B-Cell Lymphoma ICYMI

Key clinical point: Rituximab maintenance (RM) therapy after first-line bendamustine-rituximab (BR) or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) improved overall survival and disease control in older patients with mantle cell lymphoma (MCL).

Major finding: Patients who did vs did not receive RM therapy had a significantly longer overall survival (adjusted hazard ratio [aHR] 0.53; 95% CI 0.34-0.82) and approximated progression-free survival (survival or free of second-line therapy; aHR 0.51; 95% CI 0.36-0.72).

Study details: This real-world study included 131 propensity-score matched pairs of autologous stem cell transplant-ineligible patients aged ≥66 years with MCL who did and did not receive RM after first-line treatment with BR or R-CHOP.

Disclosures: This study did not receive any financial support. No information on conflicts of interest was reported.

Source: Di M et al. Treatment patterns and real-world effectiveness of rituximab maintenance in older patients with mantle cell lymphoma: A population-based analysis. Haematologica. 2023 (Jan 19). Doi: 10.3324/haematol.2022.282252

Key clinical point: Rituximab maintenance (RM) therapy after first-line bendamustine-rituximab (BR) or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) improved overall survival and disease control in older patients with mantle cell lymphoma (MCL).

Major finding: Patients who did vs did not receive RM therapy had a significantly longer overall survival (adjusted hazard ratio [aHR] 0.53; 95% CI 0.34-0.82) and approximated progression-free survival (survival or free of second-line therapy; aHR 0.51; 95% CI 0.36-0.72).

Study details: This real-world study included 131 propensity-score matched pairs of autologous stem cell transplant-ineligible patients aged ≥66 years with MCL who did and did not receive RM after first-line treatment with BR or R-CHOP.

Disclosures: This study did not receive any financial support. No information on conflicts of interest was reported.

Source: Di M et al. Treatment patterns and real-world effectiveness of rituximab maintenance in older patients with mantle cell lymphoma: A population-based analysis. Haematologica. 2023 (Jan 19). Doi: 10.3324/haematol.2022.282252

Key clinical point: Rituximab maintenance (RM) therapy after first-line bendamustine-rituximab (BR) or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) improved overall survival and disease control in older patients with mantle cell lymphoma (MCL).

Major finding: Patients who did vs did not receive RM therapy had a significantly longer overall survival (adjusted hazard ratio [aHR] 0.53; 95% CI 0.34-0.82) and approximated progression-free survival (survival or free of second-line therapy; aHR 0.51; 95% CI 0.36-0.72).

Study details: This real-world study included 131 propensity-score matched pairs of autologous stem cell transplant-ineligible patients aged ≥66 years with MCL who did and did not receive RM after first-line treatment with BR or R-CHOP.

Disclosures: This study did not receive any financial support. No information on conflicts of interest was reported.

Source: Di M et al. Treatment patterns and real-world effectiveness of rituximab maintenance in older patients with mantle cell lymphoma: A population-based analysis. Haematologica. 2023 (Jan 19). Doi: 10.3324/haematol.2022.282252

Key clinical point: In the real-world setting, dose reductions and therapy delays are more common among elderly vs younger patients receiving first-line bendamustine-rituximab (BR) for indolent non-Hodgkin's lymphoma (iNHL) or mantle cell lymphoma (MCL); however, the efficacy and safety of BR is unaffected across age groups.

Major finding: At a median follow-up of 42 months, the elderly vs younger patient group had a significantly lower proportion of patients receiving full doses of bendamustine (54% vs 79.5%; P < .001) and higher treatment delay rate (54% vs 43.2%; P < .001) but similar disease-free survival (P = .069). The number of all-grade adverse events per patient was similar between the groups across each BR cycle.

Study details: This retrospective observational cohort study included 201 patients (elderly [≥70 years] n = 113 or younger [18-70 years] n = 88) with iNHL or MCL who received BR therapy.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Kotchetkov R et al. Bendamustine and rituximab is well-tolerated and efficient in the treatment of indolent non-Hodgkin's lymphoma and mantle cell lymphoma in elderly: A single center observational study. Int J Cancer. 2022 (Dec 22). Doi: 10.1002/ijc.34412

Key clinical point: In the real-world setting, dose reductions and therapy delays are more common among elderly vs younger patients receiving first-line bendamustine-rituximab (BR) for indolent non-Hodgkin's lymphoma (iNHL) or mantle cell lymphoma (MCL); however, the efficacy and safety of BR is unaffected across age groups.

Major finding: At a median follow-up of 42 months, the elderly vs younger patient group had a significantly lower proportion of patients receiving full doses of bendamustine (54% vs 79.5%; P < .001) and higher treatment delay rate (54% vs 43.2%; P < .001) but similar disease-free survival (P = .069). The number of all-grade adverse events per patient was similar between the groups across each BR cycle.

Study details: This retrospective observational cohort study included 201 patients (elderly [≥70 years] n = 113 or younger [18-70 years] n = 88) with iNHL or MCL who received BR therapy.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Kotchetkov R et al. Bendamustine and rituximab is well-tolerated and efficient in the treatment of indolent non-Hodgkin's lymphoma and mantle cell lymphoma in elderly: A single center observational study. Int J Cancer. 2022 (Dec 22). Doi: 10.1002/ijc.34412

Key clinical point: In the real-world setting, dose reductions and therapy delays are more common among elderly vs younger patients receiving first-line bendamustine-rituximab (BR) for indolent non-Hodgkin's lymphoma (iNHL) or mantle cell lymphoma (MCL); however, the efficacy and safety of BR is unaffected across age groups.

Major finding: At a median follow-up of 42 months, the elderly vs younger patient group had a significantly lower proportion of patients receiving full doses of bendamustine (54% vs 79.5%; P < .001) and higher treatment delay rate (54% vs 43.2%; P < .001) but similar disease-free survival (P = .069). The number of all-grade adverse events per patient was similar between the groups across each BR cycle.

Study details: This retrospective observational cohort study included 201 patients (elderly [≥70 years] n = 113 or younger [18-70 years] n = 88) with iNHL or MCL who received BR therapy.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Kotchetkov R et al. Bendamustine and rituximab is well-tolerated and efficient in the treatment of indolent non-Hodgkin's lymphoma and mantle cell lymphoma in elderly: A single center observational study. Int J Cancer. 2022 (Dec 22). Doi: 10.1002/ijc.34412

Key clinical point: Fixed-duration glofitamab treatment led to durable complete responses and a grade ≥3 adverse event (AE) rate of >50% in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

Major finding: At a median follow-up of 12.6 months, 39% (95% CI 32%-48%) and 52% (95% CI 43%-60%) of patients achieved complete and objective responses, respectively. The median time to a complete response was 42 (95% CI 42-44) days; 78% of patients with a complete response continued to be in remission at 12 months. The grade ≥3 AE rate was 62%.

Study details: This phase 2 part of a phase 1-2 study included 155 adult patients with relapsed/refractory DLBCL previously treated with ≥2 lines of therapy who received obinutuzumab pretreatment followed by fixed-duration glofitamab monotherapy for 12 cycles.

Disclosures: This study was funded by F. Hoffmann-La Roche. Some authors reported ties with various organizations, including F. Hoffmann-La Roche. Two authors declared being employees of and holding stock or stock options in F. Hoffmann-La Roche.

Source: Dickinson MJ et al. Glofitamab for relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2022;387(24):2220-2231 (Dec 11). Doi: 10.1056/NEJMoa2206913

Key clinical point: Fixed-duration glofitamab treatment led to durable complete responses and a grade ≥3 adverse event (AE) rate of >50% in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

Major finding: At a median follow-up of 12.6 months, 39% (95% CI 32%-48%) and 52% (95% CI 43%-60%) of patients achieved complete and objective responses, respectively. The median time to a complete response was 42 (95% CI 42-44) days; 78% of patients with a complete response continued to be in remission at 12 months. The grade ≥3 AE rate was 62%.

Study details: This phase 2 part of a phase 1-2 study included 155 adult patients with relapsed/refractory DLBCL previously treated with ≥2 lines of therapy who received obinutuzumab pretreatment followed by fixed-duration glofitamab monotherapy for 12 cycles.

Disclosures: This study was funded by F. Hoffmann-La Roche. Some authors reported ties with various organizations, including F. Hoffmann-La Roche. Two authors declared being employees of and holding stock or stock options in F. Hoffmann-La Roche.

Source: Dickinson MJ et al. Glofitamab for relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2022;387(24):2220-2231 (Dec 11). Doi: 10.1056/NEJMoa2206913

Key clinical point: Fixed-duration glofitamab treatment led to durable complete responses and a grade ≥3 adverse event (AE) rate of >50% in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

Major finding: At a median follow-up of 12.6 months, 39% (95% CI 32%-48%) and 52% (95% CI 43%-60%) of patients achieved complete and objective responses, respectively. The median time to a complete response was 42 (95% CI 42-44) days; 78% of patients with a complete response continued to be in remission at 12 months. The grade ≥3 AE rate was 62%.

