Jennifer Smith

ORLANDO – Adding navitoclax to ruxolitinib improved responses in a phase 2 trial of patients with uncontrolled myelofibrosis (MF) and prolonged exposure to ruxolitinib.

Navitoclax and ruxolitinib yielded “clinically meaningful” spleen responses, improved total symptom scores, and produced “encouraging” reductions in bone marrow fibrosis among patients with primary or secondary MF, according to Jacqueline S. Garcia, MD, of Dana-Farber Cancer Institute in Boston.

Dr. Garcia presented these results at the annual meeting of the American Society of Hematology.

Navitoclax binds with high affinity to BCL-XL, BCL-2, and BCL-W, Dr. Garcia noted. Preclinical research has shown that combining Janus kinase 2 (JAK2) inhibition with BCL-XL/BCL-2 inhibition has a synergistic cytotoxic effect on JAK2-mutated cells (Blood. 2009 Feb 12;113[7]:1522-5), and BCL-XL inhibition can overcome resistance to JAK2 inhibition (Cell Rep. 2013 Nov 27;5[4]:1047-59).

These findings led to the theory that combining navitoclax and ruxolitinib could overcome resistance to JAK2 inhibition in MF. The researchers tested this theory in a phase 2 trial (NCT03222609) of 34 MF patients.

The patients had primary MF (n = 16), post–polycythemia vera MF (n = 13), and post–essential thrombocythemia MF (n = 5). At baseline, their median age was 68 years (range 42-86 years), and 68% of them were men.

There were 33 patients with genetic testing results available. None of them were triple negative, 27 had JAK2 mutations, and 7 had CALR mutations. Roughly half of patients (n = 17) were classified as high molecular risk, with mutations in ASXL1, EZH2, IDH1/2, SRSF2, or U2AF1.
 

Treatment

All patients had received ruxolitinib for at least 12 weeks prior to their first dose of navitoclax. They had been receiving a stable dose of 10 mg or greater, twice daily, for at least 8 weeks. The median duration of prior ruxolitinib exposure was 21 months (range, 4-71 months).

On study, patients received navitoclax once daily plus the current stable dose of ruxolitinib (10 mg or greater twice daily). Navitoclax dosing started at 50 mg, but weekly dose escalation was allowed to a maximum daily dose of 300 mg. Treatment could continue until the loss of clinical benefit, unacceptable toxicity, or discontinuation.

There were 23 patients who received the maximum dose of navitoclax, and the median duration of navitoclax treatment was 330 days (range, 29-588 days). Of the 25 patients who started the study on a ruxolitinib dose higher than 10 mg twice daily, 22 had their dose reduced to 10 mg twice daily.

Nine patients discontinued study treatment – three due to adverse events, two due to progressive disease, and four for other reasons.
 

Efficacy

Navitoclax appears to overcome ruxolitinib resistance, Dr. Garcia said, citing improvements in spleen size, symptom scores, bone marrow fibrosis, white blood cell counts, and transfusion needs.

Thirty patients were evaluable for spleen response. At week 24, 30% had a spleen volume reduction of 35% or greater from baseline. At any time on study, 43% of patients had a spleen volume reduction of 35% or greater from baseline. More than half of patients (53%) had a resolution of palpable splenomegaly.

Eight of 32 patients (25%) had a reduction in bone marrow fibrosis, four with a one-grade reduction and four with a two-grade reduction.

Seventeen patients were evaluable for change in total symptom score. Eleven patients (65%) experienced a reduction in symptoms, and six (35%) had a 50% or greater reduction in symptoms. The median total symptom score was 12 (range, 0-30) at baseline and 7 (range, 0-23) at 24 weeks.

Patients had a significant reduction in white blood cells on study. The mean white blood cell reduction at week 24 was 25.8 x 10⁹/L.

Patients’ hemoglobin levels remained stable over time, but a few patients had a decreased need for transfusions on study. Seven patients entered the study having received at least one unit of packed red blood cells in the prior 12 weeks. Four of them (57%) have had a transfusion-free period of at least 12 weeks on study.
 

Safety

“Navitoclax in combination with ruxolitinib appears to be well tolerated,” Dr. Garcia said.

She noted that treatment resulted in reduced platelet counts, but counts stabilized after 6-8 weeks. The mean platelet count was 232 x 10⁹/L at baseline and 95 x 10⁹/L at week 8.

In fact, the most common adverse event was thrombocytopenia, with any-grade thrombocytopenia occurring in 85% of patients and grade 3/4 occurring in 44%. One patient had grade 4 thrombocytopenia, but it was reversed by withholding treatment and subsequent dose modification.

Other common treatment-emergent adverse events were diarrhea (68%), fatigue (53%), nausea (35%), anemia (29%), dizziness (27%), confusion (27%), and vomiting (24%).

All 34 patients experienced at least one adverse event. Eight patients (24%) had serious adverse events, including anemia, pancytopenia, splenic infarction, upper abdominal pain, vomiting, chest pain, pneumonia, and abnormal liver function test.

One patient had a grade 5 adverse event – pneumonia – that was deemed unrelated to navitoclax.

This trial is sponsored by AbbVie. Dr. Garcia reported relationships with AbbVie, Genentech, and Pfizer.

[email protected]

SOURCE: Garcia JS et al. ASH 2019, Abstract 671.

ORLANDO – Adding navitoclax to ruxolitinib improved responses in a phase 2 trial of patients with uncontrolled myelofibrosis (MF) and prolonged exposure to ruxolitinib.

Navitoclax and ruxolitinib yielded “clinically meaningful” spleen responses, improved total symptom scores, and produced “encouraging” reductions in bone marrow fibrosis among patients with primary or secondary MF, according to Jacqueline S. Garcia, MD, of Dana-Farber Cancer Institute in Boston.

Dr. Garcia presented these results at the annual meeting of the American Society of Hematology.

Navitoclax binds with high affinity to BCL-XL, BCL-2, and BCL-W, Dr. Garcia noted. Preclinical research has shown that combining Janus kinase 2 (JAK2) inhibition with BCL-XL/BCL-2 inhibition has a synergistic cytotoxic effect on JAK2-mutated cells (Blood. 2009 Feb 12;113[7]:1522-5), and BCL-XL inhibition can overcome resistance to JAK2 inhibition (Cell Rep. 2013 Nov 27;5[4]:1047-59).

These findings led to the theory that combining navitoclax and ruxolitinib could overcome resistance to JAK2 inhibition in MF. The researchers tested this theory in a phase 2 trial (NCT03222609) of 34 MF patients.

The patients had primary MF (n = 16), post–polycythemia vera MF (n = 13), and post–essential thrombocythemia MF (n = 5). At baseline, their median age was 68 years (range 42-86 years), and 68% of them were men.

There were 33 patients with genetic testing results available. None of them were triple negative, 27 had JAK2 mutations, and 7 had CALR mutations. Roughly half of patients (n = 17) were classified as high molecular risk, with mutations in ASXL1, EZH2, IDH1/2, SRSF2, or U2AF1.
 

Treatment

All patients had received ruxolitinib for at least 12 weeks prior to their first dose of navitoclax. They had been receiving a stable dose of 10 mg or greater, twice daily, for at least 8 weeks. The median duration of prior ruxolitinib exposure was 21 months (range, 4-71 months).

On study, patients received navitoclax once daily plus the current stable dose of ruxolitinib (10 mg or greater twice daily). Navitoclax dosing started at 50 mg, but weekly dose escalation was allowed to a maximum daily dose of 300 mg. Treatment could continue until the loss of clinical benefit, unacceptable toxicity, or discontinuation.

There were 23 patients who received the maximum dose of navitoclax, and the median duration of navitoclax treatment was 330 days (range, 29-588 days). Of the 25 patients who started the study on a ruxolitinib dose higher than 10 mg twice daily, 22 had their dose reduced to 10 mg twice daily.

Nine patients discontinued study treatment – three due to adverse events, two due to progressive disease, and four for other reasons.
 

Efficacy

Navitoclax appears to overcome ruxolitinib resistance, Dr. Garcia said, citing improvements in spleen size, symptom scores, bone marrow fibrosis, white blood cell counts, and transfusion needs.

Thirty patients were evaluable for spleen response. At week 24, 30% had a spleen volume reduction of 35% or greater from baseline. At any time on study, 43% of patients had a spleen volume reduction of 35% or greater from baseline. More than half of patients (53%) had a resolution of palpable splenomegaly.

Eight of 32 patients (25%) had a reduction in bone marrow fibrosis, four with a one-grade reduction and four with a two-grade reduction.

Seventeen patients were evaluable for change in total symptom score. Eleven patients (65%) experienced a reduction in symptoms, and six (35%) had a 50% or greater reduction in symptoms. The median total symptom score was 12 (range, 0-30) at baseline and 7 (range, 0-23) at 24 weeks.

Patients had a significant reduction in white blood cells on study. The mean white blood cell reduction at week 24 was 25.8 x 10⁹/L.

Patients’ hemoglobin levels remained stable over time, but a few patients had a decreased need for transfusions on study. Seven patients entered the study having received at least one unit of packed red blood cells in the prior 12 weeks. Four of them (57%) have had a transfusion-free period of at least 12 weeks on study.
 

Safety

“Navitoclax in combination with ruxolitinib appears to be well tolerated,” Dr. Garcia said.

She noted that treatment resulted in reduced platelet counts, but counts stabilized after 6-8 weeks. The mean platelet count was 232 x 10⁹/L at baseline and 95 x 10⁹/L at week 8.

In fact, the most common adverse event was thrombocytopenia, with any-grade thrombocytopenia occurring in 85% of patients and grade 3/4 occurring in 44%. One patient had grade 4 thrombocytopenia, but it was reversed by withholding treatment and subsequent dose modification.

Other common treatment-emergent adverse events were diarrhea (68%), fatigue (53%), nausea (35%), anemia (29%), dizziness (27%), confusion (27%), and vomiting (24%).

All 34 patients experienced at least one adverse event. Eight patients (24%) had serious adverse events, including anemia, pancytopenia, splenic infarction, upper abdominal pain, vomiting, chest pain, pneumonia, and abnormal liver function test.

One patient had a grade 5 adverse event – pneumonia – that was deemed unrelated to navitoclax.

This trial is sponsored by AbbVie. Dr. Garcia reported relationships with AbbVie, Genentech, and Pfizer.

[email protected]

SOURCE: Garcia JS et al. ASH 2019, Abstract 671.

ORLANDO – Adding navitoclax to ruxolitinib improved responses in a phase 2 trial of patients with uncontrolled myelofibrosis (MF) and prolonged exposure to ruxolitinib.

Navitoclax and ruxolitinib yielded “clinically meaningful” spleen responses, improved total symptom scores, and produced “encouraging” reductions in bone marrow fibrosis among patients with primary or secondary MF, according to Jacqueline S. Garcia, MD, of Dana-Farber Cancer Institute in Boston.

Dr. Garcia presented these results at the annual meeting of the American Society of Hematology.

Navitoclax binds with high affinity to BCL-XL, BCL-2, and BCL-W, Dr. Garcia noted. Preclinical research has shown that combining Janus kinase 2 (JAK2) inhibition with BCL-XL/BCL-2 inhibition has a synergistic cytotoxic effect on JAK2-mutated cells (Blood. 2009 Feb 12;113[7]:1522-5), and BCL-XL inhibition can overcome resistance to JAK2 inhibition (Cell Rep. 2013 Nov 27;5[4]:1047-59).

These findings led to the theory that combining navitoclax and ruxolitinib could overcome resistance to JAK2 inhibition in MF. The researchers tested this theory in a phase 2 trial (NCT03222609) of 34 MF patients.

The patients had primary MF (n = 16), post–polycythemia vera MF (n = 13), and post–essential thrombocythemia MF (n = 5). At baseline, their median age was 68 years (range 42-86 years), and 68% of them were men.

There were 33 patients with genetic testing results available. None of them were triple negative, 27 had JAK2 mutations, and 7 had CALR mutations. Roughly half of patients (n = 17) were classified as high molecular risk, with mutations in ASXL1, EZH2, IDH1/2, SRSF2, or U2AF1.
 

Treatment

All patients had received ruxolitinib for at least 12 weeks prior to their first dose of navitoclax. They had been receiving a stable dose of 10 mg or greater, twice daily, for at least 8 weeks. The median duration of prior ruxolitinib exposure was 21 months (range, 4-71 months).

On study, patients received navitoclax once daily plus the current stable dose of ruxolitinib (10 mg or greater twice daily). Navitoclax dosing started at 50 mg, but weekly dose escalation was allowed to a maximum daily dose of 300 mg. Treatment could continue until the loss of clinical benefit, unacceptable toxicity, or discontinuation.

There were 23 patients who received the maximum dose of navitoclax, and the median duration of navitoclax treatment was 330 days (range, 29-588 days). Of the 25 patients who started the study on a ruxolitinib dose higher than 10 mg twice daily, 22 had their dose reduced to 10 mg twice daily.

