Hematology Times

Photo by Daniel Sone

Researchers say hybrid capture sequencing is an accurate and sensitive method for identifying actionable gene mutations in lymphoid malignancies.

This method revealed potentially actionable mutations in 91% of patients studied, who had diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or chronic lymphocytic leukemia (CLL).

The researchers therefore believe hybrid capture sequencing will bring the benefits of precision diagnosis and individualized therapy to patients with lymphoid malignancies.

“To realize the benefits of the most recent progress in cancer genomics, clinical implementation of precision medicine approaches is needed in the form of novel biomarker assays,” said study author Christian Steidl, MD, of the University of British Columbia in Vancouver, Canada.

“Fully implemented targeted sequencing-based assays in routine diagnostic pathology laboratories are currently lacking in lymphoid cancer care. Our findings demonstrate the feasibility and outline the clinical utility of integrating a lymphoma-specific pipeline into personalized cancer care.”

Dr Steidl and his colleagues reported these findings in The Journal of Molecular Diagnostics.

The researchers first compared capture hybridization and amplicon sequencing using samples from 8 patients with lymphoma. Fresh-frozen and formalin-fixed, paraffin-embedded tumor samples were sequenced using a panel of 20 lymphoma-specific genes.

The team found that capture hybridization provided “deep, more uniform coverage” and yielded “higher sensitivity for variant calling” than amplicon sequencing.

The researchers then developed a targeted sequencing pipeline using a 32-gene panel. The panel was developed with input from a group of 6 specialists who kept updating it based on the latest available information.

“This allows for continuous integration of additional gene features as our knowledge base improves,” Dr Steidl noted.

He and his colleagues then applied the hybrid capture sequencing assay and 32-gene panel to tissues from 219 patients—114 with FL, 76 with DLBCL, and 29 with CLL—who were treated in British Columbia between 2013 and 2016.

Results revealed at least one actionable mutation in 91% of the tumors. And the assay uncovered subtype-specific mutational profiles that were highly similar to published mutational profiles for FL, DLBCL, and CLL.

Furthermore, the assay had 93% concordance with whole-genome sequencing.

“Our developed assay harnesses the power of modern sequencing for clinical diagnostics purposes and potentially better deployment of novel treatments in lymphoid cancers,” Dr Steidl said. “We believe our study will help establish evidence-based approaches to decision making in lymphoid cancer care.”

“The next steps are to implement sequencing-based biomarker assays, such as reported in our study, in accredited pathology laboratories. Toward the goal of biomarker-driven clinical decision making, testing of potentially predictive biomarker assays is needed alongside clinical trials investigating novel cancer therapeutics.”

Photo by Daniel Sone

Researchers say hybrid capture sequencing is an accurate and sensitive method for identifying actionable gene mutations in lymphoid malignancies.

This method revealed potentially actionable mutations in 91% of patients studied, who had diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or chronic lymphocytic leukemia (CLL).

The researchers therefore believe hybrid capture sequencing will bring the benefits of precision diagnosis and individualized therapy to patients with lymphoid malignancies.

“To realize the benefits of the most recent progress in cancer genomics, clinical implementation of precision medicine approaches is needed in the form of novel biomarker assays,” said study author Christian Steidl, MD, of the University of British Columbia in Vancouver, Canada.

“Fully implemented targeted sequencing-based assays in routine diagnostic pathology laboratories are currently lacking in lymphoid cancer care. Our findings demonstrate the feasibility and outline the clinical utility of integrating a lymphoma-specific pipeline into personalized cancer care.”

Dr Steidl and his colleagues reported these findings in The Journal of Molecular Diagnostics.

The researchers first compared capture hybridization and amplicon sequencing using samples from 8 patients with lymphoma. Fresh-frozen and formalin-fixed, paraffin-embedded tumor samples were sequenced using a panel of 20 lymphoma-specific genes.

The team found that capture hybridization provided “deep, more uniform coverage” and yielded “higher sensitivity for variant calling” than amplicon sequencing.

The researchers then developed a targeted sequencing pipeline using a 32-gene panel. The panel was developed with input from a group of 6 specialists who kept updating it based on the latest available information.

“This allows for continuous integration of additional gene features as our knowledge base improves,” Dr Steidl noted.

He and his colleagues then applied the hybrid capture sequencing assay and 32-gene panel to tissues from 219 patients—114 with FL, 76 with DLBCL, and 29 with CLL—who were treated in British Columbia between 2013 and 2016.

Results revealed at least one actionable mutation in 91% of the tumors. And the assay uncovered subtype-specific mutational profiles that were highly similar to published mutational profiles for FL, DLBCL, and CLL.

Furthermore, the assay had 93% concordance with whole-genome sequencing.

“Our developed assay harnesses the power of modern sequencing for clinical diagnostics purposes and potentially better deployment of novel treatments in lymphoid cancers,” Dr Steidl said. “We believe our study will help establish evidence-based approaches to decision making in lymphoid cancer care.”

“The next steps are to implement sequencing-based biomarker assays, such as reported in our study, in accredited pathology laboratories. Toward the goal of biomarker-driven clinical decision making, testing of potentially predictive biomarker assays is needed alongside clinical trials investigating novel cancer therapeutics.”

Photo by Daniel Sone

Researchers say hybrid capture sequencing is an accurate and sensitive method for identifying actionable gene mutations in lymphoid malignancies.

This method revealed potentially actionable mutations in 91% of patients studied, who had diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or chronic lymphocytic leukemia (CLL).

The researchers therefore believe hybrid capture sequencing will bring the benefits of precision diagnosis and individualized therapy to patients with lymphoid malignancies.

“To realize the benefits of the most recent progress in cancer genomics, clinical implementation of precision medicine approaches is needed in the form of novel biomarker assays,” said study author Christian Steidl, MD, of the University of British Columbia in Vancouver, Canada.

“Fully implemented targeted sequencing-based assays in routine diagnostic pathology laboratories are currently lacking in lymphoid cancer care. Our findings demonstrate the feasibility and outline the clinical utility of integrating a lymphoma-specific pipeline into personalized cancer care.”

Dr Steidl and his colleagues reported these findings in The Journal of Molecular Diagnostics.

The researchers first compared capture hybridization and amplicon sequencing using samples from 8 patients with lymphoma. Fresh-frozen and formalin-fixed, paraffin-embedded tumor samples were sequenced using a panel of 20 lymphoma-specific genes.

The team found that capture hybridization provided “deep, more uniform coverage” and yielded “higher sensitivity for variant calling” than amplicon sequencing.

The researchers then developed a targeted sequencing pipeline using a 32-gene panel. The panel was developed with input from a group of 6 specialists who kept updating it based on the latest available information.

“This allows for continuous integration of additional gene features as our knowledge base improves,” Dr Steidl noted.

He and his colleagues then applied the hybrid capture sequencing assay and 32-gene panel to tissues from 219 patients—114 with FL, 76 with DLBCL, and 29 with CLL—who were treated in British Columbia between 2013 and 2016.

Results revealed at least one actionable mutation in 91% of the tumors. And the assay uncovered subtype-specific mutational profiles that were highly similar to published mutational profiles for FL, DLBCL, and CLL.

Furthermore, the assay had 93% concordance with whole-genome sequencing.

“Our developed assay harnesses the power of modern sequencing for clinical diagnostics purposes and potentially better deployment of novel treatments in lymphoid cancers,” Dr Steidl said. “We believe our study will help establish evidence-based approaches to decision making in lymphoid cancer care.”

“The next steps are to implement sequencing-based biomarker assays, such as reported in our study, in accredited pathology laboratories. Toward the goal of biomarker-driven clinical decision making, testing of potentially predictive biomarker assays is needed alongside clinical trials investigating novel cancer therapeutics.”

Photo by Bill Branson

Azacitidine for injection (Vidaza®) is now available in China.

The nucleoside metabolic inhibitor was approved in China to treat patients with intermediate-2/high-risk myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) with 20% to 30% bone marrow blasts, and chronic myelomonocytic leukemia (CMML).

Azacitidine for injection is marketed in China by BeiGene Ltd. under an exclusive license from Celgene Corporation.

“Vidaza is the only approved hypomethylating agent shown to prolong survival for patients with MDS and the first new treatment for MDS patients approved in China since 2009,” said John V. Oyler, founder, chief executive officer, and chairman of BeiGene.

“We are excited to announce that the first prescription was made in January 2018. From now on, Chinese patients can benefit from Vidaza in hospitals around China.”

Azacitidine was evaluated in a global phase 3 trial of patients with intermediate-2- and high-risk MDS, CMML, or AML (AZA-001). Results from this trial were published in The Lancet Oncology in 2009.

Patients were randomized to receive azacitidine plus best supportive care (BSC, n=179) or conventional care regimens plus BSC (105 to BSC alone, 49 to low-dose cytarabine, and 25 to chemotherapy with cytarabine and anthracycline).

Azacitidine was given subcutaneously at a dose of 75 mg/m² daily for 7 consecutive days every 28 days until disease progression, relapse after response, or unacceptable toxicity.

The median overall survival was 24.5 months with azacitidine, compared to 15 months for patients treated with conventional care regimens.

There was a higher hematologic response rate in the azacitidine arm than the conventional care arm—29% and 12%, respectively.

In the azacitidine group, 45% of patients who were dependent on red blood cell transfusions at baseline became transfusion independent, compared with 11% in the conventional care group.

Forty-six percent of patients in the azacitidine arm and 63% in the conventional care arm died.

Grade 3/4 hematologic toxicity (in the azacitidine and conventional care arms, respectively) included neutropenia (91% and 76%), thrombocytopenia (85% and 80%), and anemia (57% and 68%).

Photo by Bill Branson

Azacitidine for injection (Vidaza®) is now available in China.

The nucleoside metabolic inhibitor was approved in China to treat patients with intermediate-2/high-risk myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) with 20% to 30% bone marrow blasts, and chronic myelomonocytic leukemia (CMML).

Azacitidine for injection is marketed in China by BeiGene Ltd. under an exclusive license from Celgene Corporation.

“Vidaza is the only approved hypomethylating agent shown to prolong survival for patients with MDS and the first new treatment for MDS patients approved in China since 2009,” said John V. Oyler, founder, chief executive officer, and chairman of BeiGene.

“We are excited to announce that the first prescription was made in January 2018. From now on, Chinese patients can benefit from Vidaza in hospitals around China.”

Azacitidine was evaluated in a global phase 3 trial of patients with intermediate-2- and high-risk MDS, CMML, or AML (AZA-001). Results from this trial were published in The Lancet Oncology in 2009.

Patients were randomized to receive azacitidine plus best supportive care (BSC, n=179) or conventional care regimens plus BSC (105 to BSC alone, 49 to low-dose cytarabine, and 25 to chemotherapy with cytarabine and anthracycline).

Azacitidine was given subcutaneously at a dose of 75 mg/m² daily for 7 consecutive days every 28 days until disease progression, relapse after response, or unacceptable toxicity.

The median overall survival was 24.5 months with azacitidine, compared to 15 months for patients treated with conventional care regimens.

There was a higher hematologic response rate in the azacitidine arm than the conventional care arm—29% and 12%, respectively.

In the azacitidine group, 45% of patients who were dependent on red blood cell transfusions at baseline became transfusion independent, compared with 11% in the conventional care group.

Forty-six percent of patients in the azacitidine arm and 63% in the conventional care arm died.

Grade 3/4 hematologic toxicity (in the azacitidine and conventional care arms, respectively) included neutropenia (91% and 76%), thrombocytopenia (85% and 80%), and anemia (57% and 68%).

Photo by Bill Branson

Azacitidine for injection (Vidaza®) is now available in China.