Study details: This phase 2 part of a phase 1-2 study included 155 adult patients with relapsed/refractory DLBCL previously treated with ≥2 lines of therapy who received obinutuzumab pretreatment followed by fixed-duration glofitamab monotherapy for 12 cycles.

Disclosures: This study was funded by F. Hoffmann-La Roche. Some authors reported ties with various organizations, including F. Hoffmann-La Roche. Two authors declared being employees of and holding stock or stock options in F. Hoffmann-La Roche.

Source: Dickinson MJ et al. Glofitamab for relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2022;387(24):2220-2231 (Dec 11). Doi: 10.1056/NEJMoa2206913

Key clinical point: Compared with ibrutinib, zanubrutinib prolonged progression-free survival and demonstrated an improved safety profile in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Major finding: At a median follow-up of 29.6 months, the zanubrutinib vs ibrutinib group had a 35% decreased risk for progression or death (hazard ratio 0.65; P = .002) and a lower incidence of cardiac disorders (21.3% vs 29.6%) and adverse events leading to treatment discontinuation (15.4% vs 22.2%).

Study details: Findings are from the multicenter phase 3 ALPINE trial including 652 adult patients with relapsed or refractory CLL/SLL treated with ≥1 previous line of therapy who were randomly assigned to receive zanubrutinib (n = 327) or ibrutinib (n = 325).

Disclosures: This study was funded by BeiGene. Some authors reported ties with various organizations, including BeiGene. Six authors declared being employees of or holding stock or stock options in BeiGene.

Source: Brown JR et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2022;388(4):319-332 (Dec 13). Doi: 10.1056/NEJMoa2211582

Key clinical point: Compared with ibrutinib, zanubrutinib prolonged progression-free survival and demonstrated an improved safety profile in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Major finding: At a median follow-up of 29.6 months, the zanubrutinib vs ibrutinib group had a 35% decreased risk for progression or death (hazard ratio 0.65; P = .002) and a lower incidence of cardiac disorders (21.3% vs 29.6%) and adverse events leading to treatment discontinuation (15.4% vs 22.2%).

Study details: Findings are from the multicenter phase 3 ALPINE trial including 652 adult patients with relapsed or refractory CLL/SLL treated with ≥1 previous line of therapy who were randomly assigned to receive zanubrutinib (n = 327) or ibrutinib (n = 325).

Disclosures: This study was funded by BeiGene. Some authors reported ties with various organizations, including BeiGene. Six authors declared being employees of or holding stock or stock options in BeiGene.

Source: Brown JR et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2022;388(4):319-332 (Dec 13). Doi: 10.1056/NEJMoa2211582

Key clinical point: Compared with ibrutinib, zanubrutinib prolonged progression-free survival and demonstrated an improved safety profile in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Major finding: At a median follow-up of 29.6 months, the zanubrutinib vs ibrutinib group had a 35% decreased risk for progression or death (hazard ratio 0.65; P = .002) and a lower incidence of cardiac disorders (21.3% vs 29.6%) and adverse events leading to treatment discontinuation (15.4% vs 22.2%).

Study details: Findings are from the multicenter phase 3 ALPINE trial including 652 adult patients with relapsed or refractory CLL/SLL treated with ≥1 previous line of therapy who were randomly assigned to receive zanubrutinib (n = 327) or ibrutinib (n = 325).

Disclosures: This study was funded by BeiGene. Some authors reported ties with various organizations, including BeiGene. Six authors declared being employees of or holding stock or stock options in BeiGene.

Source: Brown JR et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2022;388(4):319-332 (Dec 13). Doi: 10.1056/NEJMoa2211582

Key clinical point: Rituximab+cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) compared with standard myeloablative radiochemotherapy and autologous stem cell transplantation (ASCT; R-CHOP arm), an alternating R-CHOP/rituximab+dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP) induction therapy with high-dose cytarabine-containing myeloablative radiochemotherapy and ASCT (R-DHAP arm) led to longer time to treatment failure (TTF) and overall survival (OS) in patients with mantle cell lymphoma (MCL).

Major finding: After a median follow-up of 10.6 years, the R-DHAP vs R-CHOP arm continued to have a significantly longer TTF (hazard ratio [HR] 0.59; P = .038) and OS (Mantle Cell Lymphoma International Prognostic Index+Ki-67-adjusted HR 0.60; P = .0066).

Study details: This long-term analysis of the phase 3 MCL Younger trial included 497 patients aged ≥18 to <66 years with previously untreated MCL who were randomly assigned to the R-CHOP (n = 249) or R-DHAP (n = 248) arm.

Disclosures: This study was supported by European Commission, Lymphoma Research Foundation, and Roche. Some authors reported ties with various organizations, including Roche.

Source: Hermine O et al. High-dose cytarabine and autologous stem-cell transplantation in mantle cell lymphoma: Long-term follow-up of the randomized mantle cell lymphoma younger trial of the European Mantle Cell Lymphoma Network. J Clin Oncol. 2022;41(3):479-484 (Dec 5). Doi: 10.1200/JCO.22.01780

Key clinical point: Rituximab+cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) compared with standard myeloablative radiochemotherapy and autologous stem cell transplantation (ASCT; R-CHOP arm), an alternating R-CHOP/rituximab+dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP) induction therapy with high-dose cytarabine-containing myeloablative radiochemotherapy and ASCT (R-DHAP arm) led to longer time to treatment failure (TTF) and overall survival (OS) in patients with mantle cell lymphoma (MCL).

Major finding: After a median follow-up of 10.6 years, the R-DHAP vs R-CHOP arm continued to have a significantly longer TTF (hazard ratio [HR] 0.59; P = .038) and OS (Mantle Cell Lymphoma International Prognostic Index+Ki-67-adjusted HR 0.60; P = .0066).

Study details: This long-term analysis of the phase 3 MCL Younger trial included 497 patients aged ≥18 to <66 years with previously untreated MCL who were randomly assigned to the R-CHOP (n = 249) or R-DHAP (n = 248) arm.

Disclosures: This study was supported by European Commission, Lymphoma Research Foundation, and Roche. Some authors reported ties with various organizations, including Roche.

Source: Hermine O et al. High-dose cytarabine and autologous stem-cell transplantation in mantle cell lymphoma: Long-term follow-up of the randomized mantle cell lymphoma younger trial of the European Mantle Cell Lymphoma Network. J Clin Oncol. 2022;41(3):479-484 (Dec 5). Doi: 10.1200/JCO.22.01780

Key clinical point: Rituximab+cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) compared with standard myeloablative radiochemotherapy and autologous stem cell transplantation (ASCT; R-CHOP arm), an alternating R-CHOP/rituximab+dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP) induction therapy with high-dose cytarabine-containing myeloablative radiochemotherapy and ASCT (R-DHAP arm) led to longer time to treatment failure (TTF) and overall survival (OS) in patients with mantle cell lymphoma (MCL).

Major finding: After a median follow-up of 10.6 years, the R-DHAP vs R-CHOP arm continued to have a significantly longer TTF (hazard ratio [HR] 0.59; P = .038) and OS (Mantle Cell Lymphoma International Prognostic Index+Ki-67-adjusted HR 0.60; P = .0066).

Study details: This long-term analysis of the phase 3 MCL Younger trial included 497 patients aged ≥18 to <66 years with previously untreated MCL who were randomly assigned to the R-CHOP (n = 249) or R-DHAP (n = 248) arm.

Disclosures: This study was supported by European Commission, Lymphoma Research Foundation, and Roche. Some authors reported ties with various organizations, including Roche.

Source: Hermine O et al. High-dose cytarabine and autologous stem-cell transplantation in mantle cell lymphoma: Long-term follow-up of the randomized mantle cell lymphoma younger trial of the European Mantle Cell Lymphoma Network. J Clin Oncol. 2022;41(3):479-484 (Dec 5). Doi: 10.1200/JCO.22.01780

PARIS – Two tyrosine kinase inhibitors (TKI) used in the treatment of chronic myeloid leukemia (CML) – nilotinib (Tasigna) and ponatinib (Iclusig) – may cause atherosclerotic arterial diseases. This common side effect, which has even been seen in patients without cardiovascular risk factors, has gone unnoticed in clinical trials. So what can be done to prevent it?

Cardiologist Gabrielle Sarlon, MD, PhD, a professor at Marseille (France) University Hospital, offered her recommendations at the European Days of the French Society of Cardiology Conference 2023.

In the literature, we find many hypotheses that seek to explain why these drugs bring about the formation of atheromatous plaque. The findings of one French study led Dr. Sarlon to state, “I firmly believe that, in some patients, these treatments make LDL cholesterol go up.” This would be the main cause of the coronary and peripheral arterial diseases that are being seen.

Therefore, “LDL-C should start being monitored when the therapy starts, and a statin may have to be prescribed,” she said.

