the end of induction therapy, patients were classified into low-risk (29%), standard-risk (33%), high-risk (34%), and very-high-risk (4%) groups for further treatment allocation. The variables used for risk classification were age, initial white blood cell count, extramedullary disease status, blast cytogenetics, and early treatment response based on bone marrow morphology and day 29 MRD.

Patients with very-high-risk features (BCR-ABL1, hypodiploidy, induction failure, or poor response at day 43) did not continue on AALL0232/AALL0331 post-induction but did have outcome data captured for analysis.

Response and survival

Rapid early response was defined as M1 (<5% blasts) bone marrow by day 15 plus flow cytometry-based MRD <0.1% on day 29 of induction. Patients with either M2/M3 (≥5% blasts) day 15 marrow or MRD ≥0.1% at day 29 were deemed slow early responders.

Eighty-four percent of patients had a rapid early response to induction, and 16% had a slow early response.

For rapid early responders, the 5-year EFS was 89.3%, and the 5-year OS was 95.2%. For slow early responders, the EFS and OS rates were 67.9% and 84.3%, respectively (P<0.0001 for both EFS and OS comparisons).

Survival according to cytogenetics

Having favorable cytogenetic abnormalities (triple trisomies of chromosomes 4, 10, and 17 or ETV6-RUNX1 fusion) was associated with significantly better EFS and OS than having unfavorable cytogenetics (hypodiploidy [DNA index <0.81 or chromosomes < 44], MLL rearrangements, BCR-ABL1, or iAMP21).

And Dr Raetz pointed out that the 5-year OS exceeded 98% for patients with either standard- or high-risk disease who had favorable cytogenetics.

For patients who were ETV6-RUNX1-positive, the EFS was 93.2% and the OS was 98.3%. For patients who were ETV6-RUNX1 negative, the rates were 83.5% and 92%, respectively (P<0.0001).

For patients with triple trisomy, EFS was 94.7% and OS was 98.7%. For those without triple trisomy, the rates were 83.6% and 92.2%, respectively (P<0.0001).

For patients with MLL rearrangement, the EFS was 73.9% and the OS was 83.1%. For patients without MLL rearrangement, the rates were 85.9% and 93.6%, respectively (P<0.0001).

For patients who were positive for iAMP21, the EFS was 69.5% and the OS was 90.1%. For iAMP21-negative patients, the rates were 86.1% and 93.4%, respectively (P<0.0001 for PFS comparison and P=0.0026 for OS comparison).

Survival according to risk group and MRD

The researchers also assessed EFS and OS among patients with favorable cytogenetics according to NCI risk group and MRD at days 8 and 29.

“One thing to point out is that, regardless of having favorable cytogenetics, those individuals who had end-induction MRD values of greater than 0.01% had inferior outcomes, so that was still a prognostic marker,” Dr Raetz said.

“And one thing that we were pleasantly surprised to see was that, among the NCI high-risk patients, those who had very rapid MRD responses—so less than 1% at day 8 in the blood and less than 0.01% in the marrow on day 29—had a 94.9% 5-year event-free survival and 98.1% overall survival.”

The researchers also divided this group according to age—patients younger than 10 and those 10 years or older. There was no significant difference in EFS or OS between the age groups (P=0.126 and P=0.411).

Standard-risk group

Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 95.7% and the OS was 99.1%.

Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 91.7% and the OS was 99.4%.

Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 88.1% and the OS was 96.8%.

High-risk group

Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 94.9% and the OS was 98.1%.

Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 93.6% and the OS was 95.5%.

Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 75.4% and the OS was 90.4%.

In closing, Dr Raetz said this study showed that real‐time classification incorporating clinical features, blast cytogenetics, and early response was feasible in a large group of patients enrolled on COG ALL trials and identified patients with varying outcomes for risk‐based treatment allocation.

She noted that early response by marrow morphology was not prognostic when MRD response was used and is therefore no longer used in COG studies.