The nucleoside metabolic inhibitor was approved in China to treat patients with intermediate-2/high-risk myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) with 20% to 30% bone marrow blasts, and chronic myelomonocytic leukemia (CMML).

Azacitidine for injection is marketed in China by BeiGene Ltd. under an exclusive license from Celgene Corporation.

“Vidaza is the only approved hypomethylating agent shown to prolong survival for patients with MDS and the first new treatment for MDS patients approved in China since 2009,” said John V. Oyler, founder, chief executive officer, and chairman of BeiGene.

“We are excited to announce that the first prescription was made in January 2018. From now on, Chinese patients can benefit from Vidaza in hospitals around China.”

Azacitidine was evaluated in a global phase 3 trial of patients with intermediate-2- and high-risk MDS, CMML, or AML (AZA-001). Results from this trial were published in The Lancet Oncology in 2009.

Patients were randomized to receive azacitidine plus best supportive care (BSC, n=179) or conventional care regimens plus BSC (105 to BSC alone, 49 to low-dose cytarabine, and 25 to chemotherapy with cytarabine and anthracycline).

Azacitidine was given subcutaneously at a dose of 75 mg/m² daily for 7 consecutive days every 28 days until disease progression, relapse after response, or unacceptable toxicity.

The median overall survival was 24.5 months with azacitidine, compared to 15 months for patients treated with conventional care regimens.

There was a higher hematologic response rate in the azacitidine arm than the conventional care arm—29% and 12%, respectively.

In the azacitidine group, 45% of patients who were dependent on red blood cell transfusions at baseline became transfusion independent, compared with 11% in the conventional care group.

Forty-six percent of patients in the azacitidine arm and 63% in the conventional care arm died.

Grade 3/4 hematologic toxicity (in the azacitidine and conventional care arms, respectively) included neutropenia (91% and 76%), thrombocytopenia (85% and 80%), and anemia (57% and 68%).

Photo by Larry Young

LA JOLLA, CA—Results of a phase 2 study suggest chidamide can produce durable responses in patients with relapsed/refractory natural killer/T-cell lymphoma (NKTCL).

The overall response rate was 57.2% in these patients, and the complete response (CR) rate was 28.6%.

Seven of 14 evaluable patients were still receiving chidamide and still in response at last follow-up. For one patient, this was 50 weeks from initiating treatment with chidamide.

“The response is quite promising and encouraging,” said study investigator Huiqiang Huang, MD, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China.

“In terms of safety, the toxicity is mild to moderate.”

Dr Huang presented these results at the 10th Annual T-cell Lymphoma Forum.

This investigator-sponsored trial enrolled patients with relapsed/refractory non-Hodgkin lymphoma, but Dr Huang presented results in NKTCL patients only.

There were 15 NKTCL patients, most of whom were male (n=12). Their median age was 41 (range, 17-65). All 15 had an ECOG status of 0 or 1, 9 had stage I/II disease, and 6 had B symptoms.

Nine patients had Epstein-Barr virus (EBV) DNA levels of at least 1000 copy/mL at baseline, and 5 patients had lactate dehydrogenase levels of at least 245 U/L.

The patients had a median of 2 prior systemic therapies (range, 1-3), and 2 patients had undergone a transplant.

Efficacy

Patients received chidamide at 2 doses—10 mg daily or 30 mg twice a week. Dr Huang said both doses were effective against the lymphoma types studied, but the 30 mg twice-weekly dose appeared to be more effective for patients with NKTCL.

Fourteen NKTCL patients were evaluable for efficacy, and the median follow-up was 17.6 weeks (range, 2.6-50).

The overall response rate was 68.2% (6/14), and the CR rate was 28.6% (4/14). The disease control rate was 71.4%, meaning 10 of 14 patients had a CR, partial response (PR), or stable disease (SD).

Dr Huang noted that response was associated with elevated H3 acetylation level.

The median time to response was 5.25 weeks (range, 1.1-6.6).

As for duration of response, the 4 complete responders were still on treatment and in CR at last follow-up, which was 22.7 weeks, 38.1 weeks, 41.3 weeks, and 50 weeks, respectively, from treatment initiation.

Three of the 4 partial responders were still on treatment and in PR at 14.1 weeks, 26.9 weeks, and 32 weeks, respectively. Two patients with SD were still on treatment and in SD at 15.3 weeks and 15.9 weeks, respectively.

Three patients progressed while on treatment and died. A fourth patient died 2.6 weeks after treatment initiation.

Safety

Dr Huang noted that adverse events (AEs) were similar with the 2 dose groups. However, patients who received 30 mg biweekly had a higher incidence of gastrointestinal AEs.

Overall, the most common AEs were hematologic—anemia, thrombocytopenia, etc.—but dose reductions allowed for quick resolution of these AEs, according to Dr Huang.

AEs included:

• Lymphopenia—10 grade 1/2 and 1 grade 3/4
• Anemia—9 grade 1/2 and 3 grade 3/4
• Thrombocytopenia—7 grade 1/2 and grade 3/4
• Leukopenia—7 grade 1/2 and 6 grade 3/4
• Increased alanine aminotransferase—7 grade 1/2
• Neutropenia—6 grade 1/2 and 7 grade 3/4
• Increased aspartate aminotransferase—5 grade 1/2
• Hypoalbuminemia—4 grade 1/2
• Nausea—4 grade 1/2 and 1 grade 3/4
• Vomiting—3 grade 1/2
• Mucositis—2 grade 1/2
• Fatigue—2 grade 1/2
• Epistaxis—2 grade 1/2
• Abdominal distension—1 grade 1/2
• Loss of appetite—1 grade 1/2
• Diarrhea—1 grade 1/2
• Hyperbilirubinemia—1 grade 1/2
• Fever—1 grade 1/2 and grade 3/4
• Pain—1 grade 1/2
• Cough—1 grade 1/2
• Constipation—1 grade 1/2.

Dr Huang said EBV reactivation was not confirmed in this study. An elevated EBV DNA load was only observed in 2 patients with progressive disease.

Photo by Larry Young

LA JOLLA, CA—Results of a phase 2 study suggest chidamide can produce durable responses in patients with relapsed/refractory natural killer/T-cell lymphoma (NKTCL).

The overall response rate was 57.2% in these patients, and the complete response (CR) rate was 28.6%.

Seven of 14 evaluable patients were still receiving chidamide and still in response at last follow-up. For one patient, this was 50 weeks from initiating treatment with chidamide.

“The response is quite promising and encouraging,” said study investigator Huiqiang Huang, MD, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China.

“In terms of safety, the toxicity is mild to moderate.”

Dr Huang presented these results at the 10th Annual T-cell Lymphoma Forum.

This investigator-sponsored trial enrolled patients with relapsed/refractory non-Hodgkin lymphoma, but Dr Huang presented results in NKTCL patients only.

There were 15 NKTCL patients, most of whom were male (n=12). Their median age was 41 (range, 17-65). All 15 had an ECOG status of 0 or 1, 9 had stage I/II disease, and 6 had B symptoms.

Nine patients had Epstein-Barr virus (EBV) DNA levels of at least 1000 copy/mL at baseline, and 5 patients had lactate dehydrogenase levels of at least 245 U/L.

The patients had a median of 2 prior systemic therapies (range, 1-3), and 2 patients had undergone a transplant.

Efficacy

Patients received chidamide at 2 doses—10 mg daily or 30 mg twice a week. Dr Huang said both doses were effective against the lymphoma types studied, but the 30 mg twice-weekly dose appeared to be more effective for patients with NKTCL.

Fourteen NKTCL patients were evaluable for efficacy, and the median follow-up was 17.6 weeks (range, 2.6-50).

The overall response rate was 68.2% (6/14), and the CR rate was 28.6% (4/14). The disease control rate was 71.4%, meaning 10 of 14 patients had a CR, partial response (PR), or stable disease (SD).

Dr Huang noted that response was associated with elevated H3 acetylation level.

The median time to response was 5.25 weeks (range, 1.1-6.6).

As for duration of response, the 4 complete responders were still on treatment and in CR at last follow-up, which was 22.7 weeks, 38.1 weeks, 41.3 weeks, and 50 weeks, respectively, from treatment initiation.

Three of the 4 partial responders were still on treatment and in PR at 14.1 weeks, 26.9 weeks, and 32 weeks, respectively. Two patients with SD were still on treatment and in SD at 15.3 weeks and 15.9 weeks, respectively.

Three patients progressed while on treatment and died. A fourth patient died 2.6 weeks after treatment initiation.

Safety

Dr Huang noted that adverse events (AEs) were similar with the 2 dose groups. However, patients who received 30 mg biweekly had a higher incidence of gastrointestinal AEs.

Overall, the most common AEs were hematologic—anemia, thrombocytopenia, etc.—but dose reductions allowed for quick resolution of these AEs, according to Dr Huang.

AEs included:

• Lymphopenia—10 grade 1/2 and 1 grade 3/4
• Anemia—9 grade 1/2 and 3 grade 3/4
• Thrombocytopenia—7 grade 1/2 and grade 3/4
• Leukopenia—7 grade 1/2 and 6 grade 3/4
• Increased alanine aminotransferase—7 grade 1/2
• Neutropenia—6 grade 1/2 and 7 grade 3/4
• Increased aspartate aminotransferase—5 grade 1/2
• Hypoalbuminemia—4 grade 1/2
• Nausea—4 grade 1/2 and 1 grade 3/4
• Vomiting—3 grade 1/2
• Mucositis—2 grade 1/2
• Fatigue—2 grade 1/2
• Epistaxis—2 grade 1/2
• Abdominal distension—1 grade 1/2
• Loss of appetite—1 grade 1/2
• Diarrhea—1 grade 1/2
• Hyperbilirubinemia—1 grade 1/2
• Fever—1 grade 1/2 and grade 3/4
• Pain—1 grade 1/2
• Cough—1 grade 1/2
• Constipation—1 grade 1/2.

Dr Huang said EBV reactivation was not confirmed in this study. An elevated EBV DNA load was only observed in 2 patients with progressive disease.

Photo by Larry Young

LA JOLLA, CA—Results of a phase 2 study suggest chidamide can produce durable responses in patients with relapsed/refractory natural killer/T-cell lymphoma (NKTCL).

The overall response rate was 57.2% in these patients, and the complete response (CR) rate was 28.6%.

Seven of 14 evaluable patients were still receiving chidamide and still in response at last follow-up. For one patient, this was 50 weeks from initiating treatment with chidamide.

“The response is quite promising and encouraging,” said study investigator Huiqiang Huang, MD, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China.

“In terms of safety, the toxicity is mild to moderate.”

Dr Huang presented these results at the 10th Annual T-cell Lymphoma Forum.

This investigator-sponsored trial enrolled patients with relapsed/refractory non-Hodgkin lymphoma, but Dr Huang presented results in NKTCL patients only.

There were 15 NKTCL patients, most of whom were male (n=12). Their median age was 41 (range, 17-65). All 15 had an ECOG status of 0 or 1, 9 had stage I/II disease, and 6 had B symptoms.

Nine patients had Epstein-Barr virus (EBV) DNA levels of at least 1000 copy/mL at baseline, and 5 patients had lactate dehydrogenase levels of at least 245 U/L.

The patients had a median of 2 prior systemic therapies (range, 1-3), and 2 patients had undergone a transplant.

Efficacy

Patients received chidamide at 2 doses—10 mg daily or 30 mg twice a week. Dr Huang said both doses were effective against the lymphoma types studied, but the 30 mg twice-weekly dose appeared to be more effective for patients with NKTCL.

Fourteen NKTCL patients were evaluable for efficacy, and the median follow-up was 17.6 weeks (range, 2.6-50).

The overall response rate was 68.2% (6/14), and the CR rate was 28.6% (4/14). The disease control rate was 71.4%, meaning 10 of 14 patients had a CR, partial response (PR), or stable disease (SD).