Arterial diseases

By bringing about a marked improvement in patients’ chances of survival, TKIs “have revolutionized the management of chronic myeloid leukemia,” Dr. Sarlon added. But these treatments have side effects. The most common is high blood pressure, “an effect that attests to the efficacy of targeted therapies and that must be quickly treated” with antihypertensives.

It is well known that the targeted therapies cause the rise in blood pressure. What was unexpected, though, was the vascular toxicity seen with the latest generation of TKIs. “This is a real toxicity that we need to know about, detect, and manage,” said Dr. Sarlon.

The prevalence of arterial diseases induced by nilotinib, a second-generation TKI, can be as high as 10%. Single-center studies have indicated much higher numbers. In a small study that Dr. Sarlon and her team conducted at Marseille University Hospital, atherosclerotic-type arterial injuries were observed in more than 30% of patients treated with nilotinib.

Dr. Sarlon noted that the signs of arterial toxicity occurring with this treatment have not appeared in clinical trials. Observations of the real-life use of nilotinib led French and German teams to sound the alarm. They noticed that some patients treated for CML had developed claudication and progression to critical limb ischemia of the lower extremities.

Risk factors uncovered

The first retrospective analysis to explore this risk was carried out by a German team. They included 179 patients who received nilotinib and found that 11 (6.2%) developed severe and previously unrecognized lower-extremity peripheral arterial disease (PAD) that required invasive therapy. The mean time from initiation of nilotinib to the first PAD event was 105.1 weeks (range = 16-212 weeks).

The following have emerged as major risk factors for nilotinib-induced PAD: the presence of cardiovascular risk factors, age older than 60 years, and long duration of exposure to nilotinib. Some of these factors were confirmed in the more recent study conducted at Marseille University Hospital involving patients treated with nilotinib. According to other research, there seems to be a correlation between this risk and the dose administered.

In the case of ponatinib, the side effects are even more common – so much so that, a few months after this third-generation TKI was authorized, a warning was issued about its use. A long-term follow-up study reported a 28% prevalence of cardiovascular events, while arterial diseases were observed in 20% of cases after 1-2 years on the treatment.

In terms of pathophysiology, the Marseilles University Hospital study found that arterial injuries were associated with stenosis greater than 50% in almost half of cases. “The atheromatous plaques were found where they typically are,” with the carotid bulb being the most involved territory, according to the researchers. But they’re also found in other arteries – femoral, vertebral, even renal – “sometimes in patients without cardiovascular risk factors.”

One distinctive characteristic to keep in mind is that “lipid-rich atheromatous plaques appear very dark on imaging” and thus can go unnoticed during a Doppler ultrasound. And, Dr. Sarlon added, “surprisingly, the thickening can extend to the external carotid artery.”

Ankle-brachial index

Published last year, the first European Society of Cardiology Guidelines on Cardio-Oncology present specific baseline risk-assessment and monitoring recommendations regarding patients treated with nilotinib and ponatinib. One suggests that a cardiovascular risk assessment be done every 3 months during the first year and every 6-12 months thereafter. This assessment would include such items as ECGs, blood pressure measurements, and lipid profile tests.

In addition, it is advised that every 6 months an ankle-brachial index test be performed to check for PAD. At Marseille University Hospital, a Doppler ultrasound is also done at each follow-up appointment to look for arterial plaques, “even for patients at low risk for cardiovascular disease,” said Dr. Sarlon. “It seems, above all, absolutely necessary that hematologists order an LDL-C test and, if needed, consider statin therapy,” all the while keeping in mind that “the target LDL-C level is 1 gram per liter.”

This article was translated from the Medscape French edition. A version of this article first appeared on Medscape.com.

PARIS – Two tyrosine kinase inhibitors (TKI) used in the treatment of chronic myeloid leukemia (CML) – nilotinib (Tasigna) and ponatinib (Iclusig) – may cause atherosclerotic arterial diseases. This common side effect, which has even been seen in patients without cardiovascular risk factors, has gone unnoticed in clinical trials. So what can be done to prevent it?

Cardiologist Gabrielle Sarlon, MD, PhD, a professor at Marseille (France) University Hospital, offered her recommendations at the European Days of the French Society of Cardiology Conference 2023.

In the literature, we find many hypotheses that seek to explain why these drugs bring about the formation of atheromatous plaque. The findings of one French study led Dr. Sarlon to state, “I firmly believe that, in some patients, these treatments make LDL cholesterol go up.” This would be the main cause of the coronary and peripheral arterial diseases that are being seen.

Therefore, “LDL-C should start being monitored when the therapy starts, and a statin may have to be prescribed,” she said.

Arterial diseases

By bringing about a marked improvement in patients’ chances of survival, TKIs “have revolutionized the management of chronic myeloid leukemia,” Dr. Sarlon added. But these treatments have side effects. The most common is high blood pressure, “an effect that attests to the efficacy of targeted therapies and that must be quickly treated” with antihypertensives.

It is well known that the targeted therapies cause the rise in blood pressure. What was unexpected, though, was the vascular toxicity seen with the latest generation of TKIs. “This is a real toxicity that we need to know about, detect, and manage,” said Dr. Sarlon.

The prevalence of arterial diseases induced by nilotinib, a second-generation TKI, can be as high as 10%. Single-center studies have indicated much higher numbers. In a small study that Dr. Sarlon and her team conducted at Marseille University Hospital, atherosclerotic-type arterial injuries were observed in more than 30% of patients treated with nilotinib.

Dr. Sarlon noted that the signs of arterial toxicity occurring with this treatment have not appeared in clinical trials. Observations of the real-life use of nilotinib led French and German teams to sound the alarm. They noticed that some patients treated for CML had developed claudication and progression to critical limb ischemia of the lower extremities.

Risk factors uncovered

The first retrospective analysis to explore this risk was carried out by a German team. They included 179 patients who received nilotinib and found that 11 (6.2%) developed severe and previously unrecognized lower-extremity peripheral arterial disease (PAD) that required invasive therapy. The mean time from initiation of nilotinib to the first PAD event was 105.1 weeks (range = 16-212 weeks).

The following have emerged as major risk factors for nilotinib-induced PAD: the presence of cardiovascular risk factors, age older than 60 years, and long duration of exposure to nilotinib. Some of these factors were confirmed in the more recent study conducted at Marseille University Hospital involving patients treated with nilotinib. According to other research, there seems to be a correlation between this risk and the dose administered.

In the case of ponatinib, the side effects are even more common – so much so that, a few months after this third-generation TKI was authorized, a warning was issued about its use. A long-term follow-up study reported a 28% prevalence of cardiovascular events, while arterial diseases were observed in 20% of cases after 1-2 years on the treatment.

In terms of pathophysiology, the Marseilles University Hospital study found that arterial injuries were associated with stenosis greater than 50% in almost half of cases. “The atheromatous plaques were found where they typically are,” with the carotid bulb being the most involved territory, according to the researchers. But they’re also found in other arteries – femoral, vertebral, even renal – “sometimes in patients without cardiovascular risk factors.”

One distinctive characteristic to keep in mind is that “lipid-rich atheromatous plaques appear very dark on imaging” and thus can go unnoticed during a Doppler ultrasound. And, Dr. Sarlon added, “surprisingly, the thickening can extend to the external carotid artery.”

Ankle-brachial index

Published last year, the first European Society of Cardiology Guidelines on Cardio-Oncology present specific baseline risk-assessment and monitoring recommendations regarding patients treated with nilotinib and ponatinib. One suggests that a cardiovascular risk assessment be done every 3 months during the first year and every 6-12 months thereafter. This assessment would include such items as ECGs, blood pressure measurements, and lipid profile tests.

In addition, it is advised that every 6 months an ankle-brachial index test be performed to check for PAD. At Marseille University Hospital, a Doppler ultrasound is also done at each follow-up appointment to look for arterial plaques, “even for patients at low risk for cardiovascular disease,” said Dr. Sarlon. “It seems, above all, absolutely necessary that hematologists order an LDL-C test and, if needed, consider statin therapy,” all the while keeping in mind that “the target LDL-C level is 1 gram per liter.”

This article was translated from the Medscape French edition. A version of this article first appeared on Medscape.com.

PARIS – Two tyrosine kinase inhibitors (TKI) used in the treatment of chronic myeloid leukemia (CML) – nilotinib (Tasigna) and ponatinib (Iclusig) – may cause atherosclerotic arterial diseases. This common side effect, which has even been seen in patients without cardiovascular risk factors, has gone unnoticed in clinical trials. So what can be done to prevent it?

Cardiologist Gabrielle Sarlon, MD, PhD, a professor at Marseille (France) University Hospital, offered her recommendations at the European Days of the French Society of Cardiology Conference 2023.

In the literature, we find many hypotheses that seek to explain why these drugs bring about the formation of atheromatous plaque. The findings of one French study led Dr. Sarlon to state, “I firmly believe that, in some patients, these treatments make LDL cholesterol go up.” This would be the main cause of the coronary and peripheral arterial diseases that are being seen.