And although favorable cytogenetic features were not prognostic in NCI high-risk B‐ALL patients in prior COG studies, the current study indicates that these patients can have “excellent outcomes” if they have no evidence of CNS leukemia and are rapid MRD responders. So these patients will not benefit from further chemotherapy intensification.

 

 

Micrograph showing DLBCL

 

ORLANDO, FL—Updated results of a phase 1 study suggest the EZH2 inhibitor tazemetostat (EPZ-6438) can produce durable responses in patients with advanced non-Hodgkin lymphoma (NHL).

The drug has demonstrated activity against diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and marginal zone lymphoma (MZL).

The overall response rate among NHL patients in this study was 56%, and 1 patient has maintained a response for more than 21 months.

In addition, the drug’s safety profile is “still acceptable,” according to Vincent Ribrag, MD, of Institut Gustave Roussy in Villejuif, France.

Dr Ribrag presented the results of this study at the 2015 ASH Annual Meeting (abstract 473*). The research, which was previously presented at the 13th International Conference on Malignant Lymphoma, was sponsored by Epizyme, Inc., the company developing tazemetostat.

The trial has enrolled 58 patients, 21 with relapsed or refractory B-cell NHL and 37 with advanced solid tumors. The NHL cohort includes 5 patients with germinal center B-cell (GCB) DLBCL, 6 cases of non-GCB DLBCL, 3 DLBCL cases of an undetermined subtype, 6 patients with FL, and 1 case of MZL.

At baseline, the NHL patients had a median age of 63 (range, 24-84) and were heavily pretreated. Eighty-five percent of patients had received 3 or more prior therapies, and 33% had received 5 or more. Thirty-eight percent of patients had undergone an autologous transplant, and 57% had received radiotherapy.

The patients received tazemetostat twice daily at a range of doses. For the dose-escalation portion of the trial, they received 100 mg, 200 mg, 400 mg, 800 mg, or 1600 mg. For the dose-expansion phase, they received 800 mg or 1600 mg.

The researchers are now conducting a drug-drug interaction substudy in which patients receive 800 mg of tazemetostat twice daily and a food-effect substudy in which patients receive the drug at 400 mg twice daily.

Dr Ribrag said the recommended phase 2 dose of tazemetostat is 800 mg twice daily.

Safety

At the data cutoff point (November 7, 2015), 55 patients—20 with NHL and 35 with solid tumors—were evaluable for safety.

Treatment-related adverse events in these patients included asthenia (n=13), nausea (n=8), thrombocytopenia (n=7), dysgeusia (n=5), vomiting (n=5), dry skin (n=4), decreased appetite (n=4), diarrhea (n=4), muscle spasms (n=3), neutropenia (n=3), anemia (n=3), night sweats (n=3), hypertension (n=2), constipation (n=2), peripheral edema (n=2), hypophosphatemia (n=1), anxiety (n=1), depression (n=1), abdominal pain (n=1), and hepatocellular injury (n=1).

There were 4 grade 3 or higher adverse events that were considered treatment-related, including nausea, hypertension, neutropenia, and hepatocellular injury.

Efficacy

Sixteen of the NHL patients were evaluable for efficacy. Nine patients responded to treatment, 2 with complete responses (CRs) and 7 with partial responses (PRs).

Five of the 10 DLBCL patients responded, 4 with PRs and 1 with a CR. Three of the 5 FL patients responded, 2 with PRs and 1 with a CR. The patient with MZL achieved a PR.

Four responders remain on study—2 with DLBCL and 2 with FL.

One DLBCL patient with an EZH2 mutation (Y646H) had relapsed after or was refractory to 6 previous treatment regimens. This patient achieved a PR after 16 weeks of tazemetostat. The patient is still in PR at week 44 and remains on study.

Based on these results, Epizyme is currently enrolling patients in a phase 2 study of tazemetostat monotherapy. The trial is open to patients with DLBCL or FL in France, Australia, and the UK.

*Data in the abstract differ from the presentation.

 

 

Micrograph showing DLBCL

 

ORLANDO, FL—Updated results of a phase 1 study suggest the EZH2 inhibitor tazemetostat (EPZ-6438) can produce durable responses in patients with advanced non-Hodgkin lymphoma (NHL).