Dr Huang noted that response was associated with elevated H3 acetylation level.

The median time to response was 5.25 weeks (range, 1.1-6.6).

As for duration of response, the 4 complete responders were still on treatment and in CR at last follow-up, which was 22.7 weeks, 38.1 weeks, 41.3 weeks, and 50 weeks, respectively, from treatment initiation.

Three of the 4 partial responders were still on treatment and in PR at 14.1 weeks, 26.9 weeks, and 32 weeks, respectively. Two patients with SD were still on treatment and in SD at 15.3 weeks and 15.9 weeks, respectively.

Three patients progressed while on treatment and died. A fourth patient died 2.6 weeks after treatment initiation.

Safety

Dr Huang noted that adverse events (AEs) were similar with the 2 dose groups. However, patients who received 30 mg biweekly had a higher incidence of gastrointestinal AEs.

Overall, the most common AEs were hematologic—anemia, thrombocytopenia, etc.—but dose reductions allowed for quick resolution of these AEs, according to Dr Huang.

AEs included:

• Lymphopenia—10 grade 1/2 and 1 grade 3/4
• Anemia—9 grade 1/2 and 3 grade 3/4
• Thrombocytopenia—7 grade 1/2 and grade 3/4
• Leukopenia—7 grade 1/2 and 6 grade 3/4
• Increased alanine aminotransferase—7 grade 1/2
• Neutropenia—6 grade 1/2 and 7 grade 3/4
• Increased aspartate aminotransferase—5 grade 1/2
• Hypoalbuminemia—4 grade 1/2
• Nausea—4 grade 1/2 and 1 grade 3/4
• Vomiting—3 grade 1/2
• Mucositis—2 grade 1/2
• Fatigue—2 grade 1/2
• Epistaxis—2 grade 1/2
• Abdominal distension—1 grade 1/2
• Loss of appetite—1 grade 1/2
• Diarrhea—1 grade 1/2
• Hyperbilirubinemia—1 grade 1/2
• Fever—1 grade 1/2 and grade 3/4
• Pain—1 grade 1/2
• Cough—1 grade 1/2
• Constipation—1 grade 1/2.

Dr Huang said EBV reactivation was not confirmed in this study. An elevated EBV DNA load was only observed in 2 patients with progressive disease.

Cancer Center

Adults with relapsed or refractory acute lymphoblastic leukemia (ALL) have better outcomes if they have a low disease burden when receiving chimeric antigen receptor (CAR) T-cell therapy, according to research published in NEJM.

The final analysis of a phase 1 trial showed that patients with a low disease burden at baseline had superior event-free survival (EFS) and overall survival (OS) after therapy, compared to patients with a high disease burden.

Patients with a low disease burden also had a lower rate of cytokine release syndrome (CRS) and neurotoxic events.

“This is the longest follow-up study of people with ALL treated with CAR therapy,” said study author Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

“With the long follow-up, we were able to demonstrate, for the first time, that patients with a lower disease burden benefited the most from CAR therapy, with significantly improved survival and reduced toxicity.”

The study included 53 adults with ALL who had a median age of 44 (range, 23-74).

They were heavily pretreated, with 68% receiving CAR T-cell therapy as a third or later salvage treatment. Thirty-six percent of patients had received an allogeneic transplant, and 23% had primary refractory disease.

In this trial, patients received a single infusion of 19-28z CAR T cells after conditioning chemotherapy. The maximum follow-up time was 5.5 years, with a median follow-up of 29 months.

In all, 83% of patients achieved a complete response. The median EFS was 6.1 months, and the median OS was 12.9 months.

The median EFS was significantly longer for patients with a low disease burden (<5% bone marrow blasts) compared to a high disease burden (≥5% bone marrow blasts or extramedullary disease)—10.6 months and 5.6 months, respectively (P=0.01).

The same was true for the median OS, which was 20.1 months in patients with a low disease burden and 12.4 months in those with a high disease burden (P=0.02).

For the entire study population, the rate of CRS was 85%, and 26% of patients had severe CRS. One patient died of severe CRS and multi-organ failure before the researchers began modifying the dose of CAR T cells according to the pretreatment disease burden.

Severe CRS occurred in 41% of patients with a high disease burden and 5% of those with a low disease burden.

In the entire study population, 2% of patients had grade 2 neurotoxic effects, 36% had grade 3, 6% had grade 4, and none had grade 5. The rate of severe neurotoxicity was 42%.

Neurotoxic effects occurred in 59% of patients with a high disease burden and 14% of those with a low disease burden.

“Among all of the clinical and disease factors we examined, pretreatment disease burden was the strongest predictor of long-term outcome after CAR therapy,” Dr Park said. “Our data supports the incorporation of CAR therapy in an earlier treatment setting in ALL, when the disease volume is small, so as to achieve the greatest long-term efficacy and lowest toxicity.”

This work was supported by Juno Therapeutics, the National Institutes of Health, the Carson Family Charitable Trust, the Emerald Foundation, the Mr. and Mrs. Goodwyn Commonwealth Fund, the Terry Fox Run for Cancer Research organized by the Canadian Association of New York, Kate’s Team, William Laurence and Blanche Hughes Foundation, the Center for Experimental Therapeutics at Memorial Sloan Kettering, and the Lake Road Foundation.

Cancer Center

Adults with relapsed or refractory acute lymphoblastic leukemia (ALL) have better outcomes if they have a low disease burden when receiving chimeric antigen receptor (CAR) T-cell therapy, according to research published in NEJM.

The final analysis of a phase 1 trial showed that patients with a low disease burden at baseline had superior event-free survival (EFS) and overall survival (OS) after therapy, compared to patients with a high disease burden.

Patients with a low disease burden also had a lower rate of cytokine release syndrome (CRS) and neurotoxic events.

“This is the longest follow-up study of people with ALL treated with CAR therapy,” said study author Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

“With the long follow-up, we were able to demonstrate, for the first time, that patients with a lower disease burden benefited the most from CAR therapy, with significantly improved survival and reduced toxicity.”

The study included 53 adults with ALL who had a median age of 44 (range, 23-74).

They were heavily pretreated, with 68% receiving CAR T-cell therapy as a third or later salvage treatment. Thirty-six percent of patients had received an allogeneic transplant, and 23% had primary refractory disease.

In this trial, patients received a single infusion of 19-28z CAR T cells after conditioning chemotherapy. The maximum follow-up time was 5.5 years, with a median follow-up of 29 months.

In all, 83% of patients achieved a complete response. The median EFS was 6.1 months, and the median OS was 12.9 months.

The median EFS was significantly longer for patients with a low disease burden (<5% bone marrow blasts) compared to a high disease burden (≥5% bone marrow blasts or extramedullary disease)—10.6 months and 5.6 months, respectively (P=0.01).

The same was true for the median OS, which was 20.1 months in patients with a low disease burden and 12.4 months in those with a high disease burden (P=0.02).

For the entire study population, the rate of CRS was 85%, and 26% of patients had severe CRS. One patient died of severe CRS and multi-organ failure before the researchers began modifying the dose of CAR T cells according to the pretreatment disease burden.

Severe CRS occurred in 41% of patients with a high disease burden and 5% of those with a low disease burden.

In the entire study population, 2% of patients had grade 2 neurotoxic effects, 36% had grade 3, 6% had grade 4, and none had grade 5. The rate of severe neurotoxicity was 42%.

Neurotoxic effects occurred in 59% of patients with a high disease burden and 14% of those with a low disease burden.

“Among all of the clinical and disease factors we examined, pretreatment disease burden was the strongest predictor of long-term outcome after CAR therapy,” Dr Park said. “Our data supports the incorporation of CAR therapy in an earlier treatment setting in ALL, when the disease volume is small, so as to achieve the greatest long-term efficacy and lowest toxicity.”

This work was supported by Juno Therapeutics, the National Institutes of Health, the Carson Family Charitable Trust, the Emerald Foundation, the Mr. and Mrs. Goodwyn Commonwealth Fund, the Terry Fox Run for Cancer Research organized by the Canadian Association of New York, Kate’s Team, William Laurence and Blanche Hughes Foundation, the Center for Experimental Therapeutics at Memorial Sloan Kettering, and the Lake Road Foundation.

Cancer Center

Adults with relapsed or refractory acute lymphoblastic leukemia (ALL) have better outcomes if they have a low disease burden when receiving chimeric antigen receptor (CAR) T-cell therapy, according to research published in NEJM.

The final analysis of a phase 1 trial showed that patients with a low disease burden at baseline had superior event-free survival (EFS) and overall survival (OS) after therapy, compared to patients with a high disease burden.

Patients with a low disease burden also had a lower rate of cytokine release syndrome (CRS) and neurotoxic events.

“This is the longest follow-up study of people with ALL treated with CAR therapy,” said study author Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

“With the long follow-up, we were able to demonstrate, for the first time, that patients with a lower disease burden benefited the most from CAR therapy, with significantly improved survival and reduced toxicity.”

The study included 53 adults with ALL who had a median age of 44 (range, 23-74).

They were heavily pretreated, with 68% receiving CAR T-cell therapy as a third or later salvage treatment. Thirty-six percent of patients had received an allogeneic transplant, and 23% had primary refractory disease.

In this trial, patients received a single infusion of 19-28z CAR T cells after conditioning chemotherapy. The maximum follow-up time was 5.5 years, with a median follow-up of 29 months.

In all, 83% of patients achieved a complete response. The median EFS was 6.1 months, and the median OS was 12.9 months.

The median EFS was significantly longer for patients with a low disease burden (<5% bone marrow blasts) compared to a high disease burden (≥5% bone marrow blasts or extramedullary disease)—10.6 months and 5.6 months, respectively (P=0.01).

The same was true for the median OS, which was 20.1 months in patients with a low disease burden and 12.4 months in those with a high disease burden (P=0.02).

For the entire study population, the rate of CRS was 85%, and 26% of patients had severe CRS. One patient died of severe CRS and multi-organ failure before the researchers began modifying the dose of CAR T cells according to the pretreatment disease burden.

Severe CRS occurred in 41% of patients with a high disease burden and 5% of those with a low disease burden.

In the entire study population, 2% of patients had grade 2 neurotoxic effects, 36% had grade 3, 6% had grade 4, and none had grade 5. The rate of severe neurotoxicity was 42%.

Neurotoxic effects occurred in 59% of patients with a high disease burden and 14% of those with a low disease burden.

“Among all of the clinical and disease factors we examined, pretreatment disease burden was the strongest predictor of long-term outcome after CAR therapy,” Dr Park said. “Our data supports the incorporation of CAR therapy in an earlier treatment setting in ALL, when the disease volume is small, so as to achieve the greatest long-term efficacy and lowest toxicity.”

This work was supported by Juno Therapeutics, the National Institutes of Health, the Carson Family Charitable Trust, the Emerald Foundation, the Mr. and Mrs. Goodwyn Commonwealth Fund, the Terry Fox Run for Cancer Research organized by the Canadian Association of New York, Kate’s Team, William Laurence and Blanche Hughes Foundation, the Center for Experimental Therapeutics at Memorial Sloan Kettering, and the Lake Road Foundation.

Photo courtesy of NIH

Researchers have recommended changes to international guidelines used in the development of clinical trials.

The group’s goal is to improve the use of patient-reported outcomes (PROs)—feedback from patients about how the clinical trial has affected their overall health and quality of life.

“Patient-reported outcome data from clinical trials can provide valuable evidence to inform shared-decision making, pharmaceutical labeling claims, clinical guidelines, and health policy,” said Melanie Calvert, PhD, of the University of Birmingham in Edgbaston, Birmingham, England.