Nine patients discontinued study treatment – three due to adverse events, two due to progressive disease, and four for other reasons.
 

Efficacy

Navitoclax appears to overcome ruxolitinib resistance, Dr. Garcia said, citing improvements in spleen size, symptom scores, bone marrow fibrosis, white blood cell counts, and transfusion needs.

Thirty patients were evaluable for spleen response. At week 24, 30% had a spleen volume reduction of 35% or greater from baseline. At any time on study, 43% of patients had a spleen volume reduction of 35% or greater from baseline. More than half of patients (53%) had a resolution of palpable splenomegaly.

Eight of 32 patients (25%) had a reduction in bone marrow fibrosis, four with a one-grade reduction and four with a two-grade reduction.

Seventeen patients were evaluable for change in total symptom score. Eleven patients (65%) experienced a reduction in symptoms, and six (35%) had a 50% or greater reduction in symptoms. The median total symptom score was 12 (range, 0-30) at baseline and 7 (range, 0-23) at 24 weeks.

Patients had a significant reduction in white blood cells on study. The mean white blood cell reduction at week 24 was 25.8 x 10⁹/L.

Patients’ hemoglobin levels remained stable over time, but a few patients had a decreased need for transfusions on study. Seven patients entered the study having received at least one unit of packed red blood cells in the prior 12 weeks. Four of them (57%) have had a transfusion-free period of at least 12 weeks on study.
 

Safety

“Navitoclax in combination with ruxolitinib appears to be well tolerated,” Dr. Garcia said.

She noted that treatment resulted in reduced platelet counts, but counts stabilized after 6-8 weeks. The mean platelet count was 232 x 10⁹/L at baseline and 95 x 10⁹/L at week 8.

In fact, the most common adverse event was thrombocytopenia, with any-grade thrombocytopenia occurring in 85% of patients and grade 3/4 occurring in 44%. One patient had grade 4 thrombocytopenia, but it was reversed by withholding treatment and subsequent dose modification.

Other common treatment-emergent adverse events were diarrhea (68%), fatigue (53%), nausea (35%), anemia (29%), dizziness (27%), confusion (27%), and vomiting (24%).

All 34 patients experienced at least one adverse event. Eight patients (24%) had serious adverse events, including anemia, pancytopenia, splenic infarction, upper abdominal pain, vomiting, chest pain, pneumonia, and abnormal liver function test.

One patient had a grade 5 adverse event – pneumonia – that was deemed unrelated to navitoclax.

This trial is sponsored by AbbVie. Dr. Garcia reported relationships with AbbVie, Genentech, and Pfizer.

[email protected]

SOURCE: Garcia JS et al. ASH 2019, Abstract 671.

ORLANDO – Anti-CD5 chimeric antigen receptor (CAR) T cells can produce complete responses (CRs) in patients with relapsed or refractory T-cell malignancies, according to findings from a phase 1 trial.

Jennifer Smith/MDedge News

Three of 11 patients achieved a CR after CAR T-cell therapy, and one patient achieved a mixed response that deepened to a CR after transplant. Three responders, all of whom had T-cell lymphoma, were still alive and in CR at last follow-up.

There were no cases of severe cytokine release syndrome (CRS) or severe neurotoxicity, no serious infectious complications, and no nonhematologic grade 4 adverse events in this trial.

LaQuisa C. Hill, MD, of Baylor College of Medicine, Houston, presented these results at the annual meeting of the American Society of Hematology.

“While CD19 CAR T cells have revolutionized the treatment of relapsed/refractory B-cell malignancies, development of CAR T-cell platforms targeting T-cell-driven malignancies have been hindered by three main factors: CAR T-cell fratricide due to shared expression of target antigens leading to impaired expansion, ablation of normal T cells continuing to cause profound immunodeficiency, and the potential of transduced tumor cells providing a means of tumor escape,” Dr. Hill said.

Researchers have theorized that anti-CD5 CAR T cells can overcome these obstacles. In preclinical studies, anti-CD5 CAR T cells eliminated malignant blasts in vitro and in vivo and resulted in “limited and transient” fratricide (Blood. 2015 Aug 20;126[8]:983-92).

With this in mind, Dr. Hill and her colleagues tested CD5.28z CAR T cells in a phase 1 trial (NCT03081910). Eleven patients have been treated thus far – five with T-cell acute lymphoblastic leukemia (T-ALL), three with peripheral T-cell lymphoma (PTCL), two with angioimmunoblastic T-cell lymphoma (AITL), and one with Sézary syndrome.

The patients’ median age at baseline was 62 years (range, 21-71 years), and 63% were men. They had received a median of 5 prior therapies (range, 3-18). Two patients had relapsed after allogeneic hematopoietic stem cell transplant (HSCT), three had relapsed after autologous HSCT, and five were primary refractory.

Patients underwent lymphodepletion with fludarabine and cyclophosphamide, then received CAR T cells at doses of 1 x 10⁷ or 5 x 10⁷.
 

Response

Three lymphoma patients – two with AITL and one with PTCL – were still alive and in CR at last follow-up. The PTCL patient achieved a CR after CAR T-cell therapy and declined a subsequent HSCT. The patient has not received additional therapy and has retained the CR for 7 months.

One AITL patient achieved a CR and declined transplant as well. He relapsed after 7 months but received subsequent therapy and achieved another CR. The other AITL patient had a mixed response to CAR T-cell therapy but proceeded to allogeneic HSCT and achieved a CR that has lasted 9 months.

The remaining three lymphoma patients – two with PTCL and one with Sézary syndrome – progressed and died.

One T-ALL patient achieved a CR lasting 6 weeks, but the patient died while undergoing transplant workup. Two T-ALL patients did not respond to treatment and died. The remaining two patients progressed, and one of them died. The other patient who progressed is still alive and in CR after receiving subsequent therapy.

Factors associated with response

Dr. Hill said a shortened manufacturing process may be associated with enhanced response, as all responders received CAR T cells produced via a shorter manufacturing process. The shortened process involves freezing cells on day 4-5 post transduction, as opposed to day 7.

“While the numbers are too small to make any definitive conclusions, this seems to correlate with less terminal differentiation, which might improve potency,” Dr. Hill said. “However, additional analyses are ongoing.”

Dr. Hill also pointed out that CAR T-cell expansion was observed in all patients, with higher peak levels observed at the higher dose. In addition, CAR T-cell persistence was durable at both dose levels.

“We have been able to detect the CAR transgene at all follow-up time points, out to 9 months for some patients,” Dr. Hill said. “While limited persistence may play a role in nonresponders, it does not appear to be the only factor.”

Safety

“Surprisingly, no selective ablation of normal T cells has been observed,” Dr. Hill said. “As CAR T cells dwindled [after infusion], we were able to see recovery of normal T cells, all of which expressed normal levels of CD5. This was observed in all patients on study, except for one patient who had prolonged pancytopenia.”

Cytopenias were the most common grade 3/4 adverse events, including neutropenia (n = 8), anemia (n = 7), and thrombocytopenia (n = 5). Other grade 3/4 events included elevated aspartate aminotransferase (n = 2), hypoalbuminemia (n = 1), hyponatremia (n = 1), hypophosphatemia (n = 1), and elevated alanine aminotransferase (n = 1). There were no grade 5 adverse events.

Two patients developed grade 1 CRS, and two had grade 2 CRS. Both patients with grade 2 CRS were treated with tocilizumab, and their symptoms resolved.

One patient developed grade 2 immune effector cell-associated neurotoxicity syndrome, but this resolved with supportive care.

One patient had a central line–associated bloodstream infection (coagulase-negative staphylococci), and one had cytomegalovirus and BK virus reactivation. There were no fungal infections.

“We have demonstrated that CD5 CAR T cells can be manufactured from heavily pretreated patients with T-cell malignancies, and therapy is well tolerated,” Dr. Hill said. “We have seen strong and promising activity in T-cell lymphoma, which we hope to be able to translate to T-ALL as well.”

Dr. Hill said she and her colleagues hope to improve upon these results with a higher dose level of CD5 CAR T cells (1 x 10⁸), which the team plans to start testing soon. The researchers may also investigate other target antigens, such as CD7, as well as the use of donor-derived CAR T cells for patients who have relapsed after allogeneic HSCT.

Dr. Hill said she has no relevant disclosures. Baylor College of Medicine is sponsoring this trial.

[email protected]

SOURCE: Hill L et al. ASH 2019. Abstract 199.

ORLANDO – Anti-CD5 chimeric antigen receptor (CAR) T cells can produce complete responses (CRs) in patients with relapsed or refractory T-cell malignancies, according to findings from a phase 1 trial.

Jennifer Smith/MDedge News

Three of 11 patients achieved a CR after CAR T-cell therapy, and one patient achieved a mixed response that deepened to a CR after transplant. Three responders, all of whom had T-cell lymphoma, were still alive and in CR at last follow-up.

There were no cases of severe cytokine release syndrome (CRS) or severe neurotoxicity, no serious infectious complications, and no nonhematologic grade 4 adverse events in this trial.

LaQuisa C. Hill, MD, of Baylor College of Medicine, Houston, presented these results at the annual meeting of the American Society of Hematology.

“While CD19 CAR T cells have revolutionized the treatment of relapsed/refractory B-cell malignancies, development of CAR T-cell platforms targeting T-cell-driven malignancies have been hindered by three main factors: CAR T-cell fratricide due to shared expression of target antigens leading to impaired expansion, ablation of normal T cells continuing to cause profound immunodeficiency, and the potential of transduced tumor cells providing a means of tumor escape,” Dr. Hill said.

Researchers have theorized that anti-CD5 CAR T cells can overcome these obstacles. In preclinical studies, anti-CD5 CAR T cells eliminated malignant blasts in vitro and in vivo and resulted in “limited and transient” fratricide (Blood. 2015 Aug 20;126[8]:983-92).

With this in mind, Dr. Hill and her colleagues tested CD5.28z CAR T cells in a phase 1 trial (NCT03081910). Eleven patients have been treated thus far – five with T-cell acute lymphoblastic leukemia (T-ALL), three with peripheral T-cell lymphoma (PTCL), two with angioimmunoblastic T-cell lymphoma (AITL), and one with Sézary syndrome.

The patients’ median age at baseline was 62 years (range, 21-71 years), and 63% were men. They had received a median of 5 prior therapies (range, 3-18). Two patients had relapsed after allogeneic hematopoietic stem cell transplant (HSCT), three had relapsed after autologous HSCT, and five were primary refractory.

Patients underwent lymphodepletion with fludarabine and cyclophosphamide, then received CAR T cells at doses of 1 x 10⁷ or 5 x 10⁷.
 

Response

Three lymphoma patients – two with AITL and one with PTCL – were still alive and in CR at last follow-up. The PTCL patient achieved a CR after CAR T-cell therapy and declined a subsequent HSCT. The patient has not received additional therapy and has retained the CR for 7 months.

One AITL patient achieved a CR and declined transplant as well. He relapsed after 7 months but received subsequent therapy and achieved another CR. The other AITL patient had a mixed response to CAR T-cell therapy but proceeded to allogeneic HSCT and achieved a CR that has lasted 9 months.

The remaining three lymphoma patients – two with PTCL and one with Sézary syndrome – progressed and died.

One T-ALL patient achieved a CR lasting 6 weeks, but the patient died while undergoing transplant workup. Two T-ALL patients did not respond to treatment and died. The remaining two patients progressed, and one of them died. The other patient who progressed is still alive and in CR after receiving subsequent therapy.

Factors associated with response

Dr. Hill said a shortened manufacturing process may be associated with enhanced response, as all responders received CAR T cells produced via a shorter manufacturing process. The shortened process involves freezing cells on day 4-5 post transduction, as opposed to day 7.

“While the numbers are too small to make any definitive conclusions, this seems to correlate with less terminal differentiation, which might improve potency,” Dr. Hill said. “However, additional analyses are ongoing.”

Dr. Hill also pointed out that CAR T-cell expansion was observed in all patients, with higher peak levels observed at the higher dose. In addition, CAR T-cell persistence was durable at both dose levels.

“We have been able to detect the CAR transgene at all follow-up time points, out to 9 months for some patients,” Dr. Hill said. “While limited persistence may play a role in nonresponders, it does not appear to be the only factor.”

Safety

“Surprisingly, no selective ablation of normal T cells has been observed,” Dr. Hill said. “As CAR T cells dwindled [after infusion], we were able to see recovery of normal T cells, all of which expressed normal levels of CD5. This was observed in all patients on study, except for one patient who had prolonged pancytopenia.”

Cytopenias were the most common grade 3/4 adverse events, including neutropenia (n = 8), anemia (n = 7), and thrombocytopenia (n = 5). Other grade 3/4 events included elevated aspartate aminotransferase (n = 2), hypoalbuminemia (n = 1), hyponatremia (n = 1), hypophosphatemia (n = 1), and elevated alanine aminotransferase (n = 1). There were no grade 5 adverse events.

