CLL

The first report on responses to COVID-19 vaccination among patients with cancer suggests that, for these patients, the immune response that occurs after the first dose of vaccine is reduced, in comparison with the response that occurs in healthy individuals.

The new findings, which are soon to be published as a preprint, cast doubt on the current U.K. policy of delaying the second dose of the vaccine.

Delaying the second dose can leave most patients with cancer wholly or partially unprotected, according to the researchers. Moreover, such a delay has implications for transmission of SARS-CoV-2 in the cancer patient’s environs as well as for the evolution of virus variants that could be of concern, the researchers concluded.

The data come from a British study that included 151 patients with cancer and 54 healthy control persons. All participants received the COVID-19 mRNA BNT162b2 vaccine (Pfizer-BioNTech).

This vaccine requires two doses. The first few participants in this study were given the second dose 21 days after they had received the first dose, but then national guidelines changed, and the remaining participants had to wait 12 weeks to receive their second dose.

The researchers reported that, among health controls, the immune efficacy of the first dose was very high (97% efficacious). By contrast, among patients with solid tumors, the immune efficacy of a single dose was strikingly low (39%), and it was even lower in patients with hematologic malignancies (13%).

The second dose of vaccine greatly and rapidly increased the immune efficacy in patients with solid tumors (95% within 2 weeks of receiving the second dose), the researchers added.

Too few patients with hematologic cancers had received the second dose before the study ended for clear conclusions to be drawn. Nevertheless, the available data suggest that 50% of patients with hematologic cancers who had received the booster at day 21 were seropositive at 5 weeks vs. only 8% of those who had not received the booster.

“Our data provide the first real-world evidence of immune efficacy following one dose of the Pfizer vaccine in immunocompromised patient populations [and] clearly show that the poor one-dose efficacy in cancer patients can be rescued with an early booster at day 21,” commented senior author Sheeba Irshad, MD, senior clinical lecturer, King’s College London.

“Based on our findings, we would recommend an urgent review of the vaccine strategy for clinically extremely vulnerable groups. Until then, it is important that cancer patients continue to observe all public health measures in place, such as social distancing and shielding when attending hospitals, even after vaccination,” Dr. Irshad added.

The paper, with first author Leticia Monin-Aldama, PhD, is scheduled to appear on the preprint server medRxiv. It has not undergone peer review. The paper was distributed to journalists, with comments from experts not involved in the study, by the UK Science Media Centre.

These data are “of immediate importance” to patients with cancer, commented Shoba Amarnath, PhD, Newcastle University research fellow, Laboratory of T-cell Regulation, Newcastle University Center for Cancer, Newcastle upon Tyne, England.

“These findings are consistent with our understanding. … We know that the immune system within cancer patients is compromised as compared to healthy controls,” Dr. Amarnath said. “The data in the study support the notion that, in solid cancer patients, a considerable delay in second dose will extend the period when cancer patients are at risk of SARS-CoV-2 infection.”

Although more data are required, “this study does raise the issue of whether patients with cancer, other diseases, or those undergoing therapies that affect the body’s immune response should be fast-tracked for their second vaccine dose,” commented Lawrence Young, PhD, professor of molecular oncology and director of the Warwick Cancer Research Center, University of Warwick, Coventry, England.

Stephen Evans, MSc, professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, underlined that the study is “essentially” observational and “inevitable limitations must be taken into account.

“Nevertheless, these results do suggest that the vaccines may well not protect those patients with cancer as well as those without cancer,” Mr. Evans said. He added that it is “important that this population continues to observe all COVID-19–associated measures, such as social distancing and shielding when attending hospitals, even after vaccination.”

Study details

Previous studies have shown that some patients with cancer have prolonged responses to SARS-CoV-2 infection, with ongoing immune dysregulation, inefficient seroconversion, and prolonged viral shedding.

There are few data, however, on how these patients respond to COVID-19 vaccination. The authors point out that, among the 18,860 individuals who received the Pfizer vaccine during its development trials, “none with an active oncological diagnosis was included.”

To investigate this issue, they launched the SARS-CoV-2 for Cancer Patients (SOAP-02) study.

The 151 patients with cancer who participated in this study were mostly elderly, the authors noted (75% were older than 65 years; the median age was 73 years). The majority (63%) had solid-tumor malignancies. Of those, 8% had late-stage disease and had been living with their cancer for more than 24 months.

The healthy control persons were vaccine-eligible primary health care workers who were not age matched to the cancer patients.

All participants received the first dose of vaccine; 31 (of 151) patients with cancer and 16 (of 54) healthy control persons received the second dose on day 21.

The remaining participants were scheduled to receive their second dose 12 weeks later (after the study ended), in line with the changes in the national guidelines.

The team reported that, approximately 21 days after receiving the first vaccine dose, the immune efficacy of the vaccine was estimated to be 97% among healthy control persons vs. 39% for patients with solid tumors and only 13% for those with hematologic malignancies (P < .0001 for both).

T-cell responses, as assessed via interferon-gamma and/or interleukin-2 production, were observed in 82% of healthy control persons, 71% of patients with solid tumors, and 50% of those with hematologic cancers.

Vaccine boosting at day 21 resulted in immune efficacy of 100% for healthy control persons and 95% for patients with solid tumors. In contrast, only 43% of those who did not receive the second dose were seropositive 2 weeks later.

Further analysis suggested that participants who did not have a serologic response were “spread evenly” across different cancer types, but the reduced responses were more frequent among patients who had received the vaccine within 15 days of cancer treatment, especially chemotherapy, and had undergone intensive treatments.

The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas Trust Foundation NHS Trust. It is funded from grants from the KCL Charity, Cancer Research UK, and program grants from Breast Cancer Now. The investigators have disclosed no relevant financial relationships.

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

The first report on responses to COVID-19 vaccination among patients with cancer suggests that, for these patients, the immune response that occurs after the first dose of vaccine is reduced, in comparison with the response that occurs in healthy individuals.

The new findings, which are soon to be published as a preprint, cast doubt on the current U.K. policy of delaying the second dose of the vaccine.

Delaying the second dose can leave most patients with cancer wholly or partially unprotected, according to the researchers. Moreover, such a delay has implications for transmission of SARS-CoV-2 in the cancer patient’s environs as well as for the evolution of virus variants that could be of concern, the researchers concluded.

The data come from a British study that included 151 patients with cancer and 54 healthy control persons. All participants received the COVID-19 mRNA BNT162b2 vaccine (Pfizer-BioNTech).

This vaccine requires two doses. The first few participants in this study were given the second dose 21 days after they had received the first dose, but then national guidelines changed, and the remaining participants had to wait 12 weeks to receive their second dose.

The researchers reported that, among health controls, the immune efficacy of the first dose was very high (97% efficacious). By contrast, among patients with solid tumors, the immune efficacy of a single dose was strikingly low (39%), and it was even lower in patients with hematologic malignancies (13%).

The second dose of vaccine greatly and rapidly increased the immune efficacy in patients with solid tumors (95% within 2 weeks of receiving the second dose), the researchers added.

Too few patients with hematologic cancers had received the second dose before the study ended for clear conclusions to be drawn. Nevertheless, the available data suggest that 50% of patients with hematologic cancers who had received the booster at day 21 were seropositive at 5 weeks vs. only 8% of those who had not received the booster.

“Our data provide the first real-world evidence of immune efficacy following one dose of the Pfizer vaccine in immunocompromised patient populations [and] clearly show that the poor one-dose efficacy in cancer patients can be rescued with an early booster at day 21,” commented senior author Sheeba Irshad, MD, senior clinical lecturer, King’s College London.

“Based on our findings, we would recommend an urgent review of the vaccine strategy for clinically extremely vulnerable groups. Until then, it is important that cancer patients continue to observe all public health measures in place, such as social distancing and shielding when attending hospitals, even after vaccination,” Dr. Irshad added.

The paper, with first author Leticia Monin-Aldama, PhD, is scheduled to appear on the preprint server medRxiv. It has not undergone peer review. The paper was distributed to journalists, with comments from experts not involved in the study, by the UK Science Media Centre.

These data are “of immediate importance” to patients with cancer, commented Shoba Amarnath, PhD, Newcastle University research fellow, Laboratory of T-cell Regulation, Newcastle University Center for Cancer, Newcastle upon Tyne, England.

“These findings are consistent with our understanding. … We know that the immune system within cancer patients is compromised as compared to healthy controls,” Dr. Amarnath said. “The data in the study support the notion that, in solid cancer patients, a considerable delay in second dose will extend the period when cancer patients are at risk of SARS-CoV-2 infection.”

Although more data are required, “this study does raise the issue of whether patients with cancer, other diseases, or those undergoing therapies that affect the body’s immune response should be fast-tracked for their second vaccine dose,” commented Lawrence Young, PhD, professor of molecular oncology and director of the Warwick Cancer Research Center, University of Warwick, Coventry, England.

Stephen Evans, MSc, professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, underlined that the study is “essentially” observational and “inevitable limitations must be taken into account.

“Nevertheless, these results do suggest that the vaccines may well not protect those patients with cancer as well as those without cancer,” Mr. Evans said. He added that it is “important that this population continues to observe all COVID-19–associated measures, such as social distancing and shielding when attending hospitals, even after vaccination.”

Study details

Previous studies have shown that some patients with cancer have prolonged responses to SARS-CoV-2 infection, with ongoing immune dysregulation, inefficient seroconversion, and prolonged viral shedding.

There are few data, however, on how these patients respond to COVID-19 vaccination. The authors point out that, among the 18,860 individuals who received the Pfizer vaccine during its development trials, “none with an active oncological diagnosis was included.”