The drug has demonstrated activity against diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and marginal zone lymphoma (MZL).

The overall response rate among NHL patients in this study was 56%, and 1 patient has maintained a response for more than 21 months.

In addition, the drug’s safety profile is “still acceptable,” according to Vincent Ribrag, MD, of Institut Gustave Roussy in Villejuif, France.

Dr Ribrag presented the results of this study at the 2015 ASH Annual Meeting (abstract 473*). The research, which was previously presented at the 13th International Conference on Malignant Lymphoma, was sponsored by Epizyme, Inc., the company developing tazemetostat.

The trial has enrolled 58 patients, 21 with relapsed or refractory B-cell NHL and 37 with advanced solid tumors. The NHL cohort includes 5 patients with germinal center B-cell (GCB) DLBCL, 6 cases of non-GCB DLBCL, 3 DLBCL cases of an undetermined subtype, 6 patients with FL, and 1 case of MZL.

At baseline, the NHL patients had a median age of 63 (range, 24-84) and were heavily pretreated. Eighty-five percent of patients had received 3 or more prior therapies, and 33% had received 5 or more. Thirty-eight percent of patients had undergone an autologous transplant, and 57% had received radiotherapy.

The patients received tazemetostat twice daily at a range of doses. For the dose-escalation portion of the trial, they received 100 mg, 200 mg, 400 mg, 800 mg, or 1600 mg. For the dose-expansion phase, they received 800 mg or 1600 mg.

The researchers are now conducting a drug-drug interaction substudy in which patients receive 800 mg of tazemetostat twice daily and a food-effect substudy in which patients receive the drug at 400 mg twice daily.

Dr Ribrag said the recommended phase 2 dose of tazemetostat is 800 mg twice daily.

Safety

At the data cutoff point (November 7, 2015), 55 patients—20 with NHL and 35 with solid tumors—were evaluable for safety.

Treatment-related adverse events in these patients included asthenia (n=13), nausea (n=8), thrombocytopenia (n=7), dysgeusia (n=5), vomiting (n=5), dry skin (n=4), decreased appetite (n=4), diarrhea (n=4), muscle spasms (n=3), neutropenia (n=3), anemia (n=3), night sweats (n=3), hypertension (n=2), constipation (n=2), peripheral edema (n=2), hypophosphatemia (n=1), anxiety (n=1), depression (n=1), abdominal pain (n=1), and hepatocellular injury (n=1).

There were 4 grade 3 or higher adverse events that were considered treatment-related, including nausea, hypertension, neutropenia, and hepatocellular injury.

Efficacy

Sixteen of the NHL patients were evaluable for efficacy. Nine patients responded to treatment, 2 with complete responses (CRs) and 7 with partial responses (PRs).

Five of the 10 DLBCL patients responded, 4 with PRs and 1 with a CR. Three of the 5 FL patients responded, 2 with PRs and 1 with a CR. The patient with MZL achieved a PR.

Four responders remain on study—2 with DLBCL and 2 with FL.

One DLBCL patient with an EZH2 mutation (Y646H) had relapsed after or was refractory to 6 previous treatment regimens. This patient achieved a PR after 16 weeks of tazemetostat. The patient is still in PR at week 44 and remains on study.

Based on these results, Epizyme is currently enrolling patients in a phase 2 study of tazemetostat monotherapy. The trial is open to patients with DLBCL or FL in France, Australia, and the UK.

*Data in the abstract differ from the presentation.

 

 

Micrograph showing DLBCL

 

ORLANDO, FL—Updated results of a phase 1 study suggest the EZH2 inhibitor tazemetostat (EPZ-6438) can produce durable responses in patients with advanced non-Hodgkin lymphoma (NHL).

The drug has demonstrated activity against diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and marginal zone lymphoma (MZL).

The overall response rate among NHL patients in this study was 56%, and 1 patient has maintained a response for more than 21 months.

In addition, the drug’s safety profile is “still acceptable,” according to Vincent Ribrag, MD, of Institut Gustave Roussy in Villejuif, France.