Therefore, “LDL-C should start being monitored when the therapy starts, and a statin may have to be prescribed,” she said.

Arterial diseases

By bringing about a marked improvement in patients’ chances of survival, TKIs “have revolutionized the management of chronic myeloid leukemia,” Dr. Sarlon added. But these treatments have side effects. The most common is high blood pressure, “an effect that attests to the efficacy of targeted therapies and that must be quickly treated” with antihypertensives.

It is well known that the targeted therapies cause the rise in blood pressure. What was unexpected, though, was the vascular toxicity seen with the latest generation of TKIs. “This is a real toxicity that we need to know about, detect, and manage,” said Dr. Sarlon.

The prevalence of arterial diseases induced by nilotinib, a second-generation TKI, can be as high as 10%. Single-center studies have indicated much higher numbers. In a small study that Dr. Sarlon and her team conducted at Marseille University Hospital, atherosclerotic-type arterial injuries were observed in more than 30% of patients treated with nilotinib.

Dr. Sarlon noted that the signs of arterial toxicity occurring with this treatment have not appeared in clinical trials. Observations of the real-life use of nilotinib led French and German teams to sound the alarm. They noticed that some patients treated for CML had developed claudication and progression to critical limb ischemia of the lower extremities.

Risk factors uncovered

The first retrospective analysis to explore this risk was carried out by a German team. They included 179 patients who received nilotinib and found that 11 (6.2%) developed severe and previously unrecognized lower-extremity peripheral arterial disease (PAD) that required invasive therapy. The mean time from initiation of nilotinib to the first PAD event was 105.1 weeks (range = 16-212 weeks).

The following have emerged as major risk factors for nilotinib-induced PAD: the presence of cardiovascular risk factors, age older than 60 years, and long duration of exposure to nilotinib. Some of these factors were confirmed in the more recent study conducted at Marseille University Hospital involving patients treated with nilotinib. According to other research, there seems to be a correlation between this risk and the dose administered.

In the case of ponatinib, the side effects are even more common – so much so that, a few months after this third-generation TKI was authorized, a warning was issued about its use. A long-term follow-up study reported a 28% prevalence of cardiovascular events, while arterial diseases were observed in 20% of cases after 1-2 years on the treatment.

In terms of pathophysiology, the Marseilles University Hospital study found that arterial injuries were associated with stenosis greater than 50% in almost half of cases. “The atheromatous plaques were found where they typically are,” with the carotid bulb being the most involved territory, according to the researchers. But they’re also found in other arteries – femoral, vertebral, even renal – “sometimes in patients without cardiovascular risk factors.”

One distinctive characteristic to keep in mind is that “lipid-rich atheromatous plaques appear very dark on imaging” and thus can go unnoticed during a Doppler ultrasound. And, Dr. Sarlon added, “surprisingly, the thickening can extend to the external carotid artery.”

Ankle-brachial index

Published last year, the first European Society of Cardiology Guidelines on Cardio-Oncology present specific baseline risk-assessment and monitoring recommendations regarding patients treated with nilotinib and ponatinib. One suggests that a cardiovascular risk assessment be done every 3 months during the first year and every 6-12 months thereafter. This assessment would include such items as ECGs, blood pressure measurements, and lipid profile tests.

In addition, it is advised that every 6 months an ankle-brachial index test be performed to check for PAD. At Marseille University Hospital, a Doppler ultrasound is also done at each follow-up appointment to look for arterial plaques, “even for patients at low risk for cardiovascular disease,” said Dr. Sarlon. “It seems, above all, absolutely necessary that hematologists order an LDL-C test and, if needed, consider statin therapy,” all the while keeping in mind that “the target LDL-C level is 1 gram per liter.”

This article was translated from the Medscape French edition. A version of this article first appeared on Medscape.com.

Thanks to treatment advancements, patients with chronic lymphocytic leukemia (CLL) are living much longer – and at greater risk of developing other types of cancer. A new Dutch study has found that patients with CLL face higher risks of second primary malignancies (SPM) than the rest of the population, especially those who were treated with antineoplastic therapy.

The report, which appeared in January in Blood Cancer Journal, found that patients diagnosed with CLL between 1989 and 2019 were 63% more likely to were diagnosed with SPM than a matched population: standardized incidence ratio = 1.63, 95% confidence interval (CI), 1.59-1.68.

“Our results provide patients and their treating physicians with an overview of the risk of SPM development. This information can be used in treatment decision-making and for planning appropriate surveillance activities and interventions,” study lead author Lina van der Straten, MD, PhD, of the Albert Schweitzer Hospital and Erasmus University Medical Center in the Netherlands, said in an interview.

Ohio State University hematologist David Bond, MD, who’s familiar with the findings, said in an interview that “it’s been well-established that patients with CLL are at increased risk for second primary malignancies. This is thought to be due to impaired immune surveillance and possibly carcinogenic effects of CLL treatments.” It’s not clear, he said, “whether the rate of second cancers differs between chemoimmunotherapy-treated patients and those receiving newer oral kinase inhibitors.”

Previous research into CLL and SPM has been sparse, Dr. van der Straten said, and most studies haven’t looked at SPM over time and taken into account the widespread use of chemoimmunotherapy and agents such as ibrutinib and venetoclax.

It’s important to study this topic, she said, since “cancers diagnosed after the CLL diagnosis can outweigh the improved longevity and contribute to excess morbidity and mortality in long-term CLL survivors.”

With the help of the Netherlands Cancer Registry, researchers tracked 24,815 patients with CLL who were diagnosed over the 20-year period; 4,369 developed SPM. “We demonstrated that the risk of SPM development was higher than in the general population with an excess of 125 malignancies per 10,000 person-years in the CLL cohort,” Dr. van der Straten said. “The risk of SPM development was found to be heightened in solid and hematological cancers. Patients with CLL had an increased risk of developing cancers at the following sites or types: skin, acute myeloid leukemia, soft-tissue sarcomas, thyroid, kidney, unknown primary localization, non-Hodgkin lymphomas, lung and bronchus, and colon and rectum.”

Specifically, the study reports that “elevated risk was observed for solid (SIR = 1.67; 95% CI, 1.65-1.75) and hematological SPMs (SIR = 1.42; 95% CI, 1.24-1.62). The highest risk for SPMs was noted beyond 5 years post diagnosis (SIR = 1.70; 95% CI, 1.62-1.77), for male individuals (SIR = 1.70; 95% CI, 1.64-1.77), and patients aged 18-69 years (SR = 1.92; 95% CI, 1.79-2.05).

“Patients with CLL exposed to treatment have a higher risk of SPM development than patients who will never receive therapy,” Dr. van der Straten said. Research has shown that “treatment with fludarabine, cyclophosphamide, and rituximab has been associated with a 2.38 increased risk for SPM development, particularly acute myeloid leukemia. Indeed, we found an increased risk for hematological malignancies in patients diagnosed between 2003-2009 and 2010-2019, which might be explained by the broader administration of fludarabine-based strategies in these calendar periods.”

Multiple factors could explain the higher risk of SPM in patients with CLL, including “a dysregulated immune system, treatment-related effects, and surveillance bias,” Dr. van der Straten said. “In addition, it is proposed that the immune dysfunctional nature of CLL might enhance the effect of common carcinogens, such as UV exposure and smoking, in increasing the probability of skin and respiratory cancers.”

She added that “the risk and the spectrum of SPMs were comparable for the 2003-2009 and 2010-2019 periods, suggesting that both the introduction of chemoimmunotherapy and, in part, targeted therapies did not dramatically alter the SPM landscape. However, due to the short follow-up period for the small cohort of patients receiving targeted therapies, further research is warranted.”

Dr. Bond said the findings “are largely in line with prior studies and strengthen their conclusions. Immune surveillance appears to be critical to reducing the risk for some but not all malignancies including lung cancer and melanoma, and the treatments given for CLL can cause immune suppression and thus may increase the risk.”

Moving forward, he said, “this research highlights the importance of second cancers to patients with CLL. It also highlights the need for secondary cancer screening for CLL patients, patient education to avoid known cancer risk factors including smoking and excess UV light exposure, and the need as a field to continue to invest in research into characteristics of second cancers and mitigation strategies.”

Study funding was not reported. The authors and Dr. Bond report no disclosures.

Thanks to treatment advancements, patients with chronic lymphocytic leukemia (CLL) are living much longer – and at greater risk of developing other types of cancer. A new Dutch study has found that patients with CLL face higher risks of second primary malignancies (SPM) than the rest of the population, especially those who were treated with antineoplastic therapy.

The report, which appeared in January in Blood Cancer Journal, found that patients diagnosed with CLL between 1989 and 2019 were 63% more likely to were diagnosed with SPM than a matched population: standardized incidence ratio = 1.63, 95% confidence interval (CI), 1.59-1.68.

