Hematologic Malignancies

For B-cell malignancies, synthetic lethality is a viable treatment approach, according to preliminary clinical trial data with once-daily oral DTRM-555. The triple combination therapy, DTRM-555, combines a Bruton’s tyrosine kinase (BTK) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor and pomalidomide, an immunomodulatory imide drug (IMiD), according to Anthony R. Mato, MD, in a presentation at the annual meeting of the American Society of Hematology, which was held virtually.
 

Richter’s transformation, a rare event

Dr. Mato’s phase 1 clinical trial included 13 patients with Richter’s transformation (RT) and 11 with diffuse large B-cell lymphoma (DLBCL). Richter’s transformation, a rare event occurring in 5%-7% of chronic lymphocytic leukemia (CLL) cases, has no clear standard of care and universally poor outcomes (overall survival, 3-12 months) once it becomes refractory to anthracycline-based chemotherapy, according to Dr. Mato.

Despite great progress in treating DLBCL, cure rates with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), the standard of care, are in the 50%-60% range and much lower (30%-40%) with poor-risk features. Furthermore, most (60%-70%) patients receiving autologous stem cell transplant or CAR-T still require additional lines of therapy.

The “synthetic lethality” (SL) strategy, which has become a focus of cancer treatment in the last decade, identifies multiple disease primary aberrant and compensatory pathways and then inhibits them together in a manner lethal to cell survival. Preclinical studies have shown low doses of a BTK inhibitor/mTOR inhibitor/IMiD to synergistically kill malignant B cells. DTRM-555 is an optimized, oral, once-daily triplet combination of a novel and clinically differentiated irreversible BTK inhibitor (DTRM-12), everolimus and pomalidomide, Dr. Mato explained.

Individuals (38% women) included in the trial had a median of 2 (1-10) prior lines of therapy, with a CD20 monoclonal antibody as one of them in all cases, and 83% with R-CHOP. All patients had life expectancy >12 weeks, with 0-1 performance status and adequate organ and hematologic function.

DTRM-12 plasma concentrations, Dr. Mato noted, were unaffected by coadministration with everolimus with or without pomalidomide.
 

Manageable adverse events

Among adverse events, neutropenia (grade 3-4, 33%/21%) and thrombocytopenia (grade 3-4, 29%/8%) were most common. One patient had grade 4 leukopenia (4%). No patients discontinued treatment on account of adverse events, however, and nonhematologic adverse event rates were low, without grade 4 events. Eight different grade 3 adverse events (atrial fibrillation [with prior history], diarrhea, hyponatremia pneumonia, pulmonary opportunistic infection, rash maculopapular, rash acneiform, skin ulceration) were reported, each in one patient. Pharmacokinetic data supported once-daily dosing for DTRM-12, with an estimated half-life of 5-9 hours that was comparable with that of once-daily ibrutinib, and longer than that of other agents of the same class. The recommended phase 2 dose going forward was 200 mg for DTRM-12, 5 mg for everolimus and 2 mg for pomalidomide.
 

Favorable responses

In efficacy analysis for 22 evaluable patients (11 in the RT group, 11 in the DLBCL ), there was 1 complete response in the RT group and 2 in the DLBCL group, with partial responses in 4 and 3, respectively, giving overall response rates of 46% in the RT group and 45% in the DLBCL group. Two and four patients, respectively, in the RT and DLBCL groups, had stable disease, Dr. Mato said, and most patients (71%) had SPD (sum of the product of the diameters) lymph node reductions, with lymph node reductions of 50% or more in 43%.

“Encouraging clinical activity was observed in high-risk, heavily pretreated Richter’s transformation and diffuse large B-cell lymphoma patients,” Dr. Mato concluded. He also noted that the main safety findings were “expected and manageable.”

The session moderator, Chaitra S. Ujjani, MD, of the Seattle Health Care Alliance, asked if the DTRM-555 regimen should be considered definitive therapy in patients who are responding, or if moving on to cellular therapies or a consolidative approach should be considered.

“If they are responding, it is reasonable to consider consolidating with a cellular therapy at this point in time,” Dr. Mato replied. He did observe, however, that many of the included patients had tried experimental therapies, including cellular therapy. “Without [data from] a much larger patient population and longer-term follow-up, I think that, for responding patients with a durable remission who have a [chimeric antigen receptor] T or transplant option, these, at the least, have to be discussed with them.”

To an additional question as to whether any of the subjects had prior exposure to BTK inhibitors, Dr. Mato responded, “There is a high exposure to BTK inhibitors, and almost universally these patients were progressors. So again, this is supportive of the hypothesis that hitting multiple pathways simultaneously is somewhat different from hitting just BTK by itself, even in the setting of progression.”

A DTRM-555 triple fixed-dose combination tablet is under development, and a double fixed-dose tablet (DTRM-505) is ready for the ongoing phase 2 U.S. study (NCT04030544) among patients with relapsed/refractory CLL or non-Hodgkin lymphoma (RT, DLBCL or transformed follicular lymphoma) with prior exposure to a novel agent.

Dr. Mato, disclosed consultancy and research funding relationships with multiple pharmaceutical and biotechnology companies.

SOURCE: Mato AR et al. ASH 2020, Abstract 126.

For B-cell malignancies, synthetic lethality is a viable treatment approach, according to preliminary clinical trial data with once-daily oral DTRM-555. The triple combination therapy, DTRM-555, combines a Bruton’s tyrosine kinase (BTK) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor and pomalidomide, an immunomodulatory imide drug (IMiD), according to Anthony R. Mato, MD, in a presentation at the annual meeting of the American Society of Hematology, which was held virtually.
 

Richter’s transformation, a rare event

Dr. Mato’s phase 1 clinical trial included 13 patients with Richter’s transformation (RT) and 11 with diffuse large B-cell lymphoma (DLBCL). Richter’s transformation, a rare event occurring in 5%-7% of chronic lymphocytic leukemia (CLL) cases, has no clear standard of care and universally poor outcomes (overall survival, 3-12 months) once it becomes refractory to anthracycline-based chemotherapy, according to Dr. Mato.

Despite great progress in treating DLBCL, cure rates with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), the standard of care, are in the 50%-60% range and much lower (30%-40%) with poor-risk features. Furthermore, most (60%-70%) patients receiving autologous stem cell transplant or CAR-T still require additional lines of therapy.

The “synthetic lethality” (SL) strategy, which has become a focus of cancer treatment in the last decade, identifies multiple disease primary aberrant and compensatory pathways and then inhibits them together in a manner lethal to cell survival. Preclinical studies have shown low doses of a BTK inhibitor/mTOR inhibitor/IMiD to synergistically kill malignant B cells. DTRM-555 is an optimized, oral, once-daily triplet combination of a novel and clinically differentiated irreversible BTK inhibitor (DTRM-12), everolimus and pomalidomide, Dr. Mato explained.

Individuals (38% women) included in the trial had a median of 2 (1-10) prior lines of therapy, with a CD20 monoclonal antibody as one of them in all cases, and 83% with R-CHOP. All patients had life expectancy >12 weeks, with 0-1 performance status and adequate organ and hematologic function.

DTRM-12 plasma concentrations, Dr. Mato noted, were unaffected by coadministration with everolimus with or without pomalidomide.
 

Manageable adverse events

Among adverse events, neutropenia (grade 3-4, 33%/21%) and thrombocytopenia (grade 3-4, 29%/8%) were most common. One patient had grade 4 leukopenia (4%). No patients discontinued treatment on account of adverse events, however, and nonhematologic adverse event rates were low, without grade 4 events. Eight different grade 3 adverse events (atrial fibrillation [with prior history], diarrhea, hyponatremia pneumonia, pulmonary opportunistic infection, rash maculopapular, rash acneiform, skin ulceration) were reported, each in one patient. Pharmacokinetic data supported once-daily dosing for DTRM-12, with an estimated half-life of 5-9 hours that was comparable with that of once-daily ibrutinib, and longer than that of other agents of the same class. The recommended phase 2 dose going forward was 200 mg for DTRM-12, 5 mg for everolimus and 2 mg for pomalidomide.
 

Favorable responses

In efficacy analysis for 22 evaluable patients (11 in the RT group, 11 in the DLBCL ), there was 1 complete response in the RT group and 2 in the DLBCL group, with partial responses in 4 and 3, respectively, giving overall response rates of 46% in the RT group and 45% in the DLBCL group. Two and four patients, respectively, in the RT and DLBCL groups, had stable disease, Dr. Mato said, and most patients (71%) had SPD (sum of the product of the diameters) lymph node reductions, with lymph node reductions of 50% or more in 43%.

“Encouraging clinical activity was observed in high-risk, heavily pretreated Richter’s transformation and diffuse large B-cell lymphoma patients,” Dr. Mato concluded. He also noted that the main safety findings were “expected and manageable.”

The session moderator, Chaitra S. Ujjani, MD, of the Seattle Health Care Alliance, asked if the DTRM-555 regimen should be considered definitive therapy in patients who are responding, or if moving on to cellular therapies or a consolidative approach should be considered.

“If they are responding, it is reasonable to consider consolidating with a cellular therapy at this point in time,” Dr. Mato replied. He did observe, however, that many of the included patients had tried experimental therapies, including cellular therapy. “Without [data from] a much larger patient population and longer-term follow-up, I think that, for responding patients with a durable remission who have a [chimeric antigen receptor] T or transplant option, these, at the least, have to be discussed with them.”

To an additional question as to whether any of the subjects had prior exposure to BTK inhibitors, Dr. Mato responded, “There is a high exposure to BTK inhibitors, and almost universally these patients were progressors. So again, this is supportive of the hypothesis that hitting multiple pathways simultaneously is somewhat different from hitting just BTK by itself, even in the setting of progression.”

A DTRM-555 triple fixed-dose combination tablet is under development, and a double fixed-dose tablet (DTRM-505) is ready for the ongoing phase 2 U.S. study (NCT04030544) among patients with relapsed/refractory CLL or non-Hodgkin lymphoma (RT, DLBCL or transformed follicular lymphoma) with prior exposure to a novel agent.

Dr. Mato, disclosed consultancy and research funding relationships with multiple pharmaceutical and biotechnology companies.

SOURCE: Mato AR et al. ASH 2020, Abstract 126.

For B-cell malignancies, synthetic lethality is a viable treatment approach, according to preliminary clinical trial data with once-daily oral DTRM-555. The triple combination therapy, DTRM-555, combines a Bruton’s tyrosine kinase (BTK) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor and pomalidomide, an immunomodulatory imide drug (IMiD), according to Anthony R. Mato, MD, in a presentation at the annual meeting of the American Society of Hematology, which was held virtually.
 

Richter’s transformation, a rare event

Dr. Mato’s phase 1 clinical trial included 13 patients with Richter’s transformation (RT) and 11 with diffuse large B-cell lymphoma (DLBCL). Richter’s transformation, a rare event occurring in 5%-7% of chronic lymphocytic leukemia (CLL) cases, has no clear standard of care and universally poor outcomes (overall survival, 3-12 months) once it becomes refractory to anthracycline-based chemotherapy, according to Dr. Mato.

Despite great progress in treating DLBCL, cure rates with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), the standard of care, are in the 50%-60% range and much lower (30%-40%) with poor-risk features. Furthermore, most (60%-70%) patients receiving autologous stem cell transplant or CAR-T still require additional lines of therapy.

The “synthetic lethality” (SL) strategy, which has become a focus of cancer treatment in the last decade, identifies multiple disease primary aberrant and compensatory pathways and then inhibits them together in a manner lethal to cell survival. Preclinical studies have shown low doses of a BTK inhibitor/mTOR inhibitor/IMiD to synergistically kill malignant B cells. DTRM-555 is an optimized, oral, once-daily triplet combination of a novel and clinically differentiated irreversible BTK inhibitor (DTRM-12), everolimus and pomalidomide, Dr. Mato explained.

Individuals (38% women) included in the trial had a median of 2 (1-10) prior lines of therapy, with a CD20 monoclonal antibody as one of them in all cases, and 83% with R-CHOP. All patients had life expectancy >12 weeks, with 0-1 performance status and adequate organ and hematologic function.

DTRM-12 plasma concentrations, Dr. Mato noted, were unaffected by coadministration with everolimus with or without pomalidomide.
 

Manageable adverse events

Among adverse events, neutropenia (grade 3-4, 33%/21%) and thrombocytopenia (grade 3-4, 29%/8%) were most common. One patient had grade 4 leukopenia (4%). No patients discontinued treatment on account of adverse events, however, and nonhematologic adverse event rates were low, without grade 4 events. Eight different grade 3 adverse events (atrial fibrillation [with prior history], diarrhea, hyponatremia pneumonia, pulmonary opportunistic infection, rash maculopapular, rash acneiform, skin ulceration) were reported, each in one patient. Pharmacokinetic data supported once-daily dosing for DTRM-12, with an estimated half-life of 5-9 hours that was comparable with that of once-daily ibrutinib, and longer than that of other agents of the same class. The recommended phase 2 dose going forward was 200 mg for DTRM-12, 5 mg for everolimus and 2 mg for pomalidomide.
 

Favorable responses

In efficacy analysis for 22 evaluable patients (11 in the RT group, 11 in the DLBCL ), there was 1 complete response in the RT group and 2 in the DLBCL group, with partial responses in 4 and 3, respectively, giving overall response rates of 46% in the RT group and 45% in the DLBCL group. Two and four patients, respectively, in the RT and DLBCL groups, had stable disease, Dr. Mato said, and most patients (71%) had SPD (sum of the product of the diameters) lymph node reductions, with lymph node reductions of 50% or more in 43%.

“Encouraging clinical activity was observed in high-risk, heavily pretreated Richter’s transformation and diffuse large B-cell lymphoma patients,” Dr. Mato concluded. He also noted that the main safety findings were “expected and manageable.”

