User login
Insights from the 5-year follow-up of CTL019 in CLL
Photo courtesy of the
University of Pennsylvania
NEW YORK—The 5-year follow-up of the phase 1 trial of CTL019 in relapsed or refractory chronic lymphoblastic leukemia (CLL) is allowing investigators to define more clearly who will respond to chimeric antigen receptor (CAR) T cells directed against CD19.
One thing investigators have determined is that persistence of the CARs is essential for long-term responses.
In the first 2 patients who achieved a complete remission (CR), CAR T cells persisted for more than 4 years. In addition, no patient in CR has relapsed to date.
Of the 14 patients enrolled in the trial, 4 (28%) achieved a CR, 4 (28%) achieved a partial response, and 6 (43%) had no response, for an overall response rate of 57%.
These results were recently published in Science Translational Medicine.
Carl June, MD, of the University of Pennsylvania in Philadelphia, shared some insights into the research with attendees at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.
Dr June explained that CTL019 is a CD19-directed single chain variable fragment with a 4-1BB signaling module that transduces T cells with a lentiviral vector. The technology was developed at the University of Pennsylvania and subsequently licensed to Novartis.
In the phase 1 trial of CTL019 in CLL, patients who achieved complete remission have very high levels of CARs—100% of the circulating T cells—but the non-responders don’t. The CARs engrafted in non-responders but did not proliferate.
“So the biomarker correlate of success is persistence and proliferation, in CLL at least,” Dr June said.
The investigators performed IGH next-generation sequencing and found no detectable CLL clones in the complete responders, including 1 patient at 3.5 years and another at 4 years post-infusion.
“There was no clinically evident disease in these patients,” Dr June said, “and so the responses are durable.”
The team also believes that at least a subset of the cells remains functional because the patients still had B-cell aplasia.
The investigators have not observed a CD19 loss in any CLL patient who responded.
“Patients who have gone into remission stay in remission,” Dr June added.
Kinetics of delayed CR
Dr June discussed in detail Patient 10, whose response was somewhat different from the other complete responders. Patient 10 achieved a CR, but the response was delayed. It took 51 days after infusion, compared to about 10 days in the other complete responders.
Patient 10 was initially scored as a failure at the 28-day evaluation. Eventually, he had marked improvement, and, by a year, he was in CR.
He required hospitalization for tumor lysis syndrome and treatment with tocilizumab for cytokine release syndrome.
Patient 10 had a single cell that investigators surmise could have been responsible for the tumor elimination.
“In fact, on day 28, when he still had tumor, his CARs were polyclonal,” Dr June said. “So we stained and isolated his CARs by sorting, and, at time of tumor elimination, he had descendants of 1 CAR.”
Nevertheless, Patient 10’s response is durable. He is now 81 years old and remains engrafted with CAR19 cells.
Investigators hypothesize that the kinetics and CAR proliferation were so different in Patient 10 because Tet2 was disrupted by the integration of the CAR into the intronic region.
“What we don’t know is whether Tet2 was a passenger or a driver here,” Dr June observed. “Did it actually aid the function of the CAR cells or was it just a marker?”
He noted that Tet2 has been shown in acute myeloid leukemia to increase stem cell renewal, “and it may well have done that in this patient.” 
Photo courtesy of the
University of Pennsylvania
NEW YORK—The 5-year follow-up of the phase 1 trial of CTL019 in relapsed or refractory chronic lymphoblastic leukemia (CLL) is allowing investigators to define more clearly who will respond to chimeric antigen receptor (CAR) T cells directed against CD19.
One thing investigators have determined is that persistence of the CARs is essential for long-term responses.
In the first 2 patients who achieved a complete remission (CR), CAR T cells persisted for more than 4 years. In addition, no patient in CR has relapsed to date.
Of the 14 patients enrolled in the trial, 4 (28%) achieved a CR, 4 (28%) achieved a partial response, and 6 (43%) had no response, for an overall response rate of 57%.
These results were recently published in Science Translational Medicine.
Carl June, MD, of the University of Pennsylvania in Philadelphia, shared some insights into the research with attendees at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.
Dr June explained that CTL019 is a CD19-directed single chain variable fragment with a 4-1BB signaling module that transduces T cells with a lentiviral vector. The technology was developed at the University of Pennsylvania and subsequently licensed to Novartis.
In the phase 1 trial of CTL019 in CLL, patients who achieved complete remission have very high levels of CARs—100% of the circulating T cells—but the non-responders don’t. The CARs engrafted in non-responders but did not proliferate.
“So the biomarker correlate of success is persistence and proliferation, in CLL at least,” Dr June said.
The investigators performed IGH next-generation sequencing and found no detectable CLL clones in the complete responders, including 1 patient at 3.5 years and another at 4 years post-infusion.
“There was no clinically evident disease in these patients,” Dr June said, “and so the responses are durable.”
The team also believes that at least a subset of the cells remains functional because the patients still had B-cell aplasia.
The investigators have not observed a CD19 loss in any CLL patient who responded.
“Patients who have gone into remission stay in remission,” Dr June added.
Kinetics of delayed CR
Dr June discussed in detail Patient 10, whose response was somewhat different from the other complete responders. Patient 10 achieved a CR, but the response was delayed. It took 51 days after infusion, compared to about 10 days in the other complete responders.
Patient 10 was initially scored as a failure at the 28-day evaluation. Eventually, he had marked improvement, and, by a year, he was in CR.
He required hospitalization for tumor lysis syndrome and treatment with tocilizumab for cytokine release syndrome.
Patient 10 had a single cell that investigators surmise could have been responsible for the tumor elimination.
“In fact, on day 28, when he still had tumor, his CARs were polyclonal,” Dr June said. “So we stained and isolated his CARs by sorting, and, at time of tumor elimination, he had descendants of 1 CAR.”
Nevertheless, Patient 10’s response is durable. He is now 81 years old and remains engrafted with CAR19 cells.
Investigators hypothesize that the kinetics and CAR proliferation were so different in Patient 10 because Tet2 was disrupted by the integration of the CAR into the intronic region.
“What we don’t know is whether Tet2 was a passenger or a driver here,” Dr June observed. “Did it actually aid the function of the CAR cells or was it just a marker?”
He noted that Tet2 has been shown in acute myeloid leukemia to increase stem cell renewal, “and it may well have done that in this patient.”
Photo courtesy of the
University of Pennsylvania
NEW YORK—The 5-year follow-up of the phase 1 trial of CTL019 in relapsed or refractory chronic lymphoblastic leukemia (CLL) is allowing investigators to define more clearly who will respond to chimeric antigen receptor (CAR) T cells directed against CD19.
One thing investigators have determined is that persistence of the CARs is essential for long-term responses.
In the first 2 patients who achieved a complete remission (CR), CAR T cells persisted for more than 4 years. In addition, no patient in CR has relapsed to date.
Of the 14 patients enrolled in the trial, 4 (28%) achieved a CR, 4 (28%) achieved a partial response, and 6 (43%) had no response, for an overall response rate of 57%.
These results were recently published in Science Translational Medicine.
Carl June, MD, of the University of Pennsylvania in Philadelphia, shared some insights into the research with attendees at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.
Dr June explained that CTL019 is a CD19-directed single chain variable fragment with a 4-1BB signaling module that transduces T cells with a lentiviral vector. The technology was developed at the University of Pennsylvania and subsequently licensed to Novartis.
In the phase 1 trial of CTL019 in CLL, patients who achieved complete remission have very high levels of CARs—100% of the circulating T cells—but the non-responders don’t. The CARs engrafted in non-responders but did not proliferate.
“So the biomarker correlate of success is persistence and proliferation, in CLL at least,” Dr June said.
The investigators performed IGH next-generation sequencing and found no detectable CLL clones in the complete responders, including 1 patient at 3.5 years and another at 4 years post-infusion.
“There was no clinically evident disease in these patients,” Dr June said, “and so the responses are durable.”
The team also believes that at least a subset of the cells remains functional because the patients still had B-cell aplasia.
The investigators have not observed a CD19 loss in any CLL patient who responded.
“Patients who have gone into remission stay in remission,” Dr June added.
Kinetics of delayed CR
Dr June discussed in detail Patient 10, whose response was somewhat different from the other complete responders. Patient 10 achieved a CR, but the response was delayed. It took 51 days after infusion, compared to about 10 days in the other complete responders.
Patient 10 was initially scored as a failure at the 28-day evaluation. Eventually, he had marked improvement, and, by a year, he was in CR.
He required hospitalization for tumor lysis syndrome and treatment with tocilizumab for cytokine release syndrome.
Patient 10 had a single cell that investigators surmise could have been responsible for the tumor elimination.
“In fact, on day 28, when he still had tumor, his CARs were polyclonal,” Dr June said. “So we stained and isolated his CARs by sorting, and, at time of tumor elimination, he had descendants of 1 CAR.”
Nevertheless, Patient 10’s response is durable. He is now 81 years old and remains engrafted with CAR19 cells.
Investigators hypothesize that the kinetics and CAR proliferation were so different in Patient 10 because Tet2 was disrupted by the integration of the CAR into the intronic region.
“What we don’t know is whether Tet2 was a passenger or a driver here,” Dr June observed. “Did it actually aid the function of the CAR cells or was it just a marker?”
He noted that Tet2 has been shown in acute myeloid leukemia to increase stem cell renewal, “and it may well have done that in this patient.”
CAR T-cell therapy tested in Sweden
NEW YORK—For the first time, according to researchers, chimeric antigen receptor (CAR) T-cell therapy has been tested in a clinical trial in Sweden.
Early results have shown the treatment can produce complete responses (CRs) in leukemia and lymphoma, although most patients ultimately progressed.
Hannah Karlsson, PhD, of Uppsala University in Sweden, presented data from the phase 1/2a trial of the third-generation CD19 CAR T-cell therapy (abstract A041*) at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.
The trial is a collaboration between Uppsala University and Baylor College of Medicine and was funded by AFA Insurances AB and the Swedish Cancer Society.
“Third-generation CAR T cells are being tested in clinical trials for leukemia patients in the United States with success,” said senior study author Angelica Loskog, PhD, also of Uppsala University.
“[T]he main purpose of our clinical trial was to evaluate whether we could reproduce the successful results in leukemia patients in Sweden and to also test if patients with lymphoma will also respond to this treatment.”
So the investigators enrolled 13 patients, 11 of whom were evaluable for efficacy at 3 months after CAR T-cell infusion. All patients had relapsed or refractory, CD19-positive, B-cell disease.
Two patients had acute lymphoblastic leukemia (ALL), 2 had chronic lymphocytic leukemia (CLL), and 7 had lymphoma—3 with diffuse large B-cell lymphoma (DLBCL), 2 with mantle cell lymphoma (MCL), 1 with follicular lymphoma (FL)/DLBCL, and 1 with Burkitt lymphoma.
All of the lymphoma patients received chemotherapy before CAR T-cell infusion to shrink their tumors. Seven patients—3 with leukemia and 4 with lymphoma—received pre-conditioning with cyclophosphamide plus fludarabine to reduce their immunosuppressive cell counts.
The investigators used CAR T cells containing signaling domains from both CD28 and 4-1BB and manufactured using a gamma retrovirus.
Patients received a single infusion of the CAR T cells, 2 patients at a dose of 2 x 107 cells/m2, 4 at a dose of 1 x 108 cells/m2, and 5 at 2 x 108 cells/m2.
Response and toxicity
Six patients had achieved a CR at the time of evaluation.
One patient with DLBCL experienced mild cytokine release syndrome (CRS) before achieving CR. However, the patient relapsed after a second CRS occurred (after 3 months).
Another DLBCL patient achieved a CR prior to T-cell infusion and remained in CR for 6 months before progressing.
One CLL patient and another DLBCL patient responded prior to T-cell infusion and remained in CR for more than 3 months. The CLL patient was still in CR at the time of the meeting.
One of the ALL patients achieved a CR after transient central nervous system toxicity but relapsed at 3 months with CD19-negative ALL. The other ALL patient was in CR for more than a month after experiencing CRS but ultimately progressed.
One CLL patient and 2 MCL patients had all progressed by 3 months.
The FL/DLBCL patient progressed after 1 month, with mild CRS. And the patient with Burkitt lymphoma had major CRS and progressive disease.
The investigators noted that 5 of the 6 patients who received pre-conditioning treatment had initial CRs.
The team is now analyzing whether there is any correlation between the level of immunosuppressive cells and patient response.
*Information presented at the meeting differs from the abstract.
NEW YORK—For the first time, according to researchers, chimeric antigen receptor (CAR) T-cell therapy has been tested in a clinical trial in Sweden.
Early results have shown the treatment can produce complete responses (CRs) in leukemia and lymphoma, although most patients ultimately progressed.
Hannah Karlsson, PhD, of Uppsala University in Sweden, presented data from the phase 1/2a trial of the third-generation CD19 CAR T-cell therapy (abstract A041*) at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.
The trial is a collaboration between Uppsala University and Baylor College of Medicine and was funded by AFA Insurances AB and the Swedish Cancer Society.
“Third-generation CAR T cells are being tested in clinical trials for leukemia patients in the United States with success,” said senior study author Angelica Loskog, PhD, also of Uppsala University.
“[T]he main purpose of our clinical trial was to evaluate whether we could reproduce the successful results in leukemia patients in Sweden and to also test if patients with lymphoma will also respond to this treatment.”
So the investigators enrolled 13 patients, 11 of whom were evaluable for efficacy at 3 months after CAR T-cell infusion. All patients had relapsed or refractory, CD19-positive, B-cell disease.
Two patients had acute lymphoblastic leukemia (ALL), 2 had chronic lymphocytic leukemia (CLL), and 7 had lymphoma—3 with diffuse large B-cell lymphoma (DLBCL), 2 with mantle cell lymphoma (MCL), 1 with follicular lymphoma (FL)/DLBCL, and 1 with Burkitt lymphoma.
All of the lymphoma patients received chemotherapy before CAR T-cell infusion to shrink their tumors. Seven patients—3 with leukemia and 4 with lymphoma—received pre-conditioning with cyclophosphamide plus fludarabine to reduce their immunosuppressive cell counts.
The investigators used CAR T cells containing signaling domains from both CD28 and 4-1BB and manufactured using a gamma retrovirus.
Patients received a single infusion of the CAR T cells, 2 patients at a dose of 2 x 107 cells/m2, 4 at a dose of 1 x 108 cells/m2, and 5 at 2 x 108 cells/m2.
Response and toxicity
Six patients had achieved a CR at the time of evaluation.
One patient with DLBCL experienced mild cytokine release syndrome (CRS) before achieving CR. However, the patient relapsed after a second CRS occurred (after 3 months).
Another DLBCL patient achieved a CR prior to T-cell infusion and remained in CR for 6 months before progressing.
One CLL patient and another DLBCL patient responded prior to T-cell infusion and remained in CR for more than 3 months. The CLL patient was still in CR at the time of the meeting.
One of the ALL patients achieved a CR after transient central nervous system toxicity but relapsed at 3 months with CD19-negative ALL. The other ALL patient was in CR for more than a month after experiencing CRS but ultimately progressed.
One CLL patient and 2 MCL patients had all progressed by 3 months.
The FL/DLBCL patient progressed after 1 month, with mild CRS. And the patient with Burkitt lymphoma had major CRS and progressive disease.
The investigators noted that 5 of the 6 patients who received pre-conditioning treatment had initial CRs.
The team is now analyzing whether there is any correlation between the level of immunosuppressive cells and patient response.
*Information presented at the meeting differs from the abstract.
NEW YORK—For the first time, according to researchers, chimeric antigen receptor (CAR) T-cell therapy has been tested in a clinical trial in Sweden.
Early results have shown the treatment can produce complete responses (CRs) in leukemia and lymphoma, although most patients ultimately progressed.
Hannah Karlsson, PhD, of Uppsala University in Sweden, presented data from the phase 1/2a trial of the third-generation CD19 CAR T-cell therapy (abstract A041*) at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.
The trial is a collaboration between Uppsala University and Baylor College of Medicine and was funded by AFA Insurances AB and the Swedish Cancer Society.
“Third-generation CAR T cells are being tested in clinical trials for leukemia patients in the United States with success,” said senior study author Angelica Loskog, PhD, also of Uppsala University.
“[T]he main purpose of our clinical trial was to evaluate whether we could reproduce the successful results in leukemia patients in Sweden and to also test if patients with lymphoma will also respond to this treatment.”
So the investigators enrolled 13 patients, 11 of whom were evaluable for efficacy at 3 months after CAR T-cell infusion. All patients had relapsed or refractory, CD19-positive, B-cell disease.
Two patients had acute lymphoblastic leukemia (ALL), 2 had chronic lymphocytic leukemia (CLL), and 7 had lymphoma—3 with diffuse large B-cell lymphoma (DLBCL), 2 with mantle cell lymphoma (MCL), 1 with follicular lymphoma (FL)/DLBCL, and 1 with Burkitt lymphoma.
All of the lymphoma patients received chemotherapy before CAR T-cell infusion to shrink their tumors. Seven patients—3 with leukemia and 4 with lymphoma—received pre-conditioning with cyclophosphamide plus fludarabine to reduce their immunosuppressive cell counts.