“Our results provide patients and their treating physicians with an overview of the risk of SPM development. This information can be used in treatment decision-making and for planning appropriate surveillance activities and interventions,” study lead author Lina van der Straten, MD, PhD, of the Albert Schweitzer Hospital and Erasmus University Medical Center in the Netherlands, said in an interview.

Ohio State University hematologist David Bond, MD, who’s familiar with the findings, said in an interview that “it’s been well-established that patients with CLL are at increased risk for second primary malignancies. This is thought to be due to impaired immune surveillance and possibly carcinogenic effects of CLL treatments.” It’s not clear, he said, “whether the rate of second cancers differs between chemoimmunotherapy-treated patients and those receiving newer oral kinase inhibitors.”

Previous research into CLL and SPM has been sparse, Dr. van der Straten said, and most studies haven’t looked at SPM over time and taken into account the widespread use of chemoimmunotherapy and agents such as ibrutinib and venetoclax.

It’s important to study this topic, she said, since “cancers diagnosed after the CLL diagnosis can outweigh the improved longevity and contribute to excess morbidity and mortality in long-term CLL survivors.”

With the help of the Netherlands Cancer Registry, researchers tracked 24,815 patients with CLL who were diagnosed over the 20-year period; 4,369 developed SPM. “We demonstrated that the risk of SPM development was higher than in the general population with an excess of 125 malignancies per 10,000 person-years in the CLL cohort,” Dr. van der Straten said. “The risk of SPM development was found to be heightened in solid and hematological cancers. Patients with CLL had an increased risk of developing cancers at the following sites or types: skin, acute myeloid leukemia, soft-tissue sarcomas, thyroid, kidney, unknown primary localization, non-Hodgkin lymphomas, lung and bronchus, and colon and rectum.”

Specifically, the study reports that “elevated risk was observed for solid (SIR = 1.67; 95% CI, 1.65-1.75) and hematological SPMs (SIR = 1.42; 95% CI, 1.24-1.62). The highest risk for SPMs was noted beyond 5 years post diagnosis (SIR = 1.70; 95% CI, 1.62-1.77), for male individuals (SIR = 1.70; 95% CI, 1.64-1.77), and patients aged 18-69 years (SR = 1.92; 95% CI, 1.79-2.05).

“Patients with CLL exposed to treatment have a higher risk of SPM development than patients who will never receive therapy,” Dr. van der Straten said. Research has shown that “treatment with fludarabine, cyclophosphamide, and rituximab has been associated with a 2.38 increased risk for SPM development, particularly acute myeloid leukemia. Indeed, we found an increased risk for hematological malignancies in patients diagnosed between 2003-2009 and 2010-2019, which might be explained by the broader administration of fludarabine-based strategies in these calendar periods.”

Multiple factors could explain the higher risk of SPM in patients with CLL, including “a dysregulated immune system, treatment-related effects, and surveillance bias,” Dr. van der Straten said. “In addition, it is proposed that the immune dysfunctional nature of CLL might enhance the effect of common carcinogens, such as UV exposure and smoking, in increasing the probability of skin and respiratory cancers.”

She added that “the risk and the spectrum of SPMs were comparable for the 2003-2009 and 2010-2019 periods, suggesting that both the introduction of chemoimmunotherapy and, in part, targeted therapies did not dramatically alter the SPM landscape. However, due to the short follow-up period for the small cohort of patients receiving targeted therapies, further research is warranted.”

Dr. Bond said the findings “are largely in line with prior studies and strengthen their conclusions. Immune surveillance appears to be critical to reducing the risk for some but not all malignancies including lung cancer and melanoma, and the treatments given for CLL can cause immune suppression and thus may increase the risk.”

Moving forward, he said, “this research highlights the importance of second cancers to patients with CLL. It also highlights the need for secondary cancer screening for CLL patients, patient education to avoid known cancer risk factors including smoking and excess UV light exposure, and the need as a field to continue to invest in research into characteristics of second cancers and mitigation strategies.”

Study funding was not reported. The authors and Dr. Bond report no disclosures.

Thanks to treatment advancements, patients with chronic lymphocytic leukemia (CLL) are living much longer – and at greater risk of developing other types of cancer. A new Dutch study has found that patients with CLL face higher risks of second primary malignancies (SPM) than the rest of the population, especially those who were treated with antineoplastic therapy.

The report, which appeared in January in Blood Cancer Journal, found that patients diagnosed with CLL between 1989 and 2019 were 63% more likely to were diagnosed with SPM than a matched population: standardized incidence ratio = 1.63, 95% confidence interval (CI), 1.59-1.68.

“Our results provide patients and their treating physicians with an overview of the risk of SPM development. This information can be used in treatment decision-making and for planning appropriate surveillance activities and interventions,” study lead author Lina van der Straten, MD, PhD, of the Albert Schweitzer Hospital and Erasmus University Medical Center in the Netherlands, said in an interview.

Ohio State University hematologist David Bond, MD, who’s familiar with the findings, said in an interview that “it’s been well-established that patients with CLL are at increased risk for second primary malignancies. This is thought to be due to impaired immune surveillance and possibly carcinogenic effects of CLL treatments.” It’s not clear, he said, “whether the rate of second cancers differs between chemoimmunotherapy-treated patients and those receiving newer oral kinase inhibitors.”

Previous research into CLL and SPM has been sparse, Dr. van der Straten said, and most studies haven’t looked at SPM over time and taken into account the widespread use of chemoimmunotherapy and agents such as ibrutinib and venetoclax.

It’s important to study this topic, she said, since “cancers diagnosed after the CLL diagnosis can outweigh the improved longevity and contribute to excess morbidity and mortality in long-term CLL survivors.”

With the help of the Netherlands Cancer Registry, researchers tracked 24,815 patients with CLL who were diagnosed over the 20-year period; 4,369 developed SPM. “We demonstrated that the risk of SPM development was higher than in the general population with an excess of 125 malignancies per 10,000 person-years in the CLL cohort,” Dr. van der Straten said. “The risk of SPM development was found to be heightened in solid and hematological cancers. Patients with CLL had an increased risk of developing cancers at the following sites or types: skin, acute myeloid leukemia, soft-tissue sarcomas, thyroid, kidney, unknown primary localization, non-Hodgkin lymphomas, lung and bronchus, and colon and rectum.”

Specifically, the study reports that “elevated risk was observed for solid (SIR = 1.67; 95% CI, 1.65-1.75) and hematological SPMs (SIR = 1.42; 95% CI, 1.24-1.62). The highest risk for SPMs was noted beyond 5 years post diagnosis (SIR = 1.70; 95% CI, 1.62-1.77), for male individuals (SIR = 1.70; 95% CI, 1.64-1.77), and patients aged 18-69 years (SR = 1.92; 95% CI, 1.79-2.05).

“Patients with CLL exposed to treatment have a higher risk of SPM development than patients who will never receive therapy,” Dr. van der Straten said. Research has shown that “treatment with fludarabine, cyclophosphamide, and rituximab has been associated with a 2.38 increased risk for SPM development, particularly acute myeloid leukemia. Indeed, we found an increased risk for hematological malignancies in patients diagnosed between 2003-2009 and 2010-2019, which might be explained by the broader administration of fludarabine-based strategies in these calendar periods.”

Multiple factors could explain the higher risk of SPM in patients with CLL, including “a dysregulated immune system, treatment-related effects, and surveillance bias,” Dr. van der Straten said. “In addition, it is proposed that the immune dysfunctional nature of CLL might enhance the effect of common carcinogens, such as UV exposure and smoking, in increasing the probability of skin and respiratory cancers.”

She added that “the risk and the spectrum of SPMs were comparable for the 2003-2009 and 2010-2019 periods, suggesting that both the introduction of chemoimmunotherapy and, in part, targeted therapies did not dramatically alter the SPM landscape. However, due to the short follow-up period for the small cohort of patients receiving targeted therapies, further research is warranted.”

Dr. Bond said the findings “are largely in line with prior studies and strengthen their conclusions. Immune surveillance appears to be critical to reducing the risk for some but not all malignancies including lung cancer and melanoma, and the treatments given for CLL can cause immune suppression and thus may increase the risk.”

Moving forward, he said, “this research highlights the importance of second cancers to patients with CLL. It also highlights the need for secondary cancer screening for CLL patients, patient education to avoid known cancer risk factors including smoking and excess UV light exposure, and the need as a field to continue to invest in research into characteristics of second cancers and mitigation strategies.”

Study funding was not reported. The authors and Dr. Bond report no disclosures.

While it’s well known that COVID-19 vaccines are less effective in patients with chronic lymphocytic leukemia (CLL) who take immunity-lowering drugs, a new study offers fresh insight into what’s happening inside the body. In these patients, the vaccines often don’t boost B cells, which produce antibodies, but they do strengthen T cells, potentially providing crucial protection against severe illness and death.

These findings don’t reveal whether the T-cell boost actually provides extra protection against COVID-19. Still, the study suggests that patients with CLL should be vaccinated no matter which medications they’re taking, coauthor and hematologist/oncologist Clemens-Martin Wendtner, MD, of the Munich (Germany) Clinic, said in an interview.