To investigate this issue, they launched the SARS-CoV-2 for Cancer Patients (SOAP-02) study.

The 151 patients with cancer who participated in this study were mostly elderly, the authors noted (75% were older than 65 years; the median age was 73 years). The majority (63%) had solid-tumor malignancies. Of those, 8% had late-stage disease and had been living with their cancer for more than 24 months.

The healthy control persons were vaccine-eligible primary health care workers who were not age matched to the cancer patients.

All participants received the first dose of vaccine; 31 (of 151) patients with cancer and 16 (of 54) healthy control persons received the second dose on day 21.

The remaining participants were scheduled to receive their second dose 12 weeks later (after the study ended), in line with the changes in the national guidelines.

The team reported that, approximately 21 days after receiving the first vaccine dose, the immune efficacy of the vaccine was estimated to be 97% among healthy control persons vs. 39% for patients with solid tumors and only 13% for those with hematologic malignancies (P < .0001 for both).

T-cell responses, as assessed via interferon-gamma and/or interleukin-2 production, were observed in 82% of healthy control persons, 71% of patients with solid tumors, and 50% of those with hematologic cancers.

Vaccine boosting at day 21 resulted in immune efficacy of 100% for healthy control persons and 95% for patients with solid tumors. In contrast, only 43% of those who did not receive the second dose were seropositive 2 weeks later.

Further analysis suggested that participants who did not have a serologic response were “spread evenly” across different cancer types, but the reduced responses were more frequent among patients who had received the vaccine within 15 days of cancer treatment, especially chemotherapy, and had undergone intensive treatments.

The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas Trust Foundation NHS Trust. It is funded from grants from the KCL Charity, Cancer Research UK, and program grants from Breast Cancer Now. The investigators have disclosed no relevant financial relationships.

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

The first report on responses to COVID-19 vaccination among patients with cancer suggests that, for these patients, the immune response that occurs after the first dose of vaccine is reduced, in comparison with the response that occurs in healthy individuals.

The new findings, which are soon to be published as a preprint, cast doubt on the current U.K. policy of delaying the second dose of the vaccine.

Delaying the second dose can leave most patients with cancer wholly or partially unprotected, according to the researchers. Moreover, such a delay has implications for transmission of SARS-CoV-2 in the cancer patient’s environs as well as for the evolution of virus variants that could be of concern, the researchers concluded.

The data come from a British study that included 151 patients with cancer and 54 healthy control persons. All participants received the COVID-19 mRNA BNT162b2 vaccine (Pfizer-BioNTech).

This vaccine requires two doses. The first few participants in this study were given the second dose 21 days after they had received the first dose, but then national guidelines changed, and the remaining participants had to wait 12 weeks to receive their second dose.

The researchers reported that, among health controls, the immune efficacy of the first dose was very high (97% efficacious). By contrast, among patients with solid tumors, the immune efficacy of a single dose was strikingly low (39%), and it was even lower in patients with hematologic malignancies (13%).

The second dose of vaccine greatly and rapidly increased the immune efficacy in patients with solid tumors (95% within 2 weeks of receiving the second dose), the researchers added.

Too few patients with hematologic cancers had received the second dose before the study ended for clear conclusions to be drawn. Nevertheless, the available data suggest that 50% of patients with hematologic cancers who had received the booster at day 21 were seropositive at 5 weeks vs. only 8% of those who had not received the booster.

“Our data provide the first real-world evidence of immune efficacy following one dose of the Pfizer vaccine in immunocompromised patient populations [and] clearly show that the poor one-dose efficacy in cancer patients can be rescued with an early booster at day 21,” commented senior author Sheeba Irshad, MD, senior clinical lecturer, King’s College London.

“Based on our findings, we would recommend an urgent review of the vaccine strategy for clinically extremely vulnerable groups. Until then, it is important that cancer patients continue to observe all public health measures in place, such as social distancing and shielding when attending hospitals, even after vaccination,” Dr. Irshad added.

The paper, with first author Leticia Monin-Aldama, PhD, is scheduled to appear on the preprint server medRxiv. It has not undergone peer review. The paper was distributed to journalists, with comments from experts not involved in the study, by the UK Science Media Centre.

These data are “of immediate importance” to patients with cancer, commented Shoba Amarnath, PhD, Newcastle University research fellow, Laboratory of T-cell Regulation, Newcastle University Center for Cancer, Newcastle upon Tyne, England.

“These findings are consistent with our understanding. … We know that the immune system within cancer patients is compromised as compared to healthy controls,” Dr. Amarnath said. “The data in the study support the notion that, in solid cancer patients, a considerable delay in second dose will extend the period when cancer patients are at risk of SARS-CoV-2 infection.”

Although more data are required, “this study does raise the issue of whether patients with cancer, other diseases, or those undergoing therapies that affect the body’s immune response should be fast-tracked for their second vaccine dose,” commented Lawrence Young, PhD, professor of molecular oncology and director of the Warwick Cancer Research Center, University of Warwick, Coventry, England.

Stephen Evans, MSc, professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, underlined that the study is “essentially” observational and “inevitable limitations must be taken into account.

“Nevertheless, these results do suggest that the vaccines may well not protect those patients with cancer as well as those without cancer,” Mr. Evans said. He added that it is “important that this population continues to observe all COVID-19–associated measures, such as social distancing and shielding when attending hospitals, even after vaccination.”

Study details

Previous studies have shown that some patients with cancer have prolonged responses to SARS-CoV-2 infection, with ongoing immune dysregulation, inefficient seroconversion, and prolonged viral shedding.

There are few data, however, on how these patients respond to COVID-19 vaccination. The authors point out that, among the 18,860 individuals who received the Pfizer vaccine during its development trials, “none with an active oncological diagnosis was included.”

To investigate this issue, they launched the SARS-CoV-2 for Cancer Patients (SOAP-02) study.

The 151 patients with cancer who participated in this study were mostly elderly, the authors noted (75% were older than 65 years; the median age was 73 years). The majority (63%) had solid-tumor malignancies. Of those, 8% had late-stage disease and had been living with their cancer for more than 24 months.

The healthy control persons were vaccine-eligible primary health care workers who were not age matched to the cancer patients.

All participants received the first dose of vaccine; 31 (of 151) patients with cancer and 16 (of 54) healthy control persons received the second dose on day 21.

The remaining participants were scheduled to receive their second dose 12 weeks later (after the study ended), in line with the changes in the national guidelines.

The team reported that, approximately 21 days after receiving the first vaccine dose, the immune efficacy of the vaccine was estimated to be 97% among healthy control persons vs. 39% for patients with solid tumors and only 13% for those with hematologic malignancies (P < .0001 for both).

T-cell responses, as assessed via interferon-gamma and/or interleukin-2 production, were observed in 82% of healthy control persons, 71% of patients with solid tumors, and 50% of those with hematologic cancers.

Vaccine boosting at day 21 resulted in immune efficacy of 100% for healthy control persons and 95% for patients with solid tumors. In contrast, only 43% of those who did not receive the second dose were seropositive 2 weeks later.

Further analysis suggested that participants who did not have a serologic response were “spread evenly” across different cancer types, but the reduced responses were more frequent among patients who had received the vaccine within 15 days of cancer treatment, especially chemotherapy, and had undergone intensive treatments.

The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas Trust Foundation NHS Trust. It is funded from grants from the KCL Charity, Cancer Research UK, and program grants from Breast Cancer Now. The investigators have disclosed no relevant financial relationships.

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

Pirtobrutinib treatment yielded promising outcomes in chronic lymphocytic leukemia (CLL) and other patients with B-cell malignancies who discontinued prior Bruton’s tyrosine kinase (BTK)–inhibitor treatment due to resistance or intolerance, according to the results of the BRUIN trial, a phase 1/2 study.

Pirtobrutinib (formerly known as LOXO-305) is an oral-dose, highly selective, reversible BTK inhibitor, which might address a growing, unmet need for alternative therapies in BTK-inhibitor treatment failure patients, according to Anthony R. Mato, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues. Their report was published in The Lancet.

The study included 109 women (34%) and 214 men (66%), with a median age of 68 years, who were treated with pirtobrutinib. Of these, 203 patients were assigned to pirtobrutinib (25-300 mg once per day) in the phase 1 portion of the study, and 120 patients were assigned to pirtobrutinib (200 mg once per day) in phase 2.
 

Promising outcomes

Pirtobrutinib, showed promising efficacy and tolerable safety in patients with CLL or small lymphocytic lymphoma, mantle cell lymphoma, and Waldenström macroglobulinemia who were previously treated with a BTK inhibitor. In 121 efficacy-evaluable patients with CLL or SLL treated with a previous covalent BTK inhibitor, the overall response rate with pirtobrutinib was 62% (95% confidence interval, 53-71). The ORR was similar in CLL patients with previous covalent BTK inhibitor resistance (67%), covalent BTK inhibitor intolerance (52%), BTK C481-mutant (71%), and BTK wild-type (66%) disease.

In 52 efficacy-evaluable patients with mantle cell lymphoma (MCL) previously treated with covalent BTK inhibitors, the ORR was 52% (95% CI, 38-66). Of 117 patients with CLL, SLL, or MCL who responded, all but 8 remain progression free to date, the authors stated.

In 19 efficacy-evaluable patients with Waldenström macroglobulinemia, the ORR was 68%. Among eight patients with follicular lymphoma who were efficacy evaluable, responses were observed in four (50%) patients, and six (75%) of eight efficacy evaluable patients with Richter’s transformation identified before enrollment responded to treatment, the authors stated.