The investigators used CAR T cells containing signaling domains from both CD28 and 4-1BB and manufactured using a gamma retrovirus.
Patients received a single infusion of the CAR T cells, 2 patients at a dose of 2 x 107 cells/m2, 4 at a dose of 1 x 108 cells/m2, and 5 at 2 x 108 cells/m2.
Response and toxicity
Six patients had achieved a CR at the time of evaluation.
One patient with DLBCL experienced mild cytokine release syndrome (CRS) before achieving CR. However, the patient relapsed after a second CRS occurred (after 3 months).
Another DLBCL patient achieved a CR prior to T-cell infusion and remained in CR for 6 months before progressing.
One CLL patient and another DLBCL patient responded prior to T-cell infusion and remained in CR for more than 3 months. The CLL patient was still in CR at the time of the meeting.
One of the ALL patients achieved a CR after transient central nervous system toxicity but relapsed at 3 months with CD19-negative ALL. The other ALL patient was in CR for more than a month after experiencing CRS but ultimately progressed.
One CLL patient and 2 MCL patients had all progressed by 3 months.
The FL/DLBCL patient progressed after 1 month, with mild CRS. And the patient with Burkitt lymphoma had major CRS and progressive disease.
The investigators noted that 5 of the 6 patients who received pre-conditioning treatment had initial CRs.
The team is now analyzing whether there is any correlation between the level of immunosuppressive cells and patient response.
*Information presented at the meeting differs from the abstract.
Novel mAb targeting CD70 shows activity in TCL
Photo by Linda Bartlett
LUGANO—The defucosylated monoclonal antibody (mAb) ARGX-110, which is active against CD70-bearing tumor cells and CD70-dependent stimulation of regulatory T cells, has shown activity in relapsed/refractory T-cell lymphoma (TCL), according to investigators.
Of the 8 TCL patients enrolled in a phase 1 trial of ARGX-110, 3 had a biological response to the mAb.
In this dose-escalation trial, the maximum tolerated dose of ARGX-110 was not reached.
Marie Maerevoet, MD, of the Institut Jules Bordet in Brussels, Belgium, presented results from the lymphoma cohort of this trial at the 13th International Congress on Malignant Lymphoma (abstract 040*). The study was sponsored by arGEN-X, the company developing ARGX-110.
Dr Maerevoet pointed out that more than half the tumor cells in 71% of patients with cutaneous T-cell lymphoma (CTCL) and 22% with peripheral T-cell lymphoma (PTCL) are CD70-positive. CD70 signaling occurs via CD27, and CD27 shedding is a biomarker for an active pathway.
Since ARGX-110 has an affinity for CD70, inhibits CD27 signaling, and mediates the lysis of TCL in Sézary syndrome (SS), mycosis fungoides, and anaplastic large cell lymphoma (ALCL) cell lines, researchers decided to investigate the safety and clinical pharmacology of ARGX-110 monotherapy in metastatic, relapsed or refractory, solid tumors and hematologic malignancies.
Patients’ tumors had to express CD70 by immunohistochemistry, defined as more than 10% tumor cells of 2+ or 3+ intensity.
The primary endpoint was to determine the maximum tolerated dose. Secondary endpoints were pharmacology, immunogenicity, and efficacy signals.
Patient demographics
Between February 2013 and April 2015, investigators assigned 63 patients to receive ARGX-110 at doses ranging from 0.1 to 10 mg/kg intravenously once every 3 weeks until disease progression or withdrawal due to toxicity. Patients were pre-medicated with corticoid regimens.
Eighteen patients had lymphoid malignancies—8 with B-cell lymphomas, 8 with TCL, and 2 with Hodgkin lymphoma.
The TCL cohort consisted of 1 patient with SS, 1 with transformed SS, 1 with T-helper CTCL, 2 with angioimmunoblastic T-cell lymphoma (AITL), 2 with PTCL not otherwise specified (NOS), and 1 with ALCL.
Patients were a median age of 62 (range, 55–78), had a median of 4 prior treatment regimens (range, 2–6), and received a median of 2 cycles of ARGX-110 (range, 1–6).
Dr Maerevoet noted that most lymphoma patients received a dose of 5 mg/kg every 3 weeks.
Safety
In the entire lymphoma cohort of 18 patients, 4 patients (22%) experienced a grade 1 or 2 infusion-related reaction. Three patients (18%) developed grade 3 sepsis—1 with Waldenstrom’s macroglobulinemia, 1 with AITL, and 1 with PTCL-NOS.
Two patients (11%) had hematologic toxicity consisting of a grade 3 decrease in hemoglobin and absolute neutrophil count, which was considered not related to treatment with ARGX-110.
“The maximum tolerated dose was not reached,” Dr Maerevoet said. “We didn’t observe auto-immune adverse events or impact on serum IgG or IgM.”
Efficacy outcomes
The main reason for withdrawal was progressive disease, which occurred in 14 lymphoma patients.
Two patients—1 with Waldenstrom’s macroglobulinemia and 1 with AITL—withdrew due to adverse events of sepsis (catheter infection, pneumonia), 1 patient with SS withdrew for social reasons, and 1 patient with follicular T-cell lymphoma (currently classified as PTCL-NOS) remains on study.
Dr Maerevoet described the 3 TCL patients who had a biologic response to ARGX-110. One patient with SS had a hematologic complete remission after 6 cycles at the 0.1 mg/kg dose.
Another patient with transformed SS experienced a depletion of circulating clones after 2 cycles of the 10 mg/kg dose. However, the patient ultimately died of progressive disease.
A third patient had resolution of autoimmune hemolytic anemia. This 61-year-old male with AITL achieved a partial response with normalization of LDH levels and an increase in hemoglobin to 7.9 g/dL without transfusion support after 2 doses of ARGX-110 at 5 mg/kg.
The patient became Coombs-negative and had a 16% reduction in tumor size by CT scan. However, the patient subsequently died of pneumonia.
The investigators also observed clinical activity in the peripheral blood, lymph nodes, and skin of 2 additional patients.
The biological activity of ARGX-110 as demonstrated by these TCL patients, in addition to the safety and tolerability of this mAb, led the team to conclude that further clinical investigation of ARGX-110 in TCL is warranted.
*Information in the abstract differs from that presented at the meeting.
Photo by Linda Bartlett
LUGANO—The defucosylated monoclonal antibody (mAb) ARGX-110, which is active against CD70-bearing tumor cells and CD70-dependent stimulation of regulatory T cells, has shown activity in relapsed/refractory T-cell lymphoma (TCL), according to investigators.
Of the 8 TCL patients enrolled in a phase 1 trial of ARGX-110, 3 had a biological response to the mAb.
In this dose-escalation trial, the maximum tolerated dose of ARGX-110 was not reached.
Marie Maerevoet, MD, of the Institut Jules Bordet in Brussels, Belgium, presented results from the lymphoma cohort of this trial at the 13th International Congress on Malignant Lymphoma (abstract 040*). The study was sponsored by arGEN-X, the company developing ARGX-110.
Dr Maerevoet pointed out that more than half the tumor cells in 71% of patients with cutaneous T-cell lymphoma (CTCL) and 22% with peripheral T-cell lymphoma (PTCL) are CD70-positive. CD70 signaling occurs via CD27, and CD27 shedding is a biomarker for an active pathway.
Since ARGX-110 has an affinity for CD70, inhibits CD27 signaling, and mediates the lysis of TCL in Sézary syndrome (SS), mycosis fungoides, and anaplastic large cell lymphoma (ALCL) cell lines, researchers decided to investigate the safety and clinical pharmacology of ARGX-110 monotherapy in metastatic, relapsed or refractory, solid tumors and hematologic malignancies.
Patients’ tumors had to express CD70 by immunohistochemistry, defined as more than 10% tumor cells of 2+ or 3+ intensity.
The primary endpoint was to determine the maximum tolerated dose. Secondary endpoints were pharmacology, immunogenicity, and efficacy signals.
Patient demographics
Between February 2013 and April 2015, investigators assigned 63 patients to receive ARGX-110 at doses ranging from 0.1 to 10 mg/kg intravenously once every 3 weeks until disease progression or withdrawal due to toxicity. Patients were pre-medicated with corticoid regimens.
Eighteen patients had lymphoid malignancies—8 with B-cell lymphomas, 8 with TCL, and 2 with Hodgkin lymphoma.
The TCL cohort consisted of 1 patient with SS, 1 with transformed SS, 1 with T-helper CTCL, 2 with angioimmunoblastic T-cell lymphoma (AITL), 2 with PTCL not otherwise specified (NOS), and 1 with ALCL.
Patients were a median age of 62 (range, 55–78), had a median of 4 prior treatment regimens (range, 2–6), and received a median of 2 cycles of ARGX-110 (range, 1–6).
Dr Maerevoet noted that most lymphoma patients received a dose of 5 mg/kg every 3 weeks.
Safety
In the entire lymphoma cohort of 18 patients, 4 patients (22%) experienced a grade 1 or 2 infusion-related reaction. Three patients (18%) developed grade 3 sepsis—1 with Waldenstrom’s macroglobulinemia, 1 with AITL, and 1 with PTCL-NOS.
Two patients (11%) had hematologic toxicity consisting of a grade 3 decrease in hemoglobin and absolute neutrophil count, which was considered not related to treatment with ARGX-110.
“The maximum tolerated dose was not reached,” Dr Maerevoet said. “We didn’t observe auto-immune adverse events or impact on serum IgG or IgM.”
Efficacy outcomes
The main reason for withdrawal was progressive disease, which occurred in 14 lymphoma patients.
Two patients—1 with Waldenstrom’s macroglobulinemia and 1 with AITL—withdrew due to adverse events of sepsis (catheter infection, pneumonia), 1 patient with SS withdrew for social reasons, and 1 patient with follicular T-cell lymphoma (currently classified as PTCL-NOS) remains on study.
Dr Maerevoet described the 3 TCL patients who had a biologic response to ARGX-110. One patient with SS had a hematologic complete remission after 6 cycles at the 0.1 mg/kg dose.
Another patient with transformed SS experienced a depletion of circulating clones after 2 cycles of the 10 mg/kg dose. However, the patient ultimately died of progressive disease.
A third patient had resolution of autoimmune hemolytic anemia. This 61-year-old male with AITL achieved a partial response with normalization of LDH levels and an increase in hemoglobin to 7.9 g/dL without transfusion support after 2 doses of ARGX-110 at 5 mg/kg.
The patient became Coombs-negative and had a 16% reduction in tumor size by CT scan. However, the patient subsequently died of pneumonia.
The investigators also observed clinical activity in the peripheral blood, lymph nodes, and skin of 2 additional patients.
The biological activity of ARGX-110 as demonstrated by these TCL patients, in addition to the safety and tolerability of this mAb, led the team to conclude that further clinical investigation of ARGX-110 in TCL is warranted.
*Information in the abstract differs from that presented at the meeting.
Photo by Linda Bartlett
LUGANO—The defucosylated monoclonal antibody (mAb) ARGX-110, which is active against CD70-bearing tumor cells and CD70-dependent stimulation of regulatory T cells, has shown activity in relapsed/refractory T-cell lymphoma (TCL), according to investigators.
Of the 8 TCL patients enrolled in a phase 1 trial of ARGX-110, 3 had a biological response to the mAb.
In this dose-escalation trial, the maximum tolerated dose of ARGX-110 was not reached.
Marie Maerevoet, MD, of the Institut Jules Bordet in Brussels, Belgium, presented results from the lymphoma cohort of this trial at the 13th International Congress on Malignant Lymphoma (abstract 040*). The study was sponsored by arGEN-X, the company developing ARGX-110.
Dr Maerevoet pointed out that more than half the tumor cells in 71% of patients with cutaneous T-cell lymphoma (CTCL) and 22% with peripheral T-cell lymphoma (PTCL) are CD70-positive. CD70 signaling occurs via CD27, and CD27 shedding is a biomarker for an active pathway.
Since ARGX-110 has an affinity for CD70, inhibits CD27 signaling, and mediates the lysis of TCL in Sézary syndrome (SS), mycosis fungoides, and anaplastic large cell lymphoma (ALCL) cell lines, researchers decided to investigate the safety and clinical pharmacology of ARGX-110 monotherapy in metastatic, relapsed or refractory, solid tumors and hematologic malignancies.
Patients’ tumors had to express CD70 by immunohistochemistry, defined as more than 10% tumor cells of 2+ or 3+ intensity.
The primary endpoint was to determine the maximum tolerated dose. Secondary endpoints were pharmacology, immunogenicity, and efficacy signals.
Patient demographics
Between February 2013 and April 2015, investigators assigned 63 patients to receive ARGX-110 at doses ranging from 0.1 to 10 mg/kg intravenously once every 3 weeks until disease progression or withdrawal due to toxicity. Patients were pre-medicated with corticoid regimens.
Eighteen patients had lymphoid malignancies—8 with B-cell lymphomas, 8 with TCL, and 2 with Hodgkin lymphoma.
The TCL cohort consisted of 1 patient with SS, 1 with transformed SS, 1 with T-helper CTCL, 2 with angioimmunoblastic T-cell lymphoma (AITL), 2 with PTCL not otherwise specified (NOS), and 1 with ALCL.
Patients were a median age of 62 (range, 55–78), had a median of 4 prior treatment regimens (range, 2–6), and received a median of 2 cycles of ARGX-110 (range, 1–6).
Dr Maerevoet noted that most lymphoma patients received a dose of 5 mg/kg every 3 weeks.
Safety
In the entire lymphoma cohort of 18 patients, 4 patients (22%) experienced a grade 1 or 2 infusion-related reaction. Three patients (18%) developed grade 3 sepsis—1 with Waldenstrom’s macroglobulinemia, 1 with AITL, and 1 with PTCL-NOS.
Two patients (11%) had hematologic toxicity consisting of a grade 3 decrease in hemoglobin and absolute neutrophil count, which was considered not related to treatment with ARGX-110.
“The maximum tolerated dose was not reached,” Dr Maerevoet said. “We didn’t observe auto-immune adverse events or impact on serum IgG or IgM.”
Efficacy outcomes
The main reason for withdrawal was progressive disease, which occurred in 14 lymphoma patients.
Two patients—1 with Waldenstrom’s macroglobulinemia and 1 with AITL—withdrew due to adverse events of sepsis (catheter infection, pneumonia), 1 patient with SS withdrew for social reasons, and 1 patient with follicular T-cell lymphoma (currently classified as PTCL-NOS) remains on study.
Dr Maerevoet described the 3 TCL patients who had a biologic response to ARGX-110. One patient with SS had a hematologic complete remission after 6 cycles at the 0.1 mg/kg dose.
Another patient with transformed SS experienced a depletion of circulating clones after 2 cycles of the 10 mg/kg dose. However, the patient ultimately died of progressive disease.
A third patient had resolution of autoimmune hemolytic anemia. This 61-year-old male with AITL achieved a partial response with normalization of LDH levels and an increase in hemoglobin to 7.9 g/dL without transfusion support after 2 doses of ARGX-110 at 5 mg/kg.
The patient became Coombs-negative and had a 16% reduction in tumor size by CT scan. However, the patient subsequently died of pneumonia.
The investigators also observed clinical activity in the peripheral blood, lymph nodes, and skin of 2 additional patients.
The biological activity of ARGX-110 as demonstrated by these TCL patients, in addition to the safety and tolerability of this mAb, led the team to conclude that further clinical investigation of ARGX-110 in TCL is warranted.
*Information in the abstract differs from that presented at the meeting.
Novel SYK inhibitor shows ‘good early evidence’ of activity
LUGANO—The phase 1, first-in-human study of the novel SYK inhibitor TAK-659 is showing “good early evidence” of antitumor activity in patients with lymphoma, according to investigators.
The agent also appears to be fairly well tolerated, with 10 categories of adverse events occurring in 2 or more patients.
Adam M. Petrich, MD, of Northwestern University in Evanston, Illinois, presented results from this ongoing study at the 13th International Congress on Malignant Lymphoma (13-ICML) as abstract 039.*
The study is supported by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
Dr Petrich said the B-cell receptor signaling pathway is “very fertile ground with respect to development for novel targeting, particularly of B-cell malignancies, and SYK—the spleen tyrosine kinase—is an integral component of this.”
Investigators believe SYK has implications beyond B-cell lymphoma, including EBV-related malignancies, solid tumors, and myeloid leukemias.
Preclinical findings
In vitro experiments with TAK-659 showed “profound inhibition” of both SYK and FLT3, as indicated by the low IC50 levels, Dr Petrich said.
He also pointed out that the EC50 levels compare favorably to ibrutinib and idelalisib, with generally lower numbers in a broad panel of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia.
In animal models, TAK-659 exhibited a dose-dependent tumor-inhibitory property.
“And if we look at both germinal center B and non-germinal center B subtypes of large-cell lymphoma, we see activity across both types,” Dr Petrich said.