“However, clinical trial protocols often lack important information regarding the collection of quality of life and symptom data. Working in collaboration with international stakeholders, we have developed consensus-based, PRO-specific protocol guidance to help ensure high-quality data to inform patient-centered care.”

Dr Calvert and her colleagues published the guidance in JAMA.

The guidance is known as the SPIRIT-PRO Extension. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement, which was published in 2013, was intended to improve trial protocols by providing evidence-based recommendations for the minimum set of items to be addressed.

To add a PRO component to SPIRIT, Dr Calvert and her colleagues conducted a systematic review of existing PRO-specific protocol guidance. A taskforce used this data to compile a list of potential PRO-specific protocol items.

The review revealed 162 PRO-specific protocol recommendations, and the task force reduced this to 56. After 138 international stakeholders and 99 Delphi panelists weighed in, the final recommendations were agreed upon by 29 participants at a consensus meeting.

The final recommendations include 11 extensions and 5 elaborations to the SPIRIT checklist. The recommendations focus on PRO-specific issues relating to objectives, eligibility criteria, data collection, monitoring, and other aspects of trials.

“While this guidance has been developed for trials where PROs are a primary or key secondary outcome, we are actively encouraging protocol writers to consider use of this guidance in all trials or clinical research studies where PROs are collected,” Dr Calvert said.

“The guidance does not aim to be prescriptive, but instead to encourage and facilitate careful planning of PRO components of trials and thereby improve PRO trial design, which we hope will help staff and patients understand the rationale for PRO assessment, improve PRO data completeness and quality, facilitate high-quality analysis and reporting, and ultimately improve the quality of the global PRO evidence base.”

Photo courtesy of NIH

Researchers have recommended changes to international guidelines used in the development of clinical trials.

The group’s goal is to improve the use of patient-reported outcomes (PROs)—feedback from patients about how the clinical trial has affected their overall health and quality of life.

“Patient-reported outcome data from clinical trials can provide valuable evidence to inform shared-decision making, pharmaceutical labeling claims, clinical guidelines, and health policy,” said Melanie Calvert, PhD, of the University of Birmingham in Edgbaston, Birmingham, England.

“However, clinical trial protocols often lack important information regarding the collection of quality of life and symptom data. Working in collaboration with international stakeholders, we have developed consensus-based, PRO-specific protocol guidance to help ensure high-quality data to inform patient-centered care.”

Dr Calvert and her colleagues published the guidance in JAMA.

The guidance is known as the SPIRIT-PRO Extension. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement, which was published in 2013, was intended to improve trial protocols by providing evidence-based recommendations for the minimum set of items to be addressed.

To add a PRO component to SPIRIT, Dr Calvert and her colleagues conducted a systematic review of existing PRO-specific protocol guidance. A taskforce used this data to compile a list of potential PRO-specific protocol items.

The review revealed 162 PRO-specific protocol recommendations, and the task force reduced this to 56. After 138 international stakeholders and 99 Delphi panelists weighed in, the final recommendations were agreed upon by 29 participants at a consensus meeting.

The final recommendations include 11 extensions and 5 elaborations to the SPIRIT checklist. The recommendations focus on PRO-specific issues relating to objectives, eligibility criteria, data collection, monitoring, and other aspects of trials.

“While this guidance has been developed for trials where PROs are a primary or key secondary outcome, we are actively encouraging protocol writers to consider use of this guidance in all trials or clinical research studies where PROs are collected,” Dr Calvert said.

“The guidance does not aim to be prescriptive, but instead to encourage and facilitate careful planning of PRO components of trials and thereby improve PRO trial design, which we hope will help staff and patients understand the rationale for PRO assessment, improve PRO data completeness and quality, facilitate high-quality analysis and reporting, and ultimately improve the quality of the global PRO evidence base.”

Photo courtesy of NIH

Researchers have recommended changes to international guidelines used in the development of clinical trials.

The group’s goal is to improve the use of patient-reported outcomes (PROs)—feedback from patients about how the clinical trial has affected their overall health and quality of life.

“Patient-reported outcome data from clinical trials can provide valuable evidence to inform shared-decision making, pharmaceutical labeling claims, clinical guidelines, and health policy,” said Melanie Calvert, PhD, of the University of Birmingham in Edgbaston, Birmingham, England.

“However, clinical trial protocols often lack important information regarding the collection of quality of life and symptom data. Working in collaboration with international stakeholders, we have developed consensus-based, PRO-specific protocol guidance to help ensure high-quality data to inform patient-centered care.”

Dr Calvert and her colleagues published the guidance in JAMA.

The guidance is known as the SPIRIT-PRO Extension. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement, which was published in 2013, was intended to improve trial protocols by providing evidence-based recommendations for the minimum set of items to be addressed.

To add a PRO component to SPIRIT, Dr Calvert and her colleagues conducted a systematic review of existing PRO-specific protocol guidance. A taskforce used this data to compile a list of potential PRO-specific protocol items.

The review revealed 162 PRO-specific protocol recommendations, and the task force reduced this to 56. After 138 international stakeholders and 99 Delphi panelists weighed in, the final recommendations were agreed upon by 29 participants at a consensus meeting.

The final recommendations include 11 extensions and 5 elaborations to the SPIRIT checklist. The recommendations focus on PRO-specific issues relating to objectives, eligibility criteria, data collection, monitoring, and other aspects of trials.

“While this guidance has been developed for trials where PROs are a primary or key secondary outcome, we are actively encouraging protocol writers to consider use of this guidance in all trials or clinical research studies where PROs are collected,” Dr Calvert said.

“The guidance does not aim to be prescriptive, but instead to encourage and facilitate careful planning of PRO components of trials and thereby improve PRO trial design, which we hope will help staff and patients understand the rationale for PRO assessment, improve PRO data completeness and quality, facilitate high-quality analysis and reporting, and ultimately improve the quality of the global PRO evidence base.”

Photo by Larry Young

LA JOLLA, CA—A 2-drug combination has demonstrated preferential activity in T-cell lymphomas over B-cell lymphomas, according to researchers.

In a small, phase 1/2 study, treatment with oral 5-azacitidine and romidepsin produced a higher overall response rate (ORR) and prolonged progression-free survival (PFS) in patients with T-cell lymphomas.

“In a very limited sample, we’ve definitely observed exquisite activity of the combination in patients with T-cell lymphoma compared to all other subtypes,” said Lorenzo Falchi, MD, of Columbia University Medical Center in New York, New York.

Dr Falchi presented these results at the 10th Annual T-cell Lymphoma Forum.

The research was funded by the Leukemia and Lymphoma Society, the Lymphoma Research Fund at Columbia University, and Celgene.

The phase 1 portion of this study included patients with previously treated non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma. The phase 2 portion included only patients with T-cell lymphomas, newly diagnosed or previously treated.

Thirty-three patients were enrolled—12 with Hodgkin lymphoma, 8 with B-cell NHL, and 13 with T-cell NHL.

The patients’ median age was 54 (range, 23-79). Fifty-seven percent (n=19) were male. Sixty-one percent of patients were non-Hispanic white (n=20), 24% (n=8) were black, and 12% (n=4) were Asian.

“This was a very heavily pretreated patient population,” Dr Falchi noted. “I’d like to emphasize that the median number of prior treatments is 5 [range, 0-15].”

“Over half of patients had had stem cell transplantation [17 autologous and 5 allogeneic]. And, if you look at the subtypes by histology, all patients, pretty much, at some point, received all the standard chemotherapy or treatment approaches that are typically used for that subtype.”

Treatment

Patients were divided into 7 dosing cohorts. Azacitidine doses ranged from 100 mg to 300 mg on days 1-14 or days 1-21 per cycle.

Romidepsin doses ranged from 10 mg/m² to 14 mg/m². The drug was given on days 8 and 15 every 21 or 28 days, or it was given on days 8, 15, and 22 every 35 days.

There were 2 dose-limiting toxicities (DLTs) in cohort 2—grade 3 thrombocytopenia and grade 3 pleural effusion. In this cohort, 3 patients received azacitidine at 200 mg on days 1-14 plus romidepsin at 10 mg/m² on days 8 and 15 every 21 days.

There were 3 DLTs in cohort 7—2 cases of grade 4 neutropenia and 1 case of grade 3 thrombocytopenia. In this cohort, 5 patients received azacitidine at 300 mg on days 1 to 21 plus romidepsin at 14 mg/m² on days 8, 15, and 22 every 35 days.

Because of the DLTs in cohort 7, cohort 6 was chosen as the maximum tolerated dose. In cohort 6, 3 patients received azacitidine at 300 mg on days 1-14 plus romidepsin at 14 mg/m² on days 8, 15, and 22 every 35 days.

Patients in the expansion cohort received treatment at the maximum tolerated dose. This cohort included 7 patients with T-cell lymphoma.

Safety

Treatment-emergent adverse events occurring in at least 5% of patients included:

• Anemia—3% grade 3
• Anorexia—9% grade 1
• Back pain—6% grade 2
• Constipation—6% grade 1
• Cough—9% grade 1
• Depression—3% grade 1 and 2
• Diarrhea—15% grade 1 and 6% grade 2
• Dyspnea—3% grade 1 and 2
• Fatigue—21% grade 1, 9% grade 2, and 3% grade 3
• Febrile neutropenia—3% grade 3 and 4
• Fever—6% grade 1 and 3% grade 2
• General disorders and administration site conditions—15% grade 1
• Hyperglycemia—3% grade 3
• Hypokalemia—6% grade 1
• Hypotension—3% grade 3
• Insomnia—6% grade 1
• Oral mucositis—9% grade 1 and 3% grade 2
• Nausea—18% grade 1, 27% grade 2, and 3% grade 3
• Neutrophil count decrease—3% grade 3 and 4
• Pain—3% grade 1 and 6% grade 2
• Pain of skin—3% grade 1 and 2
• Platelet count decrease—6% grade 2, 9% grade 3, and 6% grade 4
• Urinary tract infection—3% grade 3
• Vomiting—18% grade 1 and 21% grade 2.

Efficacy

Twenty-eight patients were evaluable for efficacy. The ORR for these patients was 36% (n=10).

The complete response (CR) rate was 22% (n=6), and the partial response (PR) rate was 14% (n=4). Twenty-five percent of patients (n=7) had stable disease, and 39% (n=11) progressed.

Dr Falchi noted that the ORR was “much higher” in patients with T-cell lymphoma than in those with B-cell lymphoma—80% (n=8) and 11% (n=2), respectively.

The CR rates were 50% (n=5) in T-cell lymphoma patients and 5.5% (n=1) in B-cell patients. PR rates were 30% (n=3) and 5.5% (n=1), respectively. Thirty-nine percent (n=7) of B-cell patients had stable disease, but none of the T-cell patients did.

“Patients with non-T-cell lymphoma were much more likely to progress on treatment,” Dr Falchi noted. “Half of them did so [n=9].”

This is in comparison to the 20% of T-cell lymphoma patients who progressed on treatment (n=2).

Disease subtypes for complete responders included transformed follicular lymphoma (n=1), T-lymphoblastic lymphoma (n=1), adult T-cell leukemia/lymphoma (n=1), extranodal NK/T-cell lymphoma (n=1), and angioimmunoblastic T-cell lymphoma (n=2).

Partial responders had follicular lymphoma (n=1), cutaneous peripheral T-cell lymphoma (n=1), cutaneous anaplastic large-cell lymphoma (n=1), and angioimmunoblastic T-cell lymphoma (n=1).

The 2 responders with B-cell lymphoma (1 CR and 1 PR) ultimately progressed and died.

Of the 8 responders with T-cell lymphoma, 3 have an ongoing CR, and 2 of these patients proceeded to transplant.

One T-cell patient who achieved a CR and proceeded to transplant was lost to follow-up. Another died after transplant.