The session moderator, Chaitra S. Ujjani, MD, of the Seattle Health Care Alliance, asked if the DTRM-555 regimen should be considered definitive therapy in patients who are responding, or if moving on to cellular therapies or a consolidative approach should be considered.

“If they are responding, it is reasonable to consider consolidating with a cellular therapy at this point in time,” Dr. Mato replied. He did observe, however, that many of the included patients had tried experimental therapies, including cellular therapy. “Without [data from] a much larger patient population and longer-term follow-up, I think that, for responding patients with a durable remission who have a [chimeric antigen receptor] T or transplant option, these, at the least, have to be discussed with them.”

To an additional question as to whether any of the subjects had prior exposure to BTK inhibitors, Dr. Mato responded, “There is a high exposure to BTK inhibitors, and almost universally these patients were progressors. So again, this is supportive of the hypothesis that hitting multiple pathways simultaneously is somewhat different from hitting just BTK by itself, even in the setting of progression.”

A DTRM-555 triple fixed-dose combination tablet is under development, and a double fixed-dose tablet (DTRM-505) is ready for the ongoing phase 2 U.S. study (NCT04030544) among patients with relapsed/refractory CLL or non-Hodgkin lymphoma (RT, DLBCL or transformed follicular lymphoma) with prior exposure to a novel agent.

Dr. Mato, disclosed consultancy and research funding relationships with multiple pharmaceutical and biotechnology companies.

SOURCE: Mato AR et al. ASH 2020, Abstract 126.

Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with sequential blinatumomab is highly effective as frontline therapy for Philadelphia Chromosome (Ph)–negative B-cell acute lymphoblastic leukemia (ALL), according to results of a phase 2 study reported at the annual meeting of the American Society of Hematology.

Favorable minimal residual disease (MRD) negativity and overall survival with low higher-grade toxicities suggest that reductions in chemotherapy in this setting are feasible, said Nicholas J. Short, MD, of the University of Texas MD Anderson Cancer Center, Houston.

While complete response rates with current ALL therapy are 80%-90%, long-term overall survival is only 40%-50%. Blinatumomab, a bispecific T-cell–engaging CD3-CD19 antibody, has been shown to be superior to chemotherapy in relapsed/refractory B-cell ALL, and to produce high rates of MRD eradication, the most important prognostic factor in ALL, Dr. Short said at the meeting, which was held virtually.

The hypothesis of the current study was that early incorporation of blinatumomab with hyper-CVAD in patients with newly diagnosed Ph-negative B-cell ALL would decrease the need for intensive chemotherapy and lead to higher efficacy and cure rates with less myelosuppression. Patients were required to have a performance status of 3 or less, total bilirubin 2 mg/dL or less and creatinine 2 mg/dL or less. Investigators enrolled 38 patients (mean age, 37 years,; range, 17-59) with most (79%) in performance status 0-1. The primary endpoint was relapse-free survival (RFS).
 

Study details

Patients received hyper-CVAD alternating with high-dose methotrexate and cytarabine for up to four cycles followed by four cycles of blinatumomab at standard doses. Those with CD20-positive disease (1% or greater percentage of the cells) received eight doses of ofatumumab or rituximab, and prophylactic intrathecal chemotherapy was given eight times in the first four cycles. Maintenance consisted of alternating blocks of POMP (6-mercaptopurine, vincristine, methotrexate, prednisone) and blinatumomab. When two patients with high-risk features experienced early relapse, investigators amended the protocol to allow blinatumomab after only two cycles of hyper-CVAD in those with high-risk features (e.g., CRLF2 positive by flow cytometry, complex karyotype, KMT2A rearranged, low hypodiploidy/near triploidy, TP53 mutation, or persistent MRD). Nineteen patients (56%) had at least one high-risk feature, and 82% received ofatumumab or rituximab. Six patients were in complete remission at the start of the study (four of them MRD negative).

Complete responses

After induction, complete responses were achieved in 81% (26/32), with all patients achieving a complete response at some point, according to Dr. Short. The MRD negativity rate was 71% (24/34) after induction and 97% (33/34) at any time. Among the 38 patients, all with complete response at median follow-up of 24 months (range, 2-45), relapses occurred only in those 5 patients with high-risk features. Twelve patients underwent transplant in the first remission. Two relapsed, both with high-risk features. The other 21 patients had ongoing complete responses.

RFS at 1- and 2-years was 80% and 71%, respectively. Five among seven relapses were without hematopoietic stem cell transplantation, and 2 were post HSCT. Two deaths occurred in patients with complete responses (one pulmonary embolism and one with post-HSCT complications). Overall survival at 1 and 2 years was 85% and 80%, respectively, with the 2-year rate comparable with prior reports for hyper-CVAD plus ofatumumab, Dr. Short said.

The most common nonhematologic grade 3-4 adverse events with hyper-CVAD plus blinatumomab were ALT/AST elevation (24%) and hyperglycemia (21%). The overall cytokine release syndrome rate was 13%, with 3% for higher-grade reactions. The rate for blinatumomab-related neurologic events was 45% overall and 13% for higher grades, with 1 discontinuation attributed to grade 2 encephalopathy and dysphasia.

“Overall, this study shows the potential benefit of incorporating frontline blinatumomab into the treatment of younger adults with newly diagnosed Philadelphia chromosome–negative B-cell lymphoma, and shows, as well, that reduction of chemotherapy in this context is feasible,” Dr. Short stated.

“Ultimately, often for any patients with acute leukemias and ALL, our only chance to cure them is in the frontline setting, so our approach is to include all of the most effective agents we have. So that means including blinatumomab in all of our frontline regimens in clinical trials – and now we’ve amended that to add inotuzumab ozogamicin with the goal of deepening responses and increasing cure rates,” he added.

Dr. Short reported consulting with Takeda Oncology and Astrazeneca, and receiving research funding and honoraria from Amgen, Astella, and Takeda Oncology.

SOURCE: Short NG et al. ASH 2020, Abstract 464.

Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with sequential blinatumomab is highly effective as frontline therapy for Philadelphia Chromosome (Ph)–negative B-cell acute lymphoblastic leukemia (ALL), according to results of a phase 2 study reported at the annual meeting of the American Society of Hematology.

Favorable minimal residual disease (MRD) negativity and overall survival with low higher-grade toxicities suggest that reductions in chemotherapy in this setting are feasible, said Nicholas J. Short, MD, of the University of Texas MD Anderson Cancer Center, Houston.

While complete response rates with current ALL therapy are 80%-90%, long-term overall survival is only 40%-50%. Blinatumomab, a bispecific T-cell–engaging CD3-CD19 antibody, has been shown to be superior to chemotherapy in relapsed/refractory B-cell ALL, and to produce high rates of MRD eradication, the most important prognostic factor in ALL, Dr. Short said at the meeting, which was held virtually.

The hypothesis of the current study was that early incorporation of blinatumomab with hyper-CVAD in patients with newly diagnosed Ph-negative B-cell ALL would decrease the need for intensive chemotherapy and lead to higher efficacy and cure rates with less myelosuppression. Patients were required to have a performance status of 3 or less, total bilirubin 2 mg/dL or less and creatinine 2 mg/dL or less. Investigators enrolled 38 patients (mean age, 37 years,; range, 17-59) with most (79%) in performance status 0-1. The primary endpoint was relapse-free survival (RFS).
 

Study details

Patients received hyper-CVAD alternating with high-dose methotrexate and cytarabine for up to four cycles followed by four cycles of blinatumomab at standard doses. Those with CD20-positive disease (1% or greater percentage of the cells) received eight doses of ofatumumab or rituximab, and prophylactic intrathecal chemotherapy was given eight times in the first four cycles. Maintenance consisted of alternating blocks of POMP (6-mercaptopurine, vincristine, methotrexate, prednisone) and blinatumomab. When two patients with high-risk features experienced early relapse, investigators amended the protocol to allow blinatumomab after only two cycles of hyper-CVAD in those with high-risk features (e.g., CRLF2 positive by flow cytometry, complex karyotype, KMT2A rearranged, low hypodiploidy/near triploidy, TP53 mutation, or persistent MRD). Nineteen patients (56%) had at least one high-risk feature, and 82% received ofatumumab or rituximab. Six patients were in complete remission at the start of the study (four of them MRD negative).

Complete responses

After induction, complete responses were achieved in 81% (26/32), with all patients achieving a complete response at some point, according to Dr. Short. The MRD negativity rate was 71% (24/34) after induction and 97% (33/34) at any time. Among the 38 patients, all with complete response at median follow-up of 24 months (range, 2-45), relapses occurred only in those 5 patients with high-risk features. Twelve patients underwent transplant in the first remission. Two relapsed, both with high-risk features. The other 21 patients had ongoing complete responses.

RFS at 1- and 2-years was 80% and 71%, respectively. Five among seven relapses were without hematopoietic stem cell transplantation, and 2 were post HSCT. Two deaths occurred in patients with complete responses (one pulmonary embolism and one with post-HSCT complications). Overall survival at 1 and 2 years was 85% and 80%, respectively, with the 2-year rate comparable with prior reports for hyper-CVAD plus ofatumumab, Dr. Short said.

The most common nonhematologic grade 3-4 adverse events with hyper-CVAD plus blinatumomab were ALT/AST elevation (24%) and hyperglycemia (21%). The overall cytokine release syndrome rate was 13%, with 3% for higher-grade reactions. The rate for blinatumomab-related neurologic events was 45% overall and 13% for higher grades, with 1 discontinuation attributed to grade 2 encephalopathy and dysphasia.

“Overall, this study shows the potential benefit of incorporating frontline blinatumomab into the treatment of younger adults with newly diagnosed Philadelphia chromosome–negative B-cell lymphoma, and shows, as well, that reduction of chemotherapy in this context is feasible,” Dr. Short stated.

“Ultimately, often for any patients with acute leukemias and ALL, our only chance to cure them is in the frontline setting, so our approach is to include all of the most effective agents we have. So that means including blinatumomab in all of our frontline regimens in clinical trials – and now we’ve amended that to add inotuzumab ozogamicin with the goal of deepening responses and increasing cure rates,” he added.

Dr. Short reported consulting with Takeda Oncology and Astrazeneca, and receiving research funding and honoraria from Amgen, Astella, and Takeda Oncology.

SOURCE: Short NG et al. ASH 2020, Abstract 464.

Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with sequential blinatumomab is highly effective as frontline therapy for Philadelphia Chromosome (Ph)–negative B-cell acute lymphoblastic leukemia (ALL), according to results of a phase 2 study reported at the annual meeting of the American Society of Hematology.

Favorable minimal residual disease (MRD) negativity and overall survival with low higher-grade toxicities suggest that reductions in chemotherapy in this setting are feasible, said Nicholas J. Short, MD, of the University of Texas MD Anderson Cancer Center, Houston.

While complete response rates with current ALL therapy are 80%-90%, long-term overall survival is only 40%-50%. Blinatumomab, a bispecific T-cell–engaging CD3-CD19 antibody, has been shown to be superior to chemotherapy in relapsed/refractory B-cell ALL, and to produce high rates of MRD eradication, the most important prognostic factor in ALL, Dr. Short said at the meeting, which was held virtually.

The hypothesis of the current study was that early incorporation of blinatumomab with hyper-CVAD in patients with newly diagnosed Ph-negative B-cell ALL would decrease the need for intensive chemotherapy and lead to higher efficacy and cure rates with less myelosuppression. Patients were required to have a performance status of 3 or less, total bilirubin 2 mg/dL or less and creatinine 2 mg/dL or less. Investigators enrolled 38 patients (mean age, 37 years,; range, 17-59) with most (79%) in performance status 0-1. The primary endpoint was relapse-free survival (RFS).
 

Study details

Patients received hyper-CVAD alternating with high-dose methotrexate and cytarabine for up to four cycles followed by four cycles of blinatumomab at standard doses. Those with CD20-positive disease (1% or greater percentage of the cells) received eight doses of ofatumumab or rituximab, and prophylactic intrathecal chemotherapy was given eight times in the first four cycles. Maintenance consisted of alternating blocks of POMP (6-mercaptopurine, vincristine, methotrexate, prednisone) and blinatumomab. When two patients with high-risk features experienced early relapse, investigators amended the protocol to allow blinatumomab after only two cycles of hyper-CVAD in those with high-risk features (e.g., CRLF2 positive by flow cytometry, complex karyotype, KMT2A rearranged, low hypodiploidy/near triploidy, TP53 mutation, or persistent MRD). Nineteen patients (56%) had at least one high-risk feature, and 82% received ofatumumab or rituximab. Six patients were in complete remission at the start of the study (four of them MRD negative).

Complete responses

After induction, complete responses were achieved in 81% (26/32), with all patients achieving a complete response at some point, according to Dr. Short. The MRD negativity rate was 71% (24/34) after induction and 97% (33/34) at any time. Among the 38 patients, all with complete response at median follow-up of 24 months (range, 2-45), relapses occurred only in those 5 patients with high-risk features. Twelve patients underwent transplant in the first remission. Two relapsed, both with high-risk features. The other 21 patients had ongoing complete responses.

RFS at 1- and 2-years was 80% and 71%, respectively. Five among seven relapses were without hematopoietic stem cell transplantation, and 2 were post HSCT. Two deaths occurred in patients with complete responses (one pulmonary embolism and one with post-HSCT complications). Overall survival at 1 and 2 years was 85% and 80%, respectively, with the 2-year rate comparable with prior reports for hyper-CVAD plus ofatumumab, Dr. Short said.

The most common nonhematologic grade 3-4 adverse events with hyper-CVAD plus blinatumomab were ALT/AST elevation (24%) and hyperglycemia (21%). The overall cytokine release syndrome rate was 13%, with 3% for higher-grade reactions. The rate for blinatumomab-related neurologic events was 45% overall and 13% for higher grades, with 1 discontinuation attributed to grade 2 encephalopathy and dysphasia.

“Overall, this study shows the potential benefit of incorporating frontline blinatumomab into the treatment of younger adults with newly diagnosed Philadelphia chromosome–negative B-cell lymphoma, and shows, as well, that reduction of chemotherapy in this context is feasible,” Dr. Short stated.