No dose-limiting toxicities were observed and the maximum tolerated dose was not reached, according to the researchers. The recommended phase 2 dose was 200 mg daily. The adverse events, which occurred in at least 10% of 323 patients, were fatigue (20%), diarrhea (17%), and contusion (13%). The most common grade 3 or higher adverse event was neutropenia (10%). Five patients (1%) discontinued treatment because of a treatment-related adverse event.

In this “first-in-human trial of pirtobrutinib, we showed promising efficacy and safety in patients with B-cell malignancies, including CLL or SLL, MCL, Waldenström macroglobulinemia, and follicular lymphoma. Activity was observed in heavily pretreated patients, including patients with resistance and intolerance to previous covalent BTK inhibitor treatment. Global randomized phase 3 studies in CLL or SLL, and MCL are planned,” the researchers concluded.
 

Birth of a third generation?

“The pirtobrutinib study, by opening the way for a third generation of BTK inhibitors, could improve such a personalized molecular approach in the treatment of B-cell malignancies,” according to accompanying editorial comment by Jean-Marie Michot, MD, and Vincent Ribrag, MD, both of the Institut de Cancérologie Gustave Roussy, Villejuif, France.

They discussed how BTK inhibitors have been a considerable therapeutic advance in the treatment of NHL-B and CLL and how the three currently approved BTK inhibitors, namely ibrutinib, acalabrutinib, and zanubrutinib, are all covalent and irreversible inhibitors at the protein – the C481 binding site. “Ibrutinib was the first approved drug. The second-generation inhibitors, acalabrutinib and zanubrutinib, were designed to be more BTK selective,” they added. However, the covalency and irreversibility of the drugs, considered therapeutic strengths, have resulted in induced resistance mutations occurring at the covalent binding, rendering the drugs inactive. “Two advantages of this new drug class are highlighted. First, the selectivity of the drug on BTK appears to be increased,” they wrote. “Second, this class does not bind BTK to the C481 residue, and the efficacy of the drug is therefore not affected by mutations in the BTK binding site.”

Several of the study authors reported receiving grants and personal fees from Loxo Oncology (a wholly owned subsidiary of Eli Lilly), which sponsored the study, as well as financial relationships with other pharmaceutical and biotechnology companies.

Dr. Michot and Dr. Ribrag reported that they had no disclosures relevant to the discussion.

[email protected]

Pirtobrutinib treatment yielded promising outcomes in chronic lymphocytic leukemia (CLL) and other patients with B-cell malignancies who discontinued prior Bruton’s tyrosine kinase (BTK)–inhibitor treatment due to resistance or intolerance, according to the results of the BRUIN trial, a phase 1/2 study.

Pirtobrutinib (formerly known as LOXO-305) is an oral-dose, highly selective, reversible BTK inhibitor, which might address a growing, unmet need for alternative therapies in BTK-inhibitor treatment failure patients, according to Anthony R. Mato, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues. Their report was published in The Lancet.

The study included 109 women (34%) and 214 men (66%), with a median age of 68 years, who were treated with pirtobrutinib. Of these, 203 patients were assigned to pirtobrutinib (25-300 mg once per day) in the phase 1 portion of the study, and 120 patients were assigned to pirtobrutinib (200 mg once per day) in phase 2.
 

Promising outcomes

Pirtobrutinib, showed promising efficacy and tolerable safety in patients with CLL or small lymphocytic lymphoma, mantle cell lymphoma, and Waldenström macroglobulinemia who were previously treated with a BTK inhibitor. In 121 efficacy-evaluable patients with CLL or SLL treated with a previous covalent BTK inhibitor, the overall response rate with pirtobrutinib was 62% (95% confidence interval, 53-71). The ORR was similar in CLL patients with previous covalent BTK inhibitor resistance (67%), covalent BTK inhibitor intolerance (52%), BTK C481-mutant (71%), and BTK wild-type (66%) disease.

In 52 efficacy-evaluable patients with mantle cell lymphoma (MCL) previously treated with covalent BTK inhibitors, the ORR was 52% (95% CI, 38-66). Of 117 patients with CLL, SLL, or MCL who responded, all but 8 remain progression free to date, the authors stated.

In 19 efficacy-evaluable patients with Waldenström macroglobulinemia, the ORR was 68%. Among eight patients with follicular lymphoma who were efficacy evaluable, responses were observed in four (50%) patients, and six (75%) of eight efficacy evaluable patients with Richter’s transformation identified before enrollment responded to treatment, the authors stated.

No dose-limiting toxicities were observed and the maximum tolerated dose was not reached, according to the researchers. The recommended phase 2 dose was 200 mg daily. The adverse events, which occurred in at least 10% of 323 patients, were fatigue (20%), diarrhea (17%), and contusion (13%). The most common grade 3 or higher adverse event was neutropenia (10%). Five patients (1%) discontinued treatment because of a treatment-related adverse event.

In this “first-in-human trial of pirtobrutinib, we showed promising efficacy and safety in patients with B-cell malignancies, including CLL or SLL, MCL, Waldenström macroglobulinemia, and follicular lymphoma. Activity was observed in heavily pretreated patients, including patients with resistance and intolerance to previous covalent BTK inhibitor treatment. Global randomized phase 3 studies in CLL or SLL, and MCL are planned,” the researchers concluded.
 

Birth of a third generation?

“The pirtobrutinib study, by opening the way for a third generation of BTK inhibitors, could improve such a personalized molecular approach in the treatment of B-cell malignancies,” according to accompanying editorial comment by Jean-Marie Michot, MD, and Vincent Ribrag, MD, both of the Institut de Cancérologie Gustave Roussy, Villejuif, France.

They discussed how BTK inhibitors have been a considerable therapeutic advance in the treatment of NHL-B and CLL and how the three currently approved BTK inhibitors, namely ibrutinib, acalabrutinib, and zanubrutinib, are all covalent and irreversible inhibitors at the protein – the C481 binding site. “Ibrutinib was the first approved drug. The second-generation inhibitors, acalabrutinib and zanubrutinib, were designed to be more BTK selective,” they added. However, the covalency and irreversibility of the drugs, considered therapeutic strengths, have resulted in induced resistance mutations occurring at the covalent binding, rendering the drugs inactive. “Two advantages of this new drug class are highlighted. First, the selectivity of the drug on BTK appears to be increased,” they wrote. “Second, this class does not bind BTK to the C481 residue, and the efficacy of the drug is therefore not affected by mutations in the BTK binding site.”

Several of the study authors reported receiving grants and personal fees from Loxo Oncology (a wholly owned subsidiary of Eli Lilly), which sponsored the study, as well as financial relationships with other pharmaceutical and biotechnology companies.

Dr. Michot and Dr. Ribrag reported that they had no disclosures relevant to the discussion.

[email protected]

Pirtobrutinib treatment yielded promising outcomes in chronic lymphocytic leukemia (CLL) and other patients with B-cell malignancies who discontinued prior Bruton’s tyrosine kinase (BTK)–inhibitor treatment due to resistance or intolerance, according to the results of the BRUIN trial, a phase 1/2 study.

Pirtobrutinib (formerly known as LOXO-305) is an oral-dose, highly selective, reversible BTK inhibitor, which might address a growing, unmet need for alternative therapies in BTK-inhibitor treatment failure patients, according to Anthony R. Mato, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues. Their report was published in The Lancet.

The study included 109 women (34%) and 214 men (66%), with a median age of 68 years, who were treated with pirtobrutinib. Of these, 203 patients were assigned to pirtobrutinib (25-300 mg once per day) in the phase 1 portion of the study, and 120 patients were assigned to pirtobrutinib (200 mg once per day) in phase 2.
 

Promising outcomes

Pirtobrutinib, showed promising efficacy and tolerable safety in patients with CLL or small lymphocytic lymphoma, mantle cell lymphoma, and Waldenström macroglobulinemia who were previously treated with a BTK inhibitor. In 121 efficacy-evaluable patients with CLL or SLL treated with a previous covalent BTK inhibitor, the overall response rate with pirtobrutinib was 62% (95% confidence interval, 53-71). The ORR was similar in CLL patients with previous covalent BTK inhibitor resistance (67%), covalent BTK inhibitor intolerance (52%), BTK C481-mutant (71%), and BTK wild-type (66%) disease.

In 52 efficacy-evaluable patients with mantle cell lymphoma (MCL) previously treated with covalent BTK inhibitors, the ORR was 52% (95% CI, 38-66). Of 117 patients with CLL, SLL, or MCL who responded, all but 8 remain progression free to date, the authors stated.

In 19 efficacy-evaluable patients with Waldenström macroglobulinemia, the ORR was 68%. Among eight patients with follicular lymphoma who were efficacy evaluable, responses were observed in four (50%) patients, and six (75%) of eight efficacy evaluable patients with Richter’s transformation identified before enrollment responded to treatment, the authors stated.

No dose-limiting toxicities were observed and the maximum tolerated dose was not reached, according to the researchers. The recommended phase 2 dose was 200 mg daily. The adverse events, which occurred in at least 10% of 323 patients, were fatigue (20%), diarrhea (17%), and contusion (13%). The most common grade 3 or higher adverse event was neutropenia (10%). Five patients (1%) discontinued treatment because of a treatment-related adverse event.

In this “first-in-human trial of pirtobrutinib, we showed promising efficacy and safety in patients with B-cell malignancies, including CLL or SLL, MCL, Waldenström macroglobulinemia, and follicular lymphoma. Activity was observed in heavily pretreated patients, including patients with resistance and intolerance to previous covalent BTK inhibitor treatment. Global randomized phase 3 studies in CLL or SLL, and MCL are planned,” the researchers concluded.
 