Two T-cell patients who achieved a PR progressed and died. And 1 patient has an ongoing PR.

In total, 75% of patients (n=21) progressed. The median PFS for the entire study cohort was 3.6 months (range, 1.5-5.7).

The median PFS was 2.2 months (range, 1.1-3.2) for patients with B-cell lymphomas and was not reached for the T-cell lymphoma patients.

Eighty-nine percent of B-cell patients progressed (n=16), as did 40% of T-cell patients (n=4).

Dr Falchi and his colleagues are now conducting studies to correlate the pharmacokinetics of azacitidine-romidepsin with genome-wide methylation and correlate TET2, IDH2, and DNMT3A mutation status with clinical response.

Photo by Larry Young

LA JOLLA, CA—A 2-drug combination has demonstrated preferential activity in T-cell lymphomas over B-cell lymphomas, according to researchers.

In a small, phase 1/2 study, treatment with oral 5-azacitidine and romidepsin produced a higher overall response rate (ORR) and prolonged progression-free survival (PFS) in patients with T-cell lymphomas.

“In a very limited sample, we’ve definitely observed exquisite activity of the combination in patients with T-cell lymphoma compared to all other subtypes,” said Lorenzo Falchi, MD, of Columbia University Medical Center in New York, New York.

Dr Falchi presented these results at the 10th Annual T-cell Lymphoma Forum.

The research was funded by the Leukemia and Lymphoma Society, the Lymphoma Research Fund at Columbia University, and Celgene.

The phase 1 portion of this study included patients with previously treated non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma. The phase 2 portion included only patients with T-cell lymphomas, newly diagnosed or previously treated.

Thirty-three patients were enrolled—12 with Hodgkin lymphoma, 8 with B-cell NHL, and 13 with T-cell NHL.

The patients’ median age was 54 (range, 23-79). Fifty-seven percent (n=19) were male. Sixty-one percent of patients were non-Hispanic white (n=20), 24% (n=8) were black, and 12% (n=4) were Asian.

“This was a very heavily pretreated patient population,” Dr Falchi noted. “I’d like to emphasize that the median number of prior treatments is 5 [range, 0-15].”

“Over half of patients had had stem cell transplantation [17 autologous and 5 allogeneic]. And, if you look at the subtypes by histology, all patients, pretty much, at some point, received all the standard chemotherapy or treatment approaches that are typically used for that subtype.”

Treatment

Patients were divided into 7 dosing cohorts. Azacitidine doses ranged from 100 mg to 300 mg on days 1-14 or days 1-21 per cycle.

Romidepsin doses ranged from 10 mg/m² to 14 mg/m². The drug was given on days 8 and 15 every 21 or 28 days, or it was given on days 8, 15, and 22 every 35 days.

There were 2 dose-limiting toxicities (DLTs) in cohort 2—grade 3 thrombocytopenia and grade 3 pleural effusion. In this cohort, 3 patients received azacitidine at 200 mg on days 1-14 plus romidepsin at 10 mg/m² on days 8 and 15 every 21 days.

There were 3 DLTs in cohort 7—2 cases of grade 4 neutropenia and 1 case of grade 3 thrombocytopenia. In this cohort, 5 patients received azacitidine at 300 mg on days 1 to 21 plus romidepsin at 14 mg/m² on days 8, 15, and 22 every 35 days.

Because of the DLTs in cohort 7, cohort 6 was chosen as the maximum tolerated dose. In cohort 6, 3 patients received azacitidine at 300 mg on days 1-14 plus romidepsin at 14 mg/m² on days 8, 15, and 22 every 35 days.

Patients in the expansion cohort received treatment at the maximum tolerated dose. This cohort included 7 patients with T-cell lymphoma.

Safety

Treatment-emergent adverse events occurring in at least 5% of patients included:

• Anemia—3% grade 3
• Anorexia—9% grade 1
• Back pain—6% grade 2
• Constipation—6% grade 1
• Cough—9% grade 1
• Depression—3% grade 1 and 2
• Diarrhea—15% grade 1 and 6% grade 2
• Dyspnea—3% grade 1 and 2
• Fatigue—21% grade 1, 9% grade 2, and 3% grade 3
• Febrile neutropenia—3% grade 3 and 4
• Fever—6% grade 1 and 3% grade 2
• General disorders and administration site conditions—15% grade 1
• Hyperglycemia—3% grade 3
• Hypokalemia—6% grade 1
• Hypotension—3% grade 3
• Insomnia—6% grade 1
• Oral mucositis—9% grade 1 and 3% grade 2
• Nausea—18% grade 1, 27% grade 2, and 3% grade 3
• Neutrophil count decrease—3% grade 3 and 4
• Pain—3% grade 1 and 6% grade 2
• Pain of skin—3% grade 1 and 2
• Platelet count decrease—6% grade 2, 9% grade 3, and 6% grade 4
• Urinary tract infection—3% grade 3
• Vomiting—18% grade 1 and 21% grade 2.

Efficacy

Twenty-eight patients were evaluable for efficacy. The ORR for these patients was 36% (n=10).

The complete response (CR) rate was 22% (n=6), and the partial response (PR) rate was 14% (n=4). Twenty-five percent of patients (n=7) had stable disease, and 39% (n=11) progressed.

Dr Falchi noted that the ORR was “much higher” in patients with T-cell lymphoma than in those with B-cell lymphoma—80% (n=8) and 11% (n=2), respectively.

The CR rates were 50% (n=5) in T-cell lymphoma patients and 5.5% (n=1) in B-cell patients. PR rates were 30% (n=3) and 5.5% (n=1), respectively. Thirty-nine percent (n=7) of B-cell patients had stable disease, but none of the T-cell patients did.

“Patients with non-T-cell lymphoma were much more likely to progress on treatment,” Dr Falchi noted. “Half of them did so [n=9].”

This is in comparison to the 20% of T-cell lymphoma patients who progressed on treatment (n=2).

Disease subtypes for complete responders included transformed follicular lymphoma (n=1), T-lymphoblastic lymphoma (n=1), adult T-cell leukemia/lymphoma (n=1), extranodal NK/T-cell lymphoma (n=1), and angioimmunoblastic T-cell lymphoma (n=2).

Partial responders had follicular lymphoma (n=1), cutaneous peripheral T-cell lymphoma (n=1), cutaneous anaplastic large-cell lymphoma (n=1), and angioimmunoblastic T-cell lymphoma (n=1).

The 2 responders with B-cell lymphoma (1 CR and 1 PR) ultimately progressed and died.

Of the 8 responders with T-cell lymphoma, 3 have an ongoing CR, and 2 of these patients proceeded to transplant.

One T-cell patient who achieved a CR and proceeded to transplant was lost to follow-up. Another died after transplant.

Two T-cell patients who achieved a PR progressed and died. And 1 patient has an ongoing PR.

In total, 75% of patients (n=21) progressed. The median PFS for the entire study cohort was 3.6 months (range, 1.5-5.7).

The median PFS was 2.2 months (range, 1.1-3.2) for patients with B-cell lymphomas and was not reached for the T-cell lymphoma patients.

Eighty-nine percent of B-cell patients progressed (n=16), as did 40% of T-cell patients (n=4).

Dr Falchi and his colleagues are now conducting studies to correlate the pharmacokinetics of azacitidine-romidepsin with genome-wide methylation and correlate TET2, IDH2, and DNMT3A mutation status with clinical response.

Photo by Larry Young

LA JOLLA, CA—A 2-drug combination has demonstrated preferential activity in T-cell lymphomas over B-cell lymphomas, according to researchers.

In a small, phase 1/2 study, treatment with oral 5-azacitidine and romidepsin produced a higher overall response rate (ORR) and prolonged progression-free survival (PFS) in patients with T-cell lymphomas.

“In a very limited sample, we’ve definitely observed exquisite activity of the combination in patients with T-cell lymphoma compared to all other subtypes,” said Lorenzo Falchi, MD, of Columbia University Medical Center in New York, New York.

Dr Falchi presented these results at the 10th Annual T-cell Lymphoma Forum.

The research was funded by the Leukemia and Lymphoma Society, the Lymphoma Research Fund at Columbia University, and Celgene.

The phase 1 portion of this study included patients with previously treated non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma. The phase 2 portion included only patients with T-cell lymphomas, newly diagnosed or previously treated.

Thirty-three patients were enrolled—12 with Hodgkin lymphoma, 8 with B-cell NHL, and 13 with T-cell NHL.

The patients’ median age was 54 (range, 23-79). Fifty-seven percent (n=19) were male. Sixty-one percent of patients were non-Hispanic white (n=20), 24% (n=8) were black, and 12% (n=4) were Asian.

“This was a very heavily pretreated patient population,” Dr Falchi noted. “I’d like to emphasize that the median number of prior treatments is 5 [range, 0-15].”

“Over half of patients had had stem cell transplantation [17 autologous and 5 allogeneic]. And, if you look at the subtypes by histology, all patients, pretty much, at some point, received all the standard chemotherapy or treatment approaches that are typically used for that subtype.”

Treatment

Patients were divided into 7 dosing cohorts. Azacitidine doses ranged from 100 mg to 300 mg on days 1-14 or days 1-21 per cycle.

Romidepsin doses ranged from 10 mg/m² to 14 mg/m². The drug was given on days 8 and 15 every 21 or 28 days, or it was given on days 8, 15, and 22 every 35 days.

There were 2 dose-limiting toxicities (DLTs) in cohort 2—grade 3 thrombocytopenia and grade 3 pleural effusion. In this cohort, 3 patients received azacitidine at 200 mg on days 1-14 plus romidepsin at 10 mg/m² on days 8 and 15 every 21 days.

There were 3 DLTs in cohort 7—2 cases of grade 4 neutropenia and 1 case of grade 3 thrombocytopenia. In this cohort, 5 patients received azacitidine at 300 mg on days 1 to 21 plus romidepsin at 14 mg/m² on days 8, 15, and 22 every 35 days.

Because of the DLTs in cohort 7, cohort 6 was chosen as the maximum tolerated dose. In cohort 6, 3 patients received azacitidine at 300 mg on days 1-14 plus romidepsin at 14 mg/m² on days 8, 15, and 22 every 35 days.

Patients in the expansion cohort received treatment at the maximum tolerated dose. This cohort included 7 patients with T-cell lymphoma.

Safety

Treatment-emergent adverse events occurring in at least 5% of patients included:

• Anemia—3% grade 3
• Anorexia—9% grade 1
• Back pain—6% grade 2
• Constipation—6% grade 1
• Cough—9% grade 1
• Depression—3% grade 1 and 2
• Diarrhea—15% grade 1 and 6% grade 2
• Dyspnea—3% grade 1 and 2
• Fatigue—21% grade 1, 9% grade 2, and 3% grade 3
• Febrile neutropenia—3% grade 3 and 4
• Fever—6% grade 1 and 3% grade 2
• General disorders and administration site conditions—15% grade 1
• Hyperglycemia—3% grade 3
• Hypokalemia—6% grade 1
• Hypotension—3% grade 3
• Insomnia—6% grade 1
• Oral mucositis—9% grade 1 and 3% grade 2
• Nausea—18% grade 1, 27% grade 2, and 3% grade 3
• Neutrophil count decrease—3% grade 3 and 4
• Pain—3% grade 1 and 6% grade 2
• Pain of skin—3% grade 1 and 2
• Platelet count decrease—6% grade 2, 9% grade 3, and 6% grade 4
• Urinary tract infection—3% grade 3
• Vomiting—18% grade 1 and 21% grade 2.

Efficacy

Twenty-eight patients were evaluable for efficacy. The ORR for these patients was 36% (n=10).