“Ultimately, often for any patients with acute leukemias and ALL, our only chance to cure them is in the frontline setting, so our approach is to include all of the most effective agents we have. So that means including blinatumomab in all of our frontline regimens in clinical trials – and now we’ve amended that to add inotuzumab ozogamicin with the goal of deepening responses and increasing cure rates,” he added.

Dr. Short reported consulting with Takeda Oncology and Astrazeneca, and receiving research funding and honoraria from Amgen, Astella, and Takeda Oncology.

SOURCE: Short NG et al. ASH 2020, Abstract 464.

Patients with cancer are at significantly increased risk for COVID-19 and worse outcomes, a new review confirms. It also found that patients with leukemia, non-Hodgkin lymphoma, and lung cancer are at greatest risk.

Blacks with cancer are at even higher risk, and for patients with colorectal cancer and non-Hodgkin lymphoma, the risk is higher for women than for men. (This contrasts with findings in noncancer populations, where men are more at risk from COVID-19 and severe outcomes than women.)

These findings come from a huge review of electronic health records of 73.4 million patients in the United States. They “highlight the need to protect and monitor patients with cancer as part of the strategy to control the pandemic,” the authors wrote.

The review was published online Dec. 10 in JAMA Oncology.

The greater risk for COVID-19 among patients with cancer is well known, but breaking the risk down by cancer type is novel, wrote the investigators, led by Quanqiu Wang, MS, Center for Artificial Intelligence in Drug Discovery, Case Western Reserve University, Cleveland.

Cancer patients are immunocompromised and have more contact with the health care system, which increases their risk for COVID-19. But which bodily systems are affected by cancer seems to matter. In patients with blood cancer, for example, COVID-19 is probably more dangerous, because blood cancer weakens the immune system directly, the authors suggested.

The increased risk for infection and hospitalization with SARS-CoV-2 among Black patients with cancer might be because of biology, but it is more likely because of factors that weren’t captured in the database review. Such factors include social adversity, economic status, access to health care, and lifestyle, the researchers noted.

For this study, the investigators analyzed electronic health records held in the IBM Watson Health Explorys system, which captures about 15% of new cancer diagnoses in the United States.

The analysis found that, as of Aug. 14, 2020, 16,570 patients (0.02%) had been diagnosed with COVID-19; about 1,200 also had been diagnosed with cancer. Of those, 690 were diagnosed with cancer in the previous year, which counted as a recent cancer diagnosis in the analysis. The study included 13 common cancers, including endometrial, kidney, liver, lung, gastrointestinal, prostate, skin, and thyroid cancers, among others.

Patients with any cancer diagnosis (adjusted odds ratio, 1.46) as well as those with a recent cancer diagnosis (aOR, 7.14) had a significantly higher risk for COVID-19 than those without cancer, after adjusting for asthma, cardiovascular diseases, nursing home stays, and other risk factors.

The risk for COVID-19 was highest among patients recently diagnosed with leukemia (aOR, 12.16), non-Hodgkin lymphoma (aOR, 8.54), and lung cancer (aOR 7.66). The risk for COVID-19 was lower for patients with cancers associated with worse prognoses, including pancreatic (aOR, 6.26) and liver (aOR, 6.49) cancer. It was weakest for patients with thyroid cancer (aOR, 3.10; P for all < .001).

Hospitalization was more common in recent cancer patients with COVID-19 than in COVID-19 patients without cancer (47.46% vs. 24.6%), as was COVID-19–related death (14.93% vs. 5.26%). Among cancer patients who did not have COVID-19, 12.39% were hospitalized, and 4.03% died. The findings suggest a synergistic effect between the COVID-19 and cancer, the team noted.

Among patients recently diagnosed with cancer, Black patients – 10.3% of the overall study population – had a significantly higher risk for COVID-19 than White patients. The racial disparity was largest for patients with breast cancer (aOR, 5.44), followed by patients with prostate cancer (aOR, 5.10), colorectal cancer (aOR, 3.30), and lung cancer (aOR, 2.53; P for all < .001).

Hospitalizations were more common among Black patients with cancer and COVID-19 than White patients. There was also a trend toward higher mortality among Black patients (18.52% vs. 13.51%; P = .11)

However, these differences may not be related to race, oncologist Aakash Desai, MBBS, of the Mayo Clinic, Rochester, Minn., and colleagues noted in an accompanying commentary. “Interestingly, a previous study of hospitalized patients with COVID-19 without cancer demonstrated that mortality rates for Black patients were comparable to those for White patients after adjustment for both comorbidities and deprivation index, suggesting that observed differences are mainly owing to societal disparities rather than biology.”

The editorialists also noted that the finding that Black patients with cancer are at greater risk for COVID-19 (aOR, 1.58-5.44, depending on cancer) echoes the findings in the general population. The Centers for Disease Control and Prevention estimates a severalfold increased risk among Black patients. These higher rates may largely be explained by social determinants, they suggested. Such factors include increased burden of comorbidities, crowded living conditions (inner cities, multigenerational homes, etc.), dependence on public transportation or child care, and higher work-related exposures. “Until such societal disparities are accounted for, we cannot presume these findings are caused by any inherent differences among racial groups,” the editorialists wrote.

“Clearly, the haunting spotlight of COVID-19 has dramatically illuminated known U.S. health care and societal disparities,” Dr. Desai and colleagues wrote. “This situation should be a wake-up call that brings much-needed improvements in U.S. equity policies, including but not limited to better health care access. Nothing appears more critical for alleviating these disparate clinical outcomes in this time of crisis and beyond,” they declared.

The study was funded by the National Institutes of Health, the American Cancer Society, and other organizations. The investigators disclosed having no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Patients with cancer are at significantly increased risk for COVID-19 and worse outcomes, a new review confirms. It also found that patients with leukemia, non-Hodgkin lymphoma, and lung cancer are at greatest risk.

Blacks with cancer are at even higher risk, and for patients with colorectal cancer and non-Hodgkin lymphoma, the risk is higher for women than for men. (This contrasts with findings in noncancer populations, where men are more at risk from COVID-19 and severe outcomes than women.)

These findings come from a huge review of electronic health records of 73.4 million patients in the United States. They “highlight the need to protect and monitor patients with cancer as part of the strategy to control the pandemic,” the authors wrote.

The review was published online Dec. 10 in JAMA Oncology.

The greater risk for COVID-19 among patients with cancer is well known, but breaking the risk down by cancer type is novel, wrote the investigators, led by Quanqiu Wang, MS, Center for Artificial Intelligence in Drug Discovery, Case Western Reserve University, Cleveland.

Cancer patients are immunocompromised and have more contact with the health care system, which increases their risk for COVID-19. But which bodily systems are affected by cancer seems to matter. In patients with blood cancer, for example, COVID-19 is probably more dangerous, because blood cancer weakens the immune system directly, the authors suggested.

The increased risk for infection and hospitalization with SARS-CoV-2 among Black patients with cancer might be because of biology, but it is more likely because of factors that weren’t captured in the database review. Such factors include social adversity, economic status, access to health care, and lifestyle, the researchers noted.

For this study, the investigators analyzed electronic health records held in the IBM Watson Health Explorys system, which captures about 15% of new cancer diagnoses in the United States.

The analysis found that, as of Aug. 14, 2020, 16,570 patients (0.02%) had been diagnosed with COVID-19; about 1,200 also had been diagnosed with cancer. Of those, 690 were diagnosed with cancer in the previous year, which counted as a recent cancer diagnosis in the analysis. The study included 13 common cancers, including endometrial, kidney, liver, lung, gastrointestinal, prostate, skin, and thyroid cancers, among others.

Patients with any cancer diagnosis (adjusted odds ratio, 1.46) as well as those with a recent cancer diagnosis (aOR, 7.14) had a significantly higher risk for COVID-19 than those without cancer, after adjusting for asthma, cardiovascular diseases, nursing home stays, and other risk factors.

The risk for COVID-19 was highest among patients recently diagnosed with leukemia (aOR, 12.16), non-Hodgkin lymphoma (aOR, 8.54), and lung cancer (aOR 7.66). The risk for COVID-19 was lower for patients with cancers associated with worse prognoses, including pancreatic (aOR, 6.26) and liver (aOR, 6.49) cancer. It was weakest for patients with thyroid cancer (aOR, 3.10; P for all < .001).

Hospitalization was more common in recent cancer patients with COVID-19 than in COVID-19 patients without cancer (47.46% vs. 24.6%), as was COVID-19–related death (14.93% vs. 5.26%). Among cancer patients who did not have COVID-19, 12.39% were hospitalized, and 4.03% died. The findings suggest a synergistic effect between the COVID-19 and cancer, the team noted.

Among patients recently diagnosed with cancer, Black patients – 10.3% of the overall study population – had a significantly higher risk for COVID-19 than White patients. The racial disparity was largest for patients with breast cancer (aOR, 5.44), followed by patients with prostate cancer (aOR, 5.10), colorectal cancer (aOR, 3.30), and lung cancer (aOR, 2.53; P for all < .001).

Hospitalizations were more common among Black patients with cancer and COVID-19 than White patients. There was also a trend toward higher mortality among Black patients (18.52% vs. 13.51%; P = .11)

However, these differences may not be related to race, oncologist Aakash Desai, MBBS, of the Mayo Clinic, Rochester, Minn., and colleagues noted in an accompanying commentary. “Interestingly, a previous study of hospitalized patients with COVID-19 without cancer demonstrated that mortality rates for Black patients were comparable to those for White patients after adjustment for both comorbidities and deprivation index, suggesting that observed differences are mainly owing to societal disparities rather than biology.”

The editorialists also noted that the finding that Black patients with cancer are at greater risk for COVID-19 (aOR, 1.58-5.44, depending on cancer) echoes the findings in the general population. The Centers for Disease Control and Prevention estimates a severalfold increased risk among Black patients. These higher rates may largely be explained by social determinants, they suggested. Such factors include increased burden of comorbidities, crowded living conditions (inner cities, multigenerational homes, etc.), dependence on public transportation or child care, and higher work-related exposures. “Until such societal disparities are accounted for, we cannot presume these findings are caused by any inherent differences among racial groups,” the editorialists wrote.

“Clearly, the haunting spotlight of COVID-19 has dramatically illuminated known U.S. health care and societal disparities,” Dr. Desai and colleagues wrote. “This situation should be a wake-up call that brings much-needed improvements in U.S. equity policies, including but not limited to better health care access. Nothing appears more critical for alleviating these disparate clinical outcomes in this time of crisis and beyond,” they declared.

The study was funded by the National Institutes of Health, the American Cancer Society, and other organizations. The investigators disclosed having no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Patients with cancer are at significantly increased risk for COVID-19 and worse outcomes, a new review confirms. It also found that patients with leukemia, non-Hodgkin lymphoma, and lung cancer are at greatest risk.

Blacks with cancer are at even higher risk, and for patients with colorectal cancer and non-Hodgkin lymphoma, the risk is higher for women than for men. (This contrasts with findings in noncancer populations, where men are more at risk from COVID-19 and severe outcomes than women.)

These findings come from a huge review of electronic health records of 73.4 million patients in the United States. They “highlight the need to protect and monitor patients with cancer as part of the strategy to control the pandemic,” the authors wrote.

The review was published online Dec. 10 in JAMA Oncology.

The greater risk for COVID-19 among patients with cancer is well known, but breaking the risk down by cancer type is novel, wrote the investigators, led by Quanqiu Wang, MS, Center for Artificial Intelligence in Drug Discovery, Case Western Reserve University, Cleveland.

Cancer patients are immunocompromised and have more contact with the health care system, which increases their risk for COVID-19. But which bodily systems are affected by cancer seems to matter. In patients with blood cancer, for example, COVID-19 is probably more dangerous, because blood cancer weakens the immune system directly, the authors suggested.

The increased risk for infection and hospitalization with SARS-CoV-2 among Black patients with cancer might be because of biology, but it is more likely because of factors that weren’t captured in the database review. Such factors include social adversity, economic status, access to health care, and lifestyle, the researchers noted.

For this study, the investigators analyzed electronic health records held in the IBM Watson Health Explorys system, which captures about 15% of new cancer diagnoses in the United States.

The analysis found that, as of Aug. 14, 2020, 16,570 patients (0.02%) had been diagnosed with COVID-19; about 1,200 also had been diagnosed with cancer. Of those, 690 were diagnosed with cancer in the previous year, which counted as a recent cancer diagnosis in the analysis. The study included 13 common cancers, including endometrial, kidney, liver, lung, gastrointestinal, prostate, skin, and thyroid cancers, among others.

Patients with any cancer diagnosis (adjusted odds ratio, 1.46) as well as those with a recent cancer diagnosis (aOR, 7.14) had a significantly higher risk for COVID-19 than those without cancer, after adjusting for asthma, cardiovascular diseases, nursing home stays, and other risk factors.

The risk for COVID-19 was highest among patients recently diagnosed with leukemia (aOR, 12.16), non-Hodgkin lymphoma (aOR, 8.54), and lung cancer (aOR 7.66). The risk for COVID-19 was lower for patients with cancers associated with worse prognoses, including pancreatic (aOR, 6.26) and liver (aOR, 6.49) cancer. It was weakest for patients with thyroid cancer (aOR, 3.10; P for all < .001).

Hospitalization was more common in recent cancer patients with COVID-19 than in COVID-19 patients without cancer (47.46% vs. 24.6%), as was COVID-19–related death (14.93% vs. 5.26%). Among cancer patients who did not have COVID-19, 12.39% were hospitalized, and 4.03% died. The findings suggest a synergistic effect between the COVID-19 and cancer, the team noted.

Among patients recently diagnosed with cancer, Black patients – 10.3% of the overall study population – had a significantly higher risk for COVID-19 than White patients. The racial disparity was largest for patients with breast cancer (aOR, 5.44), followed by patients with prostate cancer (aOR, 5.10), colorectal cancer (aOR, 3.30), and lung cancer (aOR, 2.53; P for all < .001).