Two patients developed grade 1 CRS, and two had grade 2 CRS. Both patients with grade 2 CRS were treated with tocilizumab, and their symptoms resolved.

One patient developed grade 2 immune effector cell-associated neurotoxicity syndrome, but this resolved with supportive care.

One patient had a central line–associated bloodstream infection (coagulase-negative staphylococci), and one had cytomegalovirus and BK virus reactivation. There were no fungal infections.

“We have demonstrated that CD5 CAR T cells can be manufactured from heavily pretreated patients with T-cell malignancies, and therapy is well tolerated,” Dr. Hill said. “We have seen strong and promising activity in T-cell lymphoma, which we hope to be able to translate to T-ALL as well.”

Dr. Hill said she and her colleagues hope to improve upon these results with a higher dose level of CD5 CAR T cells (1 x 10⁸), which the team plans to start testing soon. The researchers may also investigate other target antigens, such as CD7, as well as the use of donor-derived CAR T cells for patients who have relapsed after allogeneic HSCT.

Dr. Hill said she has no relevant disclosures. Baylor College of Medicine is sponsoring this trial.

[email protected]

SOURCE: Hill L et al. ASH 2019. Abstract 199.

ORLANDO – Anti-CD5 chimeric antigen receptor (CAR) T cells can produce complete responses (CRs) in patients with relapsed or refractory T-cell malignancies, according to findings from a phase 1 trial.

Jennifer Smith/MDedge News

Three of 11 patients achieved a CR after CAR T-cell therapy, and one patient achieved a mixed response that deepened to a CR after transplant. Three responders, all of whom had T-cell lymphoma, were still alive and in CR at last follow-up.

There were no cases of severe cytokine release syndrome (CRS) or severe neurotoxicity, no serious infectious complications, and no nonhematologic grade 4 adverse events in this trial.

LaQuisa C. Hill, MD, of Baylor College of Medicine, Houston, presented these results at the annual meeting of the American Society of Hematology.

“While CD19 CAR T cells have revolutionized the treatment of relapsed/refractory B-cell malignancies, development of CAR T-cell platforms targeting T-cell-driven malignancies have been hindered by three main factors: CAR T-cell fratricide due to shared expression of target antigens leading to impaired expansion, ablation of normal T cells continuing to cause profound immunodeficiency, and the potential of transduced tumor cells providing a means of tumor escape,” Dr. Hill said.

Researchers have theorized that anti-CD5 CAR T cells can overcome these obstacles. In preclinical studies, anti-CD5 CAR T cells eliminated malignant blasts in vitro and in vivo and resulted in “limited and transient” fratricide (Blood. 2015 Aug 20;126[8]:983-92).

With this in mind, Dr. Hill and her colleagues tested CD5.28z CAR T cells in a phase 1 trial (NCT03081910). Eleven patients have been treated thus far – five with T-cell acute lymphoblastic leukemia (T-ALL), three with peripheral T-cell lymphoma (PTCL), two with angioimmunoblastic T-cell lymphoma (AITL), and one with Sézary syndrome.

The patients’ median age at baseline was 62 years (range, 21-71 years), and 63% were men. They had received a median of 5 prior therapies (range, 3-18). Two patients had relapsed after allogeneic hematopoietic stem cell transplant (HSCT), three had relapsed after autologous HSCT, and five were primary refractory.

Patients underwent lymphodepletion with fludarabine and cyclophosphamide, then received CAR T cells at doses of 1 x 10⁷ or 5 x 10⁷.
 

Response

Three lymphoma patients – two with AITL and one with PTCL – were still alive and in CR at last follow-up. The PTCL patient achieved a CR after CAR T-cell therapy and declined a subsequent HSCT. The patient has not received additional therapy and has retained the CR for 7 months.

One AITL patient achieved a CR and declined transplant as well. He relapsed after 7 months but received subsequent therapy and achieved another CR. The other AITL patient had a mixed response to CAR T-cell therapy but proceeded to allogeneic HSCT and achieved a CR that has lasted 9 months.

The remaining three lymphoma patients – two with PTCL and one with Sézary syndrome – progressed and died.

One T-ALL patient achieved a CR lasting 6 weeks, but the patient died while undergoing transplant workup. Two T-ALL patients did not respond to treatment and died. The remaining two patients progressed, and one of them died. The other patient who progressed is still alive and in CR after receiving subsequent therapy.

Factors associated with response

Dr. Hill said a shortened manufacturing process may be associated with enhanced response, as all responders received CAR T cells produced via a shorter manufacturing process. The shortened process involves freezing cells on day 4-5 post transduction, as opposed to day 7.

“While the numbers are too small to make any definitive conclusions, this seems to correlate with less terminal differentiation, which might improve potency,” Dr. Hill said. “However, additional analyses are ongoing.”

Dr. Hill also pointed out that CAR T-cell expansion was observed in all patients, with higher peak levels observed at the higher dose. In addition, CAR T-cell persistence was durable at both dose levels.

“We have been able to detect the CAR transgene at all follow-up time points, out to 9 months for some patients,” Dr. Hill said. “While limited persistence may play a role in nonresponders, it does not appear to be the only factor.”

Safety

“Surprisingly, no selective ablation of normal T cells has been observed,” Dr. Hill said. “As CAR T cells dwindled [after infusion], we were able to see recovery of normal T cells, all of which expressed normal levels of CD5. This was observed in all patients on study, except for one patient who had prolonged pancytopenia.”

Cytopenias were the most common grade 3/4 adverse events, including neutropenia (n = 8), anemia (n = 7), and thrombocytopenia (n = 5). Other grade 3/4 events included elevated aspartate aminotransferase (n = 2), hypoalbuminemia (n = 1), hyponatremia (n = 1), hypophosphatemia (n = 1), and elevated alanine aminotransferase (n = 1). There were no grade 5 adverse events.

Two patients developed grade 1 CRS, and two had grade 2 CRS. Both patients with grade 2 CRS were treated with tocilizumab, and their symptoms resolved.

One patient developed grade 2 immune effector cell-associated neurotoxicity syndrome, but this resolved with supportive care.

One patient had a central line–associated bloodstream infection (coagulase-negative staphylococci), and one had cytomegalovirus and BK virus reactivation. There were no fungal infections.

“We have demonstrated that CD5 CAR T cells can be manufactured from heavily pretreated patients with T-cell malignancies, and therapy is well tolerated,” Dr. Hill said. “We have seen strong and promising activity in T-cell lymphoma, which we hope to be able to translate to T-ALL as well.”

Dr. Hill said she and her colleagues hope to improve upon these results with a higher dose level of CD5 CAR T cells (1 x 10⁸), which the team plans to start testing soon. The researchers may also investigate other target antigens, such as CD7, as well as the use of donor-derived CAR T cells for patients who have relapsed after allogeneic HSCT.

Dr. Hill said she has no relevant disclosures. Baylor College of Medicine is sponsoring this trial.

[email protected]

SOURCE: Hill L et al. ASH 2019. Abstract 199.

Edmondo Robinson, MD, is the new senior vice president and chief digital innovation officer at Moffitt Cancer Center in Tampa, Fla. In this newly created position, Dr. Robinson will “oversee Moffitt’s portfolio of digital innovation, including the development and commercialization of health products, tools, and technology.”

Dr. Robinson is also associate professor of medicine at Thomas Jefferson University’s Sidney Kimmel Medical College in Philadelphia. He was previously the chief transformation officer and senior vice-president of consumerism at ChristianaCare, a health system based in Wilmington, Del. Dr. Robinson’s research is focused on health services, particularly care transitions and how technology impacts care delivery.

In other news, Elizabeth Fox, MD, has been named senior vice president of clinical trials research at St. Jude Children’s Research Hospital in Memphis, Tenn. She will also serve as the associate director for clinical research in the St. Jude Comprehensive Cancer Center. Dr. Fox will take on these roles in January 2020.

Dr. Fox was previously director of developmental therapeutics in oncology and professor of pediatrics at Children’s Hospital of Philadelphia. According to St. Jude, Dr. Fox is an expert in integrating clinical and preclinical pharmacology in clinical trial design.

The International Society of Gastrointestinal Oncology has appointed Weijing Sun, MD, as its president-elect. After his 2-year term as president-elect, Dr. Sun will take over as president from Ghassan Abou-Alfa, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Sun is director of the division of medical oncology and associate director for clinical research at the University of Kansas Cancer Center in Kansas City. He is a gastrointestinal medical oncologist with a research focus on the development of new treatments for pancreatic, gastroesophageal, hepatobiliary, and colorectal cancers.

Finally, Elizabeth Plimack, MD, has been elected to the American Society of Clinical Oncology’s board of directors for a term of 4 years. She will begin this appointment in June 2020.

[email protected]

Edmondo Robinson, MD, is the new senior vice president and chief digital innovation officer at Moffitt Cancer Center in Tampa, Fla. In this newly created position, Dr. Robinson will “oversee Moffitt’s portfolio of digital innovation, including the development and commercialization of health products, tools, and technology.”

Dr. Robinson is also associate professor of medicine at Thomas Jefferson University’s Sidney Kimmel Medical College in Philadelphia. He was previously the chief transformation officer and senior vice-president of consumerism at ChristianaCare, a health system based in Wilmington, Del. Dr. Robinson’s research is focused on health services, particularly care transitions and how technology impacts care delivery.

In other news, Elizabeth Fox, MD, has been named senior vice president of clinical trials research at St. Jude Children’s Research Hospital in Memphis, Tenn. She will also serve as the associate director for clinical research in the St. Jude Comprehensive Cancer Center. Dr. Fox will take on these roles in January 2020.

Dr. Fox was previously director of developmental therapeutics in oncology and professor of pediatrics at Children’s Hospital of Philadelphia. According to St. Jude, Dr. Fox is an expert in integrating clinical and preclinical pharmacology in clinical trial design.

The International Society of Gastrointestinal Oncology has appointed Weijing Sun, MD, as its president-elect. After his 2-year term as president-elect, Dr. Sun will take over as president from Ghassan Abou-Alfa, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Sun is director of the division of medical oncology and associate director for clinical research at the University of Kansas Cancer Center in Kansas City. He is a gastrointestinal medical oncologist with a research focus on the development of new treatments for pancreatic, gastroesophageal, hepatobiliary, and colorectal cancers.

Finally, Elizabeth Plimack, MD, has been elected to the American Society of Clinical Oncology’s board of directors for a term of 4 years. She will begin this appointment in June 2020.

[email protected]

Edmondo Robinson, MD, is the new senior vice president and chief digital innovation officer at Moffitt Cancer Center in Tampa, Fla. In this newly created position, Dr. Robinson will “oversee Moffitt’s portfolio of digital innovation, including the development and commercialization of health products, tools, and technology.”

Dr. Robinson is also associate professor of medicine at Thomas Jefferson University’s Sidney Kimmel Medical College in Philadelphia. He was previously the chief transformation officer and senior vice-president of consumerism at ChristianaCare, a health system based in Wilmington, Del. Dr. Robinson’s research is focused on health services, particularly care transitions and how technology impacts care delivery.

In other news, Elizabeth Fox, MD, has been named senior vice president of clinical trials research at St. Jude Children’s Research Hospital in Memphis, Tenn. She will also serve as the associate director for clinical research in the St. Jude Comprehensive Cancer Center. Dr. Fox will take on these roles in January 2020.

Dr. Fox was previously director of developmental therapeutics in oncology and professor of pediatrics at Children’s Hospital of Philadelphia. According to St. Jude, Dr. Fox is an expert in integrating clinical and preclinical pharmacology in clinical trial design.

The International Society of Gastrointestinal Oncology has appointed Weijing Sun, MD, as its president-elect. After his 2-year term as president-elect, Dr. Sun will take over as president from Ghassan Abou-Alfa, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Sun is director of the division of medical oncology and associate director for clinical research at the University of Kansas Cancer Center in Kansas City. He is a gastrointestinal medical oncologist with a research focus on the development of new treatments for pancreatic, gastroesophageal, hepatobiliary, and colorectal cancers.

Finally, Elizabeth Plimack, MD, has been elected to the American Society of Clinical Oncology’s board of directors for a term of 4 years. She will begin this appointment in June 2020.

[email protected]

Results from a review and meta-analysis support the use of maintenance after first-line therapy in patients with metastatic colorectal cancer.

The data showed that continuous induction did not confer a survival benefit over observation or maintenance therapy; however, maintenance improved progression-free survival (PFS), but not overall survival (OS), compared with observation. Furthermore, maintenance including a fluoropyrimidine, with or without bevacizumab, was most likely to improve survival.

These findings suggest maintenance may be appropriate for most patients with metastatic colorectal cancer, according to Mohamad Bassam Sonbol, MD, of Mayo Clinic in Phoenix and coauthors. Dr. Sonbol is the lead author of the review and meta-analysis, which was published in JAMA Oncology.