Phase 1 study
Investigators are currently conducting the phase 1 study, which is a standard 3+3 dose-escalation schema. The data cutoff for the ICML presentation was April 13, although the dose-escalation phase was still underway, and the maximum tolerated dose was not yet reached.
Based on preclinical data, the team projected the efficacious dose for humans to be approximately 600 to 1200 mg per day. Patients were started at 60 mg, and, at the next planned step of 120 mg, 2 patients developed asymptomatic lipase elevations.
“For that reason, we revised the protocol, allowed for those to not be considered dose-limiting toxicities, and explored intermediate doses,” Dr Petrich explained.
So the protocol now includes intermediate doses of 80 and 100 mg. Dr Petrich’s presentation focused on the 4 doses—60, 80, 100, and 120 mg taken orally once daily.
He said the observed human clearance of TAK-659 was approximately 3- to 4-fold lower than predicted based on the mouse pharmacokinetic (PK) data, which led to steady-state area under the curve values 3- to 4-fold higher in humans than predicted.
Patient demographics
The investigators enrolled 21 patients, 12 with solid tumors, 6 with DLBCL, and 3 with FL. The median age was 60 years, 66% were male, and 62% had received 4 or more prior therapies.
The median number of TAK-659 treatment cycles was 2 (range, 1–10), and 5 patients are still on active treatment. Dr Petrich pointed out that 4 of the 5 longest-treated patients have DLBCL, and “the record holder with DLBCL is about to celebrate 1 year on therapy.”
Safety
“The safety profile in humans showed that [TAK-659] was actually quite tolerable,” Dr Petrich said.
There were 10 categories of treatment-related adverse events (AEs) that occurred in 2 or more patients. They were, in descending order, fatigue, anemia, diarrhea, elevated AST, hypophosphatemia, nausea, rash, elevated lipase, elevated ALT, and anorexia.
The majority of AEs were grade 1 or 2. However, there were grade 3/4 cases of anemia, diarrhea, elevated AST, and hypophosphatemia. And elevated lipase—the asymptomatic, dose-limiting toxicity for which the protocol was modified—consisted entirely of grade 3 or 4 events.
Episodes of neutropenia and thrombocytopenia occurred in 1 patient each, and both were grade 1.
“So [TAK-659] seems quite well tolerated in that regard as well,” Dr Petrich observed.
The plasma profile on days 1 and 15 of cycle 1 indicate that PK steady-state conditions are generally achieved by day 8, with moderate accumulation after repeated, once-daily dosing for 15 days.
Antitumor activity
Of the 12 evaluable patients, 5 had tumor shrinkage at the 60, 80, or 100 mg dose levels. Three of the 6 DLBCL patients experienced tumor shrinkage, and there were “2 dramatic responses in patients with follicular lymphoma, including 1 CR [complete response],” Dr Petrich said.
One of these FL patients had an aggressive phenotype and never had a previous response last longer than 20 months.
“[H]e actually achieved a CR within 2 cycles—a dramatic response for his disease—and he remains on treatment, and he’s up to cycle 5 now,” Dr Petrich said.
The team concluded that the PK data support daily dosing, despite lower clearance than originally predicted.
“[There is] good early evidence of antitumor activity and no significant safety signals,” Dr Petrich said. “And the [hematologic] toxicity profile, in particular, seems to suggest this is a well-tolerated drug.”
The investigators are conducting expansion cohorts and are considering future combination studies. They recently activated a study in acute myeloid leukemia because TAK-659 has FLT3 inhibitory properties.
*Information in the abstract differs from that presented at the meeting.
LUGANO—The phase 1, first-in-human study of the novel SYK inhibitor TAK-659 is showing “good early evidence” of antitumor activity in patients with lymphoma, according to investigators.
The agent also appears to be fairly well tolerated, with 10 categories of adverse events occurring in 2 or more patients.
Adam M. Petrich, MD, of Northwestern University in Evanston, Illinois, presented results from this ongoing study at the 13th International Congress on Malignant Lymphoma (13-ICML) as abstract 039.*
The study is supported by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
Dr Petrich said the B-cell receptor signaling pathway is “very fertile ground with respect to development for novel targeting, particularly of B-cell malignancies, and SYK—the spleen tyrosine kinase—is an integral component of this.”
Investigators believe SYK has implications beyond B-cell lymphoma, including EBV-related malignancies, solid tumors, and myeloid leukemias.
Preclinical findings
In vitro experiments with TAK-659 showed “profound inhibition” of both SYK and FLT3, as indicated by the low IC50 levels, Dr Petrich said.
He also pointed out that the EC50 levels compare favorably to ibrutinib and idelalisib, with generally lower numbers in a broad panel of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia.
In animal models, TAK-659 exhibited a dose-dependent tumor-inhibitory property.
“And if we look at both germinal center B and non-germinal center B subtypes of large-cell lymphoma, we see activity across both types,” Dr Petrich said.
Phase 1 study
Investigators are currently conducting the phase 1 study, which is a standard 3+3 dose-escalation schema. The data cutoff for the ICML presentation was April 13, although the dose-escalation phase was still underway, and the maximum tolerated dose was not yet reached.
Based on preclinical data, the team projected the efficacious dose for humans to be approximately 600 to 1200 mg per day. Patients were started at 60 mg, and, at the next planned step of 120 mg, 2 patients developed asymptomatic lipase elevations.
“For that reason, we revised the protocol, allowed for those to not be considered dose-limiting toxicities, and explored intermediate doses,” Dr Petrich explained.
So the protocol now includes intermediate doses of 80 and 100 mg. Dr Petrich’s presentation focused on the 4 doses—60, 80, 100, and 120 mg taken orally once daily.
He said the observed human clearance of TAK-659 was approximately 3- to 4-fold lower than predicted based on the mouse pharmacokinetic (PK) data, which led to steady-state area under the curve values 3- to 4-fold higher in humans than predicted.
Patient demographics
The investigators enrolled 21 patients, 12 with solid tumors, 6 with DLBCL, and 3 with FL. The median age was 60 years, 66% were male, and 62% had received 4 or more prior therapies.
The median number of TAK-659 treatment cycles was 2 (range, 1–10), and 5 patients are still on active treatment. Dr Petrich pointed out that 4 of the 5 longest-treated patients have DLBCL, and “the record holder with DLBCL is about to celebrate 1 year on therapy.”
Safety
“The safety profile in humans showed that [TAK-659] was actually quite tolerable,” Dr Petrich said.
There were 10 categories of treatment-related adverse events (AEs) that occurred in 2 or more patients. They were, in descending order, fatigue, anemia, diarrhea, elevated AST, hypophosphatemia, nausea, rash, elevated lipase, elevated ALT, and anorexia.
The majority of AEs were grade 1 or 2. However, there were grade 3/4 cases of anemia, diarrhea, elevated AST, and hypophosphatemia. And elevated lipase—the asymptomatic, dose-limiting toxicity for which the protocol was modified—consisted entirely of grade 3 or 4 events.
Episodes of neutropenia and thrombocytopenia occurred in 1 patient each, and both were grade 1.
“So [TAK-659] seems quite well tolerated in that regard as well,” Dr Petrich observed.
The plasma profile on days 1 and 15 of cycle 1 indicate that PK steady-state conditions are generally achieved by day 8, with moderate accumulation after repeated, once-daily dosing for 15 days.
Antitumor activity
Of the 12 evaluable patients, 5 had tumor shrinkage at the 60, 80, or 100 mg dose levels. Three of the 6 DLBCL patients experienced tumor shrinkage, and there were “2 dramatic responses in patients with follicular lymphoma, including 1 CR [complete response],” Dr Petrich said.
One of these FL patients had an aggressive phenotype and never had a previous response last longer than 20 months.
“[H]e actually achieved a CR within 2 cycles—a dramatic response for his disease—and he remains on treatment, and he’s up to cycle 5 now,” Dr Petrich said.
The team concluded that the PK data support daily dosing, despite lower clearance than originally predicted.
“[There is] good early evidence of antitumor activity and no significant safety signals,” Dr Petrich said. “And the [hematologic] toxicity profile, in particular, seems to suggest this is a well-tolerated drug.”
The investigators are conducting expansion cohorts and are considering future combination studies. They recently activated a study in acute myeloid leukemia because TAK-659 has FLT3 inhibitory properties.
*Information in the abstract differs from that presented at the meeting.
LUGANO—The phase 1, first-in-human study of the novel SYK inhibitor TAK-659 is showing “good early evidence” of antitumor activity in patients with lymphoma, according to investigators.
The agent also appears to be fairly well tolerated, with 10 categories of adverse events occurring in 2 or more patients.
Adam M. Petrich, MD, of Northwestern University in Evanston, Illinois, presented results from this ongoing study at the 13th International Congress on Malignant Lymphoma (13-ICML) as abstract 039.*
The study is supported by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
Dr Petrich said the B-cell receptor signaling pathway is “very fertile ground with respect to development for novel targeting, particularly of B-cell malignancies, and SYK—the spleen tyrosine kinase—is an integral component of this.”
Investigators believe SYK has implications beyond B-cell lymphoma, including EBV-related malignancies, solid tumors, and myeloid leukemias.
Preclinical findings
In vitro experiments with TAK-659 showed “profound inhibition” of both SYK and FLT3, as indicated by the low IC50 levels, Dr Petrich said.
He also pointed out that the EC50 levels compare favorably to ibrutinib and idelalisib, with generally lower numbers in a broad panel of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia.
In animal models, TAK-659 exhibited a dose-dependent tumor-inhibitory property.
“And if we look at both germinal center B and non-germinal center B subtypes of large-cell lymphoma, we see activity across both types,” Dr Petrich said.
Phase 1 study
Investigators are currently conducting the phase 1 study, which is a standard 3+3 dose-escalation schema. The data cutoff for the ICML presentation was April 13, although the dose-escalation phase was still underway, and the maximum tolerated dose was not yet reached.
Based on preclinical data, the team projected the efficacious dose for humans to be approximately 600 to 1200 mg per day. Patients were started at 60 mg, and, at the next planned step of 120 mg, 2 patients developed asymptomatic lipase elevations.
“For that reason, we revised the protocol, allowed for those to not be considered dose-limiting toxicities, and explored intermediate doses,” Dr Petrich explained.
So the protocol now includes intermediate doses of 80 and 100 mg. Dr Petrich’s presentation focused on the 4 doses—60, 80, 100, and 120 mg taken orally once daily.
He said the observed human clearance of TAK-659 was approximately 3- to 4-fold lower than predicted based on the mouse pharmacokinetic (PK) data, which led to steady-state area under the curve values 3- to 4-fold higher in humans than predicted.
Patient demographics
The investigators enrolled 21 patients, 12 with solid tumors, 6 with DLBCL, and 3 with FL. The median age was 60 years, 66% were male, and 62% had received 4 or more prior therapies.
The median number of TAK-659 treatment cycles was 2 (range, 1–10), and 5 patients are still on active treatment. Dr Petrich pointed out that 4 of the 5 longest-treated patients have DLBCL, and “the record holder with DLBCL is about to celebrate 1 year on therapy.”
Safety
“The safety profile in humans showed that [TAK-659] was actually quite tolerable,” Dr Petrich said.
There were 10 categories of treatment-related adverse events (AEs) that occurred in 2 or more patients. They were, in descending order, fatigue, anemia, diarrhea, elevated AST, hypophosphatemia, nausea, rash, elevated lipase, elevated ALT, and anorexia.
The majority of AEs were grade 1 or 2. However, there were grade 3/4 cases of anemia, diarrhea, elevated AST, and hypophosphatemia. And elevated lipase—the asymptomatic, dose-limiting toxicity for which the protocol was modified—consisted entirely of grade 3 or 4 events.
Episodes of neutropenia and thrombocytopenia occurred in 1 patient each, and both were grade 1.
“So [TAK-659] seems quite well tolerated in that regard as well,” Dr Petrich observed.
The plasma profile on days 1 and 15 of cycle 1 indicate that PK steady-state conditions are generally achieved by day 8, with moderate accumulation after repeated, once-daily dosing for 15 days.
Antitumor activity
Of the 12 evaluable patients, 5 had tumor shrinkage at the 60, 80, or 100 mg dose levels. Three of the 6 DLBCL patients experienced tumor shrinkage, and there were “2 dramatic responses in patients with follicular lymphoma, including 1 CR [complete response],” Dr Petrich said.
One of these FL patients had an aggressive phenotype and never had a previous response last longer than 20 months.
“[H]e actually achieved a CR within 2 cycles—a dramatic response for his disease—and he remains on treatment, and he’s up to cycle 5 now,” Dr Petrich said.
The team concluded that the PK data support daily dosing, despite lower clearance than originally predicted.
“[There is] good early evidence of antitumor activity and no significant safety signals,” Dr Petrich said. “And the [hematologic] toxicity profile, in particular, seems to suggest this is a well-tolerated drug.”
The investigators are conducting expansion cohorts and are considering future combination studies. They recently activated a study in acute myeloid leukemia because TAK-659 has FLT3 inhibitory properties.
*Information in the abstract differs from that presented at the meeting.
HSCT outcomes ‘encouraging’ in JAKi responders
Photo by Chad McNeeley
VIENNA—Outcomes of hematopoietic stem cell transplant (HSCT) are encouraging in myelofibrosis (MF) patients who respond well to JAK inhibitors, according to researchers.
The group found that patients with the best response to JAK inhibition had a 2-year survival probability of 91% after HSCT, compared to 32% for patients with
leukemic transformation while on a JAK inhibitor.
In addition, receiving a JAK inhibitor until HSCT could prevent the return of MF-related symptoms.
Mohamed Shanavas, MD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada, presented these findings at the 20th Congress of the European Hematology Association (abstract S450*).
The decision to undergo HSCT is a complex one in MF, particularly for those patients who are responding to JAK inhibitors. So Dr Shanavas and his colleagues undertook a retrospective, multicenter analysis to determine if there is an association between response to JAK inhibition and HSCT outcome.
The investigators analyzed the outcomes of 100 patients who had a first HSCT for primary MF, post-essential thrombocythemia MF, or post-polycythemia vera MF. Patients had to have exposure to a JAK inhibitor but no history of leukemic transformation prior to taking a JAK inhibitor.
Response criteria
The researchers stratified patients’ JAK1/2 response according to the following criteria:
- Group A: Clinical improvement: Fifty percent or greater reduction in palpable spleen length for spleen palpable by ≥ 10 cm, or complete resolution of splenomegaly for spleen < 10 cm
- Group B: Stable disease: Spleen response not meeting the criteria of clinical improvement
- Group C: A 10% to 19% increase in blasts, new onset of anemia requiring transfusions, or intolerance to treatment due to side effects
- Group D: Progressive disease: New splenomegaly > 5 cm, 100% increase in spleen 5-10 cm, or 50% increase in spleen > 10 cm
- Group E: Leukemic transformation: Bone marrow or circulating blasts ≥ 20%.
Patient and treatment characteristics
Patients were a median age of 59 (range, 32–72). Fifty-seven had primary MF, 21 had post-essential thrombocythemia MF, and 22 had post-polycythemia vera MF. Sixty-two patients had JAK2V617F-mutated disease, 37 were wild-type, and 1 had unknown JAK status.
The majority of patients had intermediate-2 or high-risk disease according to their DIPSS scores, and 42 had a transplant comorbidity index score of 3 or greater.
Most patients (n=91) had ruxolitinib as their JAK inhibitor, 6 had momelotinib, and 3 had another inhibitor.
The median duration of JAK inhibitor therapy was 5 months (range, 1–36), and 66 patients were on treatment at the time of transplant. Thirty patients had previously discontinued JAK therapy, and the status of 4 was unknown.
In terms of their response to JAK inhibitors, 23 patients were in group A (clinical improvement), 31 in group B (stable disease), 15 in group C (increased blasts/transfusion need/intolerance), 18 in group D (progressive disease), and 13 in group E (leukemic transformation).
Fifty patients received a matched unrelated donor transplant, 36 had a matched sibling donor, and 14 had either a mismatched unrelated donor or a haploidentical transplant.
Fifty-six patients had a reduced-intensity conditioning regimen, and 44 had full intensity. Fifty percent of patients had T-cell depletion prior to transplant.
Outcomes
Patients who stopped JAK inhibitor therapy 6 or more days prior to transplant (n=20) experienced more “withdrawal symptoms”—the return of MF-related symptoms—than patients in whom the interval was less than 6 days (n=46). For the most part, withdrawal symptoms were non-severe in nature.
Two patients had fatal HSCT-related toxicity of venoocclusive disease, 4 had primary graft failure, and 4 had secondary graft failure. Forty-three percent of cytomegalovirus-seropositive patients had reactivation, 6 patients had Epstein-Barr virus reactivation, 6 had adenovirus or human polyomavirus BK infections, and 7 had invasive fungal infections.
Grade 2-4 acute graft-vs-host disease (GVHD) occurred in 37% of patients at day 100, and grade 3-4 occurred in 16%. Chronic GVHD of all grades occurred in 48% of patients, and extensive chronic GVHD occurred in 23%.
The cumulative incidence of relapse at 2 years was 17%, and non-relapse mortality was 28%. Overall survival (OS) was 61%.