Hospitalizations were more common among Black patients with cancer and COVID-19 than White patients. There was also a trend toward higher mortality among Black patients (18.52% vs. 13.51%; P = .11)

However, these differences may not be related to race, oncologist Aakash Desai, MBBS, of the Mayo Clinic, Rochester, Minn., and colleagues noted in an accompanying commentary. “Interestingly, a previous study of hospitalized patients with COVID-19 without cancer demonstrated that mortality rates for Black patients were comparable to those for White patients after adjustment for both comorbidities and deprivation index, suggesting that observed differences are mainly owing to societal disparities rather than biology.”

The editorialists also noted that the finding that Black patients with cancer are at greater risk for COVID-19 (aOR, 1.58-5.44, depending on cancer) echoes the findings in the general population. The Centers for Disease Control and Prevention estimates a severalfold increased risk among Black patients. These higher rates may largely be explained by social determinants, they suggested. Such factors include increased burden of comorbidities, crowded living conditions (inner cities, multigenerational homes, etc.), dependence on public transportation or child care, and higher work-related exposures. “Until such societal disparities are accounted for, we cannot presume these findings are caused by any inherent differences among racial groups,” the editorialists wrote.

“Clearly, the haunting spotlight of COVID-19 has dramatically illuminated known U.S. health care and societal disparities,” Dr. Desai and colleagues wrote. “This situation should be a wake-up call that brings much-needed improvements in U.S. equity policies, including but not limited to better health care access. Nothing appears more critical for alleviating these disparate clinical outcomes in this time of crisis and beyond,” they declared.

The study was funded by the National Institutes of Health, the American Cancer Society, and other organizations. The investigators disclosed having no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Patients who are profoundly immunosuppressed after extensive cancer treatment, and who fall ill with COVID-19, can shed viable SARS-CoV-2 virus for at least 2 months after symptom onset and may need extended periods of isolation.

Live-virus shedding was detected in 18 patients who had undergone hematopoietic stem cell transplants or chimeric antigen receptor (CAR) T-cell therapy and in 2 patients with lymphoma. 

The finding was reported Dec. 1 in a research letter in the New England Journal of Medicine. 

Individuals who are otherwise healthy when they get COVID-19 are “no longer infectious after the first week of illness,” said lead author Mini Kamboj, MD, chief medical epidemiologist, Memorial Sloan Kettering Cancer Center, New York. 

“We need to keep an open mind about how [much] longer immunocompromised patients could pose an infection risk to others,” she added.

Dr. Kamboj said in an interview that her team’s previous experience with stem cell transplant recipients had suggested that severely immunocompromised patients shed other viruses (such as respiratory syncytial virus, parainfluenza, and influenza) for longer periods of time than do healthy controls.

Based on their latest findings, the investigators suggest that current guidelines for COVID-19 isolation precautions may need to be revised for immunocompromised patients. Even if only a small proportion of patients with cancer who have COVID-19 remain contagious for prolonged periods of time, “it’s a residual risk that we need to address,” Dr. Kamboj said. 

Dr. Kamboj also suggested that physicians follow test-based criteria to determine when a patient undergoing transplant can be released from isolation.
 

Shedding of viable virus

For this study, the investigators used cell cultures to detect viable virus in serially collected nasopharyngeal and sputum samples from 20 immunocompromised patients who had COVID-19 (diagnosed with COVID-19 between March 10 and April 20).  

Patients had lymphoma (n = 8), multiple myeloma (n= 7), acute leukemia/myelodysplastic syndrome (n = 4), and chronic leukemia (n = 1). There were 16 patients who had undergone transplant, 2 who had received CAR T-cell therapy, and 2 who had received other therapy.

There were 15 patients receiving active treatment or chemotherapy, and 11 developed severe COVID-19 infection. 

In total, 78 respiratory samples were collected.

“Viral RNA was detected for up to 78 days after the onset of symptoms,” the researchers reported, “[and] viable virus was detected in 10 of 14 nasopharyngeal samples (71%) that were available from the first day of laboratory testing.”

Five patients were followed up, and from these patients, the team grew virus in culture for up to 61 days after symptom onset. Two among this small group of five patients had received allogenic hematopoietic stem cell transplantation and one patient had been treated with CAR T-cell therapy within the previous 6 months. This patient remained seronegative for antibodies to the coronavirus.

For 11 patients, the team obtained serial sample genomes and found that  “each patient was infected by a distinct virus and there were no major changes in the consensus sequences of the original serial specimens or cultured isolates.” These findings were consistent with persistent infection, they noted.

The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients who are profoundly immunosuppressed after extensive cancer treatment, and who fall ill with COVID-19, can shed viable SARS-CoV-2 virus for at least 2 months after symptom onset and may need extended periods of isolation.

Live-virus shedding was detected in 18 patients who had undergone hematopoietic stem cell transplants or chimeric antigen receptor (CAR) T-cell therapy and in 2 patients with lymphoma. 

The finding was reported Dec. 1 in a research letter in the New England Journal of Medicine. 

Individuals who are otherwise healthy when they get COVID-19 are “no longer infectious after the first week of illness,” said lead author Mini Kamboj, MD, chief medical epidemiologist, Memorial Sloan Kettering Cancer Center, New York. 

“We need to keep an open mind about how [much] longer immunocompromised patients could pose an infection risk to others,” she added.

Dr. Kamboj said in an interview that her team’s previous experience with stem cell transplant recipients had suggested that severely immunocompromised patients shed other viruses (such as respiratory syncytial virus, parainfluenza, and influenza) for longer periods of time than do healthy controls.

Based on their latest findings, the investigators suggest that current guidelines for COVID-19 isolation precautions may need to be revised for immunocompromised patients. Even if only a small proportion of patients with cancer who have COVID-19 remain contagious for prolonged periods of time, “it’s a residual risk that we need to address,” Dr. Kamboj said. 

Dr. Kamboj also suggested that physicians follow test-based criteria to determine when a patient undergoing transplant can be released from isolation.
 

Shedding of viable virus

For this study, the investigators used cell cultures to detect viable virus in serially collected nasopharyngeal and sputum samples from 20 immunocompromised patients who had COVID-19 (diagnosed with COVID-19 between March 10 and April 20).  

Patients had lymphoma (n = 8), multiple myeloma (n= 7), acute leukemia/myelodysplastic syndrome (n = 4), and chronic leukemia (n = 1). There were 16 patients who had undergone transplant, 2 who had received CAR T-cell therapy, and 2 who had received other therapy.

There were 15 patients receiving active treatment or chemotherapy, and 11 developed severe COVID-19 infection. 

In total, 78 respiratory samples were collected.

“Viral RNA was detected for up to 78 days after the onset of symptoms,” the researchers reported, “[and] viable virus was detected in 10 of 14 nasopharyngeal samples (71%) that were available from the first day of laboratory testing.”

Five patients were followed up, and from these patients, the team grew virus in culture for up to 61 days after symptom onset. Two among this small group of five patients had received allogenic hematopoietic stem cell transplantation and one patient had been treated with CAR T-cell therapy within the previous 6 months. This patient remained seronegative for antibodies to the coronavirus.

For 11 patients, the team obtained serial sample genomes and found that  “each patient was infected by a distinct virus and there were no major changes in the consensus sequences of the original serial specimens or cultured isolates.” These findings were consistent with persistent infection, they noted.

The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients who are profoundly immunosuppressed after extensive cancer treatment, and who fall ill with COVID-19, can shed viable SARS-CoV-2 virus for at least 2 months after symptom onset and may need extended periods of isolation.

Live-virus shedding was detected in 18 patients who had undergone hematopoietic stem cell transplants or chimeric antigen receptor (CAR) T-cell therapy and in 2 patients with lymphoma. 

The finding was reported Dec. 1 in a research letter in the New England Journal of Medicine. 

Individuals who are otherwise healthy when they get COVID-19 are “no longer infectious after the first week of illness,” said lead author Mini Kamboj, MD, chief medical epidemiologist, Memorial Sloan Kettering Cancer Center, New York. 

“We need to keep an open mind about how [much] longer immunocompromised patients could pose an infection risk to others,” she added.

Dr. Kamboj said in an interview that her team’s previous experience with stem cell transplant recipients had suggested that severely immunocompromised patients shed other viruses (such as respiratory syncytial virus, parainfluenza, and influenza) for longer periods of time than do healthy controls.

Based on their latest findings, the investigators suggest that current guidelines for COVID-19 isolation precautions may need to be revised for immunocompromised patients. Even if only a small proportion of patients with cancer who have COVID-19 remain contagious for prolonged periods of time, “it’s a residual risk that we need to address,” Dr. Kamboj said. 

Dr. Kamboj also suggested that physicians follow test-based criteria to determine when a patient undergoing transplant can be released from isolation.
 

Shedding of viable virus

For this study, the investigators used cell cultures to detect viable virus in serially collected nasopharyngeal and sputum samples from 20 immunocompromised patients who had COVID-19 (diagnosed with COVID-19 between March 10 and April 20).  

Patients had lymphoma (n = 8), multiple myeloma (n= 7), acute leukemia/myelodysplastic syndrome (n = 4), and chronic leukemia (n = 1). There were 16 patients who had undergone transplant, 2 who had received CAR T-cell therapy, and 2 who had received other therapy.

There were 15 patients receiving active treatment or chemotherapy, and 11 developed severe COVID-19 infection. 

In total, 78 respiratory samples were collected.

“Viral RNA was detected for up to 78 days after the onset of symptoms,” the researchers reported, “[and] viable virus was detected in 10 of 14 nasopharyngeal samples (71%) that were available from the first day of laboratory testing.”

Five patients were followed up, and from these patients, the team grew virus in culture for up to 61 days after symptom onset. Two among this small group of five patients had received allogenic hematopoietic stem cell transplantation and one patient had been treated with CAR T-cell therapy within the previous 6 months. This patient remained seronegative for antibodies to the coronavirus.

For 11 patients, the team obtained serial sample genomes and found that  “each patient was infected by a distinct virus and there were no major changes in the consensus sequences of the original serial specimens or cultured isolates.” These findings were consistent with persistent infection, they noted.

The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Among chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients in the minimal residual disease (MRD) cohort of the phase 2 CAPTIVATE trial, a 1-year disease-free survival (DFS) rate of 95% in those randomized to placebo after 12 cycles of combined ibrutinib plus venetoclax supports a fixed-duration treatment approach, according to William G. Wierda, MD, PhD, University of Texas, MD Anderson Cancer Center, Houston.

Ibrutinib, a once-daily Bruton kinase inhibitor, is the only targeted therapy for first-line treatment of CLL that has demonstrated significant overall survival benefit in randomized phase 3 studies, Dr. Wierda said at the American Society of Hematology annual meeting, held virtually.

Ibrutinib and venetoclax have synergistic and complementary antitumor activity, he noted, through mobilizing and clearing CLL cells from protective niches and disease compartments beyond blood and bone marrow.

Fixed-duration study

CAPTIVATE (PCYC-1142), an international phase 2 study, evaluated first-line treatment with 12 cycles of the ibrutinib/venetoclax combination in MRD and fixed-duration cohorts. The current primary analysis of 1-year DFS from the MRD cohort tested whether the regimen allows for treatment-free remission in the setting of confirmed undetectable MRD (uMRD).

Patients (n = 164, median age 58 years) in the CAPTIVATE study MRD cohort had previously untreated active CLL/SLL requiring treatment per International Workshop on Chronic Lymphocytic Leukemia criteria.

They received 3 cycles of lead-in ibrutinib (420 mg once daily) followed by 12 cycles of ibrutinib (420 mg once daily plus venetoclax ramp-up to 400 mg once daily). Thereafter, in an MRD-guided 1:1 randomization stratified by immunoglobulin heavy chain (IGHV) mutational status, those with confirmed uMRD received either placebo or ibrutinib, and those with uMRD not confirmed received either ibrutinib or ibrutinib plus venetoclax (both open-label).

Among high-risk features in CAPTIVATE subjects, 60% of patients had unmutated IGHV, with del(17p)/TP53 mutation in 20%, del(11Q) in 17%, complex karyotype in 19%, cytopenias in 36%, bulky lymph nodes in 32%, and absolute neutrophil count ≥25x109/L in 76%.
 

Response findings

The ibrutinib lead-in, Dr. Wierda said, reduced tumor lysis syndrome (TLS) risk, shifting 90% of patients with high baseline TLS risk to medium or low-risk categories (from 77 to 51 patients), precluding need for hospitalization with venetoclax initiation.

The rate for best response of uMRD (defined as uMRD over at least 3 cycles in both peripheral blood and bone marrow) in evaluable patients was 75% in peripheral blood (n = 163) and 72% in bone marrow (n = 155).

Confirmed uMRD was achieved in 86/149 (58%), with uMRD not confirmed in 63/149 (uMRD 32% in bone marrow and 48% in peripheral blood). One-year DFS after the further randomization to placebo or ibrutinib in the confirmed uMRD group was 95.3% in the placebo group and 100% in the ibrutinib group (P = .1475). In the uMRD not confirmed group, 30-month progression-free survival (PFS) was 95.2% and 96.7% in the ibrutinib and ibrutinib plus venetoclax groups, respectively. Thirty-month PFS rates in the confirmed uMRD placebo and ibrutinib arms were 95.3% and 100%. “Thirty-month PFS rates were greater than 95% across all randomized arms,” Dr. Wierda stated.

In patients without confirmed uMRD after 12 cycles of combined ibrutinib plus venetoclax, additional randomized treatment led to greater increases in uMRD in the ibrutinib plus venetoclax group than in the ibrutinib alone group (bone marrow additional 10% ibrutinib alone, 34% ibrutinib plus venetoclax; peripheral blood 0% ibrutinib, 19% ibrutinib plus venetoclax).