Birth of a third generation?

“The pirtobrutinib study, by opening the way for a third generation of BTK inhibitors, could improve such a personalized molecular approach in the treatment of B-cell malignancies,” according to accompanying editorial comment by Jean-Marie Michot, MD, and Vincent Ribrag, MD, both of the Institut de Cancérologie Gustave Roussy, Villejuif, France.

They discussed how BTK inhibitors have been a considerable therapeutic advance in the treatment of NHL-B and CLL and how the three currently approved BTK inhibitors, namely ibrutinib, acalabrutinib, and zanubrutinib, are all covalent and irreversible inhibitors at the protein – the C481 binding site. “Ibrutinib was the first approved drug. The second-generation inhibitors, acalabrutinib and zanubrutinib, were designed to be more BTK selective,” they added. However, the covalency and irreversibility of the drugs, considered therapeutic strengths, have resulted in induced resistance mutations occurring at the covalent binding, rendering the drugs inactive. “Two advantages of this new drug class are highlighted. First, the selectivity of the drug on BTK appears to be increased,” they wrote. “Second, this class does not bind BTK to the C481 residue, and the efficacy of the drug is therefore not affected by mutations in the BTK binding site.”

Several of the study authors reported receiving grants and personal fees from Loxo Oncology (a wholly owned subsidiary of Eli Lilly), which sponsored the study, as well as financial relationships with other pharmaceutical and biotechnology companies.

Dr. Michot and Dr. Ribrag reported that they had no disclosures relevant to the discussion.

[email protected]

Immunogenicity of the high-dose influenza vaccine (HD IIV3) in patients with chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL, the precursor state to CLL) was found lower than reported in healthy adults according to a report in Vaccine.

In addition, immunogenicity to influenza B was found to be greater in those patients with MBL, compared with those with CLL.

“Acute and chronic leukemia patients hospitalized with influenza infection document a case fatality rate of 25%-37%,” according to Jennifer A. Whitaker, MD, of the Mayo Clinic, Rochester, Minn., and colleagues in pointing out the importance of their study.

The prospective pilot study assessed the humoral immune responses of patients to the 2013-2014 and 2014-2015 HD IIV3 (Fluzone High-Dose; Sanofi Pasteur), which was administered as part of routine clinical care in 30 patients (17 with previously untreated CLL and 13 with MBL). The median patient age was 69.5 years.

The primary outcomes were seroconversion and seroprotection, as measured by hemagglutination inhibition assay (HAI).
 

Lower response rate

At day 28 post vaccination, the seroprotection rates for the overall cohort were 19/30 (63.3%) for A/H1N1, 21/23 (91.3%) for A/H3N2, and 13/30 (43.3%) for influenza B. Patients with MBL achieved significantly higher day 28 HAI geometric mean titers (GMT), compared with CLL patients (54.1 vs. 12.1]; P = .01), In addition, MBL patients achieved higher day 28 seroprotection rates against the influenza B vaccine strain virus than did those with CLL (76.9% vs. 17.6%; P = .002). Seroconversion rates for the overall cohort were 3/30 (10%) for A/H1N1; 5/23 (21.7%) for A/H3N2; and 3/30 (10%) for influenza B. No individual with CLL demonstrated seroconversion for influenza B, according to the researchers.

“Our studies reinforce rigorous adherence to vaccination strategies in patients with hematologic malignancy, including those with CLL, given the increased risk of serious complications among those experiencing influenza infection,” the authors stated.

“Even suboptimal responses to influenza vaccination can provide partial protection, reduce hospitalization rates, and/or prevent serious disease complications. Given the recent major issue with novel and aggressive viruses such COVID-19, we absolutely must continue with larger prospective studies to confirm these findings and evaluate vaccine effectiveness in preventing influenza or other novel viruses in these populations,” the researchers concluded.

This study was funded by the National Institutes of Health. Dr. Whitaker reported having no disclosures. Several of the coauthors reported financial relationships with a variety of pharmaceutical and biotechnology companies.

[email protected]

Immunogenicity of the high-dose influenza vaccine (HD IIV3) in patients with chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL, the precursor state to CLL) was found lower than reported in healthy adults according to a report in Vaccine.

In addition, immunogenicity to influenza B was found to be greater in those patients with MBL, compared with those with CLL.

“Acute and chronic leukemia patients hospitalized with influenza infection document a case fatality rate of 25%-37%,” according to Jennifer A. Whitaker, MD, of the Mayo Clinic, Rochester, Minn., and colleagues in pointing out the importance of their study.

The prospective pilot study assessed the humoral immune responses of patients to the 2013-2014 and 2014-2015 HD IIV3 (Fluzone High-Dose; Sanofi Pasteur), which was administered as part of routine clinical care in 30 patients (17 with previously untreated CLL and 13 with MBL). The median patient age was 69.5 years.

The primary outcomes were seroconversion and seroprotection, as measured by hemagglutination inhibition assay (HAI).
 

Lower response rate

At day 28 post vaccination, the seroprotection rates for the overall cohort were 19/30 (63.3%) for A/H1N1, 21/23 (91.3%) for A/H3N2, and 13/30 (43.3%) for influenza B. Patients with MBL achieved significantly higher day 28 HAI geometric mean titers (GMT), compared with CLL patients (54.1 vs. 12.1]; P = .01), In addition, MBL patients achieved higher day 28 seroprotection rates against the influenza B vaccine strain virus than did those with CLL (76.9% vs. 17.6%; P = .002). Seroconversion rates for the overall cohort were 3/30 (10%) for A/H1N1; 5/23 (21.7%) for A/H3N2; and 3/30 (10%) for influenza B. No individual with CLL demonstrated seroconversion for influenza B, according to the researchers.

“Our studies reinforce rigorous adherence to vaccination strategies in patients with hematologic malignancy, including those with CLL, given the increased risk of serious complications among those experiencing influenza infection,” the authors stated.

“Even suboptimal responses to influenza vaccination can provide partial protection, reduce hospitalization rates, and/or prevent serious disease complications. Given the recent major issue with novel and aggressive viruses such COVID-19, we absolutely must continue with larger prospective studies to confirm these findings and evaluate vaccine effectiveness in preventing influenza or other novel viruses in these populations,” the researchers concluded.

This study was funded by the National Institutes of Health. Dr. Whitaker reported having no disclosures. Several of the coauthors reported financial relationships with a variety of pharmaceutical and biotechnology companies.

[email protected]

Immunogenicity of the high-dose influenza vaccine (HD IIV3) in patients with chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL, the precursor state to CLL) was found lower than reported in healthy adults according to a report in Vaccine.

In addition, immunogenicity to influenza B was found to be greater in those patients with MBL, compared with those with CLL.

“Acute and chronic leukemia patients hospitalized with influenza infection document a case fatality rate of 25%-37%,” according to Jennifer A. Whitaker, MD, of the Mayo Clinic, Rochester, Minn., and colleagues in pointing out the importance of their study.

The prospective pilot study assessed the humoral immune responses of patients to the 2013-2014 and 2014-2015 HD IIV3 (Fluzone High-Dose; Sanofi Pasteur), which was administered as part of routine clinical care in 30 patients (17 with previously untreated CLL and 13 with MBL). The median patient age was 69.5 years.

The primary outcomes were seroconversion and seroprotection, as measured by hemagglutination inhibition assay (HAI).
 

Lower response rate

At day 28 post vaccination, the seroprotection rates for the overall cohort were 19/30 (63.3%) for A/H1N1, 21/23 (91.3%) for A/H3N2, and 13/30 (43.3%) for influenza B. Patients with MBL achieved significantly higher day 28 HAI geometric mean titers (GMT), compared with CLL patients (54.1 vs. 12.1]; P = .01), In addition, MBL patients achieved higher day 28 seroprotection rates against the influenza B vaccine strain virus than did those with CLL (76.9% vs. 17.6%; P = .002). Seroconversion rates for the overall cohort were 3/30 (10%) for A/H1N1; 5/23 (21.7%) for A/H3N2; and 3/30 (10%) for influenza B. No individual with CLL demonstrated seroconversion for influenza B, according to the researchers.

“Our studies reinforce rigorous adherence to vaccination strategies in patients with hematologic malignancy, including those with CLL, given the increased risk of serious complications among those experiencing influenza infection,” the authors stated.

“Even suboptimal responses to influenza vaccination can provide partial protection, reduce hospitalization rates, and/or prevent serious disease complications. Given the recent major issue with novel and aggressive viruses such COVID-19, we absolutely must continue with larger prospective studies to confirm these findings and evaluate vaccine effectiveness in preventing influenza or other novel viruses in these populations,” the researchers concluded.

This study was funded by the National Institutes of Health. Dr. Whitaker reported having no disclosures. Several of the coauthors reported financial relationships with a variety of pharmaceutical and biotechnology companies.

[email protected]

COVID-19 has thrown a wrench in standard treatment protocols for patients with chronic lymphocytic leukemia (CLL). These patients already face a greater risk of dying from infections, and recent research suggests they tend to have risk factors that increase their likelihood of complications and death from COVID-19.

In August, a group of oncologists from the United States and Europe published a literature-informed expert opinion to help their colleagues navigate this new CLL treatment landscape. It offers a roadmap for balancing patients’ therapeutic needs against their risk for viral infection and outlines the safest course of action for patients who test positive for COVID-19.