Dr Ribrag presented the results of this study at the 2015 ASH Annual Meeting (abstract 473*). The research, which was previously presented at the 13th International Conference on Malignant Lymphoma, was sponsored by Epizyme, Inc., the company developing tazemetostat.

The trial has enrolled 58 patients, 21 with relapsed or refractory B-cell NHL and 37 with advanced solid tumors. The NHL cohort includes 5 patients with germinal center B-cell (GCB) DLBCL, 6 cases of non-GCB DLBCL, 3 DLBCL cases of an undetermined subtype, 6 patients with FL, and 1 case of MZL.

At baseline, the NHL patients had a median age of 63 (range, 24-84) and were heavily pretreated. Eighty-five percent of patients had received 3 or more prior therapies, and 33% had received 5 or more. Thirty-eight percent of patients had undergone an autologous transplant, and 57% had received radiotherapy.

The patients received tazemetostat twice daily at a range of doses. For the dose-escalation portion of the trial, they received 100 mg, 200 mg, 400 mg, 800 mg, or 1600 mg. For the dose-expansion phase, they received 800 mg or 1600 mg.

The researchers are now conducting a drug-drug interaction substudy in which patients receive 800 mg of tazemetostat twice daily and a food-effect substudy in which patients receive the drug at 400 mg twice daily.

Dr Ribrag said the recommended phase 2 dose of tazemetostat is 800 mg twice daily.

Safety

At the data cutoff point (November 7, 2015), 55 patients—20 with NHL and 35 with solid tumors—were evaluable for safety.

Treatment-related adverse events in these patients included asthenia (n=13), nausea (n=8), thrombocytopenia (n=7), dysgeusia (n=5), vomiting (n=5), dry skin (n=4), decreased appetite (n=4), diarrhea (n=4), muscle spasms (n=3), neutropenia (n=3), anemia (n=3), night sweats (n=3), hypertension (n=2), constipation (n=2), peripheral edema (n=2), hypophosphatemia (n=1), anxiety (n=1), depression (n=1), abdominal pain (n=1), and hepatocellular injury (n=1).

There were 4 grade 3 or higher adverse events that were considered treatment-related, including nausea, hypertension, neutropenia, and hepatocellular injury.

Efficacy

Sixteen of the NHL patients were evaluable for efficacy. Nine patients responded to treatment, 2 with complete responses (CRs) and 7 with partial responses (PRs).

Five of the 10 DLBCL patients responded, 4 with PRs and 1 with a CR. Three of the 5 FL patients responded, 2 with PRs and 1 with a CR. The patient with MZL achieved a PR.

Four responders remain on study—2 with DLBCL and 2 with FL.

One DLBCL patient with an EZH2 mutation (Y646H) had relapsed after or was refractory to 6 previous treatment regimens. This patient achieved a PR after 16 weeks of tazemetostat. The patient is still in PR at week 44 and remains on study.

Based on these results, Epizyme is currently enrolling patients in a phase 2 study of tazemetostat monotherapy. The trial is open to patients with DLBCL or FL in France, Australia, and the UK.

*Data in the abstract differ from the presentation.

Micrograph showing PMF

ORLANDO, FL—Having a higher grade of bone marrow (BM) fibrosis may confer inferior overall survival (OS) in patients with primary myelofibrosis (PMF), according to a retrospective study.

Investigators found that having a fibrosis grade of 2 or higher at diagnosis was associated with “unique clinical and molecular variables” that suggested a more aggressive disease phenotype.

And the median OS was significantly shorter in patients with higher grades of fibrosis.

However, when the investigators divided patients according to their International Prognostic Scoring System (IPSS) risk group, having a fibrosis grade of 2 or higher was only significantly associated with reduced OS among patients in the low-risk or intermediate-1-risk categories.

Paola Guglielmelli, MD, PhD, of the University of Florence in Italy, presented these findings at the 2015 ASH Annual Meeting (abstract 351*).