“We analyzed this outcome based upon the response to JAK inhibitors,” Dr Shanavas said. “Patients who were deriving clinical improvement, group A, had a superior outcome, with a probability of survival of 91% at 2 years. Patients who had leukemic transformation, group E, had an inferior OS of 32% at 2 years.”
He noted that the outcomes appeared similar in the other 3 groups, so the researchers combined them for further analysis.
“As expected,” he said, “patients who had leukemic transformation had a significantly higher relapse rate than the other groups.”
The researchers then performed a multivariate analysis and found that response to JAK inhibitors, DIPSS score prior to JAK therapy, and donor type had a significant effect on OS.
The team concluded that prior exposure to JAK inhibitors does not have a negative effect on early HSCT outcomes. And actually, patients who undergo HSCT while responding to JAK inhibitors have encouraging outcomes.
*Information in the abstract differs from that presented at the meeting.
Photo by Chad McNeeley
VIENNA—Outcomes of hematopoietic stem cell transplant (HSCT) are encouraging in myelofibrosis (MF) patients who respond well to JAK inhibitors, according to researchers.
The group found that patients with the best response to JAK inhibition had a 2-year survival probability of 91% after HSCT, compared to 32% for patients with
leukemic transformation while on a JAK inhibitor.
In addition, receiving a JAK inhibitor until HSCT could prevent the return of MF-related symptoms.
Mohamed Shanavas, MD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada, presented these findings at the 20th Congress of the European Hematology Association (abstract S450*).
The decision to undergo HSCT is a complex one in MF, particularly for those patients who are responding to JAK inhibitors. So Dr Shanavas and his colleagues undertook a retrospective, multicenter analysis to determine if there is an association between response to JAK inhibition and HSCT outcome.
The investigators analyzed the outcomes of 100 patients who had a first HSCT for primary MF, post-essential thrombocythemia MF, or post-polycythemia vera MF. Patients had to have exposure to a JAK inhibitor but no history of leukemic transformation prior to taking a JAK inhibitor.
Response criteria
The researchers stratified patients’ JAK1/2 response according to the following criteria:
- Group A: Clinical improvement: Fifty percent or greater reduction in palpable spleen length for spleen palpable by ≥ 10 cm, or complete resolution of splenomegaly for spleen < 10 cm
- Group B: Stable disease: Spleen response not meeting the criteria of clinical improvement
- Group C: A 10% to 19% increase in blasts, new onset of anemia requiring transfusions, or intolerance to treatment due to side effects
- Group D: Progressive disease: New splenomegaly > 5 cm, 100% increase in spleen 5-10 cm, or 50% increase in spleen > 10 cm
- Group E: Leukemic transformation: Bone marrow or circulating blasts ≥ 20%.
Patient and treatment characteristics
Patients were a median age of 59 (range, 32–72). Fifty-seven had primary MF, 21 had post-essential thrombocythemia MF, and 22 had post-polycythemia vera MF. Sixty-two patients had JAK2V617F-mutated disease, 37 were wild-type, and 1 had unknown JAK status.
The majority of patients had intermediate-2 or high-risk disease according to their DIPSS scores, and 42 had a transplant comorbidity index score of 3 or greater.
Most patients (n=91) had ruxolitinib as their JAK inhibitor, 6 had momelotinib, and 3 had another inhibitor.
The median duration of JAK inhibitor therapy was 5 months (range, 1–36), and 66 patients were on treatment at the time of transplant. Thirty patients had previously discontinued JAK therapy, and the status of 4 was unknown.
In terms of their response to JAK inhibitors, 23 patients were in group A (clinical improvement), 31 in group B (stable disease), 15 in group C (increased blasts/transfusion need/intolerance), 18 in group D (progressive disease), and 13 in group E (leukemic transformation).
Fifty patients received a matched unrelated donor transplant, 36 had a matched sibling donor, and 14 had either a mismatched unrelated donor or a haploidentical transplant.
Fifty-six patients had a reduced-intensity conditioning regimen, and 44 had full intensity. Fifty percent of patients had T-cell depletion prior to transplant.
Outcomes
Patients who stopped JAK inhibitor therapy 6 or more days prior to transplant (n=20) experienced more “withdrawal symptoms”—the return of MF-related symptoms—than patients in whom the interval was less than 6 days (n=46). For the most part, withdrawal symptoms were non-severe in nature.
Two patients had fatal HSCT-related toxicity of venoocclusive disease, 4 had primary graft failure, and 4 had secondary graft failure. Forty-three percent of cytomegalovirus-seropositive patients had reactivation, 6 patients had Epstein-Barr virus reactivation, 6 had adenovirus or human polyomavirus BK infections, and 7 had invasive fungal infections.
Grade 2-4 acute graft-vs-host disease (GVHD) occurred in 37% of patients at day 100, and grade 3-4 occurred in 16%. Chronic GVHD of all grades occurred in 48% of patients, and extensive chronic GVHD occurred in 23%.
The cumulative incidence of relapse at 2 years was 17%, and non-relapse mortality was 28%. Overall survival (OS) was 61%.
“We analyzed this outcome based upon the response to JAK inhibitors,” Dr Shanavas said. “Patients who were deriving clinical improvement, group A, had a superior outcome, with a probability of survival of 91% at 2 years. Patients who had leukemic transformation, group E, had an inferior OS of 32% at 2 years.”
He noted that the outcomes appeared similar in the other 3 groups, so the researchers combined them for further analysis.
“As expected,” he said, “patients who had leukemic transformation had a significantly higher relapse rate than the other groups.”
The researchers then performed a multivariate analysis and found that response to JAK inhibitors, DIPSS score prior to JAK therapy, and donor type had a significant effect on OS.
The team concluded that prior exposure to JAK inhibitors does not have a negative effect on early HSCT outcomes. And actually, patients who undergo HSCT while responding to JAK inhibitors have encouraging outcomes.
*Information in the abstract differs from that presented at the meeting.
Photo by Chad McNeeley
VIENNA—Outcomes of hematopoietic stem cell transplant (HSCT) are encouraging in myelofibrosis (MF) patients who respond well to JAK inhibitors, according to researchers.
The group found that patients with the best response to JAK inhibition had a 2-year survival probability of 91% after HSCT, compared to 32% for patients with
leukemic transformation while on a JAK inhibitor.
In addition, receiving a JAK inhibitor until HSCT could prevent the return of MF-related symptoms.
Mohamed Shanavas, MD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada, presented these findings at the 20th Congress of the European Hematology Association (abstract S450*).
The decision to undergo HSCT is a complex one in MF, particularly for those patients who are responding to JAK inhibitors. So Dr Shanavas and his colleagues undertook a retrospective, multicenter analysis to determine if there is an association between response to JAK inhibition and HSCT outcome.
The investigators analyzed the outcomes of 100 patients who had a first HSCT for primary MF, post-essential thrombocythemia MF, or post-polycythemia vera MF. Patients had to have exposure to a JAK inhibitor but no history of leukemic transformation prior to taking a JAK inhibitor.
Response criteria
The researchers stratified patients’ JAK1/2 response according to the following criteria:
- Group A: Clinical improvement: Fifty percent or greater reduction in palpable spleen length for spleen palpable by ≥ 10 cm, or complete resolution of splenomegaly for spleen < 10 cm
- Group B: Stable disease: Spleen response not meeting the criteria of clinical improvement
- Group C: A 10% to 19% increase in blasts, new onset of anemia requiring transfusions, or intolerance to treatment due to side effects
- Group D: Progressive disease: New splenomegaly > 5 cm, 100% increase in spleen 5-10 cm, or 50% increase in spleen > 10 cm
- Group E: Leukemic transformation: Bone marrow or circulating blasts ≥ 20%.
Patient and treatment characteristics
Patients were a median age of 59 (range, 32–72). Fifty-seven had primary MF, 21 had post-essential thrombocythemia MF, and 22 had post-polycythemia vera MF. Sixty-two patients had JAK2V617F-mutated disease, 37 were wild-type, and 1 had unknown JAK status.
The majority of patients had intermediate-2 or high-risk disease according to their DIPSS scores, and 42 had a transplant comorbidity index score of 3 or greater.
Most patients (n=91) had ruxolitinib as their JAK inhibitor, 6 had momelotinib, and 3 had another inhibitor.
The median duration of JAK inhibitor therapy was 5 months (range, 1–36), and 66 patients were on treatment at the time of transplant. Thirty patients had previously discontinued JAK therapy, and the status of 4 was unknown.
In terms of their response to JAK inhibitors, 23 patients were in group A (clinical improvement), 31 in group B (stable disease), 15 in group C (increased blasts/transfusion need/intolerance), 18 in group D (progressive disease), and 13 in group E (leukemic transformation).
Fifty patients received a matched unrelated donor transplant, 36 had a matched sibling donor, and 14 had either a mismatched unrelated donor or a haploidentical transplant.
Fifty-six patients had a reduced-intensity conditioning regimen, and 44 had full intensity. Fifty percent of patients had T-cell depletion prior to transplant.
Outcomes
Patients who stopped JAK inhibitor therapy 6 or more days prior to transplant (n=20) experienced more “withdrawal symptoms”—the return of MF-related symptoms—than patients in whom the interval was less than 6 days (n=46). For the most part, withdrawal symptoms were non-severe in nature.
Two patients had fatal HSCT-related toxicity of venoocclusive disease, 4 had primary graft failure, and 4 had secondary graft failure. Forty-three percent of cytomegalovirus-seropositive patients had reactivation, 6 patients had Epstein-Barr virus reactivation, 6 had adenovirus or human polyomavirus BK infections, and 7 had invasive fungal infections.
Grade 2-4 acute graft-vs-host disease (GVHD) occurred in 37% of patients at day 100, and grade 3-4 occurred in 16%. Chronic GVHD of all grades occurred in 48% of patients, and extensive chronic GVHD occurred in 23%.
The cumulative incidence of relapse at 2 years was 17%, and non-relapse mortality was 28%. Overall survival (OS) was 61%.
“We analyzed this outcome based upon the response to JAK inhibitors,” Dr Shanavas said. “Patients who were deriving clinical improvement, group A, had a superior outcome, with a probability of survival of 91% at 2 years. Patients who had leukemic transformation, group E, had an inferior OS of 32% at 2 years.”
He noted that the outcomes appeared similar in the other 3 groups, so the researchers combined them for further analysis.
“As expected,” he said, “patients who had leukemic transformation had a significantly higher relapse rate than the other groups.”
The researchers then performed a multivariate analysis and found that response to JAK inhibitors, DIPSS score prior to JAK therapy, and donor type had a significant effect on OS.
The team concluded that prior exposure to JAK inhibitors does not have a negative effect on early HSCT outcomes. And actually, patients who undergo HSCT while responding to JAK inhibitors have encouraging outcomes.
*Information in the abstract differs from that presented at the meeting.
PI3Kδ/γ inhibitor generates rapid responses in CLL
VIENNA—New research indicates that duvelisib, a dual inhibitor of PI3Kδ and PI3Kγ, can generate rapid partial responses in treatment-naïve patients with chronic lymphocytic leukemia (CLL).
The 18 patients in the expansion cohort of a phase 1 study of duvelisib had a median time to response of 3.7 months, according to iwCLL response criteria.
And 47% of the responses occurred by the first assessment on day 1 of cycle 3.
“One thing that does seem to be different with this drug is that you’re getting your [partial responses] a bit faster than you see with some of the other drugs,” said Susan O’Brien, MD, of UC Irvine Health in Orange, California.
“[W]hat that means in the long run is not completely clear, but there’s no question that the responses are very rapid.”
Dr O’Brien presented these findings at the 20th Congress of the European Hematology Association (abstract S434*). The research was funded by Infinity Pharmaceuticals, Inc., the company developing duvelisib.
Older CLL patients with comorbidities and patients with high-risk genomic alterations, such as 17p deletion and TP53 mutations, often don’t fare well on the standard chemoimmunotherapy. Duvelisib is being developed as a potential alternative for these patients and others with hematologic malignancies.
In the dose-escalation portion of this phase 1 study, duvelisib at 25 mg twice daily was well-tolerated and exhibited clinical activity in relapsed/refractory CLL, even in those patients with TP53 mutations and 17p deletion.
So investigators conducted the expansion cohort with 18 patients who received duvelisib at the same dose in 28-day cycles. Duvelisib is given continuously until patients have an adverse event or lose their response.
Patient demographics
Dr O’Brien said there was nothing unusual about the demographics of the study population, except the risk factors: 83% of the patients were over 65, “which is very different from what you would see in a chemoimmunotherapy trial.”
She noted that the patients’ median age was 74, and 56% of patients had either a 17p deletion or TP53 mutation.
“And that’s very unusual because . . . the percentage of patients with that abnormality in frontline CLL is about 5% to 10%,” she added.
Patients were a median of 3 years (range, 0–9) from their initial diagnosis, 47% had Rai stage 3 or greater disease, 44% had splenomegaly, and 11% had grade 4 cytopenia.
Response
Patients stayed on treatment for a median of 14 months (range, 1–20). Eight (44%) discontinued treatment—6 (33%) due to an adverse event, 1 withdrew consent, and 1 discontinued for other reasons.
The best overall response rate was 88%, which consisted of 15 partial responses. Two patients (12%) had stable disease, and there were no complete responses or cases of progressive disease.
One patient with a TP53 mutation/17p deletion withdrew consent prior to the first efficacy assessment.
“There’s no upfront progression,” Dr O’Brien said, “and the response rate was identical for patients with high-risk disease or 17p deletion.”
The median progression-free survival was not yet reached, and the rate was 92% at 18 months. One patient progressed at cycle 13.
The median overall survival was also not reached, with a 94% survival rate at 18 months. One patient died of progressive disease approximately 5 months after the last dose.
Adverse events
The most frequent adverse events (AEs) occurring in more than 25% of patients were, in order of frequency, diarrhea, rash, cough, neutropenia, peripheral edema, fatigue, nausea, pyrexia, ALT/AST increase, anemia, and dizziness.
Grade 3 AEs included diarrhea (22%), ALT/AST increase (17%), rash (11%), neutropenia (6%), fatigue (6%), and anemia (6%). The only grade 4 AE was neutropenia (28%).
Serious AEs in more than 1 patient included diarrhea (n=3), colitis (n=2), dehydration (n=2), pneumonia (n=2), and pneumonitis (n=2).
The AEs leading to treatment discontinuation were increased ALT/AST, dehydration, and spinal stenosis (all in 1 patient), as well as arthritis, pneumonitis, colitis, diarrhea, and stomatitis.
“We tend to see the transaminitis and the pneumonitis earlier, and then the late toxicity tends to be the diarrhea and colitis,” Dr O’ Brien said. “The one toxicity where I would not be inclined to try and re-treat a patient is pneumonitis, but I do think colitis can be successfully re-treated.”
Pharmacodynamic studies show very rapid inhibition of phosphorylated AKT following treatment, which is sustained throughout the whole first cycle. And following 1 cycle of duvelisib, there is near-complete inhibition of CLL proliferation, as evidenced by the reduction in Ki67.
Given these data, the investigators recommended further development of duvelisib in treatment-naïve CLL.
*Information in the abstract differs from that presented at the meeting.
VIENNA—New research indicates that duvelisib, a dual inhibitor of PI3Kδ and PI3Kγ, can generate rapid partial responses in treatment-naïve patients with chronic lymphocytic leukemia (CLL).
The 18 patients in the expansion cohort of a phase 1 study of duvelisib had a median time to response of 3.7 months, according to iwCLL response criteria.
And 47% of the responses occurred by the first assessment on day 1 of cycle 3.
“One thing that does seem to be different with this drug is that you’re getting your [partial responses] a bit faster than you see with some of the other drugs,” said Susan O’Brien, MD, of UC Irvine Health in Orange, California.
“[W]hat that means in the long run is not completely clear, but there’s no question that the responses are very rapid.”
Dr O’Brien presented these findings at the 20th Congress of the European Hematology Association (abstract S434*). The research was funded by Infinity Pharmaceuticals, Inc., the company developing duvelisib.
Older CLL patients with comorbidities and patients with high-risk genomic alterations, such as 17p deletion and TP53 mutations, often don’t fare well on the standard chemoimmunotherapy. Duvelisib is being developed as a potential alternative for these patients and others with hematologic malignancies.
In the dose-escalation portion of this phase 1 study, duvelisib at 25 mg twice daily was well-tolerated and exhibited clinical activity in relapsed/refractory CLL, even in those patients with TP53 mutations and 17p deletion.
So investigators conducted the expansion cohort with 18 patients who received duvelisib at the same dose in 28-day cycles. Duvelisib is given continuously until patients have an adverse event or lose their response.
Patient demographics
Dr O’Brien said there was nothing unusual about the demographics of the study population, except the risk factors: 83% of the patients were over 65, “which is very different from what you would see in a chemoimmunotherapy trial.”
She noted that the patients’ median age was 74, and 56% of patients had either a 17p deletion or TP53 mutation.
“And that’s very unusual because . . . the percentage of patients with that abnormality in frontline CLL is about 5% to 10%,” she added.