Adverse events generally decreased after the first 6 months of ibrutinib plus venetoclax treatment, with no new safety signals emerging over time. “There were no safety concerns with this highly active combination of first-line ibrutinib plus venetoclax. It’s an oral, once-daily fixed duration regimen that achieves undetectable MRD in blood or bone marrow in three-fourths of patients after 12 cycles of combined treatment.”

When asked, in a question-and-answer session after his presentation, if the findings were “practice changing,” Dr. Wierda responded: “We need additional data from ongoing studies looking at various combinations of targeted therapy. But this study does clearly show efficacy in terms of depth of remission, and it supports the concept of fixed duration treatment, particularly for those patients who achieved undetectable MRD status.”
 

SOURCE: William G. Wierda, MD, PhD. ASH 2020, Abstract 123.

Among chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients in the minimal residual disease (MRD) cohort of the phase 2 CAPTIVATE trial, a 1-year disease-free survival (DFS) rate of 95% in those randomized to placebo after 12 cycles of combined ibrutinib plus venetoclax supports a fixed-duration treatment approach, according to William G. Wierda, MD, PhD, University of Texas, MD Anderson Cancer Center, Houston.

Ibrutinib, a once-daily Bruton kinase inhibitor, is the only targeted therapy for first-line treatment of CLL that has demonstrated significant overall survival benefit in randomized phase 3 studies, Dr. Wierda said at the American Society of Hematology annual meeting, held virtually.

Ibrutinib and venetoclax have synergistic and complementary antitumor activity, he noted, through mobilizing and clearing CLL cells from protective niches and disease compartments beyond blood and bone marrow.

Fixed-duration study

CAPTIVATE (PCYC-1142), an international phase 2 study, evaluated first-line treatment with 12 cycles of the ibrutinib/venetoclax combination in MRD and fixed-duration cohorts. The current primary analysis of 1-year DFS from the MRD cohort tested whether the regimen allows for treatment-free remission in the setting of confirmed undetectable MRD (uMRD).

Patients (n = 164, median age 58 years) in the CAPTIVATE study MRD cohort had previously untreated active CLL/SLL requiring treatment per International Workshop on Chronic Lymphocytic Leukemia criteria.

They received 3 cycles of lead-in ibrutinib (420 mg once daily) followed by 12 cycles of ibrutinib (420 mg once daily plus venetoclax ramp-up to 400 mg once daily). Thereafter, in an MRD-guided 1:1 randomization stratified by immunoglobulin heavy chain (IGHV) mutational status, those with confirmed uMRD received either placebo or ibrutinib, and those with uMRD not confirmed received either ibrutinib or ibrutinib plus venetoclax (both open-label).

Among high-risk features in CAPTIVATE subjects, 60% of patients had unmutated IGHV, with del(17p)/TP53 mutation in 20%, del(11Q) in 17%, complex karyotype in 19%, cytopenias in 36%, bulky lymph nodes in 32%, and absolute neutrophil count ≥25x109/L in 76%.
 

Response findings

The ibrutinib lead-in, Dr. Wierda said, reduced tumor lysis syndrome (TLS) risk, shifting 90% of patients with high baseline TLS risk to medium or low-risk categories (from 77 to 51 patients), precluding need for hospitalization with venetoclax initiation.

The rate for best response of uMRD (defined as uMRD over at least 3 cycles in both peripheral blood and bone marrow) in evaluable patients was 75% in peripheral blood (n = 163) and 72% in bone marrow (n = 155).

Confirmed uMRD was achieved in 86/149 (58%), with uMRD not confirmed in 63/149 (uMRD 32% in bone marrow and 48% in peripheral blood). One-year DFS after the further randomization to placebo or ibrutinib in the confirmed uMRD group was 95.3% in the placebo group and 100% in the ibrutinib group (P = .1475). In the uMRD not confirmed group, 30-month progression-free survival (PFS) was 95.2% and 96.7% in the ibrutinib and ibrutinib plus venetoclax groups, respectively. Thirty-month PFS rates in the confirmed uMRD placebo and ibrutinib arms were 95.3% and 100%. “Thirty-month PFS rates were greater than 95% across all randomized arms,” Dr. Wierda stated.

In patients without confirmed uMRD after 12 cycles of combined ibrutinib plus venetoclax, additional randomized treatment led to greater increases in uMRD in the ibrutinib plus venetoclax group than in the ibrutinib alone group (bone marrow additional 10% ibrutinib alone, 34% ibrutinib plus venetoclax; peripheral blood 0% ibrutinib, 19% ibrutinib plus venetoclax).

Adverse events generally decreased after the first 6 months of ibrutinib plus venetoclax treatment, with no new safety signals emerging over time. “There were no safety concerns with this highly active combination of first-line ibrutinib plus venetoclax. It’s an oral, once-daily fixed duration regimen that achieves undetectable MRD in blood or bone marrow in three-fourths of patients after 12 cycles of combined treatment.”

When asked, in a question-and-answer session after his presentation, if the findings were “practice changing,” Dr. Wierda responded: “We need additional data from ongoing studies looking at various combinations of targeted therapy. But this study does clearly show efficacy in terms of depth of remission, and it supports the concept of fixed duration treatment, particularly for those patients who achieved undetectable MRD status.”
 

SOURCE: William G. Wierda, MD, PhD. ASH 2020, Abstract 123.

Among chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients in the minimal residual disease (MRD) cohort of the phase 2 CAPTIVATE trial, a 1-year disease-free survival (DFS) rate of 95% in those randomized to placebo after 12 cycles of combined ibrutinib plus venetoclax supports a fixed-duration treatment approach, according to William G. Wierda, MD, PhD, University of Texas, MD Anderson Cancer Center, Houston.

Ibrutinib, a once-daily Bruton kinase inhibitor, is the only targeted therapy for first-line treatment of CLL that has demonstrated significant overall survival benefit in randomized phase 3 studies, Dr. Wierda said at the American Society of Hematology annual meeting, held virtually.

Ibrutinib and venetoclax have synergistic and complementary antitumor activity, he noted, through mobilizing and clearing CLL cells from protective niches and disease compartments beyond blood and bone marrow.

Fixed-duration study

CAPTIVATE (PCYC-1142), an international phase 2 study, evaluated first-line treatment with 12 cycles of the ibrutinib/venetoclax combination in MRD and fixed-duration cohorts. The current primary analysis of 1-year DFS from the MRD cohort tested whether the regimen allows for treatment-free remission in the setting of confirmed undetectable MRD (uMRD).

Patients (n = 164, median age 58 years) in the CAPTIVATE study MRD cohort had previously untreated active CLL/SLL requiring treatment per International Workshop on Chronic Lymphocytic Leukemia criteria.

They received 3 cycles of lead-in ibrutinib (420 mg once daily) followed by 12 cycles of ibrutinib (420 mg once daily plus venetoclax ramp-up to 400 mg once daily). Thereafter, in an MRD-guided 1:1 randomization stratified by immunoglobulin heavy chain (IGHV) mutational status, those with confirmed uMRD received either placebo or ibrutinib, and those with uMRD not confirmed received either ibrutinib or ibrutinib plus venetoclax (both open-label).

Among high-risk features in CAPTIVATE subjects, 60% of patients had unmutated IGHV, with del(17p)/TP53 mutation in 20%, del(11Q) in 17%, complex karyotype in 19%, cytopenias in 36%, bulky lymph nodes in 32%, and absolute neutrophil count ≥25x109/L in 76%.
 

Response findings

The ibrutinib lead-in, Dr. Wierda said, reduced tumor lysis syndrome (TLS) risk, shifting 90% of patients with high baseline TLS risk to medium or low-risk categories (from 77 to 51 patients), precluding need for hospitalization with venetoclax initiation.

The rate for best response of uMRD (defined as uMRD over at least 3 cycles in both peripheral blood and bone marrow) in evaluable patients was 75% in peripheral blood (n = 163) and 72% in bone marrow (n = 155).

Confirmed uMRD was achieved in 86/149 (58%), with uMRD not confirmed in 63/149 (uMRD 32% in bone marrow and 48% in peripheral blood). One-year DFS after the further randomization to placebo or ibrutinib in the confirmed uMRD group was 95.3% in the placebo group and 100% in the ibrutinib group (P = .1475). In the uMRD not confirmed group, 30-month progression-free survival (PFS) was 95.2% and 96.7% in the ibrutinib and ibrutinib plus venetoclax groups, respectively. Thirty-month PFS rates in the confirmed uMRD placebo and ibrutinib arms were 95.3% and 100%. “Thirty-month PFS rates were greater than 95% across all randomized arms,” Dr. Wierda stated.

In patients without confirmed uMRD after 12 cycles of combined ibrutinib plus venetoclax, additional randomized treatment led to greater increases in uMRD in the ibrutinib plus venetoclax group than in the ibrutinib alone group (bone marrow additional 10% ibrutinib alone, 34% ibrutinib plus venetoclax; peripheral blood 0% ibrutinib, 19% ibrutinib plus venetoclax).

Adverse events generally decreased after the first 6 months of ibrutinib plus venetoclax treatment, with no new safety signals emerging over time. “There were no safety concerns with this highly active combination of first-line ibrutinib plus venetoclax. It’s an oral, once-daily fixed duration regimen that achieves undetectable MRD in blood or bone marrow in three-fourths of patients after 12 cycles of combined treatment.”

When asked, in a question-and-answer session after his presentation, if the findings were “practice changing,” Dr. Wierda responded: “We need additional data from ongoing studies looking at various combinations of targeted therapy. But this study does clearly show efficacy in terms of depth of remission, and it supports the concept of fixed duration treatment, particularly for those patients who achieved undetectable MRD status.”
 

SOURCE: William G. Wierda, MD, PhD. ASH 2020, Abstract 123.

A neoadjuvant strategy combining two immunostimulatory agents with differing mechanisms of action is efficacious and safe in patients with high-risk, resectable melanoma, according to final results of the phase 2 Neo-C-Nivo trial.

The two agents are the PD-1 inhibitor nivolumab and CMP-001, an investigational Toll-like receptor 9 agonist that activates tumor-associated plasmacytoid dendritic cells.

CMP-001 and nivolumab produced a major pathologic response in 60% of patients, and these patients had a 1-year relapse-free survival rate of 89%. About 23% of patients had grade 3 treatment-related adverse events, and there were no grade 4-5 treatment-related events.

These data were reported at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.

“Stage III melanoma is a very, very high risk disease. Despite appropriate management, which involves surgical resection followed by adjuvant immunotherapy, a large number of patients still relapse,” noted study author Diwakar Davar, MD, of the University of Pittsburgh Hillman Cancer Center.

“Neoadjuvant immunotherapy in this setting enhances the systemic T-cell response to tumor antigens,” he explained. “As a result, there is greater detection and killing of micrometastatic disease. And, indeed, neoadjuvant immunotherapy with anti–[programmed death–1] monotherapy or with anti-PD1 and anti-CTLA4 combination therapy produces high response rates, although the combination therapy is associated with significant toxicity.”
 

Patients, treatment, and response

The Neo-C-Nivo trial enrolled 31 patients with resectable stage IIIB/C/D melanoma having clinically apparent lymph node disease.

The patients were treated with three cycles of nivolumab given every 2 weeks. They also received seven weekly injections of CMP-001 subcutaneously and then intratumorally. After surgical resection, the patients received more of the same immunotherapy.

At a median follow-up of 15 months, 60% of patients had a major pathologic response, 50% had a complete response, and 10% had a major response. Some 70% of patients (after additionally including partial responders) had any pathologic response.

“More than half of the patients that we treated had more than one injectable lesion,” Dr. Davar noted. “I want to emphasize that only one lesion was injected, so the results we got illustrate that the rest of the patients who had more than one injectable lesion had regression in their injected and uninjected lesions.”

Biomarker analyses showed that response was associated with evidence of immune activation, both in the tumor and in the blood. With immunotherapy, the density of CD8 tumor-infiltrating lymphocytes increased by a median of 10.3-fold in pathologic responders as compared with only 0.8-fold in nonresponders (P < .05). In addition, responders had evidence of activated CD8-positive T cells peripherally, as well as presence of plasmacytoid dendritic cells within the tumor microenvironment.
 

Survival and safety

Patients had better median relapse-free survival if they attained a major pathologic response (not reached in either group, P = .0106) or any pathologic response (not reached vs. 5 months, P = .0001).

The landmark 1-year relapse-free survival rate was 89% for major pathologic responders and 90% for all pathologic responders.

Overall, 22.6% of patients experienced grade 3 treatment-related adverse events, the majority of which did not require medical intervention and none of which delayed planned surgery. There were no grade 4-5 treatment-related adverse events.

Cytokine release syndrome was uncommon, seen in 16.1% of patients, possibly because the cohort received prophylaxis, Dr. Davar proposed.
 

Another treatment option?

“Intratumoral CMP-001 increases clinical efficacy of PD-1 blockade with minimal additional toxicity in patients with regionally advanced melanoma. Further study of this combination in high-risk resectable melanoma is planned,” Dr. Davar concluded.

“This combination achieved high response rates and certainly should be considered for a larger trial,” agreed session cochair Brian Gastman, MD, of the Cleveland (Ohio) Clinic.

However, long-term outcomes are pending, and it is not clear how efficacy of the studied combination will ultimately stack up against that of other treatment options, Dr. Gastman cautioned in an interview. “For example, it’s hard to tell if this will lead to better results versus, say, T-VEC [talimogene laherparepvec] with an anti-PD-1 agent,” he elaborated.

Nonetheless, “the implication of these findings is that there is another potential injectable option that can be combined with checkpoint inhibitors, and it may be useful for patients with refractory disease,” Dr. Gastman concluded.

The trial was funded by Checkmate Pharmaceuticals. Dr. Davar disclosed relationships with Checkmate Pharmaceuticals, Array Biopharma, Merck, Shionogi, Vedanta, Bristol-Myers Squibb, CellSight Technologies, GlaxoSmithKline/Tesaro, and Medpacto. Dr. Gastman disclosed no relevant conflicts of interest.