The complete response (CR) rate was 22% (n=6), and the partial response (PR) rate was 14% (n=4). Twenty-five percent of patients (n=7) had stable disease, and 39% (n=11) progressed.

Dr Falchi noted that the ORR was “much higher” in patients with T-cell lymphoma than in those with B-cell lymphoma—80% (n=8) and 11% (n=2), respectively.

The CR rates were 50% (n=5) in T-cell lymphoma patients and 5.5% (n=1) in B-cell patients. PR rates were 30% (n=3) and 5.5% (n=1), respectively. Thirty-nine percent (n=7) of B-cell patients had stable disease, but none of the T-cell patients did.

“Patients with non-T-cell lymphoma were much more likely to progress on treatment,” Dr Falchi noted. “Half of them did so [n=9].”

This is in comparison to the 20% of T-cell lymphoma patients who progressed on treatment (n=2).

Disease subtypes for complete responders included transformed follicular lymphoma (n=1), T-lymphoblastic lymphoma (n=1), adult T-cell leukemia/lymphoma (n=1), extranodal NK/T-cell lymphoma (n=1), and angioimmunoblastic T-cell lymphoma (n=2).

Partial responders had follicular lymphoma (n=1), cutaneous peripheral T-cell lymphoma (n=1), cutaneous anaplastic large-cell lymphoma (n=1), and angioimmunoblastic T-cell lymphoma (n=1).

The 2 responders with B-cell lymphoma (1 CR and 1 PR) ultimately progressed and died.

Of the 8 responders with T-cell lymphoma, 3 have an ongoing CR, and 2 of these patients proceeded to transplant.

One T-cell patient who achieved a CR and proceeded to transplant was lost to follow-up. Another died after transplant.

Two T-cell patients who achieved a PR progressed and died. And 1 patient has an ongoing PR.

In total, 75% of patients (n=21) progressed. The median PFS for the entire study cohort was 3.6 months (range, 1.5-5.7).

The median PFS was 2.2 months (range, 1.1-3.2) for patients with B-cell lymphomas and was not reached for the T-cell lymphoma patients.

Eighty-nine percent of B-cell patients progressed (n=16), as did 40% of T-cell patients (n=4).

Dr Falchi and his colleagues are now conducting studies to correlate the pharmacokinetics of azacitidine-romidepsin with genome-wide methylation and correlate TET2, IDH2, and DNMT3A mutation status with clinical response.

Red blood cells

The US Food and Drug Administration (FDA) has expanded the approved indication for ferumoxytol injection (Feraheme®).

The drug is now approved to treat adults with iron deficiency anemia (IDA) who cannot tolerate or have had an unsatisfactory response to oral iron.

Ferumoxytol injection was previously approved by the FDA to treat IDA in adults with chronic kidney disease.

“Iron deficiency anemia is a serious and under-treated health condition which negatively impacts quality of life for millions of people, many of whom do not benefit from or cannot tolerate oral iron therapy,” said Michael Auerbach, MD, of Georgetown University School of Medicine in Washington, DC.

“Physicians now have a new option for patients who meet the broader ferumoxytol injection indication that can be administered in 15 minutes, providing a gram of iron in 2 doses as few as 3 days apart.”

The expanded approval for ferumoxytol injection was supported by a trio of phase 3 trials. All 3 trials included IDA patients who could not tolerate or had an unsatisfactory response to oral iron.

In the first trial (NCT01114139), researchers compared ferumoxytol injection to placebo.

The second trial (NCT01114204) was a comparison of ferumoxytol injection and iron sucrose.

In the third trial (NCT02694978), researchers compared ferumoxytol injection to ferric carboxymaltose injection (Injectafer®).

Details on these trials are included in the prescribing information for ferumoxytol injection, which is available at www.feraheme.com.

The prescribing information includes a boxed warning detailing the risk of fatal and serious hypersensitivity reactions, including anaphylaxis, in patients receiving ferumoxytol injection.

Ferumoxytol injection is a product of AMAG Pharmaceuticals, Inc.

The company has a patient access support program called AMAG Assist™. Uninsured or underinsured patients who need help paying for their ferumoxytol injection prescription can call 844-635-2624 to see if they qualify for help.

Red blood cells

The US Food and Drug Administration (FDA) has expanded the approved indication for ferumoxytol injection (Feraheme®).

The drug is now approved to treat adults with iron deficiency anemia (IDA) who cannot tolerate or have had an unsatisfactory response to oral iron.

Ferumoxytol injection was previously approved by the FDA to treat IDA in adults with chronic kidney disease.

“Iron deficiency anemia is a serious and under-treated health condition which negatively impacts quality of life for millions of people, many of whom do not benefit from or cannot tolerate oral iron therapy,” said Michael Auerbach, MD, of Georgetown University School of Medicine in Washington, DC.

“Physicians now have a new option for patients who meet the broader ferumoxytol injection indication that can be administered in 15 minutes, providing a gram of iron in 2 doses as few as 3 days apart.”

The expanded approval for ferumoxytol injection was supported by a trio of phase 3 trials. All 3 trials included IDA patients who could not tolerate or had an unsatisfactory response to oral iron.

In the first trial (NCT01114139), researchers compared ferumoxytol injection to placebo.

The second trial (NCT01114204) was a comparison of ferumoxytol injection and iron sucrose.

In the third trial (NCT02694978), researchers compared ferumoxytol injection to ferric carboxymaltose injection (Injectafer®).

Details on these trials are included in the prescribing information for ferumoxytol injection, which is available at www.feraheme.com.

The prescribing information includes a boxed warning detailing the risk of fatal and serious hypersensitivity reactions, including anaphylaxis, in patients receiving ferumoxytol injection.

Ferumoxytol injection is a product of AMAG Pharmaceuticals, Inc.

The company has a patient access support program called AMAG Assist™. Uninsured or underinsured patients who need help paying for their ferumoxytol injection prescription can call 844-635-2624 to see if they qualify for help.

Red blood cells

The US Food and Drug Administration (FDA) has expanded the approved indication for ferumoxytol injection (Feraheme®).

The drug is now approved to treat adults with iron deficiency anemia (IDA) who cannot tolerate or have had an unsatisfactory response to oral iron.

Ferumoxytol injection was previously approved by the FDA to treat IDA in adults with chronic kidney disease.

“Iron deficiency anemia is a serious and under-treated health condition which negatively impacts quality of life for millions of people, many of whom do not benefit from or cannot tolerate oral iron therapy,” said Michael Auerbach, MD, of Georgetown University School of Medicine in Washington, DC.

“Physicians now have a new option for patients who meet the broader ferumoxytol injection indication that can be administered in 15 minutes, providing a gram of iron in 2 doses as few as 3 days apart.”

The expanded approval for ferumoxytol injection was supported by a trio of phase 3 trials. All 3 trials included IDA patients who could not tolerate or had an unsatisfactory response to oral iron.

In the first trial (NCT01114139), researchers compared ferumoxytol injection to placebo.

The second trial (NCT01114204) was a comparison of ferumoxytol injection and iron sucrose.

In the third trial (NCT02694978), researchers compared ferumoxytol injection to ferric carboxymaltose injection (Injectafer®).

Details on these trials are included in the prescribing information for ferumoxytol injection, which is available at www.feraheme.com.

The prescribing information includes a boxed warning detailing the risk of fatal and serious hypersensitivity reactions, including anaphylaxis, in patients receiving ferumoxytol injection.

Ferumoxytol injection is a product of AMAG Pharmaceuticals, Inc.

The company has a patient access support program called AMAG Assist™. Uninsured or underinsured patients who need help paying for their ferumoxytol injection prescription can call 844-635-2624 to see if they qualify for help.

Photo by Larry Young

LA JOLLA, CA—Phase 1 results suggest duvelisib combination therapies can be active and well-tolerated in patients with relapsed/refractory T-cell lymphomas.

Researchers said duvelisib had an acceptable safety profile when given in combination with romidepsin or bortezomib to patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL).

Duvelisib plus romidepsin produced a 60% overall response rate (ORR) in these patients, and duvelisib plus bortezomib produced a 35% ORR.

Response rates were higher in PTCL patients than CTCL patients.

Neha Mehta-Shah, MD, of Washington University in St. Louis, Missouri, and her colleagues presented these results in a poster at the 10th Annual T-cell Lymphoma Forum.

The research was supported by the Leukemia & Lymphoma Society, Infinity Pharmaceuticals, and Verastem Inc.

This phase 1 trial consists of parallel arms evaluating duvelisib in combination with romidepsin (arm A) or bortezomib (arm B). The trial enrolled patients with PTCL or CTCL that had progressed after at least 1 prior therapy.

All patients received duvelisib at 25 mg, 50 mg, or 75 mg twice daily for 28-day cycles.

Patients in arm A received romidepsin at 10 mg/m² on days 1, 8, and 15 of each cycle.

Patients in arm B received bortezomib at 1 mg/m² on days 1, 4, 8, and 11 of each cycle.

Romidepsin combination

Sixteen patients received duvelisib plus romidepsin, and 15 of them were evaluable for efficacy. Eleven patients had PTCL, and 4 had CTCL.

The ORR was 60% (9/16), and the complete response (CR) rate was 27% (n=4). The median time to response was 51 days (range, 49-54).

The ORR was 64% in the PTCL patients and 50% in the CTCL patients. All 4 CRs occurred in PTCL patients, 2 in patients with PTCL not otherwise specified (NOS) and 2 in patients with angioimmunoblastic T-cell lymphoma (AITL).

There were 5 responses among patients who received the 75 mg dose of duvelisib (n=8) and 2 responses each in the 50 mg dose group (n=3) and 25 mg dose group (n=4).

There were no dose-limiting toxicities, so the 75 mg dose of duvelisib was considered the maximum tolerated dose.

All 16 patients were evaluable for safety. There were 2 serious adverse events (AEs) considered possibly related to treatment—grade 3 fatigue and grade 2 aspartate aminotransferase (AST) increase.

There were 2 deaths considered unrelated to treatment—diffuse alveolar hemorrhage after allogeneic transplant and sepsis in the setting of disease progression.

Treatment-related AEs (occurring in at least 2 patients) were fatigue (56%), nausea (50%), altered taste (50%), diarrhea (38%), neutropenia (38%), rash (31%), thrombocytopenia (25%), dysphagia (25%), and anorexia (25%).

Grade 3/4 treatment-related AEs included neutropenia (38%) and thrombocytopenia (6%).

One patient discontinued duvelisib-romidepsin due to toxicity, and 7 discontinued due to progressive disease.

Three patients proceeded to bone marrow transplant/donor lymphocyte infusion, and 4 patients are still receiving study treatment.

Bortezomib combination

There were 17 patients who received duvelisib plus bortezomib—10 with PTCL and 7 with CTCL.

The ORR was 35% (6/17), and the CR rate was 18% (n=3). The median time to response was 52 days (range, 47-57).

The ORR was 50% in PTCL patients and 14% among CTCL patients.

All 3 CRs occurred in the PTCL patients—1 in a patient with AITL, 1 in a patient with PTCL-NOS, and 1 in a patient who had intestinal T-cell lymphoma with B-cell lymphoproliferative disorder.

There were 3 responses among patients who received the 25 mg dose of duvelisib (n=8), 2 responses in the 50 mg dose group (n=3), and 1 response in the 75 mg dose group (n=6).

There was 1 dose-limiting toxicity—pneumonia—in a patient treated at the 25 mg dose.

The 25 mg dose was deemed optimal due to grade 3 alanine transaminase (ALT)/AST elevations observed after cycle 1 with the 50 mg dose (n=3) and the 75 mg dose (n=2).