Patients were a median of 3 years (range, 0–9) from their initial diagnosis, 47% had Rai stage 3 or greater disease, 44% had splenomegaly, and 11% had grade 4 cytopenia.
Response
Patients stayed on treatment for a median of 14 months (range, 1–20). Eight (44%) discontinued treatment—6 (33%) due to an adverse event, 1 withdrew consent, and 1 discontinued for other reasons.
The best overall response rate was 88%, which consisted of 15 partial responses. Two patients (12%) had stable disease, and there were no complete responses or cases of progressive disease.
One patient with a TP53 mutation/17p deletion withdrew consent prior to the first efficacy assessment.
“There’s no upfront progression,” Dr O’Brien said, “and the response rate was identical for patients with high-risk disease or 17p deletion.”
The median progression-free survival was not yet reached, and the rate was 92% at 18 months. One patient progressed at cycle 13.
The median overall survival was also not reached, with a 94% survival rate at 18 months. One patient died of progressive disease approximately 5 months after the last dose.
Adverse events
The most frequent adverse events (AEs) occurring in more than 25% of patients were, in order of frequency, diarrhea, rash, cough, neutropenia, peripheral edema, fatigue, nausea, pyrexia, ALT/AST increase, anemia, and dizziness.
Grade 3 AEs included diarrhea (22%), ALT/AST increase (17%), rash (11%), neutropenia (6%), fatigue (6%), and anemia (6%). The only grade 4 AE was neutropenia (28%).
Serious AEs in more than 1 patient included diarrhea (n=3), colitis (n=2), dehydration (n=2), pneumonia (n=2), and pneumonitis (n=2).
The AEs leading to treatment discontinuation were increased ALT/AST, dehydration, and spinal stenosis (all in 1 patient), as well as arthritis, pneumonitis, colitis, diarrhea, and stomatitis.
“We tend to see the transaminitis and the pneumonitis earlier, and then the late toxicity tends to be the diarrhea and colitis,” Dr O’ Brien said. “The one toxicity where I would not be inclined to try and re-treat a patient is pneumonitis, but I do think colitis can be successfully re-treated.”
Pharmacodynamic studies show very rapid inhibition of phosphorylated AKT following treatment, which is sustained throughout the whole first cycle. And following 1 cycle of duvelisib, there is near-complete inhibition of CLL proliferation, as evidenced by the reduction in Ki67.
Given these data, the investigators recommended further development of duvelisib in treatment-naïve CLL.
*Information in the abstract differs from that presented at the meeting.
VIENNA—New research indicates that duvelisib, a dual inhibitor of PI3Kδ and PI3Kγ, can generate rapid partial responses in treatment-naïve patients with chronic lymphocytic leukemia (CLL).
The 18 patients in the expansion cohort of a phase 1 study of duvelisib had a median time to response of 3.7 months, according to iwCLL response criteria.
And 47% of the responses occurred by the first assessment on day 1 of cycle 3.
“One thing that does seem to be different with this drug is that you’re getting your [partial responses] a bit faster than you see with some of the other drugs,” said Susan O’Brien, MD, of UC Irvine Health in Orange, California.
“[W]hat that means in the long run is not completely clear, but there’s no question that the responses are very rapid.”
Dr O’Brien presented these findings at the 20th Congress of the European Hematology Association (abstract S434*). The research was funded by Infinity Pharmaceuticals, Inc., the company developing duvelisib.
Older CLL patients with comorbidities and patients with high-risk genomic alterations, such as 17p deletion and TP53 mutations, often don’t fare well on the standard chemoimmunotherapy. Duvelisib is being developed as a potential alternative for these patients and others with hematologic malignancies.
In the dose-escalation portion of this phase 1 study, duvelisib at 25 mg twice daily was well-tolerated and exhibited clinical activity in relapsed/refractory CLL, even in those patients with TP53 mutations and 17p deletion.
So investigators conducted the expansion cohort with 18 patients who received duvelisib at the same dose in 28-day cycles. Duvelisib is given continuously until patients have an adverse event or lose their response.
Patient demographics
Dr O’Brien said there was nothing unusual about the demographics of the study population, except the risk factors: 83% of the patients were over 65, “which is very different from what you would see in a chemoimmunotherapy trial.”
She noted that the patients’ median age was 74, and 56% of patients had either a 17p deletion or TP53 mutation.
“And that’s very unusual because . . . the percentage of patients with that abnormality in frontline CLL is about 5% to 10%,” she added.
Patients were a median of 3 years (range, 0–9) from their initial diagnosis, 47% had Rai stage 3 or greater disease, 44% had splenomegaly, and 11% had grade 4 cytopenia.
Response
Patients stayed on treatment for a median of 14 months (range, 1–20). Eight (44%) discontinued treatment—6 (33%) due to an adverse event, 1 withdrew consent, and 1 discontinued for other reasons.
The best overall response rate was 88%, which consisted of 15 partial responses. Two patients (12%) had stable disease, and there were no complete responses or cases of progressive disease.
One patient with a TP53 mutation/17p deletion withdrew consent prior to the first efficacy assessment.
“There’s no upfront progression,” Dr O’Brien said, “and the response rate was identical for patients with high-risk disease or 17p deletion.”
The median progression-free survival was not yet reached, and the rate was 92% at 18 months. One patient progressed at cycle 13.
The median overall survival was also not reached, with a 94% survival rate at 18 months. One patient died of progressive disease approximately 5 months after the last dose.
Adverse events
The most frequent adverse events (AEs) occurring in more than 25% of patients were, in order of frequency, diarrhea, rash, cough, neutropenia, peripheral edema, fatigue, nausea, pyrexia, ALT/AST increase, anemia, and dizziness.
Grade 3 AEs included diarrhea (22%), ALT/AST increase (17%), rash (11%), neutropenia (6%), fatigue (6%), and anemia (6%). The only grade 4 AE was neutropenia (28%).
Serious AEs in more than 1 patient included diarrhea (n=3), colitis (n=2), dehydration (n=2), pneumonia (n=2), and pneumonitis (n=2).
The AEs leading to treatment discontinuation were increased ALT/AST, dehydration, and spinal stenosis (all in 1 patient), as well as arthritis, pneumonitis, colitis, diarrhea, and stomatitis.
“We tend to see the transaminitis and the pneumonitis earlier, and then the late toxicity tends to be the diarrhea and colitis,” Dr O’ Brien said. “The one toxicity where I would not be inclined to try and re-treat a patient is pneumonitis, but I do think colitis can be successfully re-treated.”
Pharmacodynamic studies show very rapid inhibition of phosphorylated AKT following treatment, which is sustained throughout the whole first cycle. And following 1 cycle of duvelisib, there is near-complete inhibition of CLL proliferation, as evidenced by the reduction in Ki67.
Given these data, the investigators recommended further development of duvelisib in treatment-naïve CLL.
*Information in the abstract differs from that presented at the meeting.
Team endorses intensified chemo for PET-positive HL
Photo by Rhoda Baer
LUGANO—Long-awaited results of the Intergroup H10 trial in PET-positive Hodgkin lymphoma (HL) patients have shown that intensifying chemotherapy significantly increases 5-year progression-free survival (PFS) and produces a non-significant increase in overall survival (OS).
Switching patients who are PET-positive after 2 cycles of ABVD to escalated BEACOPP and involved-node radiotherapy increased 5-year PFS to 91% and 5-year OS to 96%.
The trial was a cooperative effort of the European Organisation for Research and Treatment of Cancer (EORTC), Lymphoma Study Association (LYSA), and Fondazione Italiana Linfomi (FIL).
The investigators already knew that early FDG-PET scans have prognostic impact. Patients with a negative PET scan after 2 cycles of chemotherapy have very good outcomes, while those with PET-positive interim scans have poor outcomes.
So the team designed the H10 trial to learn whether they could reduce long-term toxicity in the majority of patients and improve outcomes in the unfavorable subgroups.
Results of the primary endpoint—whether chemotherapy alone is as effective as, but less toxic than, combined-modality treatment in PET-negative patients after 2 cycles of ABVD—were published in the Journal of Clinical Oncology.
The secondary endpoint was an improvement in PFS with an early change from ABVD to escalated BEACOPP in stage I or II HL patients who are PET-positive after 2 cycles of ABVD.
John M. M. Raemaekers, MD, PhD, of Radboud University Medical Center in The Netherlands, presented details on the trial’s secondary endpoint at the 13th International Congress on Malignant Lymphoma (no abstract available).
H10 trial design
The investigators enrolled patients with favorable and unfavorable prognostic characteristics.
Unfavorable characteristics consisted of age 50 or older, more than 3 nodal areas, mediastinal-to-thorax ratio of 0.35 or higher, erythrocyte sedimentation rate of 50 mm or greater without B symptoms, or erythrocyte sedimentation rate of 30 mm or greater with B symptoms.
In the standard treatment arm, patients with favorable or unfavorable characteristics were treated similarly. After 2 cycles of ABVD, a PET scan was performed, and, irrespective of the result, patients received combined-modality treatment of ABVD followed by involved-node radiotherapy.
In the experimental arm, patients who were PET-negative had chemotherapy alone without involved-node radiotherapy. PET-negative patients were not discussed further in this presentation.
For the PET-positive patients in the experimental arm, the treatment for those with favorable and unfavorable characteristics was identical.
Patients who were PET-positive after 2 cycles were switched to 2 escalated BEACOPP cycles plus involved-node radiotherapy. Patients were considered PET-positive if they had a Deauville score of 3, 4, or 5.
Randomization
The first patient was enrolled in November 2006 and the last in June 2011. Investigators randomized 1950 patients, 754 with favorable and 1196 with unfavorable characteristics. All patients had untreated, supradiaphragmatic, clinical stage I or II HL.
Nine hundred fifty-four patients were enrolled in the standard arm, 371 with favorable characteristics and 583 with unfavorable. Nine hundred seventy-one patients entered the experimental arm, 376 with favorable and 595 with unfavorable characteristics.
Twenty-five patients were excluded because they did not complete the first 2 cycles of ABVD or did not have a PET scan.
After 2 cycles of ABVD, 361 patients were PET-positive, 192 in the ABVD arm (54 favorable, 138 unfavorable), and 169 in the escalated BEACOPP arm (43 favorable, 126 unfavorable).
The median age was 30 years in both arms (range, 15 to 70), and the investigators followed patients for a median of 4.5 years.
Results
The only grade 3-4 toxicities were hematologic events and infection.
“As expected, the neutropenia, thrombocytopenia, and anemia, grade 3-4, were more frequent in the experimental BEACOPP arm,” Dr Raemaekers said.
The incidence of grade 3-4 neutropenia was 30.3% (ABVD) and 53.5% (BEACOPP), thrombocytopenia was 0% (ABVD) and 19.7% (BEACOPP), and anemia was 0% (ABVD) and 4.9% (BEACOPP).
The incidence of grade 3-4 febrile neutropenia was 1.1% (ABVD) and 23.9% (BEACOPP), and infection without neutropenia was 1.1% (ABVD) and 11.2% (BEACOPP).
Progression or relapse occurred in 18.8% of patients in the ABVD arm and 7.7% in the BEACOPP arm.
There were 18 deaths in the ABVD arm and 7 deaths in the BEACOPP arm. Eleven deaths in the ABVD arm and 3 in the BEACOPP arm were due to progressive disease or relapse.
The investigators also tallied up the number of patients who progressed, relapsed, or died, whichever occurred first. Forty-one patients in the ABVD arm fulfilled one of these criteria, compared to 16 in the BEACOPP arm.
“Progression and relapse had to be established by conventional restaging, including physical exam, chest X-ray, and CT scan,” Dr Raemaekers pointed out. “And it was based on any new lesion or increase by 50% or more in size of previously involved sites.”
Patients in the BEACOPP arm experienced a significantly better PFS than the ABVD arm, with a hazard ratio of 0.42 (P=0.002). The 5-year PFS was 91% in the BEACOPP arm and 77% in the ABVD arm.
The 5-year OS was 89% in the ABVD arm and 96% in the BEACOPP arm, a difference that was not statistically significant.
“But [the trial] was also not powered for overall survival,” Dr Raemaekers said. “[T]here is a hint, at least, that, even in overall survival, the BEACOPP arm is superior to the ABVD arm.”
Based on these findings, the investigators concluded that, despite increased toxicity, physicians should consider intensifying chemotherapy in early PET-positive patients with stage I/II HL in the combined-modality setting.
Photo by Rhoda Baer
LUGANO—Long-awaited results of the Intergroup H10 trial in PET-positive Hodgkin lymphoma (HL) patients have shown that intensifying chemotherapy significantly increases 5-year progression-free survival (PFS) and produces a non-significant increase in overall survival (OS).
Switching patients who are PET-positive after 2 cycles of ABVD to escalated BEACOPP and involved-node radiotherapy increased 5-year PFS to 91% and 5-year OS to 96%.
The trial was a cooperative effort of the European Organisation for Research and Treatment of Cancer (EORTC), Lymphoma Study Association (LYSA), and Fondazione Italiana Linfomi (FIL).
The investigators already knew that early FDG-PET scans have prognostic impact. Patients with a negative PET scan after 2 cycles of chemotherapy have very good outcomes, while those with PET-positive interim scans have poor outcomes.
So the team designed the H10 trial to learn whether they could reduce long-term toxicity in the majority of patients and improve outcomes in the unfavorable subgroups.
Results of the primary endpoint—whether chemotherapy alone is as effective as, but less toxic than, combined-modality treatment in PET-negative patients after 2 cycles of ABVD—were published in the Journal of Clinical Oncology.
The secondary endpoint was an improvement in PFS with an early change from ABVD to escalated BEACOPP in stage I or II HL patients who are PET-positive after 2 cycles of ABVD.
John M. M. Raemaekers, MD, PhD, of Radboud University Medical Center in The Netherlands, presented details on the trial’s secondary endpoint at the 13th International Congress on Malignant Lymphoma (no abstract available).
H10 trial design
The investigators enrolled patients with favorable and unfavorable prognostic characteristics.
Unfavorable characteristics consisted of age 50 or older, more than 3 nodal areas, mediastinal-to-thorax ratio of 0.35 or higher, erythrocyte sedimentation rate of 50 mm or greater without B symptoms, or erythrocyte sedimentation rate of 30 mm or greater with B symptoms.
In the standard treatment arm, patients with favorable or unfavorable characteristics were treated similarly. After 2 cycles of ABVD, a PET scan was performed, and, irrespective of the result, patients received combined-modality treatment of ABVD followed by involved-node radiotherapy.
In the experimental arm, patients who were PET-negative had chemotherapy alone without involved-node radiotherapy. PET-negative patients were not discussed further in this presentation.
For the PET-positive patients in the experimental arm, the treatment for those with favorable and unfavorable characteristics was identical.
Patients who were PET-positive after 2 cycles were switched to 2 escalated BEACOPP cycles plus involved-node radiotherapy. Patients were considered PET-positive if they had a Deauville score of 3, 4, or 5.
Randomization
The first patient was enrolled in November 2006 and the last in June 2011. Investigators randomized 1950 patients, 754 with favorable and 1196 with unfavorable characteristics. All patients had untreated, supradiaphragmatic, clinical stage I or II HL.
Nine hundred fifty-four patients were enrolled in the standard arm, 371 with favorable characteristics and 583 with unfavorable. Nine hundred seventy-one patients entered the experimental arm, 376 with favorable and 595 with unfavorable characteristics.
Twenty-five patients were excluded because they did not complete the first 2 cycles of ABVD or did not have a PET scan.
After 2 cycles of ABVD, 361 patients were PET-positive, 192 in the ABVD arm (54 favorable, 138 unfavorable), and 169 in the escalated BEACOPP arm (43 favorable, 126 unfavorable).
The median age was 30 years in both arms (range, 15 to 70), and the investigators followed patients for a median of 4.5 years.
Results
The only grade 3-4 toxicities were hematologic events and infection.
“As expected, the neutropenia, thrombocytopenia, and anemia, grade 3-4, were more frequent in the experimental BEACOPP arm,” Dr Raemaekers said.
The incidence of grade 3-4 neutropenia was 30.3% (ABVD) and 53.5% (BEACOPP), thrombocytopenia was 0% (ABVD) and 19.7% (BEACOPP), and anemia was 0% (ABVD) and 4.9% (BEACOPP).
The incidence of grade 3-4 febrile neutropenia was 1.1% (ABVD) and 23.9% (BEACOPP), and infection without neutropenia was 1.1% (ABVD) and 11.2% (BEACOPP).
Progression or relapse occurred in 18.8% of patients in the ABVD arm and 7.7% in the BEACOPP arm.
There were 18 deaths in the ABVD arm and 7 deaths in the BEACOPP arm. Eleven deaths in the ABVD arm and 3 in the BEACOPP arm were due to progressive disease or relapse.
The investigators also tallied up the number of patients who progressed, relapsed, or died, whichever occurred first. Forty-one patients in the ABVD arm fulfilled one of these criteria, compared to 16 in the BEACOPP arm.