SOURCE: Davar D et al. SITC 2020, Abstract 303.

A neoadjuvant strategy combining two immunostimulatory agents with differing mechanisms of action is efficacious and safe in patients with high-risk, resectable melanoma, according to final results of the phase 2 Neo-C-Nivo trial.

The two agents are the PD-1 inhibitor nivolumab and CMP-001, an investigational Toll-like receptor 9 agonist that activates tumor-associated plasmacytoid dendritic cells.

CMP-001 and nivolumab produced a major pathologic response in 60% of patients, and these patients had a 1-year relapse-free survival rate of 89%. About 23% of patients had grade 3 treatment-related adverse events, and there were no grade 4-5 treatment-related events.

These data were reported at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.

“Stage III melanoma is a very, very high risk disease. Despite appropriate management, which involves surgical resection followed by adjuvant immunotherapy, a large number of patients still relapse,” noted study author Diwakar Davar, MD, of the University of Pittsburgh Hillman Cancer Center.

“Neoadjuvant immunotherapy in this setting enhances the systemic T-cell response to tumor antigens,” he explained. “As a result, there is greater detection and killing of micrometastatic disease. And, indeed, neoadjuvant immunotherapy with anti–[programmed death–1] monotherapy or with anti-PD1 and anti-CTLA4 combination therapy produces high response rates, although the combination therapy is associated with significant toxicity.”
 

Patients, treatment, and response

The Neo-C-Nivo trial enrolled 31 patients with resectable stage IIIB/C/D melanoma having clinically apparent lymph node disease.

The patients were treated with three cycles of nivolumab given every 2 weeks. They also received seven weekly injections of CMP-001 subcutaneously and then intratumorally. After surgical resection, the patients received more of the same immunotherapy.

At a median follow-up of 15 months, 60% of patients had a major pathologic response, 50% had a complete response, and 10% had a major response. Some 70% of patients (after additionally including partial responders) had any pathologic response.

“More than half of the patients that we treated had more than one injectable lesion,” Dr. Davar noted. “I want to emphasize that only one lesion was injected, so the results we got illustrate that the rest of the patients who had more than one injectable lesion had regression in their injected and uninjected lesions.”

Biomarker analyses showed that response was associated with evidence of immune activation, both in the tumor and in the blood. With immunotherapy, the density of CD8 tumor-infiltrating lymphocytes increased by a median of 10.3-fold in pathologic responders as compared with only 0.8-fold in nonresponders (P < .05). In addition, responders had evidence of activated CD8-positive T cells peripherally, as well as presence of plasmacytoid dendritic cells within the tumor microenvironment.
 

Survival and safety

Patients had better median relapse-free survival if they attained a major pathologic response (not reached in either group, P = .0106) or any pathologic response (not reached vs. 5 months, P = .0001).

The landmark 1-year relapse-free survival rate was 89% for major pathologic responders and 90% for all pathologic responders.

Overall, 22.6% of patients experienced grade 3 treatment-related adverse events, the majority of which did not require medical intervention and none of which delayed planned surgery. There were no grade 4-5 treatment-related adverse events.

Cytokine release syndrome was uncommon, seen in 16.1% of patients, possibly because the cohort received prophylaxis, Dr. Davar proposed.
 

Another treatment option?

“Intratumoral CMP-001 increases clinical efficacy of PD-1 blockade with minimal additional toxicity in patients with regionally advanced melanoma. Further study of this combination in high-risk resectable melanoma is planned,” Dr. Davar concluded.

“This combination achieved high response rates and certainly should be considered for a larger trial,” agreed session cochair Brian Gastman, MD, of the Cleveland (Ohio) Clinic.

However, long-term outcomes are pending, and it is not clear how efficacy of the studied combination will ultimately stack up against that of other treatment options, Dr. Gastman cautioned in an interview. “For example, it’s hard to tell if this will lead to better results versus, say, T-VEC [talimogene laherparepvec] with an anti-PD-1 agent,” he elaborated.

Nonetheless, “the implication of these findings is that there is another potential injectable option that can be combined with checkpoint inhibitors, and it may be useful for patients with refractory disease,” Dr. Gastman concluded.

The trial was funded by Checkmate Pharmaceuticals. Dr. Davar disclosed relationships with Checkmate Pharmaceuticals, Array Biopharma, Merck, Shionogi, Vedanta, Bristol-Myers Squibb, CellSight Technologies, GlaxoSmithKline/Tesaro, and Medpacto. Dr. Gastman disclosed no relevant conflicts of interest.

SOURCE: Davar D et al. SITC 2020, Abstract 303.

A neoadjuvant strategy combining two immunostimulatory agents with differing mechanisms of action is efficacious and safe in patients with high-risk, resectable melanoma, according to final results of the phase 2 Neo-C-Nivo trial.

The two agents are the PD-1 inhibitor nivolumab and CMP-001, an investigational Toll-like receptor 9 agonist that activates tumor-associated plasmacytoid dendritic cells.

CMP-001 and nivolumab produced a major pathologic response in 60% of patients, and these patients had a 1-year relapse-free survival rate of 89%. About 23% of patients had grade 3 treatment-related adverse events, and there were no grade 4-5 treatment-related events.

These data were reported at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.

“Stage III melanoma is a very, very high risk disease. Despite appropriate management, which involves surgical resection followed by adjuvant immunotherapy, a large number of patients still relapse,” noted study author Diwakar Davar, MD, of the University of Pittsburgh Hillman Cancer Center.

“Neoadjuvant immunotherapy in this setting enhances the systemic T-cell response to tumor antigens,” he explained. “As a result, there is greater detection and killing of micrometastatic disease. And, indeed, neoadjuvant immunotherapy with anti–[programmed death–1] monotherapy or with anti-PD1 and anti-CTLA4 combination therapy produces high response rates, although the combination therapy is associated with significant toxicity.”
 

Patients, treatment, and response

The Neo-C-Nivo trial enrolled 31 patients with resectable stage IIIB/C/D melanoma having clinically apparent lymph node disease.

The patients were treated with three cycles of nivolumab given every 2 weeks. They also received seven weekly injections of CMP-001 subcutaneously and then intratumorally. After surgical resection, the patients received more of the same immunotherapy.

At a median follow-up of 15 months, 60% of patients had a major pathologic response, 50% had a complete response, and 10% had a major response. Some 70% of patients (after additionally including partial responders) had any pathologic response.

“More than half of the patients that we treated had more than one injectable lesion,” Dr. Davar noted. “I want to emphasize that only one lesion was injected, so the results we got illustrate that the rest of the patients who had more than one injectable lesion had regression in their injected and uninjected lesions.”

Biomarker analyses showed that response was associated with evidence of immune activation, both in the tumor and in the blood. With immunotherapy, the density of CD8 tumor-infiltrating lymphocytes increased by a median of 10.3-fold in pathologic responders as compared with only 0.8-fold in nonresponders (P < .05). In addition, responders had evidence of activated CD8-positive T cells peripherally, as well as presence of plasmacytoid dendritic cells within the tumor microenvironment.
 

Survival and safety

Patients had better median relapse-free survival if they attained a major pathologic response (not reached in either group, P = .0106) or any pathologic response (not reached vs. 5 months, P = .0001).

The landmark 1-year relapse-free survival rate was 89% for major pathologic responders and 90% for all pathologic responders.

Overall, 22.6% of patients experienced grade 3 treatment-related adverse events, the majority of which did not require medical intervention and none of which delayed planned surgery. There were no grade 4-5 treatment-related adverse events.

Cytokine release syndrome was uncommon, seen in 16.1% of patients, possibly because the cohort received prophylaxis, Dr. Davar proposed.
 

Another treatment option?

“Intratumoral CMP-001 increases clinical efficacy of PD-1 blockade with minimal additional toxicity in patients with regionally advanced melanoma. Further study of this combination in high-risk resectable melanoma is planned,” Dr. Davar concluded.

“This combination achieved high response rates and certainly should be considered for a larger trial,” agreed session cochair Brian Gastman, MD, of the Cleveland (Ohio) Clinic.

However, long-term outcomes are pending, and it is not clear how efficacy of the studied combination will ultimately stack up against that of other treatment options, Dr. Gastman cautioned in an interview. “For example, it’s hard to tell if this will lead to better results versus, say, T-VEC [talimogene laherparepvec] with an anti-PD-1 agent,” he elaborated.

Nonetheless, “the implication of these findings is that there is another potential injectable option that can be combined with checkpoint inhibitors, and it may be useful for patients with refractory disease,” Dr. Gastman concluded.

The trial was funded by Checkmate Pharmaceuticals. Dr. Davar disclosed relationships with Checkmate Pharmaceuticals, Array Biopharma, Merck, Shionogi, Vedanta, Bristol-Myers Squibb, CellSight Technologies, GlaxoSmithKline/Tesaro, and Medpacto. Dr. Gastman disclosed no relevant conflicts of interest.

SOURCE: Davar D et al. SITC 2020, Abstract 303.

Circulating microRNAs (miRNAs) could be a potential noninvasive biomarker for early diagnosis of multiple myeloma (MM), according to the results of a meta-analysis published online in the Journal of Bone Oncology.

In recent years, because of the rise of the miRNA technique, many scholars have studied its value in the diagnosis of MM, and have obtained good but inconsistent results, according to Shuai-Shuai Gao, of the Xi’an (China) Daxing Hospital, and colleagues. For this reason, they conducted the meta-analysis in order to more clearly determine the role of miRNA in the early diagnosis of MM. The meta-analysis ultimately assessed 32 studies from 15 articles comprising 2,053 MM patients and 1,118 healthy controls.

All the included studies involved newly diagnosed MM patients and healthy controls; the obtained miRNA was derived from serum or plasma specimens; and the report contained relevant statistics such as sensitivity, specificity, and area-under-the-curve values.
 

High sensitivity and specificity

The researchers found that the overall sensitivity and specificity of using miRNAs for the diagnosis of MM were 0.81 and 0.85, respectively. In addition, the overall positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and area under the curve were 5.5, 0.22, 25 and 0.90, respectively.

A subgroup analysis showed that the down-regulation of miRNA clusters with larger samples size of plasma type could carry out a better diagnostic accuracy of MM patients, according to the authors.

“[Circulating miRNAs] not only had high sensitivity and strong specificity, but also had noninvasive and no radiation risks. It is worth continuing to optimize its practicality. In the future, multicenter, more rigorous, and high-quality case-control studies are still needed in clinical practice to improve the efficacy of circulating miRNA in the early diagnosis of MM,” the researchers concluded.

The study did not receive any outside funding and the researchers reported that they had no conflicts.

[email protected]

SOURCE: Gao S-S et al. J Bone Oncol. 2020 Oct 21. doi: 10.1016/j.jbo.2020.100327.

Circulating microRNAs (miRNAs) could be a potential noninvasive biomarker for early diagnosis of multiple myeloma (MM), according to the results of a meta-analysis published online in the Journal of Bone Oncology.

In recent years, because of the rise of the miRNA technique, many scholars have studied its value in the diagnosis of MM, and have obtained good but inconsistent results, according to Shuai-Shuai Gao, of the Xi’an (China) Daxing Hospital, and colleagues. For this reason, they conducted the meta-analysis in order to more clearly determine the role of miRNA in the early diagnosis of MM. The meta-analysis ultimately assessed 32 studies from 15 articles comprising 2,053 MM patients and 1,118 healthy controls.

All the included studies involved newly diagnosed MM patients and healthy controls; the obtained miRNA was derived from serum or plasma specimens; and the report contained relevant statistics such as sensitivity, specificity, and area-under-the-curve values.
 

High sensitivity and specificity

The researchers found that the overall sensitivity and specificity of using miRNAs for the diagnosis of MM were 0.81 and 0.85, respectively. In addition, the overall positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and area under the curve were 5.5, 0.22, 25 and 0.90, respectively.

A subgroup analysis showed that the down-regulation of miRNA clusters with larger samples size of plasma type could carry out a better diagnostic accuracy of MM patients, according to the authors.

“[Circulating miRNAs] not only had high sensitivity and strong specificity, but also had noninvasive and no radiation risks. It is worth continuing to optimize its practicality. In the future, multicenter, more rigorous, and high-quality case-control studies are still needed in clinical practice to improve the efficacy of circulating miRNA in the early diagnosis of MM,” the researchers concluded.

The study did not receive any outside funding and the researchers reported that they had no conflicts.

[email protected]

SOURCE: Gao S-S et al. J Bone Oncol. 2020 Oct 21. doi: 10.1016/j.jbo.2020.100327.

Circulating microRNAs (miRNAs) could be a potential noninvasive biomarker for early diagnosis of multiple myeloma (MM), according to the results of a meta-analysis published online in the Journal of Bone Oncology.

In recent years, because of the rise of the miRNA technique, many scholars have studied its value in the diagnosis of MM, and have obtained good but inconsistent results, according to Shuai-Shuai Gao, of the Xi’an (China) Daxing Hospital, and colleagues. For this reason, they conducted the meta-analysis in order to more clearly determine the role of miRNA in the early diagnosis of MM. The meta-analysis ultimately assessed 32 studies from 15 articles comprising 2,053 MM patients and 1,118 healthy controls.

All the included studies involved newly diagnosed MM patients and healthy controls; the obtained miRNA was derived from serum or plasma specimens; and the report contained relevant statistics such as sensitivity, specificity, and area-under-the-curve values.
 

High sensitivity and specificity

The researchers found that the overall sensitivity and specificity of using miRNAs for the diagnosis of MM were 0.81 and 0.85, respectively. In addition, the overall positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and area under the curve were 5.5, 0.22, 25 and 0.90, respectively.

A subgroup analysis showed that the down-regulation of miRNA clusters with larger samples size of plasma type could carry out a better diagnostic accuracy of MM patients, according to the authors.