There were 6 serious AEs considered possibly related to treatment:

• Grade 3 pneumonia (n=2)
• Grade 3 infectious colitis (n=1)
• Grade 3 colitis (n=1)
• Grade 4 ALT/AST elevation (n=1)
• Grade 5 Stevens-Johnson syndrome (n=1).

The fatal case of Stevens-Johnson syndrome was considered possibly related to bortezomib, duvelisib, and trimethoprim-sulfamethoxazole, a medication that was started at the beginning of the study.

Treatment-related AEs (occurring in at least 2 patients) included diarrhea/colitis (71%), ALT/AST increase (41%), rash (24%), neutropenia (24%), nausea/vomiting (24%), chills (24%), fatigue (24%), and alkaline phosphatase increase (12%).

Grade 3/4 AEs included ALT/AST increase (35%), rash (12%), neutropenia (12%), diarrhea/colitis (6%), and alkaline phosphatase increase (6%).

Seven patients discontinued duvelisib-bortezomib due to toxicity, and 8 discontinued due to disease progression. Two patients are still on study treatment.

Photo by Larry Young

LA JOLLA, CA—Phase 1 results suggest duvelisib combination therapies can be active and well-tolerated in patients with relapsed/refractory T-cell lymphomas.

Researchers said duvelisib had an acceptable safety profile when given in combination with romidepsin or bortezomib to patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL).

Duvelisib plus romidepsin produced a 60% overall response rate (ORR) in these patients, and duvelisib plus bortezomib produced a 35% ORR.

Response rates were higher in PTCL patients than CTCL patients.

Neha Mehta-Shah, MD, of Washington University in St. Louis, Missouri, and her colleagues presented these results in a poster at the 10th Annual T-cell Lymphoma Forum.

The research was supported by the Leukemia & Lymphoma Society, Infinity Pharmaceuticals, and Verastem Inc.

This phase 1 trial consists of parallel arms evaluating duvelisib in combination with romidepsin (arm A) or bortezomib (arm B). The trial enrolled patients with PTCL or CTCL that had progressed after at least 1 prior therapy.

All patients received duvelisib at 25 mg, 50 mg, or 75 mg twice daily for 28-day cycles.

Patients in arm A received romidepsin at 10 mg/m² on days 1, 8, and 15 of each cycle.

Patients in arm B received bortezomib at 1 mg/m² on days 1, 4, 8, and 11 of each cycle.

Romidepsin combination

Sixteen patients received duvelisib plus romidepsin, and 15 of them were evaluable for efficacy. Eleven patients had PTCL, and 4 had CTCL.

The ORR was 60% (9/16), and the complete response (CR) rate was 27% (n=4). The median time to response was 51 days (range, 49-54).

The ORR was 64% in the PTCL patients and 50% in the CTCL patients. All 4 CRs occurred in PTCL patients, 2 in patients with PTCL not otherwise specified (NOS) and 2 in patients with angioimmunoblastic T-cell lymphoma (AITL).

There were 5 responses among patients who received the 75 mg dose of duvelisib (n=8) and 2 responses each in the 50 mg dose group (n=3) and 25 mg dose group (n=4).

There were no dose-limiting toxicities, so the 75 mg dose of duvelisib was considered the maximum tolerated dose.

All 16 patients were evaluable for safety. There were 2 serious adverse events (AEs) considered possibly related to treatment—grade 3 fatigue and grade 2 aspartate aminotransferase (AST) increase.

There were 2 deaths considered unrelated to treatment—diffuse alveolar hemorrhage after allogeneic transplant and sepsis in the setting of disease progression.

Treatment-related AEs (occurring in at least 2 patients) were fatigue (56%), nausea (50%), altered taste (50%), diarrhea (38%), neutropenia (38%), rash (31%), thrombocytopenia (25%), dysphagia (25%), and anorexia (25%).

Grade 3/4 treatment-related AEs included neutropenia (38%) and thrombocytopenia (6%).

One patient discontinued duvelisib-romidepsin due to toxicity, and 7 discontinued due to progressive disease.

Three patients proceeded to bone marrow transplant/donor lymphocyte infusion, and 4 patients are still receiving study treatment.

Bortezomib combination

There were 17 patients who received duvelisib plus bortezomib—10 with PTCL and 7 with CTCL.

The ORR was 35% (6/17), and the CR rate was 18% (n=3). The median time to response was 52 days (range, 47-57).

The ORR was 50% in PTCL patients and 14% among CTCL patients.

All 3 CRs occurred in the PTCL patients—1 in a patient with AITL, 1 in a patient with PTCL-NOS, and 1 in a patient who had intestinal T-cell lymphoma with B-cell lymphoproliferative disorder.

There were 3 responses among patients who received the 25 mg dose of duvelisib (n=8), 2 responses in the 50 mg dose group (n=3), and 1 response in the 75 mg dose group (n=6).

There was 1 dose-limiting toxicity—pneumonia—in a patient treated at the 25 mg dose.

The 25 mg dose was deemed optimal due to grade 3 alanine transaminase (ALT)/AST elevations observed after cycle 1 with the 50 mg dose (n=3) and the 75 mg dose (n=2).

There were 6 serious AEs considered possibly related to treatment:

• Grade 3 pneumonia (n=2)
• Grade 3 infectious colitis (n=1)
• Grade 3 colitis (n=1)
• Grade 4 ALT/AST elevation (n=1)
• Grade 5 Stevens-Johnson syndrome (n=1).

The fatal case of Stevens-Johnson syndrome was considered possibly related to bortezomib, duvelisib, and trimethoprim-sulfamethoxazole, a medication that was started at the beginning of the study.

Treatment-related AEs (occurring in at least 2 patients) included diarrhea/colitis (71%), ALT/AST increase (41%), rash (24%), neutropenia (24%), nausea/vomiting (24%), chills (24%), fatigue (24%), and alkaline phosphatase increase (12%).

Grade 3/4 AEs included ALT/AST increase (35%), rash (12%), neutropenia (12%), diarrhea/colitis (6%), and alkaline phosphatase increase (6%).

Seven patients discontinued duvelisib-bortezomib due to toxicity, and 8 discontinued due to disease progression. Two patients are still on study treatment.

Photo by Larry Young

LA JOLLA, CA—Phase 1 results suggest duvelisib combination therapies can be active and well-tolerated in patients with relapsed/refractory T-cell lymphomas.

Researchers said duvelisib had an acceptable safety profile when given in combination with romidepsin or bortezomib to patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL).

Duvelisib plus romidepsin produced a 60% overall response rate (ORR) in these patients, and duvelisib plus bortezomib produced a 35% ORR.

Response rates were higher in PTCL patients than CTCL patients.

Neha Mehta-Shah, MD, of Washington University in St. Louis, Missouri, and her colleagues presented these results in a poster at the 10th Annual T-cell Lymphoma Forum.

The research was supported by the Leukemia & Lymphoma Society, Infinity Pharmaceuticals, and Verastem Inc.

This phase 1 trial consists of parallel arms evaluating duvelisib in combination with romidepsin (arm A) or bortezomib (arm B). The trial enrolled patients with PTCL or CTCL that had progressed after at least 1 prior therapy.

All patients received duvelisib at 25 mg, 50 mg, or 75 mg twice daily for 28-day cycles.

Patients in arm A received romidepsin at 10 mg/m² on days 1, 8, and 15 of each cycle.

Patients in arm B received bortezomib at 1 mg/m² on days 1, 4, 8, and 11 of each cycle.

Romidepsin combination

Sixteen patients received duvelisib plus romidepsin, and 15 of them were evaluable for efficacy. Eleven patients had PTCL, and 4 had CTCL.

The ORR was 60% (9/16), and the complete response (CR) rate was 27% (n=4). The median time to response was 51 days (range, 49-54).

The ORR was 64% in the PTCL patients and 50% in the CTCL patients. All 4 CRs occurred in PTCL patients, 2 in patients with PTCL not otherwise specified (NOS) and 2 in patients with angioimmunoblastic T-cell lymphoma (AITL).

There were 5 responses among patients who received the 75 mg dose of duvelisib (n=8) and 2 responses each in the 50 mg dose group (n=3) and 25 mg dose group (n=4).

There were no dose-limiting toxicities, so the 75 mg dose of duvelisib was considered the maximum tolerated dose.

All 16 patients were evaluable for safety. There were 2 serious adverse events (AEs) considered possibly related to treatment—grade 3 fatigue and grade 2 aspartate aminotransferase (AST) increase.

There were 2 deaths considered unrelated to treatment—diffuse alveolar hemorrhage after allogeneic transplant and sepsis in the setting of disease progression.

Treatment-related AEs (occurring in at least 2 patients) were fatigue (56%), nausea (50%), altered taste (50%), diarrhea (38%), neutropenia (38%), rash (31%), thrombocytopenia (25%), dysphagia (25%), and anorexia (25%).

Grade 3/4 treatment-related AEs included neutropenia (38%) and thrombocytopenia (6%).

One patient discontinued duvelisib-romidepsin due to toxicity, and 7 discontinued due to progressive disease.

Three patients proceeded to bone marrow transplant/donor lymphocyte infusion, and 4 patients are still receiving study treatment.

Bortezomib combination

There were 17 patients who received duvelisib plus bortezomib—10 with PTCL and 7 with CTCL.

The ORR was 35% (6/17), and the CR rate was 18% (n=3). The median time to response was 52 days (range, 47-57).

The ORR was 50% in PTCL patients and 14% among CTCL patients.

All 3 CRs occurred in the PTCL patients—1 in a patient with AITL, 1 in a patient with PTCL-NOS, and 1 in a patient who had intestinal T-cell lymphoma with B-cell lymphoproliferative disorder.

There were 3 responses among patients who received the 25 mg dose of duvelisib (n=8), 2 responses in the 50 mg dose group (n=3), and 1 response in the 75 mg dose group (n=6).

There was 1 dose-limiting toxicity—pneumonia—in a patient treated at the 25 mg dose.

The 25 mg dose was deemed optimal due to grade 3 alanine transaminase (ALT)/AST elevations observed after cycle 1 with the 50 mg dose (n=3) and the 75 mg dose (n=2).

There were 6 serious AEs considered possibly related to treatment:

• Grade 3 pneumonia (n=2)
• Grade 3 infectious colitis (n=1)
• Grade 3 colitis (n=1)
• Grade 4 ALT/AST elevation (n=1)
• Grade 5 Stevens-Johnson syndrome (n=1).

The fatal case of Stevens-Johnson syndrome was considered possibly related to bortezomib, duvelisib, and trimethoprim-sulfamethoxazole, a medication that was started at the beginning of the study.

Treatment-related AEs (occurring in at least 2 patients) included diarrhea/colitis (71%), ALT/AST increase (41%), rash (24%), neutropenia (24%), nausea/vomiting (24%), chills (24%), fatigue (24%), and alkaline phosphatase increase (12%).

Grade 3/4 AEs included ALT/AST increase (35%), rash (12%), neutropenia (12%), diarrhea/colitis (6%), and alkaline phosphatase increase (6%).

Seven patients discontinued duvelisib-bortezomib due to toxicity, and 8 discontinued due to disease progression. Two patients are still on study treatment.

Image by Tom Ellenberger

Researchers have used high-risk pedigrees (HRPs) to identify gene variants that may cause multiple myeloma (MM).

The team’s analysis revealed shared genomic segments harboring genes with potential MM risk variants.

These single nucleotide variants (SNVs) are in USP45, a gene involved in DNA repair, and ARID1A, a gene in the SWI/SNF chromatin remodeling complex.

Nicola Camp, PhD, of the University of Utah School of Medicine in Salt Lake City, and her colleagues reported these findings in PLOS Genetics.

The researchers developed a new method to analyze HRPs (large, multi-generational families with more affected members than would be expected by chance) to identify shared regions of the genome that likely harbor MM risk variants.