“Progression and relapse had to be established by conventional restaging, including physical exam, chest X-ray, and CT scan,” Dr Raemaekers pointed out. “And it was based on any new lesion or increase by 50% or more in size of previously involved sites.”
Patients in the BEACOPP arm experienced a significantly better PFS than the ABVD arm, with a hazard ratio of 0.42 (P=0.002). The 5-year PFS was 91% in the BEACOPP arm and 77% in the ABVD arm.
The 5-year OS was 89% in the ABVD arm and 96% in the BEACOPP arm, a difference that was not statistically significant.
“But [the trial] was also not powered for overall survival,” Dr Raemaekers said. “[T]here is a hint, at least, that, even in overall survival, the BEACOPP arm is superior to the ABVD arm.”
Based on these findings, the investigators concluded that, despite increased toxicity, physicians should consider intensifying chemotherapy in early PET-positive patients with stage I/II HL in the combined-modality setting.
Photo by Rhoda Baer
LUGANO—Long-awaited results of the Intergroup H10 trial in PET-positive Hodgkin lymphoma (HL) patients have shown that intensifying chemotherapy significantly increases 5-year progression-free survival (PFS) and produces a non-significant increase in overall survival (OS).
Switching patients who are PET-positive after 2 cycles of ABVD to escalated BEACOPP and involved-node radiotherapy increased 5-year PFS to 91% and 5-year OS to 96%.
The trial was a cooperative effort of the European Organisation for Research and Treatment of Cancer (EORTC), Lymphoma Study Association (LYSA), and Fondazione Italiana Linfomi (FIL).
The investigators already knew that early FDG-PET scans have prognostic impact. Patients with a negative PET scan after 2 cycles of chemotherapy have very good outcomes, while those with PET-positive interim scans have poor outcomes.
So the team designed the H10 trial to learn whether they could reduce long-term toxicity in the majority of patients and improve outcomes in the unfavorable subgroups.
Results of the primary endpoint—whether chemotherapy alone is as effective as, but less toxic than, combined-modality treatment in PET-negative patients after 2 cycles of ABVD—were published in the Journal of Clinical Oncology.
The secondary endpoint was an improvement in PFS with an early change from ABVD to escalated BEACOPP in stage I or II HL patients who are PET-positive after 2 cycles of ABVD.
John M. M. Raemaekers, MD, PhD, of Radboud University Medical Center in The Netherlands, presented details on the trial’s secondary endpoint at the 13th International Congress on Malignant Lymphoma (no abstract available).
H10 trial design
The investigators enrolled patients with favorable and unfavorable prognostic characteristics.
Unfavorable characteristics consisted of age 50 or older, more than 3 nodal areas, mediastinal-to-thorax ratio of 0.35 or higher, erythrocyte sedimentation rate of 50 mm or greater without B symptoms, or erythrocyte sedimentation rate of 30 mm or greater with B symptoms.
In the standard treatment arm, patients with favorable or unfavorable characteristics were treated similarly. After 2 cycles of ABVD, a PET scan was performed, and, irrespective of the result, patients received combined-modality treatment of ABVD followed by involved-node radiotherapy.
In the experimental arm, patients who were PET-negative had chemotherapy alone without involved-node radiotherapy. PET-negative patients were not discussed further in this presentation.
For the PET-positive patients in the experimental arm, the treatment for those with favorable and unfavorable characteristics was identical.
Patients who were PET-positive after 2 cycles were switched to 2 escalated BEACOPP cycles plus involved-node radiotherapy. Patients were considered PET-positive if they had a Deauville score of 3, 4, or 5.
Randomization
The first patient was enrolled in November 2006 and the last in June 2011. Investigators randomized 1950 patients, 754 with favorable and 1196 with unfavorable characteristics. All patients had untreated, supradiaphragmatic, clinical stage I or II HL.
Nine hundred fifty-four patients were enrolled in the standard arm, 371 with favorable characteristics and 583 with unfavorable. Nine hundred seventy-one patients entered the experimental arm, 376 with favorable and 595 with unfavorable characteristics.
Twenty-five patients were excluded because they did not complete the first 2 cycles of ABVD or did not have a PET scan.
After 2 cycles of ABVD, 361 patients were PET-positive, 192 in the ABVD arm (54 favorable, 138 unfavorable), and 169 in the escalated BEACOPP arm (43 favorable, 126 unfavorable).
The median age was 30 years in both arms (range, 15 to 70), and the investigators followed patients for a median of 4.5 years.
Results
The only grade 3-4 toxicities were hematologic events and infection.
“As expected, the neutropenia, thrombocytopenia, and anemia, grade 3-4, were more frequent in the experimental BEACOPP arm,” Dr Raemaekers said.
The incidence of grade 3-4 neutropenia was 30.3% (ABVD) and 53.5% (BEACOPP), thrombocytopenia was 0% (ABVD) and 19.7% (BEACOPP), and anemia was 0% (ABVD) and 4.9% (BEACOPP).
The incidence of grade 3-4 febrile neutropenia was 1.1% (ABVD) and 23.9% (BEACOPP), and infection without neutropenia was 1.1% (ABVD) and 11.2% (BEACOPP).
Progression or relapse occurred in 18.8% of patients in the ABVD arm and 7.7% in the BEACOPP arm.
There were 18 deaths in the ABVD arm and 7 deaths in the BEACOPP arm. Eleven deaths in the ABVD arm and 3 in the BEACOPP arm were due to progressive disease or relapse.
The investigators also tallied up the number of patients who progressed, relapsed, or died, whichever occurred first. Forty-one patients in the ABVD arm fulfilled one of these criteria, compared to 16 in the BEACOPP arm.
“Progression and relapse had to be established by conventional restaging, including physical exam, chest X-ray, and CT scan,” Dr Raemaekers pointed out. “And it was based on any new lesion or increase by 50% or more in size of previously involved sites.”
Patients in the BEACOPP arm experienced a significantly better PFS than the ABVD arm, with a hazard ratio of 0.42 (P=0.002). The 5-year PFS was 91% in the BEACOPP arm and 77% in the ABVD arm.
The 5-year OS was 89% in the ABVD arm and 96% in the BEACOPP arm, a difference that was not statistically significant.
“But [the trial] was also not powered for overall survival,” Dr Raemaekers said. “[T]here is a hint, at least, that, even in overall survival, the BEACOPP arm is superior to the ABVD arm.”
Based on these findings, the investigators concluded that, despite increased toxicity, physicians should consider intensifying chemotherapy in early PET-positive patients with stage I/II HL in the combined-modality setting.
‘Radically different’ PI3Kδ inhibitor lacks hepatotoxicity
Photo by Larry Young
LUGANO—Updated phase 1 results with TGR-1202 suggest this next-generation PI3kδ inhibitor lacks the hepatotoxicity associated with other PI3Kδ inhibitors.
Investigators also confirmed that no case of colitis has been reported to date with TGR-1202, and only 2% of evaluable patients on this trial have experienced grade 3-4 diarrhea.
The study is an ongoing, first-in-human trial in patients with relapsed or refractory hematologic malignancies.
Owen O’Connor, MD, PhD, of Columbia University Medical Center in New York, New York, shared results from this trial at the 13th International Congress on Malignant Lymphoma (abstract 038*). The trial is sponsored by TG Therapeutics, Inc., the company developing TGR-1202.
“TGR-1202 is a radically different sort of PI3kδ inhibitor,” Dr O’Connor said. “[I]t’s really a unique chemical entity that is different from the previous 2 structures [idelalisib and duvelisib] that you’ve probably heard something about.”
Study design
This ongoing trial of TGR-1202 is open to patients with hematologic malignancies who relapsed after or were refractory to at least 1 prior treatment regimen. Patients are eligible if they have an ECOG performance status of 2 or less with adequate organ system function, including absolute neutrophil count of 750/μL or greater and platelets of 50,000/μL or greater.
TGR-1202 is dosed orally, once a day in continuous, 28-day cycles. The original dose-escalation portion of the study was a classic 3+3 design, starting at 50 mg and increasing to 1800 mg. Patients who received prior therapy with a PI3K and/or mTOR inhibitor were excluded from the dose-escalation cohorts but were allowed in the expansion cohorts.
Dr O’Connor pointed out that, through cohort 5, TGR-1202 was taken in the fasting state. However, pharmacokinetic studies performed in the fed state revealed that the area under the curve (AUC) and Cmax could be doubled by taking the drug with food. So the expansions in the ongoing 800 mg and 1200 mg cohorts are being conducted in the fed state.
Dr O’Connor also noted that a subsequent, micronized version of TGR-1202 was developed. The micronization “essentially increases the surface area of the formulation, allowing for better bioavailability and markedly increases the AUC and Cmax exposure,” he said.
So the investigators conducted a second escalation with the micronized formulation, starting at 200 mg and increasing to 800 mg. At present, they are enrolling patients to the 800 mg and 1200 mg cohorts conducted in the fed state with the micronized formulation.
Demographics
Dr O’Connor presented data on 66 patients who were evaluable for safety and 51 for efficacy. The patients’ median age was 66 (range, 22–85), and 46 were male.
In all, there were 20 patients with chronic lymphocytic leukemia (CLL), 17 with follicular lymphoma, 10 with diffuse large B-cell lymphoma, 9 with Hodgkin lymphoma, 5 with mantle cell lymphoma, 3 with marginal zone lymphoma, 1 with Waldenström’s macroglobulinemia, and 1 with hairy cell leukemia.
Patients had received a median of 3 prior therapies (range, 1–14), and 36 (55%) had 3 or more prior therapies. Thirty-four patients (52%) were refractory to their prior therapy.
Efficacy
Dr O’Connor reported that higher doses of TGR-1202—1200 mg of the initial formulation and 600 mg or more of the micronized version—demonstrated rapid and profound responses in CLL, follicular lymphoma, and marginal zone lymphoma.
Responses have been limited in diffuse large B-cell lymphoma, Hodgkin lymphoma, and mantle cell lymphoma.
Eighty-eight percent of CLL patients achieved a nodal partial remission, and 63% achieved a response according to iwCLL criteria (Hallek 2008).
Safety and tolerability
Adverse events occurring in more than 10% of patients included nausea (41%), diarrhea (32%), fatigue (32%), headache (23%), vomiting (23%), cough (21%), decreased appetite (17%), rash (17%), constipation (14%), hypokalemia (14%), anemia, dizziness, dyspnea, neutropenia, and pyrexia (12% each), and abdominal pain (11%).
The most common grade 3-4 toxicity was neutropenia, occurring in 11% of patients.
“But other than that, the bulk of the toxicities in terms of grade 3-4 events were relatively modest,” Dr O’Connor said. “[I]t’s worth pointing out that diarrhea grade 3-4 only occurred in about 2% of patients in the population.”
Approximately 50% of patients (n=31) have been on study for more than 6 months, and approximately 30% taking a higher dose level have been on study for 6 months or more. Twenty-five of 37 patients exposed to 800 mg or more of the micronized formulation currently remain on study.
“So this gives you a sense that it is a very well-tolerated drug, with patients staying on for extended periods of time,” Dr O’Connor said.
He added that time on study becomes relevant in assessing some of the gastrointestinal toxicities seen with other PI3Kδ inhibitors, where it seems the median time to gastrointestinal toxicity is beyond 6 months.
“So far, and I’m willing to concede it’s early, but with half the patients being treated for over 6 months, [diarrhea/colitis] seems to be much lower than the experience with the other PI3 kinase inhibitors,” Dr O’Connor said.
“I think one of the more important features of [TGR-1202], and one that allows me to think we might be able to integrate this drug a little more readily into various combination regimens, are the discontinuations due to other adverse events.”
“Only 4% treated with [TGR-1202] had discontinuations secondary to adverse events. [A]nd it looks like the efficacy is in line with what we’d expect with some of the other drugs, but this [study] is actively accruing still.”
*Information in the abstract differs from that presented at the meeting.
Photo by Larry Young
LUGANO—Updated phase 1 results with TGR-1202 suggest this next-generation PI3kδ inhibitor lacks the hepatotoxicity associated with other PI3Kδ inhibitors.
Investigators also confirmed that no case of colitis has been reported to date with TGR-1202, and only 2% of evaluable patients on this trial have experienced grade 3-4 diarrhea.
The study is an ongoing, first-in-human trial in patients with relapsed or refractory hematologic malignancies.
Owen O’Connor, MD, PhD, of Columbia University Medical Center in New York, New York, shared results from this trial at the 13th International Congress on Malignant Lymphoma (abstract 038*). The trial is sponsored by TG Therapeutics, Inc., the company developing TGR-1202.
“TGR-1202 is a radically different sort of PI3kδ inhibitor,” Dr O’Connor said. “[I]t’s really a unique chemical entity that is different from the previous 2 structures [idelalisib and duvelisib] that you’ve probably heard something about.”
Study design
This ongoing trial of TGR-1202 is open to patients with hematologic malignancies who relapsed after or were refractory to at least 1 prior treatment regimen. Patients are eligible if they have an ECOG performance status of 2 or less with adequate organ system function, including absolute neutrophil count of 750/μL or greater and platelets of 50,000/μL or greater.
TGR-1202 is dosed orally, once a day in continuous, 28-day cycles. The original dose-escalation portion of the study was a classic 3+3 design, starting at 50 mg and increasing to 1800 mg. Patients who received prior therapy with a PI3K and/or mTOR inhibitor were excluded from the dose-escalation cohorts but were allowed in the expansion cohorts.
Dr O’Connor pointed out that, through cohort 5, TGR-1202 was taken in the fasting state. However, pharmacokinetic studies performed in the fed state revealed that the area under the curve (AUC) and Cmax could be doubled by taking the drug with food. So the expansions in the ongoing 800 mg and 1200 mg cohorts are being conducted in the fed state.
Dr O’Connor also noted that a subsequent, micronized version of TGR-1202 was developed. The micronization “essentially increases the surface area of the formulation, allowing for better bioavailability and markedly increases the AUC and Cmax exposure,” he said.
So the investigators conducted a second escalation with the micronized formulation, starting at 200 mg and increasing to 800 mg. At present, they are enrolling patients to the 800 mg and 1200 mg cohorts conducted in the fed state with the micronized formulation.
Demographics
Dr O’Connor presented data on 66 patients who were evaluable for safety and 51 for efficacy. The patients’ median age was 66 (range, 22–85), and 46 were male.
In all, there were 20 patients with chronic lymphocytic leukemia (CLL), 17 with follicular lymphoma, 10 with diffuse large B-cell lymphoma, 9 with Hodgkin lymphoma, 5 with mantle cell lymphoma, 3 with marginal zone lymphoma, 1 with Waldenström’s macroglobulinemia, and 1 with hairy cell leukemia.
Patients had received a median of 3 prior therapies (range, 1–14), and 36 (55%) had 3 or more prior therapies. Thirty-four patients (52%) were refractory to their prior therapy.
Efficacy
Dr O’Connor reported that higher doses of TGR-1202—1200 mg of the initial formulation and 600 mg or more of the micronized version—demonstrated rapid and profound responses in CLL, follicular lymphoma, and marginal zone lymphoma.
Responses have been limited in diffuse large B-cell lymphoma, Hodgkin lymphoma, and mantle cell lymphoma.
Eighty-eight percent of CLL patients achieved a nodal partial remission, and 63% achieved a response according to iwCLL criteria (Hallek 2008).
Safety and tolerability
Adverse events occurring in more than 10% of patients included nausea (41%), diarrhea (32%), fatigue (32%), headache (23%), vomiting (23%), cough (21%), decreased appetite (17%), rash (17%), constipation (14%), hypokalemia (14%), anemia, dizziness, dyspnea, neutropenia, and pyrexia (12% each), and abdominal pain (11%).
The most common grade 3-4 toxicity was neutropenia, occurring in 11% of patients.
“But other than that, the bulk of the toxicities in terms of grade 3-4 events were relatively modest,” Dr O’Connor said. “[I]t’s worth pointing out that diarrhea grade 3-4 only occurred in about 2% of patients in the population.”
Approximately 50% of patients (n=31) have been on study for more than 6 months, and approximately 30% taking a higher dose level have been on study for 6 months or more. Twenty-five of 37 patients exposed to 800 mg or more of the micronized formulation currently remain on study.
“So this gives you a sense that it is a very well-tolerated drug, with patients staying on for extended periods of time,” Dr O’Connor said.
He added that time on study becomes relevant in assessing some of the gastrointestinal toxicities seen with other PI3Kδ inhibitors, where it seems the median time to gastrointestinal toxicity is beyond 6 months.
“So far, and I’m willing to concede it’s early, but with half the patients being treated for over 6 months, [diarrhea/colitis] seems to be much lower than the experience with the other PI3 kinase inhibitors,” Dr O’Connor said.
“I think one of the more important features of [TGR-1202], and one that allows me to think we might be able to integrate this drug a little more readily into various combination regimens, are the discontinuations due to other adverse events.”
“Only 4% treated with [TGR-1202] had discontinuations secondary to adverse events. [A]nd it looks like the efficacy is in line with what we’d expect with some of the other drugs, but this [study] is actively accruing still.”