Mazyar Shadman, MD, MPH, an associate professor in the Clinical Research Division of the Fred Hutchinson Cancer Research Center and the Division of Medical Oncology at the University of Washington School of Medicine, in Seattle, Washington, was contacted for comment to break down what clinicians need to know about treating CLL during the pandemic. This interview has been edited for length and clarity.
 

Question: What prompted you and colleagues from the United States and Europe to write these recommendations?

Dr. Shadman: When we began the collaboration earlier this year, our colleagues in Italy and the rest of Europe had more experience with COVID-19, so they led the effort. We wanted to help oncologists manage their patients with CLL during the pandemic based on the evidence we had at the time and the unknowns we faced.
 

What’s an example of how the available evidence informed your recommendations?

At the time, we didn’t know whether patients with CLL were more likely to get COVID-19, compared to the general population, but we did have evidence already that cancer increases patients’ risk of bad outcomes and death from COVID-19. CLL, for example, can increase risk factors for infection, including hypogammaglobulinemia, innate immune dysfunction, and neutropenia, which may be exacerbated by anticancer treatments. Patients’ existing immune suppression might prevent or delay their ability to react to or cope with the virus. And many patients with CLL have other conditions that increase their risk of a severe response to COVID-19, including older age (70% of CLL patients are older than 65 years), hypertension (21%), and diabetes (26%).

These factors informed our recommendations to limit patients’ exposure to COVID-19 by reducing or postponing the number of in-person visits and routine in-hospital follow-ups, especially if they could be substituted with virtual check-ins.
 

The expert opinion recommendations are divided into three main categories: patients who are newly diagnosed with CLL but have not begun receiving therapy, those already receiving therapy but are free of COVID-19, and those who test positive for COVID-19. Let’s start with the first category. What do the recommendations say about waiting versus proceeding for newly diagnosed patients?

Our priority was balancing the negative impacts of getting COVID-19 with the negative impacts of postponing cancer treatment. We suggested taking each new CLL case on a patient-by-patient basis to determine who needed treatment tomorrow and who could wait a few weeks or months. Fortunately, CLL rarely requires immediate therapy, so the preference was to postpone treatment a few weeks, depending on the local COVID-19 outbreak situation.

In my practice, for instance, we tried to postpone visits as much as we could. Before the pandemic, patients with CLL in the watch-and-wait phase – those diagnosed but who don’t require treatment immediately – would come in for bloodwork and exams every 3-6 months. But when the pandemic hit, we skipped 3-month visits for patients with stable lab results and switched to telehealth visits instead. For those who needed blood draws, we used local labs closer to the patient’s home to minimize their exposure and transportation requirements.

When treatment cannot be deferred, we’ve recommended starting patients on therapies that require fewer in-person visits and are less immune suppressive. We recommended oncologists consider Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib and acalabrutinib, as well as venetoclax. Some research suggests these inhibitors may be protective against COVID-19 by blunting a patient’s hyperinflammatory response to the virus. These drugs also require minimal routine treatment and lab visits, which helps limit patients’ potential exposure to COVID-19.

But there are risks to waiting. Even during the peak of the pandemic here in Seattle, if patients needed treatment immediately, we did not delay. Patients with significant drops in their platelet or neutrophil count or those with bulky disease, for instance, do require therapy.

It’s important to mention that we did have bad experiences with patients who needed immediate treatment and their treating physicians decided to wait because of COVID-19 risks. These patients who came in with aggressive CLL and experienced delays in care had much more complicated CLL treatment than if they had started treatment earlier.

When organ function became abnormal, for example, some patients could no longer receive certain therapies. If someone’s kidney function becomes abnormal, I wouldn’t recommend giving a drug like venetoclax. Although rare, some patients on venetoclax develop tumor lysis syndrome, which can lead to kidney failure.

Bottom line: Don’t just assume it’s a low-grade disease and that you can wait.



What about patients already receiving treatment for CLL who are free of COVID-19?

For patients on active treatment, we suggested stopping or holding treatment with monoclonal antibodies, such as rituximab and obinutuzumab, and chemotherapy regimens, such as idelalisib plus rituximab and duvelisib, when possible. We recommended oncologists consider continuing treatment for patients on BTK inhibitors.



What happens if a patient with CLL tests positive for COVID-19?

If a patient tests positive for COVID-19 but is not yet on CLL treatment, we recommend postponing CLL care until they’ve recovered from the infection. If a patient is already receiving treatment, the recommendations are similar to those above for COVID-19–negative patients: Delay care for those on chemotherapy and monoclonal antibodies, but consider continuing treatment for patients on BTK inhibitors.
 

The expert opinion was submitted in May and ultimately published in August. How has our understanding of treating CLL during the pandemic changed since then? Would you change any recommendations?

When we published this paper, it was still early on in the pandemic, and we didn’t know as much about COVID-19 and CLL as we do now. Since we published the recommendations, we have received confirmation from several studies that patients with cancer have a more complicated course of COVID-19 and have worse outcomes. But I believe the recommendations we devised early in the pandemic still hold now. Decisions about delivering treatment should be influenced by the local COVID-19 numbers and hospital resources as well as the patient’s specific situation – whether they have more stable disease and can delay or postpone care or whether they need more immediate attention.

With a further surge in cases predicted as we move even deeper into flu season, what would you recommend for initiating treatment in newly diagnosed patients?

The pandemic has created a very fluid situation for treating CLL. What’s happening now in Seattle may not be the same story in New York, California, or elsewhere. In early November [when Dr. Shadman was first contacted], in Seattle, we were not postponing care because our COVID-19 numbers were fairly good. But, as of mid December, that is starting to change as the COVID-19 numbers fluctuate.
 

If we do experience a second peak of COVID-19 cases, we would need to modify our practice as we did during the initial surge earlier this year. That would mean avoiding treatment with monoclonal antibodies and chemotherapy, as well as minimizing blood draws and drugs that require frequent in-person visits.
 

How important is it for patients to be vaccinated against COVID-19?

There are two key things to consider about a vaccine. Is the vaccine safe from the general safety standpoint that everyone is worried about? And if the vaccine is not harmful, will it work in patients will CLL?

Because we don’t yet know the complete side-effect profile of a COVID-19 vaccine, we would need to assess each patient’s condition to limit adverse reactions and to see whether the vaccine alters a patient’s immune response to the CLL drug they’re taking.

At the University of Washington, Seattle, we have a plan to start studying the effectiveness of the Pfizer and Moderna vaccines in patients with CLL – carefully assessing patients’ response to the vaccine in terms of antibody response. We already know, based on small studies, that the antibody response to the flu vaccine, for instance, is not as strong in patients with CLL, compared to those without. But, overall, as long as the vaccine won’t cause harm, I would recommend my patients get it.

Dr. Shadman has disclosed no relevant financial relationships.

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

COVID-19 has thrown a wrench in standard treatment protocols for patients with chronic lymphocytic leukemia (CLL). These patients already face a greater risk of dying from infections, and recent research suggests they tend to have risk factors that increase their likelihood of complications and death from COVID-19.

In August, a group of oncologists from the United States and Europe published a literature-informed expert opinion to help their colleagues navigate this new CLL treatment landscape. It offers a roadmap for balancing patients’ therapeutic needs against their risk for viral infection and outlines the safest course of action for patients who test positive for COVID-19.

Mazyar Shadman, MD, MPH, an associate professor in the Clinical Research Division of the Fred Hutchinson Cancer Research Center and the Division of Medical Oncology at the University of Washington School of Medicine, in Seattle, Washington, was contacted for comment to break down what clinicians need to know about treating CLL during the pandemic. This interview has been edited for length and clarity.
 

Question: What prompted you and colleagues from the United States and Europe to write these recommendations?

Dr. Shadman: When we began the collaboration earlier this year, our colleagues in Italy and the rest of Europe had more experience with COVID-19, so they led the effort. We wanted to help oncologists manage their patients with CLL during the pandemic based on the evidence we had at the time and the unknowns we faced.
 

What’s an example of how the available evidence informed your recommendations?

At the time, we didn’t know whether patients with CLL were more likely to get COVID-19, compared to the general population, but we did have evidence already that cancer increases patients’ risk of bad outcomes and death from COVID-19. CLL, for example, can increase risk factors for infection, including hypogammaglobulinemia, innate immune dysfunction, and neutropenia, which may be exacerbated by anticancer treatments. Patients’ existing immune suppression might prevent or delay their ability to react to or cope with the virus. And many patients with CLL have other conditions that increase their risk of a severe response to COVID-19, including older age (70% of CLL patients are older than 65 years), hypertension (21%), and diabetes (26%).

These factors informed our recommendations to limit patients’ exposure to COVID-19 by reducing or postponing the number of in-person visits and routine in-hospital follow-ups, especially if they could be substituted with virtual check-ins.
 

The expert opinion recommendations are divided into three main categories: patients who are newly diagnosed with CLL but have not begun receiving therapy, those already receiving therapy but are free of COVID-19, and those who test positive for COVID-19. Let’s start with the first category. What do the recommendations say about waiting versus proceeding for newly diagnosed patients?

Our priority was balancing the negative impacts of getting COVID-19 with the negative impacts of postponing cancer treatment. We suggested taking each new CLL case on a patient-by-patient basis to determine who needed treatment tomorrow and who could wait a few weeks or months. Fortunately, CLL rarely requires immediate therapy, so the preference was to postpone treatment a few weeks, depending on the local COVID-19 outbreak situation.