“Do not defer or pause treatment,” said Dr. Wendtner, whose study was published in Blood Advances.

Patients with CLL appear to have among the weakest responses to the COVID-19 vaccine among people with various types of blood cancer. A meta-analysis published in 2022 found that seropositivity rates following vaccination were just 51% in patients with CLL, compared with 80%-90% in those with acute leukemia and 76%-80% of those with myeloma.

“Usually, the response rate to vaccination among the nonimmunocompromised would be 95%,” Dr. Wendtner said.

Research has also suggested that patients treated with B-cell pathway inhibitors and anti-CD20 antibodies are especially likely to have poorer responses to COVID-19 vaccines, no surprise considering that their job is to dampen the immune system. But there’s an unanswered question, according to Dr. Wendtner: Does “just measuring B-cell response tell us everything about the immune response?”

The new prospective, single-institution study aims to answer that question in patients who each received two types of vaccines. Researchers compared peripheral blood mononuclear cell transcriptional response with antibody and T-cell response rates in 15 patients with CLL/small lymphocytic lymphoma following vaccination with both the Pfizer-BioNTech and AstraZeneca vaccines.

The average antibody response was limited. “Overall, 7/15 of patients failed to mount a humoral response even after three-dose vaccination,” the researchers reported. All of the patients were “heavily pretreated” with CLL medications such as venetoclax, an anti-CD20 monoclonal antibody.

By contrast, the T-cell response was much stronger: 80% of patients (12/15) had a robust response, a number that grew to 90% (14/15) after a booster. This response is “almost ideal” considering that the response in a nonimmunocompromised person would be about 99%, Dr. Wendtner said.

The study also revealed that vaccine responses were weaker in patients who took a combination of a Bruton tyrosine kinase inhibitor and venetoclax within a year.

Four patients developed COVID-19 infections with the Omicron variant about 6 months after vaccination. All had mild symptoms. A lone patient had a history of COVID-19 infection prior to vaccination.

The researchers noted that the study had several limitations, including its small size, its reliance on a single institution, and the differences in treatments and vaccination protocols among the patient population.

Broadly speaking, the study showed that “a vaccine is not in vain” in patients with CLL, “although the doctor might not detect an antibody response,” Dr. Wendtner said. He added that mixing vaccine types should provide more protection. Start with a viral vector vaccine followed by an mRNA vaccine or vice versa, he suggested.

In an interview, infectious disease physician Joshua A. Hill, MD, from Fred Hutchinson Cancer Center, Seattle, who wasn’t involved with the study, said it makes “important and interesting observations to reinforce other studies with similar findings.”

Specifically, Dr. Hill said, “despite the absence of a robust antibody response some of these patients who are on active treatment, patients can still generate robust cellular immune responses in the form of T-cell immunity. Our understanding is that having T cell immunity will provide important additional protection for developing severe disease, although is less easily tested.”

As for the best vaccination strategies, Dr. Hill said “patients should get vaccinated as soon as they are eligible, according to standard guidelines. If patients have not yet started therapy, they should get their indicated vaccines before starting treatment whenever possible.”

The German study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Bavarian State Ministry of Science and Art. Dr. Wendtner disclosed consultant fees from AstraZeneca and BioNTech, and another author disclosed consultant fees from AstraZeneca. The other authors reported no disclosures. Dr. Hill disclosed consultant fees from Moderna, Pfizer, and Gilead.

While it’s well known that COVID-19 vaccines are less effective in patients with chronic lymphocytic leukemia (CLL) who take immunity-lowering drugs, a new study offers fresh insight into what’s happening inside the body. In these patients, the vaccines often don’t boost B cells, which produce antibodies, but they do strengthen T cells, potentially providing crucial protection against severe illness and death.

These findings don’t reveal whether the T-cell boost actually provides extra protection against COVID-19. Still, the study suggests that patients with CLL should be vaccinated no matter which medications they’re taking, coauthor and hematologist/oncologist Clemens-Martin Wendtner, MD, of the Munich (Germany) Clinic, said in an interview.

“Do not defer or pause treatment,” said Dr. Wendtner, whose study was published in Blood Advances.

Patients with CLL appear to have among the weakest responses to the COVID-19 vaccine among people with various types of blood cancer. A meta-analysis published in 2022 found that seropositivity rates following vaccination were just 51% in patients with CLL, compared with 80%-90% in those with acute leukemia and 76%-80% of those with myeloma.

“Usually, the response rate to vaccination among the nonimmunocompromised would be 95%,” Dr. Wendtner said.

Research has also suggested that patients treated with B-cell pathway inhibitors and anti-CD20 antibodies are especially likely to have poorer responses to COVID-19 vaccines, no surprise considering that their job is to dampen the immune system. But there’s an unanswered question, according to Dr. Wendtner: Does “just measuring B-cell response tell us everything about the immune response?”

The new prospective, single-institution study aims to answer that question in patients who each received two types of vaccines. Researchers compared peripheral blood mononuclear cell transcriptional response with antibody and T-cell response rates in 15 patients with CLL/small lymphocytic lymphoma following vaccination with both the Pfizer-BioNTech and AstraZeneca vaccines.

The average antibody response was limited. “Overall, 7/15 of patients failed to mount a humoral response even after three-dose vaccination,” the researchers reported. All of the patients were “heavily pretreated” with CLL medications such as venetoclax, an anti-CD20 monoclonal antibody.

By contrast, the T-cell response was much stronger: 80% of patients (12/15) had a robust response, a number that grew to 90% (14/15) after a booster. This response is “almost ideal” considering that the response in a nonimmunocompromised person would be about 99%, Dr. Wendtner said.

The study also revealed that vaccine responses were weaker in patients who took a combination of a Bruton tyrosine kinase inhibitor and venetoclax within a year.

Four patients developed COVID-19 infections with the Omicron variant about 6 months after vaccination. All had mild symptoms. A lone patient had a history of COVID-19 infection prior to vaccination.

The researchers noted that the study had several limitations, including its small size, its reliance on a single institution, and the differences in treatments and vaccination protocols among the patient population.

Broadly speaking, the study showed that “a vaccine is not in vain” in patients with CLL, “although the doctor might not detect an antibody response,” Dr. Wendtner said. He added that mixing vaccine types should provide more protection. Start with a viral vector vaccine followed by an mRNA vaccine or vice versa, he suggested.

In an interview, infectious disease physician Joshua A. Hill, MD, from Fred Hutchinson Cancer Center, Seattle, who wasn’t involved with the study, said it makes “important and interesting observations to reinforce other studies with similar findings.”

Specifically, Dr. Hill said, “despite the absence of a robust antibody response some of these patients who are on active treatment, patients can still generate robust cellular immune responses in the form of T-cell immunity. Our understanding is that having T cell immunity will provide important additional protection for developing severe disease, although is less easily tested.”

As for the best vaccination strategies, Dr. Hill said “patients should get vaccinated as soon as they are eligible, according to standard guidelines. If patients have not yet started therapy, they should get their indicated vaccines before starting treatment whenever possible.”

The German study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Bavarian State Ministry of Science and Art. Dr. Wendtner disclosed consultant fees from AstraZeneca and BioNTech, and another author disclosed consultant fees from AstraZeneca. The other authors reported no disclosures. Dr. Hill disclosed consultant fees from Moderna, Pfizer, and Gilead.

While it’s well known that COVID-19 vaccines are less effective in patients with chronic lymphocytic leukemia (CLL) who take immunity-lowering drugs, a new study offers fresh insight into what’s happening inside the body. In these patients, the vaccines often don’t boost B cells, which produce antibodies, but they do strengthen T cells, potentially providing crucial protection against severe illness and death.

These findings don’t reveal whether the T-cell boost actually provides extra protection against COVID-19. Still, the study suggests that patients with CLL should be vaccinated no matter which medications they’re taking, coauthor and hematologist/oncologist Clemens-Martin Wendtner, MD, of the Munich (Germany) Clinic, said in an interview.

“Do not defer or pause treatment,” said Dr. Wendtner, whose study was published in Blood Advances.

Patients with CLL appear to have among the weakest responses to the COVID-19 vaccine among people with various types of blood cancer. A meta-analysis published in 2022 found that seropositivity rates following vaccination were just 51% in patients with CLL, compared with 80%-90% in those with acute leukemia and 76%-80% of those with myeloma.

“Usually, the response rate to vaccination among the nonimmunocompromised would be 95%,” Dr. Wendtner said.

Research has also suggested that patients treated with B-cell pathway inhibitors and anti-CD20 antibodies are especially likely to have poorer responses to COVID-19 vaccines, no surprise considering that their job is to dampen the immune system. But there’s an unanswered question, according to Dr. Wendtner: Does “just measuring B-cell response tell us everything about the immune response?”