“For most patients, we are recommending a period of maintenance treatment,” Dr. Sonbol said in a JAMA Oncology podcast. “With the fluoropyrimidine, in most circumstances, we’re using capecitabine. Then, if cost is not an issue and toxicity is not an issue, we’re adding bevacizumab to this combination.”

Dr. Sonbol noted that certain patients, particularly those who have experienced a lot of toxicity, may do better with observation.

To reach these conclusions, Dr. Sonbol and colleagues analyzed data from 12 randomized phase 2 and 3 trials. Data from all 12 trials were included in the qualitative synthesis, but only 11 of the trials were included in the meta-analysis because of a lack of PFS and OS data from one trial.

In all, the data included 5,540 patients with previously untreated metastatic colorectal cancer. They ranged in age from 23 to 85 years, and most of them were male (64.4%).

For induction, patients received cytotoxic chemotherapy, with or without a biologic. For 10 trials, the induction regimen included oxaliplatin with either capecitabine or fluorouracil and leucovorin. Two trials included irinotecan-based induction.

In one trial, patients were managed with either continuous induction or observation. Continuous induction did not provide a PFS benefit (hazard ratio, 0.71; 95% confidence interval, 0.46-1.09) or an OS benefit (HR, 0.95; 95% CI, 0.85-1.07). In three trials, continuous induction was compared with maintenance. There was no PFS benefit (HR, 1.22; 95% CI, 0.84-1.78) or OS benefit (HR, 1.04; 95% CI, 0.92-1.17) with continuous induction over maintenance. There were six trials comparing maintenance to observation. Maintenance did provide a PFS benefit over observation (HR, 0.58; 95% CI, 0.43-0.77), but there was no OS benefit with maintenance (HR, 0.91; 95% CI, 0.83-1.01).

To compare maintenance regimens to one another, the researchers used surface under the cumulative ranking (SUCRA) probabilities. Higher SUCRA scores reflected greater efficacy.

Maintenance including a fluoropyrimidine, with or without bevacizumab, ranked higher than bevacizumab alone for both PFS and OS. The SUCRA values for PFS were 36.5% for bevacizumab, 67.1% for fluoropyrimidine, and 99.8% for fluoropyrimidine plus bevacizumab. The SUCRA values for OS were 32.6%, 81.3%, and 73.2%, respectively.

Dr. Sonbol and colleagues noted that this research is limited by the nature of meta-analyses (as compared with a prospective trial), a lack of blinding in some of the trials evaluated, and the use of study-level data rather than individual patient data.

Still, the researchers are recommending maintenance for most patients with metastatic colorectal cancer who achieve at least stable disease after induction. The team acknowledged that some patients may fare better with observation, and factors such as toxicity, cost, and patient preference should be considered when deciding on maintenance.

Dr. Sonbol did not disclose any conflicts of interest. Other authors disclosed relationships with multiple pharmaceutical companies.

SOURCE: Sonbol MB et al. JAMA Oncol. 2019 Dec 19. doi: 10.1001/jamaoncol.2019.4489.

Results from a review and meta-analysis support the use of maintenance after first-line therapy in patients with metastatic colorectal cancer.

The data showed that continuous induction did not confer a survival benefit over observation or maintenance therapy; however, maintenance improved progression-free survival (PFS), but not overall survival (OS), compared with observation. Furthermore, maintenance including a fluoropyrimidine, with or without bevacizumab, was most likely to improve survival.

These findings suggest maintenance may be appropriate for most patients with metastatic colorectal cancer, according to Mohamad Bassam Sonbol, MD, of Mayo Clinic in Phoenix and coauthors. Dr. Sonbol is the lead author of the review and meta-analysis, which was published in JAMA Oncology.

“For most patients, we are recommending a period of maintenance treatment,” Dr. Sonbol said in a JAMA Oncology podcast. “With the fluoropyrimidine, in most circumstances, we’re using capecitabine. Then, if cost is not an issue and toxicity is not an issue, we’re adding bevacizumab to this combination.”

Dr. Sonbol noted that certain patients, particularly those who have experienced a lot of toxicity, may do better with observation.

To reach these conclusions, Dr. Sonbol and colleagues analyzed data from 12 randomized phase 2 and 3 trials. Data from all 12 trials were included in the qualitative synthesis, but only 11 of the trials were included in the meta-analysis because of a lack of PFS and OS data from one trial.

In all, the data included 5,540 patients with previously untreated metastatic colorectal cancer. They ranged in age from 23 to 85 years, and most of them were male (64.4%).

For induction, patients received cytotoxic chemotherapy, with or without a biologic. For 10 trials, the induction regimen included oxaliplatin with either capecitabine or fluorouracil and leucovorin. Two trials included irinotecan-based induction.

In one trial, patients were managed with either continuous induction or observation. Continuous induction did not provide a PFS benefit (hazard ratio, 0.71; 95% confidence interval, 0.46-1.09) or an OS benefit (HR, 0.95; 95% CI, 0.85-1.07). In three trials, continuous induction was compared with maintenance. There was no PFS benefit (HR, 1.22; 95% CI, 0.84-1.78) or OS benefit (HR, 1.04; 95% CI, 0.92-1.17) with continuous induction over maintenance. There were six trials comparing maintenance to observation. Maintenance did provide a PFS benefit over observation (HR, 0.58; 95% CI, 0.43-0.77), but there was no OS benefit with maintenance (HR, 0.91; 95% CI, 0.83-1.01).

To compare maintenance regimens to one another, the researchers used surface under the cumulative ranking (SUCRA) probabilities. Higher SUCRA scores reflected greater efficacy.

Maintenance including a fluoropyrimidine, with or without bevacizumab, ranked higher than bevacizumab alone for both PFS and OS. The SUCRA values for PFS were 36.5% for bevacizumab, 67.1% for fluoropyrimidine, and 99.8% for fluoropyrimidine plus bevacizumab. The SUCRA values for OS were 32.6%, 81.3%, and 73.2%, respectively.

Dr. Sonbol and colleagues noted that this research is limited by the nature of meta-analyses (as compared with a prospective trial), a lack of blinding in some of the trials evaluated, and the use of study-level data rather than individual patient data.

Still, the researchers are recommending maintenance for most patients with metastatic colorectal cancer who achieve at least stable disease after induction. The team acknowledged that some patients may fare better with observation, and factors such as toxicity, cost, and patient preference should be considered when deciding on maintenance.

Dr. Sonbol did not disclose any conflicts of interest. Other authors disclosed relationships with multiple pharmaceutical companies.

SOURCE: Sonbol MB et al. JAMA Oncol. 2019 Dec 19. doi: 10.1001/jamaoncol.2019.4489.

Results from a review and meta-analysis support the use of maintenance after first-line therapy in patients with metastatic colorectal cancer.

The data showed that continuous induction did not confer a survival benefit over observation or maintenance therapy; however, maintenance improved progression-free survival (PFS), but not overall survival (OS), compared with observation. Furthermore, maintenance including a fluoropyrimidine, with or without bevacizumab, was most likely to improve survival.

These findings suggest maintenance may be appropriate for most patients with metastatic colorectal cancer, according to Mohamad Bassam Sonbol, MD, of Mayo Clinic in Phoenix and coauthors. Dr. Sonbol is the lead author of the review and meta-analysis, which was published in JAMA Oncology.

“For most patients, we are recommending a period of maintenance treatment,” Dr. Sonbol said in a JAMA Oncology podcast. “With the fluoropyrimidine, in most circumstances, we’re using capecitabine. Then, if cost is not an issue and toxicity is not an issue, we’re adding bevacizumab to this combination.”

Dr. Sonbol noted that certain patients, particularly those who have experienced a lot of toxicity, may do better with observation.

To reach these conclusions, Dr. Sonbol and colleagues analyzed data from 12 randomized phase 2 and 3 trials. Data from all 12 trials were included in the qualitative synthesis, but only 11 of the trials were included in the meta-analysis because of a lack of PFS and OS data from one trial.

In all, the data included 5,540 patients with previously untreated metastatic colorectal cancer. They ranged in age from 23 to 85 years, and most of them were male (64.4%).

For induction, patients received cytotoxic chemotherapy, with or without a biologic. For 10 trials, the induction regimen included oxaliplatin with either capecitabine or fluorouracil and leucovorin. Two trials included irinotecan-based induction.

In one trial, patients were managed with either continuous induction or observation. Continuous induction did not provide a PFS benefit (hazard ratio, 0.71; 95% confidence interval, 0.46-1.09) or an OS benefit (HR, 0.95; 95% CI, 0.85-1.07). In three trials, continuous induction was compared with maintenance. There was no PFS benefit (HR, 1.22; 95% CI, 0.84-1.78) or OS benefit (HR, 1.04; 95% CI, 0.92-1.17) with continuous induction over maintenance. There were six trials comparing maintenance to observation. Maintenance did provide a PFS benefit over observation (HR, 0.58; 95% CI, 0.43-0.77), but there was no OS benefit with maintenance (HR, 0.91; 95% CI, 0.83-1.01).

To compare maintenance regimens to one another, the researchers used surface under the cumulative ranking (SUCRA) probabilities. Higher SUCRA scores reflected greater efficacy.

Maintenance including a fluoropyrimidine, with or without bevacizumab, ranked higher than bevacizumab alone for both PFS and OS. The SUCRA values for PFS were 36.5% for bevacizumab, 67.1% for fluoropyrimidine, and 99.8% for fluoropyrimidine plus bevacizumab. The SUCRA values for OS were 32.6%, 81.3%, and 73.2%, respectively.

Dr. Sonbol and colleagues noted that this research is limited by the nature of meta-analyses (as compared with a prospective trial), a lack of blinding in some of the trials evaluated, and the use of study-level data rather than individual patient data.

Still, the researchers are recommending maintenance for most patients with metastatic colorectal cancer who achieve at least stable disease after induction. The team acknowledged that some patients may fare better with observation, and factors such as toxicity, cost, and patient preference should be considered when deciding on maintenance.

Dr. Sonbol did not disclose any conflicts of interest. Other authors disclosed relationships with multiple pharmaceutical companies.

SOURCE: Sonbol MB et al. JAMA Oncol. 2019 Dec 19. doi: 10.1001/jamaoncol.2019.4489.

ORLANDO – A gamma secretase inhibitor could enhance the efficacy of B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cells in patients with relapsed or refractory multiple myeloma, a phase 1 trial suggests.

Jennifer Smith/MDedge News

The inhibitor, JSMD194, increased BCMA expression in all 10 patients studied. All patients responded to anti-BCMA CAR T-cell therapy, including three patients who had previously failed BCMA-directed therapy.

Nine patients remain alive and in response at a median follow-up of 20 weeks, with two patients being followed for more than a year. One patient experienced dose-limiting toxicity and died, which prompted a change to the study’s eligibility criteria.

Andrew J. Cowan, MD, of the University of Washington and Fred Hutchinson Cancer Research Center in Seattle, presented these results at the annual meeting of the American Society of Hematology.

Study treatment

Patients had BCMA expression measured at baseline, then underwent apheresis for CAR T-cell production.

Patients received JSMD194 at 25 mg on days 1, 3, and 5. Then, they received cyclophosphamide at 300 mg and fludarabine at 25 mg for 3 days.

Next, patients received a single CAR T-cell infusion at a dose of 50 x 10⁶ (n = 5), 150 x 10⁶ (n = 3), or 300 x 10⁶ (n = 2). They also received JSMD194 at 25 mg three times a week for 3 weeks.

Safety

“Nearly all patients had a serious adverse event, which was typically admission to the hospital for neutropenic fever,” Dr. Cowan said.

One patient experienced dose-limiting toxicity and died at day 33. The patient had a disseminating fungal infection, grade 4 cytokine release syndrome (CRS), and neurotoxicity. The patient’s death prompted the researchers to include performance status in the study’s eligibility criteria.

All patients developed CRS. Only the aforementioned patient had grade 4 CRS, and three patients had grade 3 CRS. Six patients experienced neurotoxicity. There were no cases of tumor lysis syndrome.
 

Efficacy

“All patients experienced an increase of cells expressing BCMA,” Dr. Cowan said. “While there was significant variability in BCMA expression at baseline, all cells expressed BCMA after three doses of the gamma secretase inhibitor.”

The median BCMA expression after JSMD194 treatment was 99% (range, 96%-100%), and there was a median 20-fold (range, 8- to 157-fold) increase in BCMA surface density.

The overall response rate was 100%. Two patients achieved a stringent complete response (CR), one achieved a CR, five patients had a very good partial response, and two had a partial response.

The patient with a CR received the 50 x 10⁶ dose of CAR T cells, and the patients with stringent CRs received the 150 x 10⁶ and 300 x 10⁶ doses.

Of the three patients who previously received BCMA-directed therapy, two achieved a very good partial response, and one had a partial response.