In my practice, for instance, we tried to postpone visits as much as we could. Before the pandemic, patients with CLL in the watch-and-wait phase – those diagnosed but who don’t require treatment immediately – would come in for bloodwork and exams every 3-6 months. But when the pandemic hit, we skipped 3-month visits for patients with stable lab results and switched to telehealth visits instead. For those who needed blood draws, we used local labs closer to the patient’s home to minimize their exposure and transportation requirements.

When treatment cannot be deferred, we’ve recommended starting patients on therapies that require fewer in-person visits and are less immune suppressive. We recommended oncologists consider Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib and acalabrutinib, as well as venetoclax. Some research suggests these inhibitors may be protective against COVID-19 by blunting a patient’s hyperinflammatory response to the virus. These drugs also require minimal routine treatment and lab visits, which helps limit patients’ potential exposure to COVID-19.

But there are risks to waiting. Even during the peak of the pandemic here in Seattle, if patients needed treatment immediately, we did not delay. Patients with significant drops in their platelet or neutrophil count or those with bulky disease, for instance, do require therapy.

It’s important to mention that we did have bad experiences with patients who needed immediate treatment and their treating physicians decided to wait because of COVID-19 risks. These patients who came in with aggressive CLL and experienced delays in care had much more complicated CLL treatment than if they had started treatment earlier.

When organ function became abnormal, for example, some patients could no longer receive certain therapies. If someone’s kidney function becomes abnormal, I wouldn’t recommend giving a drug like venetoclax. Although rare, some patients on venetoclax develop tumor lysis syndrome, which can lead to kidney failure.

Bottom line: Don’t just assume it’s a low-grade disease and that you can wait.



What about patients already receiving treatment for CLL who are free of COVID-19?

For patients on active treatment, we suggested stopping or holding treatment with monoclonal antibodies, such as rituximab and obinutuzumab, and chemotherapy regimens, such as idelalisib plus rituximab and duvelisib, when possible. We recommended oncologists consider continuing treatment for patients on BTK inhibitors.



What happens if a patient with CLL tests positive for COVID-19?

If a patient tests positive for COVID-19 but is not yet on CLL treatment, we recommend postponing CLL care until they’ve recovered from the infection. If a patient is already receiving treatment, the recommendations are similar to those above for COVID-19–negative patients: Delay care for those on chemotherapy and monoclonal antibodies, but consider continuing treatment for patients on BTK inhibitors.
 

The expert opinion was submitted in May and ultimately published in August. How has our understanding of treating CLL during the pandemic changed since then? Would you change any recommendations?

When we published this paper, it was still early on in the pandemic, and we didn’t know as much about COVID-19 and CLL as we do now. Since we published the recommendations, we have received confirmation from several studies that patients with cancer have a more complicated course of COVID-19 and have worse outcomes. But I believe the recommendations we devised early in the pandemic still hold now. Decisions about delivering treatment should be influenced by the local COVID-19 numbers and hospital resources as well as the patient’s specific situation – whether they have more stable disease and can delay or postpone care or whether they need more immediate attention.

With a further surge in cases predicted as we move even deeper into flu season, what would you recommend for initiating treatment in newly diagnosed patients?

The pandemic has created a very fluid situation for treating CLL. What’s happening now in Seattle may not be the same story in New York, California, or elsewhere. In early November [when Dr. Shadman was first contacted], in Seattle, we were not postponing care because our COVID-19 numbers were fairly good. But, as of mid December, that is starting to change as the COVID-19 numbers fluctuate.
 

If we do experience a second peak of COVID-19 cases, we would need to modify our practice as we did during the initial surge earlier this year. That would mean avoiding treatment with monoclonal antibodies and chemotherapy, as well as minimizing blood draws and drugs that require frequent in-person visits.
 

How important is it for patients to be vaccinated against COVID-19?

There are two key things to consider about a vaccine. Is the vaccine safe from the general safety standpoint that everyone is worried about? And if the vaccine is not harmful, will it work in patients will CLL?

Because we don’t yet know the complete side-effect profile of a COVID-19 vaccine, we would need to assess each patient’s condition to limit adverse reactions and to see whether the vaccine alters a patient’s immune response to the CLL drug they’re taking.

At the University of Washington, Seattle, we have a plan to start studying the effectiveness of the Pfizer and Moderna vaccines in patients with CLL – carefully assessing patients’ response to the vaccine in terms of antibody response. We already know, based on small studies, that the antibody response to the flu vaccine, for instance, is not as strong in patients with CLL, compared to those without. But, overall, as long as the vaccine won’t cause harm, I would recommend my patients get it.

Dr. Shadman has disclosed no relevant financial relationships.

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

COVID-19 has thrown a wrench in standard treatment protocols for patients with chronic lymphocytic leukemia (CLL). These patients already face a greater risk of dying from infections, and recent research suggests they tend to have risk factors that increase their likelihood of complications and death from COVID-19.

In August, a group of oncologists from the United States and Europe published a literature-informed expert opinion to help their colleagues navigate this new CLL treatment landscape. It offers a roadmap for balancing patients’ therapeutic needs against their risk for viral infection and outlines the safest course of action for patients who test positive for COVID-19.

Mazyar Shadman, MD, MPH, an associate professor in the Clinical Research Division of the Fred Hutchinson Cancer Research Center and the Division of Medical Oncology at the University of Washington School of Medicine, in Seattle, Washington, was contacted for comment to break down what clinicians need to know about treating CLL during the pandemic. This interview has been edited for length and clarity.
 

Question: What prompted you and colleagues from the United States and Europe to write these recommendations?

Dr. Shadman: When we began the collaboration earlier this year, our colleagues in Italy and the rest of Europe had more experience with COVID-19, so they led the effort. We wanted to help oncologists manage their patients with CLL during the pandemic based on the evidence we had at the time and the unknowns we faced.
 

What’s an example of how the available evidence informed your recommendations?

At the time, we didn’t know whether patients with CLL were more likely to get COVID-19, compared to the general population, but we did have evidence already that cancer increases patients’ risk of bad outcomes and death from COVID-19. CLL, for example, can increase risk factors for infection, including hypogammaglobulinemia, innate immune dysfunction, and neutropenia, which may be exacerbated by anticancer treatments. Patients’ existing immune suppression might prevent or delay their ability to react to or cope with the virus. And many patients with CLL have other conditions that increase their risk of a severe response to COVID-19, including older age (70% of CLL patients are older than 65 years), hypertension (21%), and diabetes (26%).

These factors informed our recommendations to limit patients’ exposure to COVID-19 by reducing or postponing the number of in-person visits and routine in-hospital follow-ups, especially if they could be substituted with virtual check-ins.
 

The expert opinion recommendations are divided into three main categories: patients who are newly diagnosed with CLL but have not begun receiving therapy, those already receiving therapy but are free of COVID-19, and those who test positive for COVID-19. Let’s start with the first category. What do the recommendations say about waiting versus proceeding for newly diagnosed patients?

Our priority was balancing the negative impacts of getting COVID-19 with the negative impacts of postponing cancer treatment. We suggested taking each new CLL case on a patient-by-patient basis to determine who needed treatment tomorrow and who could wait a few weeks or months. Fortunately, CLL rarely requires immediate therapy, so the preference was to postpone treatment a few weeks, depending on the local COVID-19 outbreak situation.

In my practice, for instance, we tried to postpone visits as much as we could. Before the pandemic, patients with CLL in the watch-and-wait phase – those diagnosed but who don’t require treatment immediately – would come in for bloodwork and exams every 3-6 months. But when the pandemic hit, we skipped 3-month visits for patients with stable lab results and switched to telehealth visits instead. For those who needed blood draws, we used local labs closer to the patient’s home to minimize their exposure and transportation requirements.

When treatment cannot be deferred, we’ve recommended starting patients on therapies that require fewer in-person visits and are less immune suppressive. We recommended oncologists consider Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib and acalabrutinib, as well as venetoclax. Some research suggests these inhibitors may be protective against COVID-19 by blunting a patient’s hyperinflammatory response to the virus. These drugs also require minimal routine treatment and lab visits, which helps limit patients’ potential exposure to COVID-19.

But there are risks to waiting. Even during the peak of the pandemic here in Seattle, if patients needed treatment immediately, we did not delay. Patients with significant drops in their platelet or neutrophil count or those with bulky disease, for instance, do require therapy.

It’s important to mention that we did have bad experiences with patients who needed immediate treatment and their treating physicians decided to wait because of COVID-19 risks. These patients who came in with aggressive CLL and experienced delays in care had much more complicated CLL treatment than if they had started treatment earlier.

When organ function became abnormal, for example, some patients could no longer receive certain therapies. If someone’s kidney function becomes abnormal, I wouldn’t recommend giving a drug like venetoclax. Although rare, some patients on venetoclax develop tumor lysis syndrome, which can lead to kidney failure.

Bottom line: Don’t just assume it’s a low-grade disease and that you can wait.



What about patients already receiving treatment for CLL who are free of COVID-19?

For patients on active treatment, we suggested stopping or holding treatment with monoclonal antibodies, such as rituximab and obinutuzumab, and chemotherapy regimens, such as idelalisib plus rituximab and duvelisib, when possible. We recommended oncologists consider continuing treatment for patients on BTK inhibitors.



What happens if a patient with CLL tests positive for COVID-19?

If a patient tests positive for COVID-19 but is not yet on CLL treatment, we recommend postponing CLL care until they’ve recovered from the infection. If a patient is already receiving treatment, the recommendations are similar to those above for COVID-19–negative patients: Delay care for those on chemotherapy and monoclonal antibodies, but consider continuing treatment for patients on BTK inhibitors.
 

The expert opinion was submitted in May and ultimately published in August. How has our understanding of treating CLL during the pandemic changed since then? Would you change any recommendations?