The team applied the method using pedigrees from 11 Utah families at risk of MM as well as whole-exome sequencing of shared genomic segments in 1063 patients with MM or monoclonal gammopathy of undetermined significance (MGUS) and 964 control subjects.

The analysis revealed 2 regions that may contribute to MM. One was a 1.8 Mb segment at 6q16 with SNVs in USP45, and the other was a 1.2 Mb segment at 1p36.11 with SNVs in ARID1A.

One of the SNVs in USP45 was a stop gain—p.Gln691*—which was shared by 3 siblings, 1 with MM and 2 with MGUS. The other was a missense SNV—p.Gln621Glu—which was shared by 2 of 4 siblings in a family, 1 with MM and 1 with MGUS.

One of the missense SNVs in ARID1A—rs752026201, p. Ser90Gly—was shared by 3 MM cases. The other missense SNV—rs140664170, p.Met890Val—was shared by 2 cousins with MM.

The researchers believe these findings show that HRPs can be effective for identifying risk variants in complex diseases.

“We are very encouraged by the new method,” Dr Camp said. “It certainly plays to the strengths of the large Utah pedigrees, revitalizing the family design for complex diseases. As we did in this study, the focused regions can be further investigated in smaller families to find genes and specific mutations. The method can be used for any complex disease.”

“We are already pursuing large pedigrees in several other domains, including other cancers, psychiatric disorders, birth defects, and pre-term birth phenotypes, with several more genome-wide significant regions found. We’re excited about the potential.”

Image by Tom Ellenberger

Researchers have used high-risk pedigrees (HRPs) to identify gene variants that may cause multiple myeloma (MM).

The team’s analysis revealed shared genomic segments harboring genes with potential MM risk variants.

These single nucleotide variants (SNVs) are in USP45, a gene involved in DNA repair, and ARID1A, a gene in the SWI/SNF chromatin remodeling complex.

Nicola Camp, PhD, of the University of Utah School of Medicine in Salt Lake City, and her colleagues reported these findings in PLOS Genetics.

The researchers developed a new method to analyze HRPs (large, multi-generational families with more affected members than would be expected by chance) to identify shared regions of the genome that likely harbor MM risk variants.

The team applied the method using pedigrees from 11 Utah families at risk of MM as well as whole-exome sequencing of shared genomic segments in 1063 patients with MM or monoclonal gammopathy of undetermined significance (MGUS) and 964 control subjects.

The analysis revealed 2 regions that may contribute to MM. One was a 1.8 Mb segment at 6q16 with SNVs in USP45, and the other was a 1.2 Mb segment at 1p36.11 with SNVs in ARID1A.

One of the SNVs in USP45 was a stop gain—p.Gln691*—which was shared by 3 siblings, 1 with MM and 2 with MGUS. The other was a missense SNV—p.Gln621Glu—which was shared by 2 of 4 siblings in a family, 1 with MM and 1 with MGUS.

One of the missense SNVs in ARID1A—rs752026201, p. Ser90Gly—was shared by 3 MM cases. The other missense SNV—rs140664170, p.Met890Val—was shared by 2 cousins with MM.

The researchers believe these findings show that HRPs can be effective for identifying risk variants in complex diseases.

“We are very encouraged by the new method,” Dr Camp said. “It certainly plays to the strengths of the large Utah pedigrees, revitalizing the family design for complex diseases. As we did in this study, the focused regions can be further investigated in smaller families to find genes and specific mutations. The method can be used for any complex disease.”

“We are already pursuing large pedigrees in several other domains, including other cancers, psychiatric disorders, birth defects, and pre-term birth phenotypes, with several more genome-wide significant regions found. We’re excited about the potential.”

Image by Tom Ellenberger

Researchers have used high-risk pedigrees (HRPs) to identify gene variants that may cause multiple myeloma (MM).

The team’s analysis revealed shared genomic segments harboring genes with potential MM risk variants.

These single nucleotide variants (SNVs) are in USP45, a gene involved in DNA repair, and ARID1A, a gene in the SWI/SNF chromatin remodeling complex.

Nicola Camp, PhD, of the University of Utah School of Medicine in Salt Lake City, and her colleagues reported these findings in PLOS Genetics.

The researchers developed a new method to analyze HRPs (large, multi-generational families with more affected members than would be expected by chance) to identify shared regions of the genome that likely harbor MM risk variants.

The team applied the method using pedigrees from 11 Utah families at risk of MM as well as whole-exome sequencing of shared genomic segments in 1063 patients with MM or monoclonal gammopathy of undetermined significance (MGUS) and 964 control subjects.

The analysis revealed 2 regions that may contribute to MM. One was a 1.8 Mb segment at 6q16 with SNVs in USP45, and the other was a 1.2 Mb segment at 1p36.11 with SNVs in ARID1A.

One of the SNVs in USP45 was a stop gain—p.Gln691*—which was shared by 3 siblings, 1 with MM and 2 with MGUS. The other was a missense SNV—p.Gln621Glu—which was shared by 2 of 4 siblings in a family, 1 with MM and 1 with MGUS.

One of the missense SNVs in ARID1A—rs752026201, p. Ser90Gly—was shared by 3 MM cases. The other missense SNV—rs140664170, p.Met890Val—was shared by 2 cousins with MM.

The researchers believe these findings show that HRPs can be effective for identifying risk variants in complex diseases.

“We are very encouraged by the new method,” Dr Camp said. “It certainly plays to the strengths of the large Utah pedigrees, revitalizing the family design for complex diseases. As we did in this study, the focused regions can be further investigated in smaller families to find genes and specific mutations. The method can be used for any complex disease.”

“We are already pursuing large pedigrees in several other domains, including other cancers, psychiatric disorders, birth defects, and pre-term birth phenotypes, with several more genome-wide significant regions found. We’re excited about the potential.”

Red and white blood cells

The US Food and Drug Administration (FDA) says it is evaluating reports of venous thromboembolism (VTE) in patients treated with the CELLEX Photopheresis System by Therakos, Inc.

This extracorporeal photopheresis (ECP) device system is FDA-approved for use in patients with cutaneous T-cell lymphoma (CTCL).

The system is used to perform ultraviolet-A irradiation of a patient’s own leukocyte-enriched blood that is then used as palliative treatment for skin manifestations of CTCL that are unresponsive to other forms of treatment.

The CELLEX Photopheresis System is also used to treat graft-vs-host disease (GVHD) that is resistant to standard immunosuppressive therapy and acute cardiac allograft rejection that is resistant to standard immunosuppressive therapy.

The CELLEX Photopheresis System uses methoxsalen as a photosensitizing agent and heparin as an anticoagulant.

Since 2012, the FDA has received 7 reports of pulmonary embolism (PE) and 2 reports of deep vein thrombosis (DVT) occurring during or soon after treatment with the CELLEX Photopheresis System.

Two of the patients who developed a PE died, although it’s not clear whether PE was the cause of death.

Four of the 7 PEs occurred in patients undergoing treatment for GVHD, including the 2 patients who died. Both DVTs occurred in patients undergoing treatment for GVHD as well.

The FDA is recommending that healthcare providers inform patients, clinical staff, and technicians that PE and DVT can occur during or after an ECP procedure.

The agency also recommends that healthcare providers consult device labeling regarding anticoagulation and use clinical judgment in adjusting a patient’s heparin dosage.

Finally, providers should report VTEs related to ECP procedures to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.

If possible, reports should include the following:

• The indication for ECP therapy
• Comorbidities that may predispose a patient to increased coagulation and history of DVT or PE
• The anticoagulation regimen used
• The number of ECP sessions the patient underwent prior to VTE onset, including the date of the first treatment session, frequency of treatment sessions, and timing of the final treatment
• Timing of the VTE in relation to the most recent treatment session
• Interventions required to manage the VTE.

Red and white blood cells

The US Food and Drug Administration (FDA) says it is evaluating reports of venous thromboembolism (VTE) in patients treated with the CELLEX Photopheresis System by Therakos, Inc.

This extracorporeal photopheresis (ECP) device system is FDA-approved for use in patients with cutaneous T-cell lymphoma (CTCL).

The system is used to perform ultraviolet-A irradiation of a patient’s own leukocyte-enriched blood that is then used as palliative treatment for skin manifestations of CTCL that are unresponsive to other forms of treatment.

The CELLEX Photopheresis System is also used to treat graft-vs-host disease (GVHD) that is resistant to standard immunosuppressive therapy and acute cardiac allograft rejection that is resistant to standard immunosuppressive therapy.

The CELLEX Photopheresis System uses methoxsalen as a photosensitizing agent and heparin as an anticoagulant.

Since 2012, the FDA has received 7 reports of pulmonary embolism (PE) and 2 reports of deep vein thrombosis (DVT) occurring during or soon after treatment with the CELLEX Photopheresis System.

Two of the patients who developed a PE died, although it’s not clear whether PE was the cause of death.

Four of the 7 PEs occurred in patients undergoing treatment for GVHD, including the 2 patients who died. Both DVTs occurred in patients undergoing treatment for GVHD as well.

The FDA is recommending that healthcare providers inform patients, clinical staff, and technicians that PE and DVT can occur during or after an ECP procedure.

The agency also recommends that healthcare providers consult device labeling regarding anticoagulation and use clinical judgment in adjusting a patient’s heparin dosage.

Finally, providers should report VTEs related to ECP procedures to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.

If possible, reports should include the following:

• The indication for ECP therapy
• Comorbidities that may predispose a patient to increased coagulation and history of DVT or PE
• The anticoagulation regimen used
• The number of ECP sessions the patient underwent prior to VTE onset, including the date of the first treatment session, frequency of treatment sessions, and timing of the final treatment
• Timing of the VTE in relation to the most recent treatment session
• Interventions required to manage the VTE.

Red and white blood cells

The US Food and Drug Administration (FDA) says it is evaluating reports of venous thromboembolism (VTE) in patients treated with the CELLEX Photopheresis System by Therakos, Inc.

This extracorporeal photopheresis (ECP) device system is FDA-approved for use in patients with cutaneous T-cell lymphoma (CTCL).

The system is used to perform ultraviolet-A irradiation of a patient’s own leukocyte-enriched blood that is then used as palliative treatment for skin manifestations of CTCL that are unresponsive to other forms of treatment.

The CELLEX Photopheresis System is also used to treat graft-vs-host disease (GVHD) that is resistant to standard immunosuppressive therapy and acute cardiac allograft rejection that is resistant to standard immunosuppressive therapy.

The CELLEX Photopheresis System uses methoxsalen as a photosensitizing agent and heparin as an anticoagulant.

Since 2012, the FDA has received 7 reports of pulmonary embolism (PE) and 2 reports of deep vein thrombosis (DVT) occurring during or soon after treatment with the CELLEX Photopheresis System.

Two of the patients who developed a PE died, although it’s not clear whether PE was the cause of death.

Four of the 7 PEs occurred in patients undergoing treatment for GVHD, including the 2 patients who died. Both DVTs occurred in patients undergoing treatment for GVHD as well.

The FDA is recommending that healthcare providers inform patients, clinical staff, and technicians that PE and DVT can occur during or after an ECP procedure.

The agency also recommends that healthcare providers consult device labeling regarding anticoagulation and use clinical judgment in adjusting a patient’s heparin dosage.

Finally, providers should report VTEs related to ECP procedures to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.

If possible, reports should include the following:

• The indication for ECP therapy
• Comorbidities that may predispose a patient to increased coagulation and history of DVT or PE
• The anticoagulation regimen used
• The number of ECP sessions the patient underwent prior to VTE onset, including the date of the first treatment session, frequency of treatment sessions, and timing of the final treatment
• Timing of the VTE in relation to the most recent treatment session
• Interventions required to manage the VTE.