Nine of the 10 patients are still alive and in response, with a median follow-up of 20 weeks. The longest follow-up is 444 days.

“To date, all patients have evidence of durable responses,” Dr. Cowan said. “Moreover, all patients had dramatic reductions in involved serum free light chain ... and serum monoclonal proteins.”

Dr. Cowan noted that longer follow-up is needed to assess CAR T-cell persistence and the durability of response.

This trial is sponsored by the Fred Hutchinson Cancer Research Center in collaboration with the National Cancer Institute. Two researchers involved in this work are employees of Juno Therapeutics. Dr. Cowan reported relationships with Juno Therapeutics, Janssen, Celgene, AbbVie, Cellectar, and Sanofi.

[email protected]

SOURCE: Cowan AJ et al. ASH 2019. Abstract 204.

ORLANDO – A gamma secretase inhibitor could enhance the efficacy of B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cells in patients with relapsed or refractory multiple myeloma, a phase 1 trial suggests.

Jennifer Smith/MDedge News

The inhibitor, JSMD194, increased BCMA expression in all 10 patients studied. All patients responded to anti-BCMA CAR T-cell therapy, including three patients who had previously failed BCMA-directed therapy.

Nine patients remain alive and in response at a median follow-up of 20 weeks, with two patients being followed for more than a year. One patient experienced dose-limiting toxicity and died, which prompted a change to the study’s eligibility criteria.

Andrew J. Cowan, MD, of the University of Washington and Fred Hutchinson Cancer Research Center in Seattle, presented these results at the annual meeting of the American Society of Hematology.

Study treatment

Patients had BCMA expression measured at baseline, then underwent apheresis for CAR T-cell production.

Patients received JSMD194 at 25 mg on days 1, 3, and 5. Then, they received cyclophosphamide at 300 mg and fludarabine at 25 mg for 3 days.

Next, patients received a single CAR T-cell infusion at a dose of 50 x 10⁶ (n = 5), 150 x 10⁶ (n = 3), or 300 x 10⁶ (n = 2). They also received JSMD194 at 25 mg three times a week for 3 weeks.

Safety

“Nearly all patients had a serious adverse event, which was typically admission to the hospital for neutropenic fever,” Dr. Cowan said.

One patient experienced dose-limiting toxicity and died at day 33. The patient had a disseminating fungal infection, grade 4 cytokine release syndrome (CRS), and neurotoxicity. The patient’s death prompted the researchers to include performance status in the study’s eligibility criteria.

All patients developed CRS. Only the aforementioned patient had grade 4 CRS, and three patients had grade 3 CRS. Six patients experienced neurotoxicity. There were no cases of tumor lysis syndrome.
 

Efficacy

“All patients experienced an increase of cells expressing BCMA,” Dr. Cowan said. “While there was significant variability in BCMA expression at baseline, all cells expressed BCMA after three doses of the gamma secretase inhibitor.”

The median BCMA expression after JSMD194 treatment was 99% (range, 96%-100%), and there was a median 20-fold (range, 8- to 157-fold) increase in BCMA surface density.

The overall response rate was 100%. Two patients achieved a stringent complete response (CR), one achieved a CR, five patients had a very good partial response, and two had a partial response.

The patient with a CR received the 50 x 10⁶ dose of CAR T cells, and the patients with stringent CRs received the 150 x 10⁶ and 300 x 10⁶ doses.

Of the three patients who previously received BCMA-directed therapy, two achieved a very good partial response, and one had a partial response.

Nine of the 10 patients are still alive and in response, with a median follow-up of 20 weeks. The longest follow-up is 444 days.

“To date, all patients have evidence of durable responses,” Dr. Cowan said. “Moreover, all patients had dramatic reductions in involved serum free light chain ... and serum monoclonal proteins.”

Dr. Cowan noted that longer follow-up is needed to assess CAR T-cell persistence and the durability of response.

This trial is sponsored by the Fred Hutchinson Cancer Research Center in collaboration with the National Cancer Institute. Two researchers involved in this work are employees of Juno Therapeutics. Dr. Cowan reported relationships with Juno Therapeutics, Janssen, Celgene, AbbVie, Cellectar, and Sanofi.

[email protected]

SOURCE: Cowan AJ et al. ASH 2019. Abstract 204.

ORLANDO – A gamma secretase inhibitor could enhance the efficacy of B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cells in patients with relapsed or refractory multiple myeloma, a phase 1 trial suggests.

Jennifer Smith/MDedge News

The inhibitor, JSMD194, increased BCMA expression in all 10 patients studied. All patients responded to anti-BCMA CAR T-cell therapy, including three patients who had previously failed BCMA-directed therapy.

Nine patients remain alive and in response at a median follow-up of 20 weeks, with two patients being followed for more than a year. One patient experienced dose-limiting toxicity and died, which prompted a change to the study’s eligibility criteria.

Andrew J. Cowan, MD, of the University of Washington and Fred Hutchinson Cancer Research Center in Seattle, presented these results at the annual meeting of the American Society of Hematology.

Study treatment

Patients had BCMA expression measured at baseline, then underwent apheresis for CAR T-cell production.

Patients received JSMD194 at 25 mg on days 1, 3, and 5. Then, they received cyclophosphamide at 300 mg and fludarabine at 25 mg for 3 days.

Next, patients received a single CAR T-cell infusion at a dose of 50 x 10⁶ (n = 5), 150 x 10⁶ (n = 3), or 300 x 10⁶ (n = 2). They also received JSMD194 at 25 mg three times a week for 3 weeks.

Safety

“Nearly all patients had a serious adverse event, which was typically admission to the hospital for neutropenic fever,” Dr. Cowan said.

One patient experienced dose-limiting toxicity and died at day 33. The patient had a disseminating fungal infection, grade 4 cytokine release syndrome (CRS), and neurotoxicity. The patient’s death prompted the researchers to include performance status in the study’s eligibility criteria.

All patients developed CRS. Only the aforementioned patient had grade 4 CRS, and three patients had grade 3 CRS. Six patients experienced neurotoxicity. There were no cases of tumor lysis syndrome.
 

Efficacy

“All patients experienced an increase of cells expressing BCMA,” Dr. Cowan said. “While there was significant variability in BCMA expression at baseline, all cells expressed BCMA after three doses of the gamma secretase inhibitor.”

The median BCMA expression after JSMD194 treatment was 99% (range, 96%-100%), and there was a median 20-fold (range, 8- to 157-fold) increase in BCMA surface density.

The overall response rate was 100%. Two patients achieved a stringent complete response (CR), one achieved a CR, five patients had a very good partial response, and two had a partial response.

The patient with a CR received the 50 x 10⁶ dose of CAR T cells, and the patients with stringent CRs received the 150 x 10⁶ and 300 x 10⁶ doses.

Of the three patients who previously received BCMA-directed therapy, two achieved a very good partial response, and one had a partial response.

Nine of the 10 patients are still alive and in response, with a median follow-up of 20 weeks. The longest follow-up is 444 days.

“To date, all patients have evidence of durable responses,” Dr. Cowan said. “Moreover, all patients had dramatic reductions in involved serum free light chain ... and serum monoclonal proteins.”

Dr. Cowan noted that longer follow-up is needed to assess CAR T-cell persistence and the durability of response.

This trial is sponsored by the Fred Hutchinson Cancer Research Center in collaboration with the National Cancer Institute. Two researchers involved in this work are employees of Juno Therapeutics. Dr. Cowan reported relationships with Juno Therapeutics, Janssen, Celgene, AbbVie, Cellectar, and Sanofi.

[email protected]

SOURCE: Cowan AJ et al. ASH 2019. Abstract 204.

ORLANDO – Updated results from the TRANSCEND NHL trial include survival data with lisocabtagene maraleucel (liso-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory B-cell lymphomas.

Jennifer Smith/MDedge News

The median progression-free survival (PFS) was 6.8 months, and the median overall survival was 21.1 months. PFS results were best among complete responders and among patients with primary mediastinal large B-cell lymphoma or transformed follicular lymphoma.

Jeremy S. Abramson, MD, of Massachusetts General Hospital in Boston, presented these results at the annual meeting of the American Society of Hematology.

“TRANSCEND NHL is the largest clinical study to date of CD19-directed CAR T cells in patients with relapsed/refractory aggressive B-cell lymphoma,” Dr. Abramson said.

The phase 1 trial (NCT02631044) includes 269 patients who received liso-cel. They were diagnosed with transformed follicular lymphoma (22%) or other indolent lymphoma (7%), high-grade B-cell lymphoma (13%), primary mediastinal large B-cell lymphoma (6%), grade 3B follicular lymphoma (1%), or diffuse large B-cell lymphoma not otherwise specified (51%).

At baseline, patients had received a median of three prior systemic therapies (range, one to eight). Some patients had received autologous (33%) or allogeneic (3%) transplant. Many patients were chemotherapy refractory (67%) or had never achieved a complete response to prior therapy (44%).

More than half of patients (59%) received bridging therapy during liso-cel manufacturing. All patients received lymphodepletion with fludarabine and cyclophosphamide, followed by liso-cel at 50 x 10⁶ CAR T cells, 100 x 10⁶ CAR T cells, or 150 x 10⁶ CAR T cells.

Response and survival

The median follow-up was 12.0 months. The overall response rate was 73%, and the complete response rate was 53%.

“Remissions were rapid, with a median of 1 month from CAR T-cell infusion, and durable, with a median duration of response that has not been reached and 55% of patients remaining in response at 1 year,” Dr. Abramson said.

The median PFS was 6.8 months overall, not reached for patients who achieved a complete response, 2.8 months for patients with a partial response, and 1.1 months for patients with stable disease or progressive disease.

The median PFS was not reached for patients with primary mediastinal large B-cell lymphoma or transformed follicular lymphoma, 5.0 months for high-grade B-cell lymphoma, 3.0 months for diffuse large B-cell lymphoma not otherwise specified, and 2.9 months in transformed indolent non-Hodgkin lymphoma.

The median overall survival was 21.1 months overall, not reached for patients who achieved a complete response, 9.0 months for patients who had a partial response, and 5.1 months for patients with stable disease or progressive disease.

Safety

Common treatment-emergent adverse events were neutropenia (63%), anemia (48%), fatigue (44%), nausea (33%), thrombocytopenia (31%), headache (30%), decreased appetite (28%), and diarrhea (26%).

Cytokine release syndrome (CRS) occurred in 42% of patients, and neurologic events occurred in 30%. Grade 3-4 CRS occurred in 2% of patients, and grade 3-4 neurologic events occurred in 10%. There were no cases of grade 5 CRS or neurologic events.

The median time to CRS onset was 5 days, and the median time to onset of neurologic events was 9 days. The median time to resolution of CRS and neurologic events was 5 days and 11 days, respectively.

“The low incidence of severe CRS and neurologic events and their late time of onset support using this product in a large range of patients and in the outpatient setting,” Dr. Abramson said.

There were seven grade 5 treatment-related adverse events, including diffuse alveolar damage, pulmonary hemorrhage, multiple organ dysfunction syndrome, cardiomyopathy, fludarabine leukoencephalopathy, septic shock, and progressive multifocal leukoencephalopathy.

This trial is sponsored by Bristol-Myers Squibb. Dr. Abramson reported relationships with Juno Therapeutics and Celgene, now owned by Bristol-Myers Squibb, and a range of other companies.

[email protected]

SOURCE: Abramson JS et al. ASH 2019, Abstract 241.

ORLANDO – Updated results from the TRANSCEND NHL trial include survival data with lisocabtagene maraleucel (liso-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory B-cell lymphomas.

Jennifer Smith/MDedge News

The median progression-free survival (PFS) was 6.8 months, and the median overall survival was 21.1 months. PFS results were best among complete responders and among patients with primary mediastinal large B-cell lymphoma or transformed follicular lymphoma.

Jeremy S. Abramson, MD, of Massachusetts General Hospital in Boston, presented these results at the annual meeting of the American Society of Hematology.

“TRANSCEND NHL is the largest clinical study to date of CD19-directed CAR T cells in patients with relapsed/refractory aggressive B-cell lymphoma,” Dr. Abramson said.

The phase 1 trial (NCT02631044) includes 269 patients who received liso-cel. They were diagnosed with transformed follicular lymphoma (22%) or other indolent lymphoma (7%), high-grade B-cell lymphoma (13%), primary mediastinal large B-cell lymphoma (6%), grade 3B follicular lymphoma (1%), or diffuse large B-cell lymphoma not otherwise specified (51%).

At baseline, patients had received a median of three prior systemic therapies (range, one to eight). Some patients had received autologous (33%) or allogeneic (3%) transplant. Many patients were chemotherapy refractory (67%) or had never achieved a complete response to prior therapy (44%).

More than half of patients (59%) received bridging therapy during liso-cel manufacturing. All patients received lymphodepletion with fludarabine and cyclophosphamide, followed by liso-cel at 50 x 10⁶ CAR T cells, 100 x 10⁶ CAR T cells, or 150 x 10⁶ CAR T cells.