When we published this paper, it was still early on in the pandemic, and we didn’t know as much about COVID-19 and CLL as we do now. Since we published the recommendations, we have received confirmation from several studies that patients with cancer have a more complicated course of COVID-19 and have worse outcomes. But I believe the recommendations we devised early in the pandemic still hold now. Decisions about delivering treatment should be influenced by the local COVID-19 numbers and hospital resources as well as the patient’s specific situation – whether they have more stable disease and can delay or postpone care or whether they need more immediate attention.

With a further surge in cases predicted as we move even deeper into flu season, what would you recommend for initiating treatment in newly diagnosed patients?

The pandemic has created a very fluid situation for treating CLL. What’s happening now in Seattle may not be the same story in New York, California, or elsewhere. In early November [when Dr. Shadman was first contacted], in Seattle, we were not postponing care because our COVID-19 numbers were fairly good. But, as of mid December, that is starting to change as the COVID-19 numbers fluctuate.
 

If we do experience a second peak of COVID-19 cases, we would need to modify our practice as we did during the initial surge earlier this year. That would mean avoiding treatment with monoclonal antibodies and chemotherapy, as well as minimizing blood draws and drugs that require frequent in-person visits.
 

How important is it for patients to be vaccinated against COVID-19?

There are two key things to consider about a vaccine. Is the vaccine safe from the general safety standpoint that everyone is worried about? And if the vaccine is not harmful, will it work in patients will CLL?

Because we don’t yet know the complete side-effect profile of a COVID-19 vaccine, we would need to assess each patient’s condition to limit adverse reactions and to see whether the vaccine alters a patient’s immune response to the CLL drug they’re taking.

At the University of Washington, Seattle, we have a plan to start studying the effectiveness of the Pfizer and Moderna vaccines in patients with CLL – carefully assessing patients’ response to the vaccine in terms of antibody response. We already know, based on small studies, that the antibody response to the flu vaccine, for instance, is not as strong in patients with CLL, compared to those without. But, overall, as long as the vaccine won’t cause harm, I would recommend my patients get it.

Dr. Shadman has disclosed no relevant financial relationships.

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

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.

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.

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.

Ibrutinib showed significant impact on circulating malignant and nonmalignant immune cells and was found to restore healthy T-cell function in patients with chronic lymphocytic leukemia (CLL), according to the results of a comparative study of CLL patients and healthy controls.

Researchers compared circulating counts of 21 immune blood cell subsets throughout the first year of treatment in 55 patients with relapsed/refractory (R/R) CLL from the RESONATE trial and 50 previously untreated CLL patients from the RESONATE-2 trial with 20 untreated age-matched healthy donors, according to a report published online in Leukemia Research.

In addition, T-cell function was assessed in response to T-cell–receptor stimulation in 21 patients with R/R CLL, compared with 18 age-matched healthy donors, according to Isabelle G. Solman, MS, an employee of Translational Medicine, Pharmacyclics, Sunnyvale, Calif. and colleagues.
 

Positive indicators

Ibrutinib significantly decreased pathologically high circulating B cells, regulatory T cells, effector/memory CD4+ and CD8+ T cells (including exhausted and chronically activated T cells), natural killer (NK) T cells, and myeloid-derived suppressor cells; preserved naive T cells and NK cells; and increased circulating classical monocytes, according to the researchers.

Ibrutinib also significantly restored T-cell proliferative ability, degranulation, and cytokine secretion. Over the same period, ofatumumab or chlorambucil did not confer the same spectrum of normalization as ibrutinib in multiple immune subsets that were examined, they added.

“These results establish that ibrutinib has a significant and likely positive impact on circulating malignant and nonmalignant immune cells and restores healthy T-cell function,” the researchers indicated.

“Ibrutinib has a significant, progressively positive impact on both malignant and nonmalignant immune cells in CLL. These positive effects on circulating nonmalignant immune cells may contribute to long-term CLL disease control, overall health status, and decreased susceptibility to infection,” they concluded.

The study was funded by Pharmacyclics, an AbbVie Company. Ms. Solman is an employee of Translational Medicine, Pharmacyclics, Sunnyvale, Calif. as were several other authors.

[email protected]

SOURCE: Solman IG et al. Leuk Res. 2020;97. doi: 10.1016/j.leukres.2020.106432.

Ibrutinib showed significant impact on circulating malignant and nonmalignant immune cells and was found to restore healthy T-cell function in patients with chronic lymphocytic leukemia (CLL), according to the results of a comparative study of CLL patients and healthy controls.

Researchers compared circulating counts of 21 immune blood cell subsets throughout the first year of treatment in 55 patients with relapsed/refractory (R/R) CLL from the RESONATE trial and 50 previously untreated CLL patients from the RESONATE-2 trial with 20 untreated age-matched healthy donors, according to a report published online in Leukemia Research.

In addition, T-cell function was assessed in response to T-cell–receptor stimulation in 21 patients with R/R CLL, compared with 18 age-matched healthy donors, according to Isabelle G. Solman, MS, an employee of Translational Medicine, Pharmacyclics, Sunnyvale, Calif. and colleagues.
 

Positive indicators

Ibrutinib significantly decreased pathologically high circulating B cells, regulatory T cells, effector/memory CD4+ and CD8+ T cells (including exhausted and chronically activated T cells), natural killer (NK) T cells, and myeloid-derived suppressor cells; preserved naive T cells and NK cells; and increased circulating classical monocytes, according to the researchers.

Ibrutinib also significantly restored T-cell proliferative ability, degranulation, and cytokine secretion. Over the same period, ofatumumab or chlorambucil did not confer the same spectrum of normalization as ibrutinib in multiple immune subsets that were examined, they added.

“These results establish that ibrutinib has a significant and likely positive impact on circulating malignant and nonmalignant immune cells and restores healthy T-cell function,” the researchers indicated.

“Ibrutinib has a significant, progressively positive impact on both malignant and nonmalignant immune cells in CLL. These positive effects on circulating nonmalignant immune cells may contribute to long-term CLL disease control, overall health status, and decreased susceptibility to infection,” they concluded.

The study was funded by Pharmacyclics, an AbbVie Company. Ms. Solman is an employee of Translational Medicine, Pharmacyclics, Sunnyvale, Calif. as were several other authors.

[email protected]

SOURCE: Solman IG et al. Leuk Res. 2020;97. doi: 10.1016/j.leukres.2020.106432.

Ibrutinib showed significant impact on circulating malignant and nonmalignant immune cells and was found to restore healthy T-cell function in patients with chronic lymphocytic leukemia (CLL), according to the results of a comparative study of CLL patients and healthy controls.

Researchers compared circulating counts of 21 immune blood cell subsets throughout the first year of treatment in 55 patients with relapsed/refractory (R/R) CLL from the RESONATE trial and 50 previously untreated CLL patients from the RESONATE-2 trial with 20 untreated age-matched healthy donors, according to a report published online in Leukemia Research.

In addition, T-cell function was assessed in response to T-cell–receptor stimulation in 21 patients with R/R CLL, compared with 18 age-matched healthy donors, according to Isabelle G. Solman, MS, an employee of Translational Medicine, Pharmacyclics, Sunnyvale, Calif. and colleagues.
 

Positive indicators

Ibrutinib significantly decreased pathologically high circulating B cells, regulatory T cells, effector/memory CD4+ and CD8+ T cells (including exhausted and chronically activated T cells), natural killer (NK) T cells, and myeloid-derived suppressor cells; preserved naive T cells and NK cells; and increased circulating classical monocytes, according to the researchers.

Ibrutinib also significantly restored T-cell proliferative ability, degranulation, and cytokine secretion. Over the same period, ofatumumab or chlorambucil did not confer the same spectrum of normalization as ibrutinib in multiple immune subsets that were examined, they added.

“These results establish that ibrutinib has a significant and likely positive impact on circulating malignant and nonmalignant immune cells and restores healthy T-cell function,” the researchers indicated.

“Ibrutinib has a significant, progressively positive impact on both malignant and nonmalignant immune cells in CLL. These positive effects on circulating nonmalignant immune cells may contribute to long-term CLL disease control, overall health status, and decreased susceptibility to infection,” they concluded.

The study was funded by Pharmacyclics, an AbbVie Company. Ms. Solman is an employee of Translational Medicine, Pharmacyclics, Sunnyvale, Calif. as were several other authors.

[email protected]

SOURCE: Solman IG et al. Leuk Res. 2020;97. doi: 10.1016/j.leukres.2020.106432.

Acalabrutinib, a next-generation Bruton tyrosine kinase inhibitor, provides prolonged progression-free survival and better tolerability, compared with standard-of-care regimens for relapsed or refractory chronic lymphocytic leukemia (CLL), according to final results from the phase 3 ASCEND study.

Courtesy Wikimedia Commons/Nephron/Creative Commons BY-SA-3.0

The estimated 18-month progression-free survival (PFS) at a median of 22 months was 82% in 155 patients treated with acalabrutinib, compared with 48% in 155 treated with investigator’s choice of either idelalisib-rituximab (IdR) or bendamustine-rituximab (BR), which were given in 119 and 36 patients, respectively, Paolo Ghia, MD, PhD, reported at the Society of Hematologic Oncology virtual meeting.

The benefits of acalabrutinib were apparent regardless of high-risk genetic characteristics: Those with and without both del(17p) and TP53 mutations had similarly good PFS outcomes with acalabrutinib versus IdR/BR (HRs, 0.11 and 0.29, respectively), as did those with versus without unmutated IgVH (HRs, 0.28 and 0.30, respectively), said Dr. Ghia, professor of medical oncology at the Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan.