“[Circulating miRNAs] not only had high sensitivity and strong specificity, but also had noninvasive and no radiation risks. It is worth continuing to optimize its practicality. In the future, multicenter, more rigorous, and high-quality case-control studies are still needed in clinical practice to improve the efficacy of circulating miRNA in the early diagnosis of MM,” the researchers concluded.

The study did not receive any outside funding and the researchers reported that they had no conflicts.

[email protected]

SOURCE: Gao S-S et al. J Bone Oncol. 2020 Oct 21. doi: 10.1016/j.jbo.2020.100327.

Risk factors for keratinocyte carcinomas, primarily pigment traits and sun sensitivity, were associated with the risk of developing non-Hodgkin lymphomas (NHL) and chronic lymphocytic leukemia (CLL) in an analysis of 92,097 women in France.

The presence of “many or very many nevi [moles]” was particularly associated with the risk of CLL among individuals in the E3N cohort, according to a report published online in Cancer Medicine. E3N is a prospective cohort of French women aged 40-65 years at inclusion in 1990. Researchers collected cancer data at baseline and every 2-3 years.

Hazard ratios and 95% confidence intervals for associations between patients pigmentary traits and sun exposure and their risk for CLL/NHL were estimated using Cox models, according to study author Louis-Marie Garcin, MD, of the Université Paris-Saclay, Villejuif, and colleagues.
 

Common etiology?

Among the 92,097 women included in the study, 622 incident cases of CLL/NHL were observed over a median of 24-years’ follow-up.

The presence of nevi was associated with CLL/NHL risk. The HR for “many or very many nevi” relative to “no nevi” was 1.56. The association with number of nevi was strongest for the risk of CLL, with an HR for “many or very many nevi” of 3.00 vs. 1.32 for NHL. In addition, the researchers found that women whose skin was highly sensitive to sunburn also had a higher risk of CLL (HR, 1.96), while no increased risk of NHL was observed. All HR values were within their respective 95% confidence intervals.

Relevant characteristics that were found to not be associated with added CLL/NHL risk were skin or hair color, number of freckles, and average daily UV dose during spring and summer in the location of residence at birth or at inclusion.

These observations suggest that CLL in particular may share some constitutional risk factors with keratinocyte cancers, according to the researchers.

“We report an association between nevi frequency and CLL/NHL risk, suggesting a partly common genetic etiology of these tumors. Future research should investigate common pathophysiological pathways that could promote the development of both skin carcinoma and CLL/NHL,” the researchers concluded.

The study was sponsored by the French government. The authors stated that they had no conflicts of interest.

[email protected]

SOURCE: Garcin L-M et al. Cancer Med. 2020. doi: 10.1002/cam4.3586.

Risk factors for keratinocyte carcinomas, primarily pigment traits and sun sensitivity, were associated with the risk of developing non-Hodgkin lymphomas (NHL) and chronic lymphocytic leukemia (CLL) in an analysis of 92,097 women in France.

The presence of “many or very many nevi [moles]” was particularly associated with the risk of CLL among individuals in the E3N cohort, according to a report published online in Cancer Medicine. E3N is a prospective cohort of French women aged 40-65 years at inclusion in 1990. Researchers collected cancer data at baseline and every 2-3 years.

Hazard ratios and 95% confidence intervals for associations between patients pigmentary traits and sun exposure and their risk for CLL/NHL were estimated using Cox models, according to study author Louis-Marie Garcin, MD, of the Université Paris-Saclay, Villejuif, and colleagues.
 

Common etiology?

Among the 92,097 women included in the study, 622 incident cases of CLL/NHL were observed over a median of 24-years’ follow-up.

The presence of nevi was associated with CLL/NHL risk. The HR for “many or very many nevi” relative to “no nevi” was 1.56. The association with number of nevi was strongest for the risk of CLL, with an HR for “many or very many nevi” of 3.00 vs. 1.32 for NHL. In addition, the researchers found that women whose skin was highly sensitive to sunburn also had a higher risk of CLL (HR, 1.96), while no increased risk of NHL was observed. All HR values were within their respective 95% confidence intervals.

Relevant characteristics that were found to not be associated with added CLL/NHL risk were skin or hair color, number of freckles, and average daily UV dose during spring and summer in the location of residence at birth or at inclusion.

These observations suggest that CLL in particular may share some constitutional risk factors with keratinocyte cancers, according to the researchers.

“We report an association between nevi frequency and CLL/NHL risk, suggesting a partly common genetic etiology of these tumors. Future research should investigate common pathophysiological pathways that could promote the development of both skin carcinoma and CLL/NHL,” the researchers concluded.

The study was sponsored by the French government. The authors stated that they had no conflicts of interest.

[email protected]

SOURCE: Garcin L-M et al. Cancer Med. 2020. doi: 10.1002/cam4.3586.

Risk factors for keratinocyte carcinomas, primarily pigment traits and sun sensitivity, were associated with the risk of developing non-Hodgkin lymphomas (NHL) and chronic lymphocytic leukemia (CLL) in an analysis of 92,097 women in France.

The presence of “many or very many nevi [moles]” was particularly associated with the risk of CLL among individuals in the E3N cohort, according to a report published online in Cancer Medicine. E3N is a prospective cohort of French women aged 40-65 years at inclusion in 1990. Researchers collected cancer data at baseline and every 2-3 years.

Hazard ratios and 95% confidence intervals for associations between patients pigmentary traits and sun exposure and their risk for CLL/NHL were estimated using Cox models, according to study author Louis-Marie Garcin, MD, of the Université Paris-Saclay, Villejuif, and colleagues.
 

Common etiology?

Among the 92,097 women included in the study, 622 incident cases of CLL/NHL were observed over a median of 24-years’ follow-up.

The presence of nevi was associated with CLL/NHL risk. The HR for “many or very many nevi” relative to “no nevi” was 1.56. The association with number of nevi was strongest for the risk of CLL, with an HR for “many or very many nevi” of 3.00 vs. 1.32 for NHL. In addition, the researchers found that women whose skin was highly sensitive to sunburn also had a higher risk of CLL (HR, 1.96), while no increased risk of NHL was observed. All HR values were within their respective 95% confidence intervals.

Relevant characteristics that were found to not be associated with added CLL/NHL risk were skin or hair color, number of freckles, and average daily UV dose during spring and summer in the location of residence at birth or at inclusion.

These observations suggest that CLL in particular may share some constitutional risk factors with keratinocyte cancers, according to the researchers.

“We report an association between nevi frequency and CLL/NHL risk, suggesting a partly common genetic etiology of these tumors. Future research should investigate common pathophysiological pathways that could promote the development of both skin carcinoma and CLL/NHL,” the researchers concluded.

The study was sponsored by the French government. The authors stated that they had no conflicts of interest.

[email protected]

SOURCE: Garcin L-M et al. Cancer Med. 2020. doi: 10.1002/cam4.3586.

Immunotherapy is a rising star among emerging therapies for acute lymphoblastic leukemia (ALL), according to Patrick A. Brown, MD.

“Most of the emerging therapies in ALL are immunotherapies that have really made an impact in the relapsed and refractory setting,” he said during a presentation at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress. “Another very exciting development is that these immunotherapies are now demonstrating efficacy and increased tolerability over chemotherapy in the minimal residual disease (MRD)-positive setting up front.”

Dr. Brown, director of the pediatric leukemia program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, focused on blinatumomab, inotuzumab, and chimeric antigen receptor (CAR) T-cell therapy for ALL, and explained the rationale for their use.
 

Why immunotherapy?

“It turns out that in normal B cell development there are a number of proteins that are expressed on the surface of B cells and these same proteins are expressed on the surface of many B-cell malignancies,” he said, noting that ALL is “probably the least differentiated of the B-lineage malignancies,” but the vast majority of ALL cases will express CD19 and CD22, and – in adults more often than pediatric patients – CD20.

These antigens make good targets for ALL therapy because they aren’t expressed on bone marrow stem cells or other tissues in the body.

“They really are specific for B cells,” he said, explaining that inotuzumab, a CD22 antibody drug conjugate (ADC), and blinatumomab, a bi-specific T cell-engaging antibody (BiTE) that targets CD19, are antibody-based immunotherapies, whereas CAR T-cell therapies are a separate category that can be single- or multi-antigen targeted.
 

Inotuzumab, blinatumomab, and CAR T cells

Inotuzumab targets the CD22 immunotoxin antigen via a T-cell independent process and is delivered as a once-weekly 1-hour infusion. It is approved for adult relapsed/refractory B-ALL. Blinatumomab binds CD19 on the surface of the tumor cells and CD3 on the surface of any T cell in the vicinity of the tumor cell.

“The recognition that blinatumomab allows between the tumor cell and the T cell is independent of the specificity of the T-cell receptor. It also does not require [major histocompatibility complex] class 1 or peptide antigens on the surface of the T cell,” he said, adding that it does, however, rely on a functional endogenous cytotoxic T-cell response, unlike inotuzumab. “It’s also very difficult technically to give because it’s given as a 28-day continuous IV infusion with bag changes required every 4-7 days.”

Blinatumomab is approved for adult and pediatric Philadelphia chromosome-negative relapsed/refractory B-cell precursor ALL and MRD-positive B-cell precursor ALL.

CAR T-cell therapy, an autologous immunotherapy, is “really kind of the pinnacle of technological advances in immunotherapy in that it combine three different modalities into one: cellular therapy, gene therapy, and immunotherapy,” he said, noting that the process of genetically engineering T cells to express a CAR is complex and costly and access is limited, but expanding with about 90 centers in the U.S. now providing CAR T-cell therapy.

Response rates with each of these therapies represent a paradigm shift in the relapsed/refractory ALL setting, Dr. Brown said.

Studies have shown complete remission (CR) and minimum residual disease (MRD)-negative CR rates of 81% and 78%, respectively, with inotuzumab, and 43% and 33%, respectively, with blinatumomab.

“This depth of remission was really not seen with prior salvage therapies,” he noted, but added that neither has shown significant durable improvement in overall survival (OS) rates.

CAR T-cell therapy, however, has the highest response rates, with tisagenlecleucel – which targets CD19 and was the first CAR T-cell therapy approved for refractory or second or greater relapse in patients up to age 26 years – showing 81% CR and MRD-negative CR rates and providing a durable survival advantage without subsequent therapy in 40-50% of patients.

“So CAR T cells can represent definitive therapy in a subset of patients,” Dr. Brown said. “One thing we’re struggling with is to be able to predict which patients those are, and there are some emerging biomarkers that may help us with that, but as of now it’s very difficult to predict which patients, when you’re treating them, are going to be in [that group].”

Toxicities and limitations

Cytokine release syndrome and neurotoxicity are the primary toxicities associated with both blinatumomab and tisagenlecleucel. Hepatotoxicity is a major concern with inotuzumab.

“This is particularly important because that hepatotoxicity appears to be primarily a problem in patients who receive inotuzumab either after or prior to hematopoietic stem cell transplant, and since this therapy does not represent definitive therapy and often is really a bridge to transplant, this ... can be a significant limitation to this product,” Dr. Brown said.

A limitation of CAR T cells is failure to manufacture the product, which occurs most often in very young and heavily pretreated patients in whom it can be difficult to obtain enough functional T cells to create the product. Failure to engraft or lack of persistence of the CAR T cells can also occur.

Endogenous or CAR T-cell exhaustion is another potential limitation with blinatumomab and CAR T-cell therapy, and antigen escape can occur with both therapies, as well.

Strategies are being investigated to overcome treatment challenges, Dr. Brown noted.

Examples include efforts to develop universal “off-the-shelf” allogeneic CAR T-cell products to address failure to manufacture, working on more co-stimulatory domains that may be more effective to promote engraftment and persistence, adding immune checkpoint inhibitors to therapy to combat endogenous or CAR T-cell exhaustion, and developing multi-antigen targeted approaches to overcome antigen escape, he said.
 

NCCN Treatment Guidelines

Based on the currently available data, the NCCN has included these immunotherapies in guidelines for both adolescent and young adult (AYA)/adult ALL and for pediatric ALL.

Each of the treatments is listed as an option to consider in both Philadelphia chromosome-positive and -negative AYA and adult patients under age 65 years. Additionally, blinatumomab is listed as an option for up-front treatment of MRD-positive Philadelphia chromosome-negative AYA patients and older patients.

Pediatric guidelines include blinatumomab and tisagenlecleucel as options for patients with MRD-positive disease after induction and for first relapse, and they include all three therapies as options in patients with multiple relapses or refractory disease, said Dr. Brown who chairs the NCCN Clinical Practice Guidelines panel for adult and pediatric ALL.
 

Treatment decision making

Asked by session moderator Ranjana H. Advani, MD, how to decide between the available immunotherapies, Dr. Brown said there is no one-size-fits-all answer.

“Is it availability, insurance coverage, the patient fits better with one therapy,” asked Dr. Advani, the Saul Rosenberg Professor of Lymphoma and the Physician Leader of the Lymphoma Clinical Care Program of Stanford Cancer Institute, Palo Alto, Calif.

“All of the above,” Dr. Brown said. “In 2020 with all these options available, we are a little bit spoiled for choice ... but every patient is an individual case and the risk -benefit ratios of all these therapies differ.”

An exception is that CAR T-cell therapy is a clear stand-out for the patient who isn’t transplant eligible, he noted, adding that CAR T cells “probably give that patient the best chance of survival.”

In a patient who could potentially go to transplant, selection is a bit more challenging, but given the risks associated with inotuzumab, blinatumomab is generally the preferred non-CAR T option, he said.

“It’s a complicated question, and the answer ... is [that it is] an individualized patient-by-patient decision,” he added.

Dr. Brown reported consulting, advisory board, or expert witness activity for Novartis Pharmaceuticals Corporation and Takeda Pharmaceuticals North America Inc.

[email protected]

Immunotherapy is a rising star among emerging therapies for acute lymphoblastic leukemia (ALL), according to Patrick A. Brown, MD.