*Information in the abstract differs from that presented at the meeting.
Photo by Larry Young
LUGANO—Updated phase 1 results with TGR-1202 suggest this next-generation PI3kδ inhibitor lacks the hepatotoxicity associated with other PI3Kδ inhibitors.
Investigators also confirmed that no case of colitis has been reported to date with TGR-1202, and only 2% of evaluable patients on this trial have experienced grade 3-4 diarrhea.
The study is an ongoing, first-in-human trial in patients with relapsed or refractory hematologic malignancies.
Owen O’Connor, MD, PhD, of Columbia University Medical Center in New York, New York, shared results from this trial at the 13th International Congress on Malignant Lymphoma (abstract 038*). The trial is sponsored by TG Therapeutics, Inc., the company developing TGR-1202.
“TGR-1202 is a radically different sort of PI3kδ inhibitor,” Dr O’Connor said. “[I]t’s really a unique chemical entity that is different from the previous 2 structures [idelalisib and duvelisib] that you’ve probably heard something about.”
Study design
This ongoing trial of TGR-1202 is open to patients with hematologic malignancies who relapsed after or were refractory to at least 1 prior treatment regimen. Patients are eligible if they have an ECOG performance status of 2 or less with adequate organ system function, including absolute neutrophil count of 750/μL or greater and platelets of 50,000/μL or greater.
TGR-1202 is dosed orally, once a day in continuous, 28-day cycles. The original dose-escalation portion of the study was a classic 3+3 design, starting at 50 mg and increasing to 1800 mg. Patients who received prior therapy with a PI3K and/or mTOR inhibitor were excluded from the dose-escalation cohorts but were allowed in the expansion cohorts.
Dr O’Connor pointed out that, through cohort 5, TGR-1202 was taken in the fasting state. However, pharmacokinetic studies performed in the fed state revealed that the area under the curve (AUC) and Cmax could be doubled by taking the drug with food. So the expansions in the ongoing 800 mg and 1200 mg cohorts are being conducted in the fed state.
Dr O’Connor also noted that a subsequent, micronized version of TGR-1202 was developed. The micronization “essentially increases the surface area of the formulation, allowing for better bioavailability and markedly increases the AUC and Cmax exposure,” he said.
So the investigators conducted a second escalation with the micronized formulation, starting at 200 mg and increasing to 800 mg. At present, they are enrolling patients to the 800 mg and 1200 mg cohorts conducted in the fed state with the micronized formulation.
Demographics
Dr O’Connor presented data on 66 patients who were evaluable for safety and 51 for efficacy. The patients’ median age was 66 (range, 22–85), and 46 were male.
In all, there were 20 patients with chronic lymphocytic leukemia (CLL), 17 with follicular lymphoma, 10 with diffuse large B-cell lymphoma, 9 with Hodgkin lymphoma, 5 with mantle cell lymphoma, 3 with marginal zone lymphoma, 1 with Waldenström’s macroglobulinemia, and 1 with hairy cell leukemia.
Patients had received a median of 3 prior therapies (range, 1–14), and 36 (55%) had 3 or more prior therapies. Thirty-four patients (52%) were refractory to their prior therapy.
Efficacy
Dr O’Connor reported that higher doses of TGR-1202—1200 mg of the initial formulation and 600 mg or more of the micronized version—demonstrated rapid and profound responses in CLL, follicular lymphoma, and marginal zone lymphoma.
Responses have been limited in diffuse large B-cell lymphoma, Hodgkin lymphoma, and mantle cell lymphoma.
Eighty-eight percent of CLL patients achieved a nodal partial remission, and 63% achieved a response according to iwCLL criteria (Hallek 2008).
Safety and tolerability
Adverse events occurring in more than 10% of patients included nausea (41%), diarrhea (32%), fatigue (32%), headache (23%), vomiting (23%), cough (21%), decreased appetite (17%), rash (17%), constipation (14%), hypokalemia (14%), anemia, dizziness, dyspnea, neutropenia, and pyrexia (12% each), and abdominal pain (11%).
The most common grade 3-4 toxicity was neutropenia, occurring in 11% of patients.
“But other than that, the bulk of the toxicities in terms of grade 3-4 events were relatively modest,” Dr O’Connor said. “[I]t’s worth pointing out that diarrhea grade 3-4 only occurred in about 2% of patients in the population.”
Approximately 50% of patients (n=31) have been on study for more than 6 months, and approximately 30% taking a higher dose level have been on study for 6 months or more. Twenty-five of 37 patients exposed to 800 mg or more of the micronized formulation currently remain on study.
“So this gives you a sense that it is a very well-tolerated drug, with patients staying on for extended periods of time,” Dr O’Connor said.
He added that time on study becomes relevant in assessing some of the gastrointestinal toxicities seen with other PI3Kδ inhibitors, where it seems the median time to gastrointestinal toxicity is beyond 6 months.
“So far, and I’m willing to concede it’s early, but with half the patients being treated for over 6 months, [diarrhea/colitis] seems to be much lower than the experience with the other PI3 kinase inhibitors,” Dr O’Connor said.
“I think one of the more important features of [TGR-1202], and one that allows me to think we might be able to integrate this drug a little more readily into various combination regimens, are the discontinuations due to other adverse events.”
“Only 4% treated with [TGR-1202] had discontinuations secondary to adverse events. [A]nd it looks like the efficacy is in line with what we’d expect with some of the other drugs, but this [study] is actively accruing still.”
*Information in the abstract differs from that presented at the meeting.
Nivolumab produces ‘dramatic’ responses in HL
Photo courtesy of UCLA
LUGANO—The PD-1 checkpoint inhibitor nivolumab produces rapid, durable, and, in some cases, “dramatic” responses in Hodgkin lymphoma (HL), according to a speaker at the 13th International Congress on Malignant Lymphoma.
The drug has also produced durable responses in follicular lymphoma (FL), cutaneous T-cell lymphoma (CTCL), and peripheral T-cell lymphoma (PTCL), although patient numbers for these malignancies are small.
John Timmerman, MD, of the University of California, Los Angeles, presented these results from a phase 1 study of patients with relapsed or refractory lymphoid malignancies and chronic HL (abstract 010).
Bristol-Myers Squibb and Ono Pharmaceutical Company are sponsors of the trial.
Original results of the study, with a data cutoff of June 2014, were reported at ASH 2014, with 40 weeks of median follow-up.
The update presented at 13-ICML, with a data lock in April 2015, includes an additional 10 months of data, for a median follow-up of 76 weeks.
Investigators enrolled 105 patients in this dose-escalation study to receive nivolumab at 1 mg/kg, then 3 mg/kg, every 2 weeks for 2 years.
Twenty-three patients had HL. Thirty-one had B-cell non-Hodgkin lymphoma (NHL), including 11 with FL and 10 with diffuse large B-cell lymphoma (DLBCL).
Twenty-three patients had T-cell NHL, including 5 with PTCL and 13 with CTCL/mycosis fungoides (MF). Twenty-seven patients had multiple myeloma (MM), and 1 had chronic myeloid leukemia.
Patients were heavily pretreated. Seventy-eight percent of HL patients and 26% of T-NHL patients had prior brentuximab vedotin. And 78% (HL), 14% (B-NHL), 9% (T-NHL), and 56% (MM) of patients had a prior autologous transplant.
The median number of prior therapies was 5 (range, 2-15) for HL patients and ranged from 1 to 16 for all patients.
The study’s primary endpoint was safety and tolerability, and the secondary endpoint was efficacy.
Safety and tolerability
Ninety-seven percent of patients had an adverse event, 69% of them related to study treatment and 21% of them treatment-related grade 3-4 events.
Fifteen patients (14%) discontinued treatment due to a related adverse event, including 3 with pneumonitis and 1 each with enteritis, stomatitis, pancreatitis, rash, conjunctivitis, sepsis, diplopia, myositis, neutropenia, myelodysplastic syndrome, increased creatinine phosphokinase, and peripheral neuropathy.
“Immune-related adverse events were generally seen early on and generally of low grade,” Dr Timmerman said. “However, it is notable that there were several grade 3 immune-related adverse events that can be seen as far as 6 months out after the start of therapy.”
These included skin, gastrointestinal, and pulmonary events. Most immune-related adverse events (83%) were resolved using protocol-prescribed procedures.
Efficacy
The overall response rate was 87% for HL, 36% for DLBCL, 40% for FL, 15% for CTCL/MF, 40% for PTCL, and 4% for MM.
Dr Timmerman pointed out that, since ASH, 2 additional conversions from partial response (PR) to complete response (CR) occurred in patients with HL. To date, 6 of 23 HL patients have achieved a CR and 14 a PR.
In B-cell NHL, there were additional conversions from PR to CR in DLBCL, while responses remained the same in FL and in the 4 responders with T-cell lymphomas.
“Intriguingly, there has been 1 late CR in the multiple myeloma cohort, which previously had shown no responses,” Dr Timmerman said.
Durability of response
This study suggests PD-1 blockade can produce durable responses in hematologic malignancies, as it does in melanoma and renal cell carcinoma.
In HL, the median response duration at a median follow-up of 86 weeks has not yet been reached, and half (n=10) of the responses are still ongoing.
In FL, CTCL, and PTCL, the median response duration has not been reached at a median follow-up of 81, 43, and 31 weeks, respectively. Of note, there are ongoing responses in at least half of patients in these tumor types.
In HL, none of the 6 patients in CR has progressed, although there have been some progressions in the PR group.
The rapidity of responses is also notable, Dr Timmerman said.
“[I]t’s very interesting that some patients have resolution of symptoms and improvement of symptoms within even 1 day of starting nivolumab therapy,” he said.
And responses to nivolumab in HL “can be very dramatic,” he added, as illustrated in the following case from the Mayo Clinic.
A patient with multiple sites of bulky FDG-avid tumors was scheduled to enter hospice. But first, he entered the nivolumab trial. Within 6 weeks of initiating treatment, he had achieved a near-CR. This response has been maintained for 2 years.
“The occurrence of very durable responses in the PR and CR groups has led us to question whether patients should go on to allogeneic stem cell transplantation after achieving responses with nivolumab or, rather, continue on nivolumab as long as their response remains,” Dr Timmerman said.
He added that an international, phase 2 trial in HL is underway and is accruing briskly.
Nivolumab was awarded breakthrough designation by the US Food and Drug Administration last year. Breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.
Photo courtesy of UCLA
LUGANO—The PD-1 checkpoint inhibitor nivolumab produces rapid, durable, and, in some cases, “dramatic” responses in Hodgkin lymphoma (HL), according to a speaker at the 13th International Congress on Malignant Lymphoma.
The drug has also produced durable responses in follicular lymphoma (FL), cutaneous T-cell lymphoma (CTCL), and peripheral T-cell lymphoma (PTCL), although patient numbers for these malignancies are small.
John Timmerman, MD, of the University of California, Los Angeles, presented these results from a phase 1 study of patients with relapsed or refractory lymphoid malignancies and chronic HL (abstract 010).
Bristol-Myers Squibb and Ono Pharmaceutical Company are sponsors of the trial.
Original results of the study, with a data cutoff of June 2014, were reported at ASH 2014, with 40 weeks of median follow-up.
The update presented at 13-ICML, with a data lock in April 2015, includes an additional 10 months of data, for a median follow-up of 76 weeks.
Investigators enrolled 105 patients in this dose-escalation study to receive nivolumab at 1 mg/kg, then 3 mg/kg, every 2 weeks for 2 years.
Twenty-three patients had HL. Thirty-one had B-cell non-Hodgkin lymphoma (NHL), including 11 with FL and 10 with diffuse large B-cell lymphoma (DLBCL).
Twenty-three patients had T-cell NHL, including 5 with PTCL and 13 with CTCL/mycosis fungoides (MF). Twenty-seven patients had multiple myeloma (MM), and 1 had chronic myeloid leukemia.
Patients were heavily pretreated. Seventy-eight percent of HL patients and 26% of T-NHL patients had prior brentuximab vedotin. And 78% (HL), 14% (B-NHL), 9% (T-NHL), and 56% (MM) of patients had a prior autologous transplant.
The median number of prior therapies was 5 (range, 2-15) for HL patients and ranged from 1 to 16 for all patients.
The study’s primary endpoint was safety and tolerability, and the secondary endpoint was efficacy.
Safety and tolerability
Ninety-seven percent of patients had an adverse event, 69% of them related to study treatment and 21% of them treatment-related grade 3-4 events.
Fifteen patients (14%) discontinued treatment due to a related adverse event, including 3 with pneumonitis and 1 each with enteritis, stomatitis, pancreatitis, rash, conjunctivitis, sepsis, diplopia, myositis, neutropenia, myelodysplastic syndrome, increased creatinine phosphokinase, and peripheral neuropathy.
“Immune-related adverse events were generally seen early on and generally of low grade,” Dr Timmerman said. “However, it is notable that there were several grade 3 immune-related adverse events that can be seen as far as 6 months out after the start of therapy.”
These included skin, gastrointestinal, and pulmonary events. Most immune-related adverse events (83%) were resolved using protocol-prescribed procedures.
Efficacy
The overall response rate was 87% for HL, 36% for DLBCL, 40% for FL, 15% for CTCL/MF, 40% for PTCL, and 4% for MM.
Dr Timmerman pointed out that, since ASH, 2 additional conversions from partial response (PR) to complete response (CR) occurred in patients with HL. To date, 6 of 23 HL patients have achieved a CR and 14 a PR.
In B-cell NHL, there were additional conversions from PR to CR in DLBCL, while responses remained the same in FL and in the 4 responders with T-cell lymphomas.
“Intriguingly, there has been 1 late CR in the multiple myeloma cohort, which previously had shown no responses,” Dr Timmerman said.
Durability of response
This study suggests PD-1 blockade can produce durable responses in hematologic malignancies, as it does in melanoma and renal cell carcinoma.
In HL, the median response duration at a median follow-up of 86 weeks has not yet been reached, and half (n=10) of the responses are still ongoing.
In FL, CTCL, and PTCL, the median response duration has not been reached at a median follow-up of 81, 43, and 31 weeks, respectively. Of note, there are ongoing responses in at least half of patients in these tumor types.
In HL, none of the 6 patients in CR has progressed, although there have been some progressions in the PR group.
The rapidity of responses is also notable, Dr Timmerman said.
“[I]t’s very interesting that some patients have resolution of symptoms and improvement of symptoms within even 1 day of starting nivolumab therapy,” he said.
And responses to nivolumab in HL “can be very dramatic,” he added, as illustrated in the following case from the Mayo Clinic.
A patient with multiple sites of bulky FDG-avid tumors was scheduled to enter hospice. But first, he entered the nivolumab trial. Within 6 weeks of initiating treatment, he had achieved a near-CR. This response has been maintained for 2 years.
“The occurrence of very durable responses in the PR and CR groups has led us to question whether patients should go on to allogeneic stem cell transplantation after achieving responses with nivolumab or, rather, continue on nivolumab as long as their response remains,” Dr Timmerman said.
He added that an international, phase 2 trial in HL is underway and is accruing briskly.
Nivolumab was awarded breakthrough designation by the US Food and Drug Administration last year. Breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.
Photo courtesy of UCLA
LUGANO—The PD-1 checkpoint inhibitor nivolumab produces rapid, durable, and, in some cases, “dramatic” responses in Hodgkin lymphoma (HL), according to a speaker at the 13th International Congress on Malignant Lymphoma.
The drug has also produced durable responses in follicular lymphoma (FL), cutaneous T-cell lymphoma (CTCL), and peripheral T-cell lymphoma (PTCL), although patient numbers for these malignancies are small.
John Timmerman, MD, of the University of California, Los Angeles, presented these results from a phase 1 study of patients with relapsed or refractory lymphoid malignancies and chronic HL (abstract 010).
Bristol-Myers Squibb and Ono Pharmaceutical Company are sponsors of the trial.
Original results of the study, with a data cutoff of June 2014, were reported at ASH 2014, with 40 weeks of median follow-up.
The update presented at 13-ICML, with a data lock in April 2015, includes an additional 10 months of data, for a median follow-up of 76 weeks.
Investigators enrolled 105 patients in this dose-escalation study to receive nivolumab at 1 mg/kg, then 3 mg/kg, every 2 weeks for 2 years.
Twenty-three patients had HL. Thirty-one had B-cell non-Hodgkin lymphoma (NHL), including 11 with FL and 10 with diffuse large B-cell lymphoma (DLBCL).
Twenty-three patients had T-cell NHL, including 5 with PTCL and 13 with CTCL/mycosis fungoides (MF). Twenty-seven patients had multiple myeloma (MM), and 1 had chronic myeloid leukemia.
Patients were heavily pretreated. Seventy-eight percent of HL patients and 26% of T-NHL patients had prior brentuximab vedotin. And 78% (HL), 14% (B-NHL), 9% (T-NHL), and 56% (MM) of patients had a prior autologous transplant.
The median number of prior therapies was 5 (range, 2-15) for HL patients and ranged from 1 to 16 for all patients.
The study’s primary endpoint was safety and tolerability, and the secondary endpoint was efficacy.