The new prospective, single-institution study aims to answer that question in patients who each received two types of vaccines. Researchers compared peripheral blood mononuclear cell transcriptional response with antibody and T-cell response rates in 15 patients with CLL/small lymphocytic lymphoma following vaccination with both the Pfizer-BioNTech and AstraZeneca vaccines.

The average antibody response was limited. “Overall, 7/15 of patients failed to mount a humoral response even after three-dose vaccination,” the researchers reported. All of the patients were “heavily pretreated” with CLL medications such as venetoclax, an anti-CD20 monoclonal antibody.

By contrast, the T-cell response was much stronger: 80% of patients (12/15) had a robust response, a number that grew to 90% (14/15) after a booster. This response is “almost ideal” considering that the response in a nonimmunocompromised person would be about 99%, Dr. Wendtner said.

The study also revealed that vaccine responses were weaker in patients who took a combination of a Bruton tyrosine kinase inhibitor and venetoclax within a year.

Four patients developed COVID-19 infections with the Omicron variant about 6 months after vaccination. All had mild symptoms. A lone patient had a history of COVID-19 infection prior to vaccination.

The researchers noted that the study had several limitations, including its small size, its reliance on a single institution, and the differences in treatments and vaccination protocols among the patient population.

Broadly speaking, the study showed that “a vaccine is not in vain” in patients with CLL, “although the doctor might not detect an antibody response,” Dr. Wendtner said. He added that mixing vaccine types should provide more protection. Start with a viral vector vaccine followed by an mRNA vaccine or vice versa, he suggested.

In an interview, infectious disease physician Joshua A. Hill, MD, from Fred Hutchinson Cancer Center, Seattle, who wasn’t involved with the study, said it makes “important and interesting observations to reinforce other studies with similar findings.”

Specifically, Dr. Hill said, “despite the absence of a robust antibody response some of these patients who are on active treatment, patients can still generate robust cellular immune responses in the form of T-cell immunity. Our understanding is that having T cell immunity will provide important additional protection for developing severe disease, although is less easily tested.”

As for the best vaccination strategies, Dr. Hill said “patients should get vaccinated as soon as they are eligible, according to standard guidelines. If patients have not yet started therapy, they should get their indicated vaccines before starting treatment whenever possible.”

The German study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Bavarian State Ministry of Science and Art. Dr. Wendtner disclosed consultant fees from AstraZeneca and BioNTech, and another author disclosed consultant fees from AstraZeneca. The other authors reported no disclosures. Dr. Hill disclosed consultant fees from Moderna, Pfizer, and Gilead.

The Food and Drug Administration has granted accelerated approval to pirtobrutinib (Jaypirca) for relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a Bruton’s tyrosine kinase inhibitor.

Pirtobrutinib is the first and only noncovalent Bruton’s tyrosine kinase inhibitor approved for use in this MCL setting, manufacturer Eli Lilly noted in a press release.

“The approval of Jaypirca represents an important advance for patients with relapsed or refractory MCL, who currently have limited options and historically have had a poor prognosis following discontinuation of treatment with a covalent Bruton’s tyrosine kinase inhibitor,” senior author Michael Wang, MD, University of Texas MD Anderson Cancer Center, Houston, said in the release.

The approval was based on efficacy demonstrated in the open-label, single-arm, phase 1/2 BRUIN trial – a multicenter study assessing 200 mg once-daily oral pirtobrutinib monotherapy in 120 patients with MCL who had previously received a Bruton’s tyrosine kinase inhibitor, most often ibrutinib (Imbruvica, 67%) acalabrutinib (Calquence, 30%) and zanubrutinib (Brukinsa, 8%). Pirtobrutinib was continued until disease progression or unacceptable toxicity.

Study participants had a median of three prior lines of therapy, and 83% discontinued their last Bruton’s tyrosine kinase inhibitor because of refractory or progressive disease.

The overall response rate in pirtobrutinib-treated patients was 50% with a complete response rate of 13%. Estimated median duration of response was 8.3 months, and the estimated duration of response at 6 months occurred in nearly two-thirds of patients.

Adverse reactions that occurred in at least 15% of patients included fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Grade 3 or 4 laboratory abnormalities occurring in at least 10% of patients included decreased neutrophil counts, lymphocyte counts, and platelet counts.

Prescribing information for pirtobrutinib includes warnings and precautions for infections, hemorrhage, cytopenias, atrial fibrillation and flutter, and second primary malignancies, noted the FDA, which granted priority review, fast track designation, and orphan drug designation for the application submitted by Eli Lilly.

“Jaypirca can reestablish Bruton’s tyrosine kinase inhibition in MCL patients previously treated with a covalent Bruton’s tyrosine kinase inhibitor (ibrutinib, acalabrutinib, or zanubrutinib) and extend the benefit of targeting the Bruton’s tyrosine kinase pathway,” according to Eli Lilly’s release.

Dr. Wang added that the agent “has the potential to meaningfully impact the treatment paradigm for relapsed and refractory MCL patients.”

Meghan Gutierrez, CEO at the Lymphoma Research Foundation, also noted that “the approval of Jaypirca brings a new treatment option and, along with that, new hope for people with relapsed or refractory MCL.”

The drug is expected to be available in the United States in the coming weeks, and the confirmatory phase 3 BRUIN trial is currently enrolling patients, Eli Lilly announced. The company also indicated the list price would be $21,000 for a 30-day supply of the 200-mg dose.

Serious adverse events believed to be associated with the use of pirtobrutinib or any medicine or device should be reported to the FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

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

The Food and Drug Administration has granted accelerated approval to pirtobrutinib (Jaypirca) for relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a Bruton’s tyrosine kinase inhibitor.

Pirtobrutinib is the first and only noncovalent Bruton’s tyrosine kinase inhibitor approved for use in this MCL setting, manufacturer Eli Lilly noted in a press release.

“The approval of Jaypirca represents an important advance for patients with relapsed or refractory MCL, who currently have limited options and historically have had a poor prognosis following discontinuation of treatment with a covalent Bruton’s tyrosine kinase inhibitor,” senior author Michael Wang, MD, University of Texas MD Anderson Cancer Center, Houston, said in the release.

The approval was based on efficacy demonstrated in the open-label, single-arm, phase 1/2 BRUIN trial – a multicenter study assessing 200 mg once-daily oral pirtobrutinib monotherapy in 120 patients with MCL who had previously received a Bruton’s tyrosine kinase inhibitor, most often ibrutinib (Imbruvica, 67%) acalabrutinib (Calquence, 30%) and zanubrutinib (Brukinsa, 8%). Pirtobrutinib was continued until disease progression or unacceptable toxicity.

Study participants had a median of three prior lines of therapy, and 83% discontinued their last Bruton’s tyrosine kinase inhibitor because of refractory or progressive disease.

The overall response rate in pirtobrutinib-treated patients was 50% with a complete response rate of 13%. Estimated median duration of response was 8.3 months, and the estimated duration of response at 6 months occurred in nearly two-thirds of patients.

Adverse reactions that occurred in at least 15% of patients included fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Grade 3 or 4 laboratory abnormalities occurring in at least 10% of patients included decreased neutrophil counts, lymphocyte counts, and platelet counts.

Prescribing information for pirtobrutinib includes warnings and precautions for infections, hemorrhage, cytopenias, atrial fibrillation and flutter, and second primary malignancies, noted the FDA, which granted priority review, fast track designation, and orphan drug designation for the application submitted by Eli Lilly.

“Jaypirca can reestablish Bruton’s tyrosine kinase inhibition in MCL patients previously treated with a covalent Bruton’s tyrosine kinase inhibitor (ibrutinib, acalabrutinib, or zanubrutinib) and extend the benefit of targeting the Bruton’s tyrosine kinase pathway,” according to Eli Lilly’s release.

Dr. Wang added that the agent “has the potential to meaningfully impact the treatment paradigm for relapsed and refractory MCL patients.”

Meghan Gutierrez, CEO at the Lymphoma Research Foundation, also noted that “the approval of Jaypirca brings a new treatment option and, along with that, new hope for people with relapsed or refractory MCL.”

The drug is expected to be available in the United States in the coming weeks, and the confirmatory phase 3 BRUIN trial is currently enrolling patients, Eli Lilly announced. The company also indicated the list price would be $21,000 for a 30-day supply of the 200-mg dose.

Serious adverse events believed to be associated with the use of pirtobrutinib or any medicine or device should be reported to the FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

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

The Food and Drug Administration has granted accelerated approval to pirtobrutinib (Jaypirca) for relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a Bruton’s tyrosine kinase inhibitor.

Pirtobrutinib is the first and only noncovalent Bruton’s tyrosine kinase inhibitor approved for use in this MCL setting, manufacturer Eli Lilly noted in a press release.

“The approval of Jaypirca represents an important advance for patients with relapsed or refractory MCL, who currently have limited options and historically have had a poor prognosis following discontinuation of treatment with a covalent Bruton’s tyrosine kinase inhibitor,” senior author Michael Wang, MD, University of Texas MD Anderson Cancer Center, Houston, said in the release.