“Most of the emerging therapies in ALL are immunotherapies that have really made an impact in the relapsed and refractory setting,” he said during a presentation at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress. “Another very exciting development is that these immunotherapies are now demonstrating efficacy and increased tolerability over chemotherapy in the minimal residual disease (MRD)-positive setting up front.”

Dr. Brown, director of the pediatric leukemia program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, focused on blinatumomab, inotuzumab, and chimeric antigen receptor (CAR) T-cell therapy for ALL, and explained the rationale for their use.
 

Why immunotherapy?

“It turns out that in normal B cell development there are a number of proteins that are expressed on the surface of B cells and these same proteins are expressed on the surface of many B-cell malignancies,” he said, noting that ALL is “probably the least differentiated of the B-lineage malignancies,” but the vast majority of ALL cases will express CD19 and CD22, and – in adults more often than pediatric patients – CD20.

These antigens make good targets for ALL therapy because they aren’t expressed on bone marrow stem cells or other tissues in the body.

“They really are specific for B cells,” he said, explaining that inotuzumab, a CD22 antibody drug conjugate (ADC), and blinatumomab, a bi-specific T cell-engaging antibody (BiTE) that targets CD19, are antibody-based immunotherapies, whereas CAR T-cell therapies are a separate category that can be single- or multi-antigen targeted.
 

Inotuzumab, blinatumomab, and CAR T cells

Inotuzumab targets the CD22 immunotoxin antigen via a T-cell independent process and is delivered as a once-weekly 1-hour infusion. It is approved for adult relapsed/refractory B-ALL. Blinatumomab binds CD19 on the surface of the tumor cells and CD3 on the surface of any T cell in the vicinity of the tumor cell.

“The recognition that blinatumomab allows between the tumor cell and the T cell is independent of the specificity of the T-cell receptor. It also does not require [major histocompatibility complex] class 1 or peptide antigens on the surface of the T cell,” he said, adding that it does, however, rely on a functional endogenous cytotoxic T-cell response, unlike inotuzumab. “It’s also very difficult technically to give because it’s given as a 28-day continuous IV infusion with bag changes required every 4-7 days.”

Blinatumomab is approved for adult and pediatric Philadelphia chromosome-negative relapsed/refractory B-cell precursor ALL and MRD-positive B-cell precursor ALL.

CAR T-cell therapy, an autologous immunotherapy, is “really kind of the pinnacle of technological advances in immunotherapy in that it combine three different modalities into one: cellular therapy, gene therapy, and immunotherapy,” he said, noting that the process of genetically engineering T cells to express a CAR is complex and costly and access is limited, but expanding with about 90 centers in the U.S. now providing CAR T-cell therapy.

Response rates with each of these therapies represent a paradigm shift in the relapsed/refractory ALL setting, Dr. Brown said.

Studies have shown complete remission (CR) and minimum residual disease (MRD)-negative CR rates of 81% and 78%, respectively, with inotuzumab, and 43% and 33%, respectively, with blinatumomab.

“This depth of remission was really not seen with prior salvage therapies,” he noted, but added that neither has shown significant durable improvement in overall survival (OS) rates.

CAR T-cell therapy, however, has the highest response rates, with tisagenlecleucel – which targets CD19 and was the first CAR T-cell therapy approved for refractory or second or greater relapse in patients up to age 26 years – showing 81% CR and MRD-negative CR rates and providing a durable survival advantage without subsequent therapy in 40-50% of patients.

“So CAR T cells can represent definitive therapy in a subset of patients,” Dr. Brown said. “One thing we’re struggling with is to be able to predict which patients those are, and there are some emerging biomarkers that may help us with that, but as of now it’s very difficult to predict which patients, when you’re treating them, are going to be in [that group].”

Toxicities and limitations

Cytokine release syndrome and neurotoxicity are the primary toxicities associated with both blinatumomab and tisagenlecleucel. Hepatotoxicity is a major concern with inotuzumab.

“This is particularly important because that hepatotoxicity appears to be primarily a problem in patients who receive inotuzumab either after or prior to hematopoietic stem cell transplant, and since this therapy does not represent definitive therapy and often is really a bridge to transplant, this ... can be a significant limitation to this product,” Dr. Brown said.

A limitation of CAR T cells is failure to manufacture the product, which occurs most often in very young and heavily pretreated patients in whom it can be difficult to obtain enough functional T cells to create the product. Failure to engraft or lack of persistence of the CAR T cells can also occur.

Endogenous or CAR T-cell exhaustion is another potential limitation with blinatumomab and CAR T-cell therapy, and antigen escape can occur with both therapies, as well.

Strategies are being investigated to overcome treatment challenges, Dr. Brown noted.

Examples include efforts to develop universal “off-the-shelf” allogeneic CAR T-cell products to address failure to manufacture, working on more co-stimulatory domains that may be more effective to promote engraftment and persistence, adding immune checkpoint inhibitors to therapy to combat endogenous or CAR T-cell exhaustion, and developing multi-antigen targeted approaches to overcome antigen escape, he said.
 

NCCN Treatment Guidelines

Based on the currently available data, the NCCN has included these immunotherapies in guidelines for both adolescent and young adult (AYA)/adult ALL and for pediatric ALL.

Each of the treatments is listed as an option to consider in both Philadelphia chromosome-positive and -negative AYA and adult patients under age 65 years. Additionally, blinatumomab is listed as an option for up-front treatment of MRD-positive Philadelphia chromosome-negative AYA patients and older patients.

Pediatric guidelines include blinatumomab and tisagenlecleucel as options for patients with MRD-positive disease after induction and for first relapse, and they include all three therapies as options in patients with multiple relapses or refractory disease, said Dr. Brown who chairs the NCCN Clinical Practice Guidelines panel for adult and pediatric ALL.
 

Treatment decision making

Asked by session moderator Ranjana H. Advani, MD, how to decide between the available immunotherapies, Dr. Brown said there is no one-size-fits-all answer.

“Is it availability, insurance coverage, the patient fits better with one therapy,” asked Dr. Advani, the Saul Rosenberg Professor of Lymphoma and the Physician Leader of the Lymphoma Clinical Care Program of Stanford Cancer Institute, Palo Alto, Calif.

“All of the above,” Dr. Brown said. “In 2020 with all these options available, we are a little bit spoiled for choice ... but every patient is an individual case and the risk -benefit ratios of all these therapies differ.”

An exception is that CAR T-cell therapy is a clear stand-out for the patient who isn’t transplant eligible, he noted, adding that CAR T cells “probably give that patient the best chance of survival.”

In a patient who could potentially go to transplant, selection is a bit more challenging, but given the risks associated with inotuzumab, blinatumomab is generally the preferred non-CAR T option, he said.

“It’s a complicated question, and the answer ... is [that it is] an individualized patient-by-patient decision,” he added.

Dr. Brown reported consulting, advisory board, or expert witness activity for Novartis Pharmaceuticals Corporation and Takeda Pharmaceuticals North America Inc.

[email protected]

Immunotherapy is a rising star among emerging therapies for acute lymphoblastic leukemia (ALL), according to Patrick A. Brown, MD.

“Most of the emerging therapies in ALL are immunotherapies that have really made an impact in the relapsed and refractory setting,” he said during a presentation at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress. “Another very exciting development is that these immunotherapies are now demonstrating efficacy and increased tolerability over chemotherapy in the minimal residual disease (MRD)-positive setting up front.”

Dr. Brown, director of the pediatric leukemia program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, focused on blinatumomab, inotuzumab, and chimeric antigen receptor (CAR) T-cell therapy for ALL, and explained the rationale for their use.
 

Why immunotherapy?

“It turns out that in normal B cell development there are a number of proteins that are expressed on the surface of B cells and these same proteins are expressed on the surface of many B-cell malignancies,” he said, noting that ALL is “probably the least differentiated of the B-lineage malignancies,” but the vast majority of ALL cases will express CD19 and CD22, and – in adults more often than pediatric patients – CD20.

These antigens make good targets for ALL therapy because they aren’t expressed on bone marrow stem cells or other tissues in the body.

“They really are specific for B cells,” he said, explaining that inotuzumab, a CD22 antibody drug conjugate (ADC), and blinatumomab, a bi-specific T cell-engaging antibody (BiTE) that targets CD19, are antibody-based immunotherapies, whereas CAR T-cell therapies are a separate category that can be single- or multi-antigen targeted.
 

Inotuzumab, blinatumomab, and CAR T cells

Inotuzumab targets the CD22 immunotoxin antigen via a T-cell independent process and is delivered as a once-weekly 1-hour infusion. It is approved for adult relapsed/refractory B-ALL. Blinatumomab binds CD19 on the surface of the tumor cells and CD3 on the surface of any T cell in the vicinity of the tumor cell.

“The recognition that blinatumomab allows between the tumor cell and the T cell is independent of the specificity of the T-cell receptor. It also does not require [major histocompatibility complex] class 1 or peptide antigens on the surface of the T cell,” he said, adding that it does, however, rely on a functional endogenous cytotoxic T-cell response, unlike inotuzumab. “It’s also very difficult technically to give because it’s given as a 28-day continuous IV infusion with bag changes required every 4-7 days.”

Blinatumomab is approved for adult and pediatric Philadelphia chromosome-negative relapsed/refractory B-cell precursor ALL and MRD-positive B-cell precursor ALL.

CAR T-cell therapy, an autologous immunotherapy, is “really kind of the pinnacle of technological advances in immunotherapy in that it combine three different modalities into one: cellular therapy, gene therapy, and immunotherapy,” he said, noting that the process of genetically engineering T cells to express a CAR is complex and costly and access is limited, but expanding with about 90 centers in the U.S. now providing CAR T-cell therapy.

Response rates with each of these therapies represent a paradigm shift in the relapsed/refractory ALL setting, Dr. Brown said.

Studies have shown complete remission (CR) and minimum residual disease (MRD)-negative CR rates of 81% and 78%, respectively, with inotuzumab, and 43% and 33%, respectively, with blinatumomab.

“This depth of remission was really not seen with prior salvage therapies,” he noted, but added that neither has shown significant durable improvement in overall survival (OS) rates.

CAR T-cell therapy, however, has the highest response rates, with tisagenlecleucel – which targets CD19 and was the first CAR T-cell therapy approved for refractory or second or greater relapse in patients up to age 26 years – showing 81% CR and MRD-negative CR rates and providing a durable survival advantage without subsequent therapy in 40-50% of patients.

“So CAR T cells can represent definitive therapy in a subset of patients,” Dr. Brown said. “One thing we’re struggling with is to be able to predict which patients those are, and there are some emerging biomarkers that may help us with that, but as of now it’s very difficult to predict which patients, when you’re treating them, are going to be in [that group].”

Toxicities and limitations

Cytokine release syndrome and neurotoxicity are the primary toxicities associated with both blinatumomab and tisagenlecleucel. Hepatotoxicity is a major concern with inotuzumab.

“This is particularly important because that hepatotoxicity appears to be primarily a problem in patients who receive inotuzumab either after or prior to hematopoietic stem cell transplant, and since this therapy does not represent definitive therapy and often is really a bridge to transplant, this ... can be a significant limitation to this product,” Dr. Brown said.

A limitation of CAR T cells is failure to manufacture the product, which occurs most often in very young and heavily pretreated patients in whom it can be difficult to obtain enough functional T cells to create the product. Failure to engraft or lack of persistence of the CAR T cells can also occur.

Endogenous or CAR T-cell exhaustion is another potential limitation with blinatumomab and CAR T-cell therapy, and antigen escape can occur with both therapies, as well.

Strategies are being investigated to overcome treatment challenges, Dr. Brown noted.

Examples include efforts to develop universal “off-the-shelf” allogeneic CAR T-cell products to address failure to manufacture, working on more co-stimulatory domains that may be more effective to promote engraftment and persistence, adding immune checkpoint inhibitors to therapy to combat endogenous or CAR T-cell exhaustion, and developing multi-antigen targeted approaches to overcome antigen escape, he said.
 

NCCN Treatment Guidelines

Based on the currently available data, the NCCN has included these immunotherapies in guidelines for both adolescent and young adult (AYA)/adult ALL and for pediatric ALL.

Each of the treatments is listed as an option to consider in both Philadelphia chromosome-positive and -negative AYA and adult patients under age 65 years. Additionally, blinatumomab is listed as an option for up-front treatment of MRD-positive Philadelphia chromosome-negative AYA patients and older patients.

Pediatric guidelines include blinatumomab and tisagenlecleucel as options for patients with MRD-positive disease after induction and for first relapse, and they include all three therapies as options in patients with multiple relapses or refractory disease, said Dr. Brown who chairs the NCCN Clinical Practice Guidelines panel for adult and pediatric ALL.
 

Treatment decision making

Asked by session moderator Ranjana H. Advani, MD, how to decide between the available immunotherapies, Dr. Brown said there is no one-size-fits-all answer.

“Is it availability, insurance coverage, the patient fits better with one therapy,” asked Dr. Advani, the Saul Rosenberg Professor of Lymphoma and the Physician Leader of the Lymphoma Clinical Care Program of Stanford Cancer Institute, Palo Alto, Calif.

“All of the above,” Dr. Brown said. “In 2020 with all these options available, we are a little bit spoiled for choice ... but every patient is an individual case and the risk -benefit ratios of all these therapies differ.”

An exception is that CAR T-cell therapy is a clear stand-out for the patient who isn’t transplant eligible, he noted, adding that CAR T cells “probably give that patient the best chance of survival.”

In a patient who could potentially go to transplant, selection is a bit more challenging, but given the risks associated with inotuzumab, blinatumomab is generally the preferred non-CAR T option, he said.

“It’s a complicated question, and the answer ... is [that it is] an individualized patient-by-patient decision,” he added.

Dr. Brown reported consulting, advisory board, or expert witness activity for Novartis Pharmaceuticals Corporation and Takeda Pharmaceuticals North America Inc.

[email protected]