The median overall survival was not reached in either arm, but estimated 18-month OS was 88% in both groups, likely because of the crossover being allowed for nonresponders in the IdR/BR groups, he noted.
 

Overall responses

The investigator-assessed overall response rates, including partial response or better, were also similar in the groups at 80% and 84%, respectively, and ORR, including partial response with lymphocytosis, was 92% versus 88%.

The duration of response was not reached in the acalabrutinib arm versus 18 months with IdR/BR, and estimated duration of response was 85% versus 49%.

The median drug exposure with acalabrutinib was approximately double that with IdR and about four times that of BR, Dr. Ghia said, noting that the difference between acalabrutinib and BR is explained by the short 6-month duration of treatment with BR, but the difference between acalabrutinib and IdR is because of adverse events (AEs).
 

Adverse events

AEs were the most common reason for treatment discontinuation in all three groups, but they led to discontinuation in only 16% with acalabrutinib versus 56% with IdR, he added.

The rates of AEs and AEs of clinical interest were generally similar to those reported at the interim analysis as presented in 2019 at the European Hematology Association annual meeting and published in the Journal of Clinical Oncology, despite the additional 6 months of follow up, he said.

Additionally, the incidence of grade 3 or higher AEs, serious AEs, and treatment-related AEs were all greater with IdR than with acalabrutinib or BR. The most common AEs with acalabrutinib were headache, neutropenia, diarrhea, and upper-respiratory infection, which were mostly grade 1 or 2. The most common grade 3 or higher AEs were neutropenia, anemia, and pneumonia, which were reported in 12%, 17%, and 7% of patients.
 

Confirmatory results

“The final results from the ASCEND study confirm the findings at the interim analysis and support the favorable efficacy and safety of acalabrutinib versus standard-of-care regimens ... in patients with relapsed/refractory CLL,” Dr. Ghia said.

“Overall, these final results from ASCENT support the use of acalabrutinib in patients with relapsed/refractory CLL, including those with high-risk genetic features.”

This study was sponsored by Acerta Pharma. Dr. Ghia reported consulting or advisory roles, grant or research funding, and/or honoraria from Abbvie, BeiGene, Janssen, Gilead Sciences, Sunesis Pharmaceuticals, Juno Therapeutics, ArQule, Adaptive Biotechnologies, Dynamo Therapeutics, MEI Pharma, and Novartis.

[email protected]

SOURCE: Ghia P et al. SOHO 2020, Abstract CLL-091.

Acalabrutinib, a next-generation Bruton tyrosine kinase inhibitor, provides prolonged progression-free survival and better tolerability, compared with standard-of-care regimens for relapsed or refractory chronic lymphocytic leukemia (CLL), according to final results from the phase 3 ASCEND study.

Courtesy Wikimedia Commons/Nephron/Creative Commons BY-SA-3.0

The estimated 18-month progression-free survival (PFS) at a median of 22 months was 82% in 155 patients treated with acalabrutinib, compared with 48% in 155 treated with investigator’s choice of either idelalisib-rituximab (IdR) or bendamustine-rituximab (BR), which were given in 119 and 36 patients, respectively, Paolo Ghia, MD, PhD, reported at the Society of Hematologic Oncology virtual meeting.

The benefits of acalabrutinib were apparent regardless of high-risk genetic characteristics: Those with and without both del(17p) and TP53 mutations had similarly good PFS outcomes with acalabrutinib versus IdR/BR (HRs, 0.11 and 0.29, respectively), as did those with versus without unmutated IgVH (HRs, 0.28 and 0.30, respectively), said Dr. Ghia, professor of medical oncology at the Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan.

The median overall survival was not reached in either arm, but estimated 18-month OS was 88% in both groups, likely because of the crossover being allowed for nonresponders in the IdR/BR groups, he noted.
 

Overall responses

The investigator-assessed overall response rates, including partial response or better, were also similar in the groups at 80% and 84%, respectively, and ORR, including partial response with lymphocytosis, was 92% versus 88%.

The duration of response was not reached in the acalabrutinib arm versus 18 months with IdR/BR, and estimated duration of response was 85% versus 49%.

The median drug exposure with acalabrutinib was approximately double that with IdR and about four times that of BR, Dr. Ghia said, noting that the difference between acalabrutinib and BR is explained by the short 6-month duration of treatment with BR, but the difference between acalabrutinib and IdR is because of adverse events (AEs).
 

Adverse events

AEs were the most common reason for treatment discontinuation in all three groups, but they led to discontinuation in only 16% with acalabrutinib versus 56% with IdR, he added.

The rates of AEs and AEs of clinical interest were generally similar to those reported at the interim analysis as presented in 2019 at the European Hematology Association annual meeting and published in the Journal of Clinical Oncology, despite the additional 6 months of follow up, he said.

Additionally, the incidence of grade 3 or higher AEs, serious AEs, and treatment-related AEs were all greater with IdR than with acalabrutinib or BR. The most common AEs with acalabrutinib were headache, neutropenia, diarrhea, and upper-respiratory infection, which were mostly grade 1 or 2. The most common grade 3 or higher AEs were neutropenia, anemia, and pneumonia, which were reported in 12%, 17%, and 7% of patients.
 

Confirmatory results

“The final results from the ASCEND study confirm the findings at the interim analysis and support the favorable efficacy and safety of acalabrutinib versus standard-of-care regimens ... in patients with relapsed/refractory CLL,” Dr. Ghia said.

“Overall, these final results from ASCENT support the use of acalabrutinib in patients with relapsed/refractory CLL, including those with high-risk genetic features.”

This study was sponsored by Acerta Pharma. Dr. Ghia reported consulting or advisory roles, grant or research funding, and/or honoraria from Abbvie, BeiGene, Janssen, Gilead Sciences, Sunesis Pharmaceuticals, Juno Therapeutics, ArQule, Adaptive Biotechnologies, Dynamo Therapeutics, MEI Pharma, and Novartis.

[email protected]

SOURCE: Ghia P et al. SOHO 2020, Abstract CLL-091.

Acalabrutinib, a next-generation Bruton tyrosine kinase inhibitor, provides prolonged progression-free survival and better tolerability, compared with standard-of-care regimens for relapsed or refractory chronic lymphocytic leukemia (CLL), according to final results from the phase 3 ASCEND study.

Courtesy Wikimedia Commons/Nephron/Creative Commons BY-SA-3.0

The estimated 18-month progression-free survival (PFS) at a median of 22 months was 82% in 155 patients treated with acalabrutinib, compared with 48% in 155 treated with investigator’s choice of either idelalisib-rituximab (IdR) or bendamustine-rituximab (BR), which were given in 119 and 36 patients, respectively, Paolo Ghia, MD, PhD, reported at the Society of Hematologic Oncology virtual meeting.

The benefits of acalabrutinib were apparent regardless of high-risk genetic characteristics: Those with and without both del(17p) and TP53 mutations had similarly good PFS outcomes with acalabrutinib versus IdR/BR (HRs, 0.11 and 0.29, respectively), as did those with versus without unmutated IgVH (HRs, 0.28 and 0.30, respectively), said Dr. Ghia, professor of medical oncology at the Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan.

The median overall survival was not reached in either arm, but estimated 18-month OS was 88% in both groups, likely because of the crossover being allowed for nonresponders in the IdR/BR groups, he noted.
 

Overall responses

The investigator-assessed overall response rates, including partial response or better, were also similar in the groups at 80% and 84%, respectively, and ORR, including partial response with lymphocytosis, was 92% versus 88%.

The duration of response was not reached in the acalabrutinib arm versus 18 months with IdR/BR, and estimated duration of response was 85% versus 49%.

The median drug exposure with acalabrutinib was approximately double that with IdR and about four times that of BR, Dr. Ghia said, noting that the difference between acalabrutinib and BR is explained by the short 6-month duration of treatment with BR, but the difference between acalabrutinib and IdR is because of adverse events (AEs).
 

Adverse events

AEs were the most common reason for treatment discontinuation in all three groups, but they led to discontinuation in only 16% with acalabrutinib versus 56% with IdR, he added.

The rates of AEs and AEs of clinical interest were generally similar to those reported at the interim analysis as presented in 2019 at the European Hematology Association annual meeting and published in the Journal of Clinical Oncology, despite the additional 6 months of follow up, he said.

Additionally, the incidence of grade 3 or higher AEs, serious AEs, and treatment-related AEs were all greater with IdR than with acalabrutinib or BR. The most common AEs with acalabrutinib were headache, neutropenia, diarrhea, and upper-respiratory infection, which were mostly grade 1 or 2. The most common grade 3 or higher AEs were neutropenia, anemia, and pneumonia, which were reported in 12%, 17%, and 7% of patients.
 

Confirmatory results

“The final results from the ASCEND study confirm the findings at the interim analysis and support the favorable efficacy and safety of acalabrutinib versus standard-of-care regimens ... in patients with relapsed/refractory CLL,” Dr. Ghia said.

“Overall, these final results from ASCENT support the use of acalabrutinib in patients with relapsed/refractory CLL, including those with high-risk genetic features.”

This study was sponsored by Acerta Pharma. Dr. Ghia reported consulting or advisory roles, grant or research funding, and/or honoraria from Abbvie, BeiGene, Janssen, Gilead Sciences, Sunesis Pharmaceuticals, Juno Therapeutics, ArQule, Adaptive Biotechnologies, Dynamo Therapeutics, MEI Pharma, and Novartis.

[email protected]

SOURCE: Ghia P et al. SOHO 2020, Abstract CLL-091.