Response and survival

The median follow-up was 12.0 months. The overall response rate was 73%, and the complete response rate was 53%.

“Remissions were rapid, with a median of 1 month from CAR T-cell infusion, and durable, with a median duration of response that has not been reached and 55% of patients remaining in response at 1 year,” Dr. Abramson said.

The median PFS was 6.8 months overall, not reached for patients who achieved a complete response, 2.8 months for patients with a partial response, and 1.1 months for patients with stable disease or progressive disease.

The median PFS was not reached for patients with primary mediastinal large B-cell lymphoma or transformed follicular lymphoma, 5.0 months for high-grade B-cell lymphoma, 3.0 months for diffuse large B-cell lymphoma not otherwise specified, and 2.9 months in transformed indolent non-Hodgkin lymphoma.

The median overall survival was 21.1 months overall, not reached for patients who achieved a complete response, 9.0 months for patients who had a partial response, and 5.1 months for patients with stable disease or progressive disease.

Safety

Common treatment-emergent adverse events were neutropenia (63%), anemia (48%), fatigue (44%), nausea (33%), thrombocytopenia (31%), headache (30%), decreased appetite (28%), and diarrhea (26%).

Cytokine release syndrome (CRS) occurred in 42% of patients, and neurologic events occurred in 30%. Grade 3-4 CRS occurred in 2% of patients, and grade 3-4 neurologic events occurred in 10%. There were no cases of grade 5 CRS or neurologic events.

The median time to CRS onset was 5 days, and the median time to onset of neurologic events was 9 days. The median time to resolution of CRS and neurologic events was 5 days and 11 days, respectively.

“The low incidence of severe CRS and neurologic events and their late time of onset support using this product in a large range of patients and in the outpatient setting,” Dr. Abramson said.

There were seven grade 5 treatment-related adverse events, including diffuse alveolar damage, pulmonary hemorrhage, multiple organ dysfunction syndrome, cardiomyopathy, fludarabine leukoencephalopathy, septic shock, and progressive multifocal leukoencephalopathy.

This trial is sponsored by Bristol-Myers Squibb. Dr. Abramson reported relationships with Juno Therapeutics and Celgene, now owned by Bristol-Myers Squibb, and a range of other companies.

[email protected]

SOURCE: Abramson JS et al. ASH 2019, Abstract 241.

ORLANDO – Updated results from the TRANSCEND NHL trial include survival data with lisocabtagene maraleucel (liso-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory B-cell lymphomas.

Jennifer Smith/MDedge News

The median progression-free survival (PFS) was 6.8 months, and the median overall survival was 21.1 months. PFS results were best among complete responders and among patients with primary mediastinal large B-cell lymphoma or transformed follicular lymphoma.

Jeremy S. Abramson, MD, of Massachusetts General Hospital in Boston, presented these results at the annual meeting of the American Society of Hematology.

“TRANSCEND NHL is the largest clinical study to date of CD19-directed CAR T cells in patients with relapsed/refractory aggressive B-cell lymphoma,” Dr. Abramson said.

The phase 1 trial (NCT02631044) includes 269 patients who received liso-cel. They were diagnosed with transformed follicular lymphoma (22%) or other indolent lymphoma (7%), high-grade B-cell lymphoma (13%), primary mediastinal large B-cell lymphoma (6%), grade 3B follicular lymphoma (1%), or diffuse large B-cell lymphoma not otherwise specified (51%).

At baseline, patients had received a median of three prior systemic therapies (range, one to eight). Some patients had received autologous (33%) or allogeneic (3%) transplant. Many patients were chemotherapy refractory (67%) or had never achieved a complete response to prior therapy (44%).

More than half of patients (59%) received bridging therapy during liso-cel manufacturing. All patients received lymphodepletion with fludarabine and cyclophosphamide, followed by liso-cel at 50 x 10⁶ CAR T cells, 100 x 10⁶ CAR T cells, or 150 x 10⁶ CAR T cells.

Response and survival

The median follow-up was 12.0 months. The overall response rate was 73%, and the complete response rate was 53%.

“Remissions were rapid, with a median of 1 month from CAR T-cell infusion, and durable, with a median duration of response that has not been reached and 55% of patients remaining in response at 1 year,” Dr. Abramson said.

The median PFS was 6.8 months overall, not reached for patients who achieved a complete response, 2.8 months for patients with a partial response, and 1.1 months for patients with stable disease or progressive disease.

The median PFS was not reached for patients with primary mediastinal large B-cell lymphoma or transformed follicular lymphoma, 5.0 months for high-grade B-cell lymphoma, 3.0 months for diffuse large B-cell lymphoma not otherwise specified, and 2.9 months in transformed indolent non-Hodgkin lymphoma.

The median overall survival was 21.1 months overall, not reached for patients who achieved a complete response, 9.0 months for patients who had a partial response, and 5.1 months for patients with stable disease or progressive disease.

Safety

Common treatment-emergent adverse events were neutropenia (63%), anemia (48%), fatigue (44%), nausea (33%), thrombocytopenia (31%), headache (30%), decreased appetite (28%), and diarrhea (26%).

Cytokine release syndrome (CRS) occurred in 42% of patients, and neurologic events occurred in 30%. Grade 3-4 CRS occurred in 2% of patients, and grade 3-4 neurologic events occurred in 10%. There were no cases of grade 5 CRS or neurologic events.

The median time to CRS onset was 5 days, and the median time to onset of neurologic events was 9 days. The median time to resolution of CRS and neurologic events was 5 days and 11 days, respectively.

“The low incidence of severe CRS and neurologic events and their late time of onset support using this product in a large range of patients and in the outpatient setting,” Dr. Abramson said.

There were seven grade 5 treatment-related adverse events, including diffuse alveolar damage, pulmonary hemorrhage, multiple organ dysfunction syndrome, cardiomyopathy, fludarabine leukoencephalopathy, septic shock, and progressive multifocal leukoencephalopathy.

This trial is sponsored by Bristol-Myers Squibb. Dr. Abramson reported relationships with Juno Therapeutics and Celgene, now owned by Bristol-Myers Squibb, and a range of other companies.

[email protected]

SOURCE: Abramson JS et al. ASH 2019, Abstract 241.

ORLANDO – A large, retrospective study suggests several factors are associated with an increased risk of intracranial hemorrhage in patients with immune thrombocytopenia.

Jennifer Smith/MDedge News

Data on more than 300,000 immune thrombocytopenia (ITP) hospitalizations indicated that older age, male sex, not having private insurance, having a gastrointestinal or “other” bleed, and receiving treatment at a hospital in the western United States, a medium- or large-sized hospital, or an urban teaching hospital were all associated with an increased risk of intracranial hemorrhage (ICH).

Mayank Sharma, of the University of Miami, detailed these findings at the annual meeting of the American Society of Hematology.

Mr. Sharma and colleagues analyzed data from the National Inpatient Sample database from 2007 to 2016. Of the 348,906 ITP hospitalizations included, there were 3,408 (0.98%) cases of ICH.

The overall incidence of ICH was low and remained stable over time, “which is reassuring,” Mr. Sharma said. However, the mortality rate was higher among patients with ICH than among those without it – 26.7% and 3.2%, respectively.

A multivariate analysis showed that female patients had a decreased likelihood of ICH, with an odds ratio of 0.81 (95% confidence interval, 0.68-0.97). Patients with private insurance had a decreased likelihood of ICH as well, with an OR of 0.81 (95% CI, 0.61-1.08).

Conversely, older patients had an increased likelihood of ICH. The OR was 2.23 (95% CI, 1.51-3.31) for patients aged 25-64 years, and the OR was 3.69 (95% CI, 2.34-5.84) for patients aged 65 years and older.

Patients with a gastrointestinal bleed or an other bleed (not including hematuria or epistaxis) had an increased likelihood of ICH. The ORs were 1.60 (95% CI, 1.18-2.16) and 1.69 (95% CI, 1.19-2.42), respectively.

Patients hospitalized in the western United States (OR, 1.62; 95% CI, 1.26-2.08), at a medium-sized hospital (OR, 1.64; 95% CI, 1.08-2.47), at a large hospital (OR, 2.42; 95% CI, 1.65-3.55), or at an urban teaching hospital (OR, 2.73; 95% CI, 1.80-4.13) all had an increased likelihood of ICH.

“Our second objective was to study the factors associated with mortality in ITP patients with ICH,” Mr. Sharma said. “We found female gender and Medicaid, private, or self-pay as primary payers to be associated with a lower mortality in ITP with ICH.

“[A]ge of 25-64 and 65 years and above, coexistence of a GI bleed or other bleed, and admission to a large or urban teaching hospital were associated with a higher mortality,” he added.

Mr. Sharma said the study’s strengths are that it is the most recent study on trends in ITP/ICH hospitalizations, and that it’s a longitudinal assessment of data from a nationally representative database.

The study’s limitations include its retrospective nature and the use of ICD codes, which could lead to inaccuracies. Data on prior therapies and long-term outcomes were not available, and the researchers were unable to differentiate between acute and chronic ITP.

Mr. Sharma said he had no relevant conflicts of interest.
 

[email protected]

SOURCE: Sharma M et al. ASH 2019, Abstract 55.

ORLANDO – A large, retrospective study suggests several factors are associated with an increased risk of intracranial hemorrhage in patients with immune thrombocytopenia.

Jennifer Smith/MDedge News

Data on more than 300,000 immune thrombocytopenia (ITP) hospitalizations indicated that older age, male sex, not having private insurance, having a gastrointestinal or “other” bleed, and receiving treatment at a hospital in the western United States, a medium- or large-sized hospital, or an urban teaching hospital were all associated with an increased risk of intracranial hemorrhage (ICH).

Mayank Sharma, of the University of Miami, detailed these findings at the annual meeting of the American Society of Hematology.

Mr. Sharma and colleagues analyzed data from the National Inpatient Sample database from 2007 to 2016. Of the 348,906 ITP hospitalizations included, there were 3,408 (0.98%) cases of ICH.

The overall incidence of ICH was low and remained stable over time, “which is reassuring,” Mr. Sharma said. However, the mortality rate was higher among patients with ICH than among those without it – 26.7% and 3.2%, respectively.

A multivariate analysis showed that female patients had a decreased likelihood of ICH, with an odds ratio of 0.81 (95% confidence interval, 0.68-0.97). Patients with private insurance had a decreased likelihood of ICH as well, with an OR of 0.81 (95% CI, 0.61-1.08).

Conversely, older patients had an increased likelihood of ICH. The OR was 2.23 (95% CI, 1.51-3.31) for patients aged 25-64 years, and the OR was 3.69 (95% CI, 2.34-5.84) for patients aged 65 years and older.

Patients with a gastrointestinal bleed or an other bleed (not including hematuria or epistaxis) had an increased likelihood of ICH. The ORs were 1.60 (95% CI, 1.18-2.16) and 1.69 (95% CI, 1.19-2.42), respectively.

Patients hospitalized in the western United States (OR, 1.62; 95% CI, 1.26-2.08), at a medium-sized hospital (OR, 1.64; 95% CI, 1.08-2.47), at a large hospital (OR, 2.42; 95% CI, 1.65-3.55), or at an urban teaching hospital (OR, 2.73; 95% CI, 1.80-4.13) all had an increased likelihood of ICH.

“Our second objective was to study the factors associated with mortality in ITP patients with ICH,” Mr. Sharma said. “We found female gender and Medicaid, private, or self-pay as primary payers to be associated with a lower mortality in ITP with ICH.

“[A]ge of 25-64 and 65 years and above, coexistence of a GI bleed or other bleed, and admission to a large or urban teaching hospital were associated with a higher mortality,” he added.

Mr. Sharma said the study’s strengths are that it is the most recent study on trends in ITP/ICH hospitalizations, and that it’s a longitudinal assessment of data from a nationally representative database.

The study’s limitations include its retrospective nature and the use of ICD codes, which could lead to inaccuracies. Data on prior therapies and long-term outcomes were not available, and the researchers were unable to differentiate between acute and chronic ITP.

Mr. Sharma said he had no relevant conflicts of interest.
 

[email protected]

SOURCE: Sharma M et al. ASH 2019, Abstract 55.

ORLANDO – A large, retrospective study suggests several factors are associated with an increased risk of intracranial hemorrhage in patients with immune thrombocytopenia.

Jennifer Smith/MDedge News

Data on more than 300,000 immune thrombocytopenia (ITP) hospitalizations indicated that older age, male sex, not having private insurance, having a gastrointestinal or “other” bleed, and receiving treatment at a hospital in the western United States, a medium- or large-sized hospital, or an urban teaching hospital were all associated with an increased risk of intracranial hemorrhage (ICH).

Mayank Sharma, of the University of Miami, detailed these findings at the annual meeting of the American Society of Hematology.