Dr Guglielmelli noted that the prognostic significance of BM fibrosis grade in PMF has been debated. So she and her colleagues set out to analyze the prognostic impact of fibrosis in 540 PMF patients from 6 Italian centers belonging to AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative).

BM biopsies were obtained at diagnosis and evaluated by local pathologists according to 2008 World Health Organization criteria. The European consensus scoring system was used to grade fibrosis on a scale of MF-0 to MF-3.

Fifty patients were classified as MF-0 (9.3%), 180 were MF-1 (33.3%), 196 were MF-2 (36.3%), and 114 were MF-3 (21.1%).

Patients in the MF-2 and MF-3 groups were significantly more likely to have constitutional symptoms (P<0.0001), splenomegaly ≥10 cm from left costal margin (P<0.0001), a peripheral blast count ≥1% (P<0.0001), a greater risk of anemia (P<0.0001) or thrombocytopenia (P=0.001), and belong to the intermediate-2 or high-risk IPSS categories (P<0.0001).

In addition, patients in the MF-2 and MF-3 groups were significantly more likely to qualify as high-molecular-risk (HMR), which was defined as having at least 1 mutation in ASXL1, EZH2, SRSF2, or IDH1/2 (P<0.0001). The frequency of HMR patients increased progressively according to fibrosis grade: MF-0 (16%), MF-1 (25.6%), MF-2 (33.7%), and MF-3 (44.7%).

Patients with 2 or more HMR mutated genes were preferentially MF-2 or MF-3. None of the MF-0 patients fell into this category, compared to 4.4% for MF-1, 10.2% for MF-2, and 10.5% for MF-3 (P<0.0001).

Survival

The median OS was significantly shorter in patients with higher BM fibrosis grades (P<0.0001). The median OS was 7.2 years in the MF-3 group (hazard ratio [HR]=8.7), 6.7 years in the MF-2 group (HR=7.3), 14.7 years in the MF-1 group (HR=3.9), and not reached in the MF-0 group (reference).

In multivariable analysis, having a BM fibrosis grade of 2 or greater was significantly associated with reduced OS (HR=3.8, P=0.01).

Other variables significantly associated with reduced OS were being in the intermediate-1 (HR=2.9, P<0.0001), intermedicate-2 (HR=10.0, P<0.0001), or high-risk IPSS categories (HR=9.7, P<0.0001); having CALR type 2 mutation (HR=3.4, P=0.010), JAK2/MPL mutation (HR=2.4, P=0.003), or being triple-negative (HR=4.5, P<0.0001); being classified as HMR (HR=2.4, P<0.0001); and having 2 or more HMR mutations (HR=4.3, P=0.009).

Dr Guglielmelli and her colleagues also assessed the impact of BM fibrosis grade according to IPSS risk score.

They found that, for patients in the low/intermediate-1-risk categories, the median OS was not reached in the MF-0 group, was 22.8 years in the MF-1 group (HR=3.9), and was 15.4 years in the MF-2 and -3 groups combined (HR=7.4, P=0.001).

In the intermediate-2/high-risk categories, the median OS was 11 years for the MF-0 group, 3.6 years for the MF-1 group (HR=2.2), and 3.6 years in the MF-2 and -3 groups (HR=2.7, P=0.28).

Dr Guglielmelli therefore concluded that BM fibrosis grade might help refine prognostic stratification for PMF patients in the lower-risk IPSS categories. However, she noted that this study had limitations, and the results should be confirmed with prospective research.

*Data in the abstract differ from the presentation.

Micrograph showing PMF

ORLANDO, FL—Having a higher grade of bone marrow (BM) fibrosis may confer inferior overall survival (OS) in patients with primary myelofibrosis (PMF), according to a retrospective study.

Investigators found that having a fibrosis grade of 2 or higher at diagnosis was associated with “unique clinical and molecular variables” that suggested a more aggressive disease phenotype.

And the median OS was significantly shorter in patients with higher grades of fibrosis.

However, when the investigators divided patients according to their International Prognostic Scoring System (IPSS) risk group, having a fibrosis grade of 2 or higher was only significantly associated with reduced OS among patients in the low-risk or intermediate-1-risk categories.