Safety and tolerability
Ninety-seven percent of patients had an adverse event, 69% of them related to study treatment and 21% of them treatment-related grade 3-4 events.
Fifteen patients (14%) discontinued treatment due to a related adverse event, including 3 with pneumonitis and 1 each with enteritis, stomatitis, pancreatitis, rash, conjunctivitis, sepsis, diplopia, myositis, neutropenia, myelodysplastic syndrome, increased creatinine phosphokinase, and peripheral neuropathy.
“Immune-related adverse events were generally seen early on and generally of low grade,” Dr Timmerman said. “However, it is notable that there were several grade 3 immune-related adverse events that can be seen as far as 6 months out after the start of therapy.”
These included skin, gastrointestinal, and pulmonary events. Most immune-related adverse events (83%) were resolved using protocol-prescribed procedures.
Efficacy
The overall response rate was 87% for HL, 36% for DLBCL, 40% for FL, 15% for CTCL/MF, 40% for PTCL, and 4% for MM.
Dr Timmerman pointed out that, since ASH, 2 additional conversions from partial response (PR) to complete response (CR) occurred in patients with HL. To date, 6 of 23 HL patients have achieved a CR and 14 a PR.
In B-cell NHL, there were additional conversions from PR to CR in DLBCL, while responses remained the same in FL and in the 4 responders with T-cell lymphomas.
“Intriguingly, there has been 1 late CR in the multiple myeloma cohort, which previously had shown no responses,” Dr Timmerman said.
Durability of response
This study suggests PD-1 blockade can produce durable responses in hematologic malignancies, as it does in melanoma and renal cell carcinoma.
In HL, the median response duration at a median follow-up of 86 weeks has not yet been reached, and half (n=10) of the responses are still ongoing.
In FL, CTCL, and PTCL, the median response duration has not been reached at a median follow-up of 81, 43, and 31 weeks, respectively. Of note, there are ongoing responses in at least half of patients in these tumor types.
In HL, none of the 6 patients in CR has progressed, although there have been some progressions in the PR group.
The rapidity of responses is also notable, Dr Timmerman said.
“[I]t’s very interesting that some patients have resolution of symptoms and improvement of symptoms within even 1 day of starting nivolumab therapy,” he said.
And responses to nivolumab in HL “can be very dramatic,” he added, as illustrated in the following case from the Mayo Clinic.
A patient with multiple sites of bulky FDG-avid tumors was scheduled to enter hospice. But first, he entered the nivolumab trial. Within 6 weeks of initiating treatment, he had achieved a near-CR. This response has been maintained for 2 years.
“The occurrence of very durable responses in the PR and CR groups has led us to question whether patients should go on to allogeneic stem cell transplantation after achieving responses with nivolumab or, rather, continue on nivolumab as long as their response remains,” Dr Timmerman said.
He added that an international, phase 2 trial in HL is underway and is accruing briskly.
Nivolumab was awarded breakthrough designation by the US Food and Drug Administration last year. Breakthrough designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.
Thiotepa, rituximab improve response in CNS lymphoma
site of 13-ICML
LUGANO—Adding thiotepa and rituximab to the treatment of primary central nervous system (CNS) lymphoma is feasible from a safety perspective and has yielded promising results, according to new research.
An analysis of the IELSG 32 trial—in which patients received methotrexate and cytarabine alone, with rituximab, or with rituximab and thiotepa—has shown the 4-drug regimen improves responses and progression-free survival.
IELSG 32 builds on the foundation of the IELSG 20 trial to determine the best induction therapy for patients with primary CNS lymphoma. In IELSG 20, the complete response (CR) rate was higher among patients receiving high-dose methotrexate and cytarabine than in patients receiving methotrexate alone.
So the researchers decided to investigate whether rituximab and/or thiotepa added to the regimen would impact patient outcome. Rituximab has been associated with improved CR rates in primary CNS lymphoma, and thiotepa is active against aggressive lymphomas. Thiotepa is also able to cross the blood–brain barrier.
Andrés J.M. Ferreri, MD, of IRCCS Ospedale San Raffaele in Milan, Italy, reported the results of this research on behalf of the International Extranodal Lymphoma Study Group (IELSG) at the 13th International Conference on Malignant Lymphoma (abstract 009).
Treatment and toxicity
The investigators randomized 227 patients from 53 centers in 5 countries to 4 cycles of treatment in 3 cohorts:
- Arm A consisted of 4 cycles of methotrexate (3.5 g/m2) on day 1 and cytarabine (2 g/m2) twice a day on days 2 and 3 every 3 weeks.
- Arm B added rituximab (375 mg/m2) on days 5 and 0 to the regimen.
- Arm C added rituximab and thiotepa (30 mg/m2) on day 4 to the regimen.
Eight patients were excluded for various reasons, including incorrect diagnosis. So 219 patients received therapy, 75 in arm A, 69 in arm B, and 75 in arm C.
Patients were a median age of 58 years in arm A and 57 in arms B and C, and the majority were male. More than 80% of patients in all arms were intermediate- or high-risk according to IELSG. And all patients had the diffuse large B-cell lymphoma histotype.
Patients in arm A received 74% of the planned courses, those in arm B received 86%, and those in arm C received 91%. The relative dose intensity across all arms of each drug administered was not significantly different among the arms.
“As expected, hematologic toxicity was common, with grade 4 neutropenia (P=0.01) and thrombocytopenia (P=0.0001) being significantly more common for arm C,” Dr Ferreri said. “However, this was not associated with an increasing array of severe infections, interruptions, toxicity, or toxic deaths.”
Peripheral blood stem cell collection was successful in 94% of patients in arms A and C and 96% of patients in arm B.
Response rates
The overall response rate (ORR) was 72% in IELSG 32, compared to 54% in IELSG 20. But the CR rate was not significantly higher in IELSG 32 than in IELSG 20, at 34% and 31%, respectively.
“There are many explanations for this,” Dr Ferreri said. “But I think it was because there were a significantly greater number of patients with higher IELSG risk [in IELSG 32], a higher proportion of poor-prognosis patients.”
Patients in arm C had significantly higher response rates than patients in the other 2 arms, with a CR rate of 49%, a partial response (PR) rate of 37%, and an ORR of 87%.
This compared to a CR rate of 23% in arm A and 30% in arm B, a PR rate of 31% in arm A and 30% in arm B, and an ORR of 53% in arm A and 74% in arm B.
The investigators also analyzed activity according to IELSG risk.
“Arm C was significantly more active in all the 3 subgroups,” Dr Ferreri observed, “and importantly, the overall response rate and complete remission rate were similar for each arm in the 3 different risk groups.”
Second randomization and survival
One hundred and eighteen patients went on to a second randomization, 35 from arm A, 35 from arm B, and 48 from arm C.
Fifty-nine patients were randomized to the whole-brain radiotherapy cohort, and 59 to the carmustine-thiotepa-autologous stem cell transplant cohort.
At a median follow-up of 21 months, 110 patients remain failure free, 32% from arm A, 54% from arm B, and 65% from arm C. Failure in 97% of the cases was due to primary site involvement, usually the brain.
Fifty-six percent of the patients are still alive, 39% in arm A, 59% in arm B, and 69% in arm C.
Ninety-seven patients died, 73 from lymphoma, 15 from toxicity of the first-line treatment, 2 from toxicity of the salvage regimen, 2 from neurotoxicity, and 5 from other causes.
Dr Ferreri concluded that the MATRIX regimen—the addition of rituximab and thiotepa to methotrexate and cytarabine—was associated with significant improvements in CR rate, ORR, and progression-free and overall survival.
The addition of rituximab and thiotepa did not increase toxicity, with the exception of greater hematologic adverse events, nor did the drugs increase the rates of severe complications. The agents also allowed for high rates of successful stem cell collection.
site of 13-ICML
LUGANO—Adding thiotepa and rituximab to the treatment of primary central nervous system (CNS) lymphoma is feasible from a safety perspective and has yielded promising results, according to new research.
An analysis of the IELSG 32 trial—in which patients received methotrexate and cytarabine alone, with rituximab, or with rituximab and thiotepa—has shown the 4-drug regimen improves responses and progression-free survival.
IELSG 32 builds on the foundation of the IELSG 20 trial to determine the best induction therapy for patients with primary CNS lymphoma. In IELSG 20, the complete response (CR) rate was higher among patients receiving high-dose methotrexate and cytarabine than in patients receiving methotrexate alone.
So the researchers decided to investigate whether rituximab and/or thiotepa added to the regimen would impact patient outcome. Rituximab has been associated with improved CR rates in primary CNS lymphoma, and thiotepa is active against aggressive lymphomas. Thiotepa is also able to cross the blood–brain barrier.
Andrés J.M. Ferreri, MD, of IRCCS Ospedale San Raffaele in Milan, Italy, reported the results of this research on behalf of the International Extranodal Lymphoma Study Group (IELSG) at the 13th International Conference on Malignant Lymphoma (abstract 009).
Treatment and toxicity
The investigators randomized 227 patients from 53 centers in 5 countries to 4 cycles of treatment in 3 cohorts:
- Arm A consisted of 4 cycles of methotrexate (3.5 g/m2) on day 1 and cytarabine (2 g/m2) twice a day on days 2 and 3 every 3 weeks.
- Arm B added rituximab (375 mg/m2) on days 5 and 0 to the regimen.
- Arm C added rituximab and thiotepa (30 mg/m2) on day 4 to the regimen.
Eight patients were excluded for various reasons, including incorrect diagnosis. So 219 patients received therapy, 75 in arm A, 69 in arm B, and 75 in arm C.
Patients were a median age of 58 years in arm A and 57 in arms B and C, and the majority were male. More than 80% of patients in all arms were intermediate- or high-risk according to IELSG. And all patients had the diffuse large B-cell lymphoma histotype.
Patients in arm A received 74% of the planned courses, those in arm B received 86%, and those in arm C received 91%. The relative dose intensity across all arms of each drug administered was not significantly different among the arms.
“As expected, hematologic toxicity was common, with grade 4 neutropenia (P=0.01) and thrombocytopenia (P=0.0001) being significantly more common for arm C,” Dr Ferreri said. “However, this was not associated with an increasing array of severe infections, interruptions, toxicity, or toxic deaths.”
Peripheral blood stem cell collection was successful in 94% of patients in arms A and C and 96% of patients in arm B.
Response rates
The overall response rate (ORR) was 72% in IELSG 32, compared to 54% in IELSG 20. But the CR rate was not significantly higher in IELSG 32 than in IELSG 20, at 34% and 31%, respectively.
“There are many explanations for this,” Dr Ferreri said. “But I think it was because there were a significantly greater number of patients with higher IELSG risk [in IELSG 32], a higher proportion of poor-prognosis patients.”
Patients in arm C had significantly higher response rates than patients in the other 2 arms, with a CR rate of 49%, a partial response (PR) rate of 37%, and an ORR of 87%.
This compared to a CR rate of 23% in arm A and 30% in arm B, a PR rate of 31% in arm A and 30% in arm B, and an ORR of 53% in arm A and 74% in arm B.
The investigators also analyzed activity according to IELSG risk.
“Arm C was significantly more active in all the 3 subgroups,” Dr Ferreri observed, “and importantly, the overall response rate and complete remission rate were similar for each arm in the 3 different risk groups.”
Second randomization and survival
One hundred and eighteen patients went on to a second randomization, 35 from arm A, 35 from arm B, and 48 from arm C.
Fifty-nine patients were randomized to the whole-brain radiotherapy cohort, and 59 to the carmustine-thiotepa-autologous stem cell transplant cohort.
At a median follow-up of 21 months, 110 patients remain failure free, 32% from arm A, 54% from arm B, and 65% from arm C. Failure in 97% of the cases was due to primary site involvement, usually the brain.
Fifty-six percent of the patients are still alive, 39% in arm A, 59% in arm B, and 69% in arm C.
Ninety-seven patients died, 73 from lymphoma, 15 from toxicity of the first-line treatment, 2 from toxicity of the salvage regimen, 2 from neurotoxicity, and 5 from other causes.
Dr Ferreri concluded that the MATRIX regimen—the addition of rituximab and thiotepa to methotrexate and cytarabine—was associated with significant improvements in CR rate, ORR, and progression-free and overall survival.
The addition of rituximab and thiotepa did not increase toxicity, with the exception of greater hematologic adverse events, nor did the drugs increase the rates of severe complications. The agents also allowed for high rates of successful stem cell collection.
site of 13-ICML
LUGANO—Adding thiotepa and rituximab to the treatment of primary central nervous system (CNS) lymphoma is feasible from a safety perspective and has yielded promising results, according to new research.
An analysis of the IELSG 32 trial—in which patients received methotrexate and cytarabine alone, with rituximab, or with rituximab and thiotepa—has shown the 4-drug regimen improves responses and progression-free survival.
IELSG 32 builds on the foundation of the IELSG 20 trial to determine the best induction therapy for patients with primary CNS lymphoma. In IELSG 20, the complete response (CR) rate was higher among patients receiving high-dose methotrexate and cytarabine than in patients receiving methotrexate alone.
So the researchers decided to investigate whether rituximab and/or thiotepa added to the regimen would impact patient outcome. Rituximab has been associated with improved CR rates in primary CNS lymphoma, and thiotepa is active against aggressive lymphomas. Thiotepa is also able to cross the blood–brain barrier.
Andrés J.M. Ferreri, MD, of IRCCS Ospedale San Raffaele in Milan, Italy, reported the results of this research on behalf of the International Extranodal Lymphoma Study Group (IELSG) at the 13th International Conference on Malignant Lymphoma (abstract 009).
Treatment and toxicity
The investigators randomized 227 patients from 53 centers in 5 countries to 4 cycles of treatment in 3 cohorts:
- Arm A consisted of 4 cycles of methotrexate (3.5 g/m2) on day 1 and cytarabine (2 g/m2) twice a day on days 2 and 3 every 3 weeks.
- Arm B added rituximab (375 mg/m2) on days 5 and 0 to the regimen.
- Arm C added rituximab and thiotepa (30 mg/m2) on day 4 to the regimen.
Eight patients were excluded for various reasons, including incorrect diagnosis. So 219 patients received therapy, 75 in arm A, 69 in arm B, and 75 in arm C.
Patients were a median age of 58 years in arm A and 57 in arms B and C, and the majority were male. More than 80% of patients in all arms were intermediate- or high-risk according to IELSG. And all patients had the diffuse large B-cell lymphoma histotype.
Patients in arm A received 74% of the planned courses, those in arm B received 86%, and those in arm C received 91%. The relative dose intensity across all arms of each drug administered was not significantly different among the arms.
“As expected, hematologic toxicity was common, with grade 4 neutropenia (P=0.01) and thrombocytopenia (P=0.0001) being significantly more common for arm C,” Dr Ferreri said. “However, this was not associated with an increasing array of severe infections, interruptions, toxicity, or toxic deaths.”
Peripheral blood stem cell collection was successful in 94% of patients in arms A and C and 96% of patients in arm B.
Response rates
The overall response rate (ORR) was 72% in IELSG 32, compared to 54% in IELSG 20. But the CR rate was not significantly higher in IELSG 32 than in IELSG 20, at 34% and 31%, respectively.
“There are many explanations for this,” Dr Ferreri said. “But I think it was because there were a significantly greater number of patients with higher IELSG risk [in IELSG 32], a higher proportion of poor-prognosis patients.”
Patients in arm C had significantly higher response rates than patients in the other 2 arms, with a CR rate of 49%, a partial response (PR) rate of 37%, and an ORR of 87%.
This compared to a CR rate of 23% in arm A and 30% in arm B, a PR rate of 31% in arm A and 30% in arm B, and an ORR of 53% in arm A and 74% in arm B.
The investigators also analyzed activity according to IELSG risk.
“Arm C was significantly more active in all the 3 subgroups,” Dr Ferreri observed, “and importantly, the overall response rate and complete remission rate were similar for each arm in the 3 different risk groups.”
Second randomization and survival
One hundred and eighteen patients went on to a second randomization, 35 from arm A, 35 from arm B, and 48 from arm C.
Fifty-nine patients were randomized to the whole-brain radiotherapy cohort, and 59 to the carmustine-thiotepa-autologous stem cell transplant cohort.
At a median follow-up of 21 months, 110 patients remain failure free, 32% from arm A, 54% from arm B, and 65% from arm C. Failure in 97% of the cases was due to primary site involvement, usually the brain.
Fifty-six percent of the patients are still alive, 39% in arm A, 59% in arm B, and 69% in arm C.
Ninety-seven patients died, 73 from lymphoma, 15 from toxicity of the first-line treatment, 2 from toxicity of the salvage regimen, 2 from neurotoxicity, and 5 from other causes.
Dr Ferreri concluded that the MATRIX regimen—the addition of rituximab and thiotepa to methotrexate and cytarabine—was associated with significant improvements in CR rate, ORR, and progression-free and overall survival.
The addition of rituximab and thiotepa did not increase toxicity, with the exception of greater hematologic adverse events, nor did the drugs increase the rates of severe complications. The agents also allowed for high rates of successful stem cell collection.