Mr. Sharma and colleagues analyzed data from the National Inpatient Sample database from 2007 to 2016. Of the 348,906 ITP hospitalizations included, there were 3,408 (0.98%) cases of ICH.

The overall incidence of ICH was low and remained stable over time, “which is reassuring,” Mr. Sharma said. However, the mortality rate was higher among patients with ICH than among those without it – 26.7% and 3.2%, respectively.

A multivariate analysis showed that female patients had a decreased likelihood of ICH, with an odds ratio of 0.81 (95% confidence interval, 0.68-0.97). Patients with private insurance had a decreased likelihood of ICH as well, with an OR of 0.81 (95% CI, 0.61-1.08).

Conversely, older patients had an increased likelihood of ICH. The OR was 2.23 (95% CI, 1.51-3.31) for patients aged 25-64 years, and the OR was 3.69 (95% CI, 2.34-5.84) for patients aged 65 years and older.

Patients with a gastrointestinal bleed or an other bleed (not including hematuria or epistaxis) had an increased likelihood of ICH. The ORs were 1.60 (95% CI, 1.18-2.16) and 1.69 (95% CI, 1.19-2.42), respectively.

Patients hospitalized in the western United States (OR, 1.62; 95% CI, 1.26-2.08), at a medium-sized hospital (OR, 1.64; 95% CI, 1.08-2.47), at a large hospital (OR, 2.42; 95% CI, 1.65-3.55), or at an urban teaching hospital (OR, 2.73; 95% CI, 1.80-4.13) all had an increased likelihood of ICH.

“Our second objective was to study the factors associated with mortality in ITP patients with ICH,” Mr. Sharma said. “We found female gender and Medicaid, private, or self-pay as primary payers to be associated with a lower mortality in ITP with ICH.

“[A]ge of 25-64 and 65 years and above, coexistence of a GI bleed or other bleed, and admission to a large or urban teaching hospital were associated with a higher mortality,” he added.

Mr. Sharma said the study’s strengths are that it is the most recent study on trends in ITP/ICH hospitalizations, and that it’s a longitudinal assessment of data from a nationally representative database.

The study’s limitations include its retrospective nature and the use of ICD codes, which could lead to inaccuracies. Data on prior therapies and long-term outcomes were not available, and the researchers were unable to differentiate between acute and chronic ITP.

Mr. Sharma said he had no relevant conflicts of interest.
 

[email protected]

SOURCE: Sharma M et al. ASH 2019, Abstract 55.

The GO2 Foundation for Lung Cancer has granted the 2019 Young Innovators Team Awards to two groups of investigators studying non-small cell lung cancer (NSCLC). Each group received $250,000 to support their work.

Dr. Guo and Dr. Davidson aim to prove that cancer cell metabolism affects the tumor microenvironment and leads to an impaired antitumor immune response. The pair’s ultimate goal is to overcome resistance to immunotherapy in KRAS-mutant NSCLC.


Matthew Bott, MD, of Memorial Sloan Kettering Cancer Center in New York, and Tuomas Tammela, MD, PhD, of Weill-Cornell Medical College in New York, won the award for their research on age-related differences in NSCLC.

[email protected]

The GO2 Foundation for Lung Cancer has granted the 2019 Young Innovators Team Awards to two groups of investigators studying non-small cell lung cancer (NSCLC). Each group received $250,000 to support their work.

Dr. Guo and Dr. Davidson aim to prove that cancer cell metabolism affects the tumor microenvironment and leads to an impaired antitumor immune response. The pair’s ultimate goal is to overcome resistance to immunotherapy in KRAS-mutant NSCLC.


Matthew Bott, MD, of Memorial Sloan Kettering Cancer Center in New York, and Tuomas Tammela, MD, PhD, of Weill-Cornell Medical College in New York, won the award for their research on age-related differences in NSCLC.

[email protected]

The GO2 Foundation for Lung Cancer has granted the 2019 Young Innovators Team Awards to two groups of investigators studying non-small cell lung cancer (NSCLC). Each group received $250,000 to support their work.

Dr. Guo and Dr. Davidson aim to prove that cancer cell metabolism affects the tumor microenvironment and leads to an impaired antitumor immune response. The pair’s ultimate goal is to overcome resistance to immunotherapy in KRAS-mutant NSCLC.


Matthew Bott, MD, of Memorial Sloan Kettering Cancer Center in New York, and Tuomas Tammela, MD, PhD, of Weill-Cornell Medical College in New York, won the award for their research on age-related differences in NSCLC.

[email protected]

ORLANDO – Updated trial results have revealed durable responses with venetoclax and ibrutinib in patients with mantle cell lymphoma (MCL), allowing some patients to stop treatment.

Jennifer Smith/MDedge News

Five of 24 patients were able to stop treatment after achieving minimal residual disease (MRD)-negative complete responses (CRs). Four of these patients remain in CR at up to 18 months off treatment, although one patient ultimately progressed and died.

“Treatment cessation was feasible for patients in MRD-negative complete responses, raising the prospect of limited-duration, targeted-agent therapy in the management of relapsed/refractory mantle cell lymphoma,” said Sasanka M. Handunnetti, MBBS, of Peter MacCallum Cancer Centre in Melbourne. Dr. Handunnetti presented these results, from the AIM trial, at the annual meeting of the American Society of Hematology.

The phase 2 trial enrolled 24 patients. At baseline, patients had a median age of 68 years (range, 47-81 years), and 88% were men. One patient was treatment-naive, but the rest had relapsed/refractory MCL. These patients had received a median of two prior therapies (range, 1-6).

The patients received venetoclax at 400 mg daily and ibrutinib at 560 mg daily.

In the primary analysis, the CR rate was 62% at week 16 and 71% overall, according to positron-emission tomography/computed tomography. MRD negativity was achieved by 67% of patients according to flow cytometry and 38% according to allele-specific oligonucleotide polymerase chain reaction (N Engl J Med. 2018 Mar 29;378[13]:1211-23).
 

Response and survival

For the current analysis, the median follow up was 37.5 months (range, 1.4-45.3 months). The median duration of response has not been reached, the median progression-free survival is 29 months, and the median overall survival is 32 months.

Thirteen patients have died, 8 of them due to progressive disease. The remaining 11 patients are still alive, and 9 of them are still in CR. One patient is still in partial response, and one has not responded but remains on ibrutinib and venetoclax.

Dr. Handunnetti pointed out that 12 patients had TP53 aberrations, and 8 of them died, but 4 remain alive and in CR. All four patients with SMARCA4 aberrations died.

Treatment status

Five patients are still receiving treatment with ibrutinib and venetoclax, and one patient is receiving only venetoclax. One patient went off study treatment due to a diagnosis of myelodysplastic syndrome, but that patient’s MCL is still in CR.

Five patients were able to stop treatment after achieving MRD-negative CR and were placed under “stringent surveillance,” Dr. Handunnetti said.

One of the five patients who stopped treatment progressed at 7 months and died. The remaining four patients are still alive and in CR at 6 months, 13 months, 17 months, and 18 months off treatment.
 

Safety update

Within the first 56 weeks of treatment, 15 patients required dose adjustments. Twelve patients required an adjustment to ibrutinib, seven to venetoclax, and four to both drugs. After 56 weeks, there were no dose adjustments.

Two patients developed therapy-related myelodysplastic syndrome. One patient had previously received FCR (fludarabine, cyclophosphamide, and rituximab) and BR (bendamustine and rituximab). The other patient had received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

This investigator-initiated trial was funded by Janssen and Abbvie. Dr. Handunnetti reported relationships with Abbvie and Gilead.

[email protected]

SOURCE: Handunnetti S et al. ASH 2019. Abstract 756.

ORLANDO – Updated trial results have revealed durable responses with venetoclax and ibrutinib in patients with mantle cell lymphoma (MCL), allowing some patients to stop treatment.

Jennifer Smith/MDedge News

Five of 24 patients were able to stop treatment after achieving minimal residual disease (MRD)-negative complete responses (CRs). Four of these patients remain in CR at up to 18 months off treatment, although one patient ultimately progressed and died.

“Treatment cessation was feasible for patients in MRD-negative complete responses, raising the prospect of limited-duration, targeted-agent therapy in the management of relapsed/refractory mantle cell lymphoma,” said Sasanka M. Handunnetti, MBBS, of Peter MacCallum Cancer Centre in Melbourne. Dr. Handunnetti presented these results, from the AIM trial, at the annual meeting of the American Society of Hematology.

The phase 2 trial enrolled 24 patients. At baseline, patients had a median age of 68 years (range, 47-81 years), and 88% were men. One patient was treatment-naive, but the rest had relapsed/refractory MCL. These patients had received a median of two prior therapies (range, 1-6).

The patients received venetoclax at 400 mg daily and ibrutinib at 560 mg daily.

In the primary analysis, the CR rate was 62% at week 16 and 71% overall, according to positron-emission tomography/computed tomography. MRD negativity was achieved by 67% of patients according to flow cytometry and 38% according to allele-specific oligonucleotide polymerase chain reaction (N Engl J Med. 2018 Mar 29;378[13]:1211-23).
 

Response and survival

For the current analysis, the median follow up was 37.5 months (range, 1.4-45.3 months). The median duration of response has not been reached, the median progression-free survival is 29 months, and the median overall survival is 32 months.

Thirteen patients have died, 8 of them due to progressive disease. The remaining 11 patients are still alive, and 9 of them are still in CR. One patient is still in partial response, and one has not responded but remains on ibrutinib and venetoclax.

Dr. Handunnetti pointed out that 12 patients had TP53 aberrations, and 8 of them died, but 4 remain alive and in CR. All four patients with SMARCA4 aberrations died.

Treatment status

Five patients are still receiving treatment with ibrutinib and venetoclax, and one patient is receiving only venetoclax. One patient went off study treatment due to a diagnosis of myelodysplastic syndrome, but that patient’s MCL is still in CR.

Five patients were able to stop treatment after achieving MRD-negative CR and were placed under “stringent surveillance,” Dr. Handunnetti said.

One of the five patients who stopped treatment progressed at 7 months and died. The remaining four patients are still alive and in CR at 6 months, 13 months, 17 months, and 18 months off treatment.
 

Safety update

Within the first 56 weeks of treatment, 15 patients required dose adjustments. Twelve patients required an adjustment to ibrutinib, seven to venetoclax, and four to both drugs. After 56 weeks, there were no dose adjustments.

Two patients developed therapy-related myelodysplastic syndrome. One patient had previously received FCR (fludarabine, cyclophosphamide, and rituximab) and BR (bendamustine and rituximab). The other patient had received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

This investigator-initiated trial was funded by Janssen and Abbvie. Dr. Handunnetti reported relationships with Abbvie and Gilead.

[email protected]

SOURCE: Handunnetti S et al. ASH 2019. Abstract 756.

ORLANDO – Updated trial results have revealed durable responses with venetoclax and ibrutinib in patients with mantle cell lymphoma (MCL), allowing some patients to stop treatment.

Jennifer Smith/MDedge News

Five of 24 patients were able to stop treatment after achieving minimal residual disease (MRD)-negative complete responses (CRs). Four of these patients remain in CR at up to 18 months off treatment, although one patient ultimately progressed and died.

“Treatment cessation was feasible for patients in MRD-negative complete responses, raising the prospect of limited-duration, targeted-agent therapy in the management of relapsed/refractory mantle cell lymphoma,” said Sasanka M. Handunnetti, MBBS, of Peter MacCallum Cancer Centre in Melbourne. Dr. Handunnetti presented these results, from the AIM trial, at the annual meeting of the American Society of Hematology.

The phase 2 trial enrolled 24 patients. At baseline, patients had a median age of 68 years (range, 47-81 years), and 88% were men. One patient was treatment-naive, but the rest had relapsed/refractory MCL. These patients had received a median of two prior therapies (range, 1-6).

The patients received venetoclax at 400 mg daily and ibrutinib at 560 mg daily.

In the primary analysis, the CR rate was 62% at week 16 and 71% overall, according to positron-emission tomography/computed tomography. MRD negativity was achieved by 67% of patients according to flow cytometry and 38% according to allele-specific oligonucleotide polymerase chain reaction (N Engl J Med. 2018 Mar 29;378[13]:1211-23).
 

Response and survival

For the current analysis, the median follow up was 37.5 months (range, 1.4-45.3 months). The median duration of response has not been reached, the median progression-free survival is 29 months, and the median overall survival is 32 months.

Thirteen patients have died, 8 of them due to progressive disease. The remaining 11 patients are still alive, and 9 of them are still in CR. One patient is still in partial response, and one has not responded but remains on ibrutinib and venetoclax.

Dr. Handunnetti pointed out that 12 patients had TP53 aberrations, and 8 of them died, but 4 remain alive and in CR. All four patients with SMARCA4 aberrations died.

Treatment status

Five patients are still receiving treatment with ibrutinib and venetoclax, and one patient is receiving only venetoclax. One patient went off study treatment due to a diagnosis of myelodysplastic syndrome, but that patient’s MCL is still in CR.