Paola Guglielmelli, MD, PhD, of the University of Florence in Italy, presented these findings at the 2015 ASH Annual Meeting (abstract 351*).

Dr Guglielmelli noted that the prognostic significance of BM fibrosis grade in PMF has been debated. So she and her colleagues set out to analyze the prognostic impact of fibrosis in 540 PMF patients from 6 Italian centers belonging to AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative).

BM biopsies were obtained at diagnosis and evaluated by local pathologists according to 2008 World Health Organization criteria. The European consensus scoring system was used to grade fibrosis on a scale of MF-0 to MF-3.

Fifty patients were classified as MF-0 (9.3%), 180 were MF-1 (33.3%), 196 were MF-2 (36.3%), and 114 were MF-3 (21.1%).

Patients in the MF-2 and MF-3 groups were significantly more likely to have constitutional symptoms (P<0.0001), splenomegaly ≥10 cm from left costal margin (P<0.0001), a peripheral blast count ≥1% (P<0.0001), a greater risk of anemia (P<0.0001) or thrombocytopenia (P=0.001), and belong to the intermediate-2 or high-risk IPSS categories (P<0.0001).

In addition, patients in the MF-2 and MF-3 groups were significantly more likely to qualify as high-molecular-risk (HMR), which was defined as having at least 1 mutation in ASXL1, EZH2, SRSF2, or IDH1/2 (P<0.0001). The frequency of HMR patients increased progressively according to fibrosis grade: MF-0 (16%), MF-1 (25.6%), MF-2 (33.7%), and MF-3 (44.7%).

Patients with 2 or more HMR mutated genes were preferentially MF-2 or MF-3. None of the MF-0 patients fell into this category, compared to 4.4% for MF-1, 10.2% for MF-2, and 10.5% for MF-3 (P<0.0001).

Survival

The median OS was significantly shorter in patients with higher BM fibrosis grades (P<0.0001). The median OS was 7.2 years in the MF-3 group (hazard ratio [HR]=8.7), 6.7 years in the MF-2 group (HR=7.3), 14.7 years in the MF-1 group (HR=3.9), and not reached in the MF-0 group (reference).

In multivariable analysis, having a BM fibrosis grade of 2 or greater was significantly associated with reduced OS (HR=3.8, P=0.01).

Other variables significantly associated with reduced OS were being in the intermediate-1 (HR=2.9, P<0.0001), intermedicate-2 (HR=10.0, P<0.0001), or high-risk IPSS categories (HR=9.7, P<0.0001); having CALR type 2 mutation (HR=3.4, P=0.010), JAK2/MPL mutation (HR=2.4, P=0.003), or being triple-negative (HR=4.5, P<0.0001); being classified as HMR (HR=2.4, P<0.0001); and having 2 or more HMR mutations (HR=4.3, P=0.009).

Dr Guglielmelli and her colleagues also assessed the impact of BM fibrosis grade according to IPSS risk score.

They found that, for patients in the low/intermediate-1-risk categories, the median OS was not reached in the MF-0 group, was 22.8 years in the MF-1 group (HR=3.9), and was 15.4 years in the MF-2 and -3 groups combined (HR=7.4, P=0.001).

In the intermediate-2/high-risk categories, the median OS was 11 years for the MF-0 group, 3.6 years for the MF-1 group (HR=2.2), and 3.6 years in the MF-2 and -3 groups (HR=2.7, P=0.28).

Dr Guglielmelli therefore concluded that BM fibrosis grade might help refine prognostic stratification for PMF patients in the lower-risk IPSS categories. However, she noted that this study had limitations, and the results should be confirmed with prospective research.

*Data in the abstract differ from the presentation.

Micrograph showing PMF

ORLANDO, FL—Having a higher grade of bone marrow (BM) fibrosis may confer inferior overall survival (OS) in patients with primary myelofibrosis (PMF), according to a retrospective study.

Investigators found that having a fibrosis grade of 2 or higher at diagnosis was associated with “unique clinical and molecular variables” that suggested a more aggressive disease phenotype.

And the median OS was significantly shorter in patients with higher grades of fibrosis.

However, when the investigators divided patients according to their International Prognostic Scoring System (IPSS) risk group, having a fibrosis grade of 2 or higher was only significantly associated with reduced OS among patients in the low-risk or intermediate-1-risk categories.

Paola Guglielmelli, MD, PhD, of the University of Florence in Italy, presented these findings at the 2015 ASH Annual Meeting (abstract 351*).

Dr Guglielmelli noted that the prognostic significance of BM fibrosis grade in PMF has been debated. So she and her colleagues set out to analyze the prognostic impact of fibrosis in 540 PMF patients from 6 Italian centers belonging to AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative).

BM biopsies were obtained at diagnosis and evaluated by local pathologists according to 2008 World Health Organization criteria. The European consensus scoring system was used to grade fibrosis on a scale of MF-0 to MF-3.

Fifty patients were classified as MF-0 (9.3%), 180 were MF-1 (33.3%), 196 were MF-2 (36.3%), and 114 were MF-3 (21.1%).

Patients in the MF-2 and MF-3 groups were significantly more likely to have constitutional symptoms (P<0.0001), splenomegaly ≥10 cm from left costal margin (P<0.0001), a peripheral blast count ≥1% (P<0.0001), a greater risk of anemia (P<0.0001) or thrombocytopenia (P=0.001), and belong to the intermediate-2 or high-risk IPSS categories (P<0.0001).

In addition, patients in the MF-2 and MF-3 groups were significantly more likely to qualify as high-molecular-risk (HMR), which was defined as having at least 1 mutation in ASXL1, EZH2, SRSF2, or IDH1/2 (P<0.0001). The frequency of HMR patients increased progressively according to fibrosis grade: MF-0 (16%), MF-1 (25.6%), MF-2 (33.7%), and MF-3 (44.7%).

Patients with 2 or more HMR mutated genes were preferentially MF-2 or MF-3. None of the MF-0 patients fell into this category, compared to 4.4% for MF-1, 10.2% for MF-2, and 10.5% for MF-3 (P<0.0001).

Survival

The median OS was significantly shorter in patients with higher BM fibrosis grades (P<0.0001). The median OS was 7.2 years in the MF-3 group (hazard ratio [HR]=8.7), 6.7 years in the MF-2 group (HR=7.3), 14.7 years in the MF-1 group (HR=3.9), and not reached in the MF-0 group (reference).

In multivariable analysis, having a BM fibrosis grade of 2 or greater was significantly associated with reduced OS (HR=3.8, P=0.01).

Other variables significantly associated with reduced OS were being in the intermediate-1 (HR=2.9, P<0.0001), intermedicate-2 (HR=10.0, P<0.0001), or high-risk IPSS categories (HR=9.7, P<0.0001); having CALR type 2 mutation (HR=3.4, P=0.010), JAK2/MPL mutation (HR=2.4, P=0.003), or being triple-negative (HR=4.5, P<0.0001); being classified as HMR (HR=2.4, P<0.0001); and having 2 or more HMR mutations (HR=4.3, P=0.009).

Dr Guglielmelli and her colleagues also assessed the impact of BM fibrosis grade according to IPSS risk score.

They found that, for patients in the low/intermediate-1-risk categories, the median OS was not reached in the MF-0 group, was 22.8 years in the MF-1 group (HR=3.9), and was 15.4 years in the MF-2 and -3 groups combined (HR=7.4, P=0.001).

In the intermediate-2/high-risk categories, the median OS was 11 years for the MF-0 group, 3.6 years for the MF-1 group (HR=2.2), and 3.6 years in the MF-2 and -3 groups (HR=2.7, P=0.28).

Dr Guglielmelli therefore concluded that BM fibrosis grade might help refine prognostic stratification for PMF patients in the lower-risk IPSS categories. However, she noted that this study had limitations, and the results should be confirmed with prospective research.

*Data in the abstract differ from the presentation.