Five patients were able to stop treatment after achieving MRD-negative CR and were placed under “stringent surveillance,” Dr. Handunnetti said.

One of the five patients who stopped treatment progressed at 7 months and died. The remaining four patients are still alive and in CR at 6 months, 13 months, 17 months, and 18 months off treatment.
 

Safety update

Within the first 56 weeks of treatment, 15 patients required dose adjustments. Twelve patients required an adjustment to ibrutinib, seven to venetoclax, and four to both drugs. After 56 weeks, there were no dose adjustments.

Two patients developed therapy-related myelodysplastic syndrome. One patient had previously received FCR (fludarabine, cyclophosphamide, and rituximab) and BR (bendamustine and rituximab). The other patient had received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

This investigator-initiated trial was funded by Janssen and Abbvie. Dr. Handunnetti reported relationships with Abbvie and Gilead.

[email protected]

SOURCE: Handunnetti S et al. ASH 2019. Abstract 756.

ORLANDO – KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, demonstrated unprecedented efficacy in the ZUMA-2 trial, according to an investigator involved in the study.

Jennifer Smith/MDedge News

KTE-X19 produced a 93% overall response rate in patients with relapsed/refractory mantle cell lymphoma (MCL). This is the highest reported response rate in patients who have failed treatment with a Bruton’s tyrosine kinase (BTK) inhibitor, said Michael L. Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston.

Dr. Wang presented results from ZUMA-2 at the annual meeting of the American Society of Hematology.

“Patients with relapsed/refractory MCL have very poor outcomes,” Dr. Wang noted. “In patients who progress after BTK inhibition therapy, the overall response rate is only between 25% and 42%, and the overall survival is only between 6 and 10 months. Few patients proceed to allogeneic transplantation.”

The phase 2 ZUMA-2 trial was designed to test KTE-X19 in these patients. KTE-X19 is an anti-CD19 CAR T-cell therapy containing a CD3-zeta T-cell activation domain and a CD28 signaling domain. KTE-X19 is distinct from axicabtagene ciloleucel (KTE-C19) because the manufacturing process for KTE-X19 removes circulating tumor cells.

The trial enrolled 74 patients, and 68 of them received KTE-X19. Manufacturing failed for three patients, two patients died of progressive disease before they could receive KTE-X19, and one patient was found to be ineligible for treatment.

The 68 patients had a median age of 65 years (range, 38-79 years), and 84% were men. A majority of patients (85%) had stage IV disease and classical (59%) or blastoid (25%) morphology. Most patients (69%) had a Ki-67 proliferation index of 50% or greater, and most (56%) were intermediate- or high-risk according to the Mantle Cell Lymphoma International Prognostic Index (MIPI).

Patients had received a median of three prior therapies (range, one to five). All had been treated with a BTK inhibitor, with 85% receiving ibrutinib, 24% receiving acalabrutinib, and 9% receiving both. Most patients (68%) were refractory to BTK inhibition, and 32% relapsed on or after BTK inhibitor therapy.

Efficacy

Sixty patients were evaluable for efficacy, and the median follow-up was 12.3 months (range, 7.0-32.3 months).

The overall response rate was 93%, with 67% of patients achieving a complete response and 27% achieving a partial response. Three percent of patients had stable disease, and 3% had progressive disease.

“The overall response rate was consistent across key subgroups, without any statistical difference,” Dr. Wang said. “This includes Ki-67, MIPI, and prior use of either steroids or bridging therapy.”

The median time to response was 1.0 month, and the median time to complete response was 3.0 months. Responses deepened over time, with 35% of patients converting from a partial response to a complete response, and 5% converting from stable disease to complete response.

The median duration of response has not been reached. At last follow-up, 57% of all patients and 78% of complete responders were still in response.

The median progression-free and overall survival have not been reached. At 12 months, the progression-free survival rate was 61%, and the overall survival rate was 83%.
 

Safety

All 68 patients were evaluable for safety. The most common adverse events were pyrexia (94%), neutropenia (87%), thrombocytopenia (74%), anemia (68%), and hypotension (51%).

Grade 3/4 adverse events included pyrexia (13%), neutropenia (85%), thrombocytopenia (51%), anemia (50%), hypotension (22%), hypoxia (21%), hypophosphatemia (22%), fatigue (1%), and headache (1%).

There were two grade 5 treatment-related adverse events – organizing pneumonia on day 37 and staphylococcal bacteremia on day 134.

Cytokine release syndrome (CRS) occurred in 91% of patients, with 15% experiencing grade 3 or higher CRS. Patients were treated with tocilizumab or corticosteroids, and all CRS events resolved.

Neurologic adverse events occurred in 63% of patients, with grade 3 or higher events occurring in 31%. Neurologic events were treated with tocilizumab or corticosteroids, and 86% of neurologic events resolved.

This trial was sponsored by Kite, a Gilead company. Dr. Wang reported financial relationships with Kite and other companies.

[email protected]

SOURCE: Wang M et al. ASH 2019. Abstract 754.

ORLANDO – KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, demonstrated unprecedented efficacy in the ZUMA-2 trial, according to an investigator involved in the study.

Jennifer Smith/MDedge News

KTE-X19 produced a 93% overall response rate in patients with relapsed/refractory mantle cell lymphoma (MCL). This is the highest reported response rate in patients who have failed treatment with a Bruton’s tyrosine kinase (BTK) inhibitor, said Michael L. Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston.

Dr. Wang presented results from ZUMA-2 at the annual meeting of the American Society of Hematology.

“Patients with relapsed/refractory MCL have very poor outcomes,” Dr. Wang noted. “In patients who progress after BTK inhibition therapy, the overall response rate is only between 25% and 42%, and the overall survival is only between 6 and 10 months. Few patients proceed to allogeneic transplantation.”

The phase 2 ZUMA-2 trial was designed to test KTE-X19 in these patients. KTE-X19 is an anti-CD19 CAR T-cell therapy containing a CD3-zeta T-cell activation domain and a CD28 signaling domain. KTE-X19 is distinct from axicabtagene ciloleucel (KTE-C19) because the manufacturing process for KTE-X19 removes circulating tumor cells.

The trial enrolled 74 patients, and 68 of them received KTE-X19. Manufacturing failed for three patients, two patients died of progressive disease before they could receive KTE-X19, and one patient was found to be ineligible for treatment.

The 68 patients had a median age of 65 years (range, 38-79 years), and 84% were men. A majority of patients (85%) had stage IV disease and classical (59%) or blastoid (25%) morphology. Most patients (69%) had a Ki-67 proliferation index of 50% or greater, and most (56%) were intermediate- or high-risk according to the Mantle Cell Lymphoma International Prognostic Index (MIPI).

Patients had received a median of three prior therapies (range, one to five). All had been treated with a BTK inhibitor, with 85% receiving ibrutinib, 24% receiving acalabrutinib, and 9% receiving both. Most patients (68%) were refractory to BTK inhibition, and 32% relapsed on or after BTK inhibitor therapy.

Efficacy

Sixty patients were evaluable for efficacy, and the median follow-up was 12.3 months (range, 7.0-32.3 months).

The overall response rate was 93%, with 67% of patients achieving a complete response and 27% achieving a partial response. Three percent of patients had stable disease, and 3% had progressive disease.

“The overall response rate was consistent across key subgroups, without any statistical difference,” Dr. Wang said. “This includes Ki-67, MIPI, and prior use of either steroids or bridging therapy.”

The median time to response was 1.0 month, and the median time to complete response was 3.0 months. Responses deepened over time, with 35% of patients converting from a partial response to a complete response, and 5% converting from stable disease to complete response.

The median duration of response has not been reached. At last follow-up, 57% of all patients and 78% of complete responders were still in response.

The median progression-free and overall survival have not been reached. At 12 months, the progression-free survival rate was 61%, and the overall survival rate was 83%.
 

Safety

All 68 patients were evaluable for safety. The most common adverse events were pyrexia (94%), neutropenia (87%), thrombocytopenia (74%), anemia (68%), and hypotension (51%).

Grade 3/4 adverse events included pyrexia (13%), neutropenia (85%), thrombocytopenia (51%), anemia (50%), hypotension (22%), hypoxia (21%), hypophosphatemia (22%), fatigue (1%), and headache (1%).

There were two grade 5 treatment-related adverse events – organizing pneumonia on day 37 and staphylococcal bacteremia on day 134.

Cytokine release syndrome (CRS) occurred in 91% of patients, with 15% experiencing grade 3 or higher CRS. Patients were treated with tocilizumab or corticosteroids, and all CRS events resolved.

Neurologic adverse events occurred in 63% of patients, with grade 3 or higher events occurring in 31%. Neurologic events were treated with tocilizumab or corticosteroids, and 86% of neurologic events resolved.

This trial was sponsored by Kite, a Gilead company. Dr. Wang reported financial relationships with Kite and other companies.

[email protected]

SOURCE: Wang M et al. ASH 2019. Abstract 754.

ORLANDO – KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, demonstrated unprecedented efficacy in the ZUMA-2 trial, according to an investigator involved in the study.

Jennifer Smith/MDedge News

KTE-X19 produced a 93% overall response rate in patients with relapsed/refractory mantle cell lymphoma (MCL). This is the highest reported response rate in patients who have failed treatment with a Bruton’s tyrosine kinase (BTK) inhibitor, said Michael L. Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston.

Dr. Wang presented results from ZUMA-2 at the annual meeting of the American Society of Hematology.

“Patients with relapsed/refractory MCL have very poor outcomes,” Dr. Wang noted. “In patients who progress after BTK inhibition therapy, the overall response rate is only between 25% and 42%, and the overall survival is only between 6 and 10 months. Few patients proceed to allogeneic transplantation.”

The phase 2 ZUMA-2 trial was designed to test KTE-X19 in these patients. KTE-X19 is an anti-CD19 CAR T-cell therapy containing a CD3-zeta T-cell activation domain and a CD28 signaling domain. KTE-X19 is distinct from axicabtagene ciloleucel (KTE-C19) because the manufacturing process for KTE-X19 removes circulating tumor cells.

The trial enrolled 74 patients, and 68 of them received KTE-X19. Manufacturing failed for three patients, two patients died of progressive disease before they could receive KTE-X19, and one patient was found to be ineligible for treatment.

The 68 patients had a median age of 65 years (range, 38-79 years), and 84% were men. A majority of patients (85%) had stage IV disease and classical (59%) or blastoid (25%) morphology. Most patients (69%) had a Ki-67 proliferation index of 50% or greater, and most (56%) were intermediate- or high-risk according to the Mantle Cell Lymphoma International Prognostic Index (MIPI).

Patients had received a median of three prior therapies (range, one to five). All had been treated with a BTK inhibitor, with 85% receiving ibrutinib, 24% receiving acalabrutinib, and 9% receiving both. Most patients (68%) were refractory to BTK inhibition, and 32% relapsed on or after BTK inhibitor therapy.

Efficacy

Sixty patients were evaluable for efficacy, and the median follow-up was 12.3 months (range, 7.0-32.3 months).

The overall response rate was 93%, with 67% of patients achieving a complete response and 27% achieving a partial response. Three percent of patients had stable disease, and 3% had progressive disease.

“The overall response rate was consistent across key subgroups, without any statistical difference,” Dr. Wang said. “This includes Ki-67, MIPI, and prior use of either steroids or bridging therapy.”

The median time to response was 1.0 month, and the median time to complete response was 3.0 months. Responses deepened over time, with 35% of patients converting from a partial response to a complete response, and 5% converting from stable disease to complete response.

The median duration of response has not been reached. At last follow-up, 57% of all patients and 78% of complete responders were still in response.

The median progression-free and overall survival have not been reached. At 12 months, the progression-free survival rate was 61%, and the overall survival rate was 83%.
 

Safety

All 68 patients were evaluable for safety. The most common adverse events were pyrexia (94%), neutropenia (87%), thrombocytopenia (74%), anemia (68%), and hypotension (51%).

Grade 3/4 adverse events included pyrexia (13%), neutropenia (85%), thrombocytopenia (51%), anemia (50%), hypotension (22%), hypoxia (21%), hypophosphatemia (22%), fatigue (1%), and headache (1%).

There were two grade 5 treatment-related adverse events – organizing pneumonia on day 37 and staphylococcal bacteremia on day 134.

Cytokine release syndrome (CRS) occurred in 91% of patients, with 15% experiencing grade 3 or higher CRS. Patients were treated with tocilizumab or corticosteroids, and all CRS events resolved.

Neurologic adverse events occurred in 63% of patients, with grade 3 or higher events occurring in 31%. Neurologic events were treated with tocilizumab or corticosteroids, and 86% of neurologic events resolved.

This trial was sponsored by Kite, a Gilead company. Dr. Wang reported financial relationships with Kite and other companies.

[email protected]

SOURCE: Wang M et al. ASH 2019. Abstract 754.