The approval was based on efficacy demonstrated in the open-label, single-arm, phase 1/2 BRUIN trial – a multicenter study assessing 200 mg once-daily oral pirtobrutinib monotherapy in 120 patients with MCL who had previously received a Bruton’s tyrosine kinase inhibitor, most often ibrutinib (Imbruvica, 67%) acalabrutinib (Calquence, 30%) and zanubrutinib (Brukinsa, 8%). Pirtobrutinib was continued until disease progression or unacceptable toxicity.

Study participants had a median of three prior lines of therapy, and 83% discontinued their last Bruton’s tyrosine kinase inhibitor because of refractory or progressive disease.

The overall response rate in pirtobrutinib-treated patients was 50% with a complete response rate of 13%. Estimated median duration of response was 8.3 months, and the estimated duration of response at 6 months occurred in nearly two-thirds of patients.

Adverse reactions that occurred in at least 15% of patients included fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Grade 3 or 4 laboratory abnormalities occurring in at least 10% of patients included decreased neutrophil counts, lymphocyte counts, and platelet counts.

Prescribing information for pirtobrutinib includes warnings and precautions for infections, hemorrhage, cytopenias, atrial fibrillation and flutter, and second primary malignancies, noted the FDA, which granted priority review, fast track designation, and orphan drug designation for the application submitted by Eli Lilly.

“Jaypirca can reestablish Bruton’s tyrosine kinase inhibition in MCL patients previously treated with a covalent Bruton’s tyrosine kinase inhibitor (ibrutinib, acalabrutinib, or zanubrutinib) and extend the benefit of targeting the Bruton’s tyrosine kinase pathway,” according to Eli Lilly’s release.

Dr. Wang added that the agent “has the potential to meaningfully impact the treatment paradigm for relapsed and refractory MCL patients.”

Meghan Gutierrez, CEO at the Lymphoma Research Foundation, also noted that “the approval of Jaypirca brings a new treatment option and, along with that, new hope for people with relapsed or refractory MCL.”

The drug is expected to be available in the United States in the coming weeks, and the confirmatory phase 3 BRUIN trial is currently enrolling patients, Eli Lilly announced. The company also indicated the list price would be $21,000 for a 30-day supply of the 200-mg dose.

Serious adverse events believed to be associated with the use of pirtobrutinib or any medicine or device should be reported to the FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

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

Adding venetoclax to ibrutinib for chronic lymphocytic leukemia (CLL) improved rates of durable, treatment-free remission among 45 patients at the University of Texas MD Anderson Cancer Center, Houston.

Investigators led by Philip Thompson, MD, a hematologist/oncologist at the center, explained that CLL patients receiving ibrutinib, a Bruton’s kinase inhibitor, “rarely achieve complete remission with undetectable measurable residual disease,” so they stay on the costly treatment indefinitely or until disease progression or accumulating adverse events force a switch to venetoclax.

Using the two agents together, instead of consecutively, may allow strong responders to stop treatment altogether and suboptimal responders to have longer remissions, they said.

“We would not advocate prolonged Bruton’s kinase inhibitor use prior to starting venetoclax in treatment-naive patients, as the safety and efficacy of commencing venetoclax after a 3-month ibrutinib monotherapy phase has been repeatedly demonstrated,” the team said.

However, the investigators noted that their “study was not intended to directly answer the question of whether combination therapy is superior to the current paradigm of sequential monotherapy.” Randomized trials are looking into the matter. The study was published recently as a preprint on ResearchSquare.com and has not been peer reviewed.
 

Complete remission in over half

The 45 adult subjects had one or more high-risk features for CLL progression and had received at least 1 year of ibrutinib at 140-420 mg once daily, depending on tolerance. They had bone marrow detectable disease at study entry but did not meet criteria for progression. Median duration of ibrutinib at baseline was 32 months, and about half the subjects were on it as their initial therapy.

Venetoclax, a BCL2 inhibitor with a completely different mechanisms of action, was added to ibrutinib for up to 2 years, escalated up to a target dose of 400 mg once daily.

On intention-to-treat analysis, venetoclax add-on improved ibrutinib response to complete remission in 55% of patients; complete remission was defined as less than 1 CLL cell per 10,000 leukocytes in bone marrow on two consecutive occasions 6 months apart.

The rate of undetectable bone marrow disease was 57% after 1 year of combined treatment and 71% after venetoclax completion, at which point 23 patients with undetectable disease stopped ibrutinib along with venetoclax.

Five patients had disease progression at a median of 41 months after venetoclax initiation, one during combined therapy, three during ibrutinib maintenance afterward, and one with Richter transformation after complete remission and discontinuation of all treatment. No patient had died from CLL.

“There has so far been no significant difference noted in” time to residual disease re-emergence, the team said, based on whether or not patients continued ibrutinib after venetoclax add-on.

There was no significant difference in the rate of bone marrow clearance according to the presence or absence of TP53 abnormalities, complex karyotypes, or prior treatment status.

The most common grade 3/4 adverse event was neutropenia in 20% of patients. Nine patients developed nonmelanoma skin cancer during the trial; six were diagnosed with other solid tumors; three came down with grade 3 infections, and two developed myelodysplastic syndrome, both with a prior history of chemotherapy.

No one stopped venetoclax because of toxicity, but about a third of subjects required dose reductions, most often because of neutropenia.

The study was funded by AbbVie, which is commercializing venetoclax along with Genentech. Investigators disclosed ties to both companies and many others. Dr. Thompson disclosed ties to AbbVie, Pharmacyclics, Lilly, Adaptive Biotechnologies, Janssen, Beigene, and Genentech.

Adding venetoclax to ibrutinib for chronic lymphocytic leukemia (CLL) improved rates of durable, treatment-free remission among 45 patients at the University of Texas MD Anderson Cancer Center, Houston.

Investigators led by Philip Thompson, MD, a hematologist/oncologist at the center, explained that CLL patients receiving ibrutinib, a Bruton’s kinase inhibitor, “rarely achieve complete remission with undetectable measurable residual disease,” so they stay on the costly treatment indefinitely or until disease progression or accumulating adverse events force a switch to venetoclax.

Using the two agents together, instead of consecutively, may allow strong responders to stop treatment altogether and suboptimal responders to have longer remissions, they said.

“We would not advocate prolonged Bruton’s kinase inhibitor use prior to starting venetoclax in treatment-naive patients, as the safety and efficacy of commencing venetoclax after a 3-month ibrutinib monotherapy phase has been repeatedly demonstrated,” the team said.

However, the investigators noted that their “study was not intended to directly answer the question of whether combination therapy is superior to the current paradigm of sequential monotherapy.” Randomized trials are looking into the matter. The study was published recently as a preprint on ResearchSquare.com and has not been peer reviewed.
 

Complete remission in over half

The 45 adult subjects had one or more high-risk features for CLL progression and had received at least 1 year of ibrutinib at 140-420 mg once daily, depending on tolerance. They had bone marrow detectable disease at study entry but did not meet criteria for progression. Median duration of ibrutinib at baseline was 32 months, and about half the subjects were on it as their initial therapy.

Venetoclax, a BCL2 inhibitor with a completely different mechanisms of action, was added to ibrutinib for up to 2 years, escalated up to a target dose of 400 mg once daily.

On intention-to-treat analysis, venetoclax add-on improved ibrutinib response to complete remission in 55% of patients; complete remission was defined as less than 1 CLL cell per 10,000 leukocytes in bone marrow on two consecutive occasions 6 months apart.

The rate of undetectable bone marrow disease was 57% after 1 year of combined treatment and 71% after venetoclax completion, at which point 23 patients with undetectable disease stopped ibrutinib along with venetoclax.

Five patients had disease progression at a median of 41 months after venetoclax initiation, one during combined therapy, three during ibrutinib maintenance afterward, and one with Richter transformation after complete remission and discontinuation of all treatment. No patient had died from CLL.

“There has so far been no significant difference noted in” time to residual disease re-emergence, the team said, based on whether or not patients continued ibrutinib after venetoclax add-on.

There was no significant difference in the rate of bone marrow clearance according to the presence or absence of TP53 abnormalities, complex karyotypes, or prior treatment status.

The most common grade 3/4 adverse event was neutropenia in 20% of patients. Nine patients developed nonmelanoma skin cancer during the trial; six were diagnosed with other solid tumors; three came down with grade 3 infections, and two developed myelodysplastic syndrome, both with a prior history of chemotherapy.

No one stopped venetoclax because of toxicity, but about a third of subjects required dose reductions, most often because of neutropenia.

The study was funded by AbbVie, which is commercializing venetoclax along with Genentech. Investigators disclosed ties to both companies and many others. Dr. Thompson disclosed ties to AbbVie, Pharmacyclics, Lilly, Adaptive Biotechnologies, Janssen, Beigene, and Genentech.

Adding venetoclax to ibrutinib for chronic lymphocytic leukemia (CLL) improved rates of durable, treatment-free remission among 45 patients at the University of Texas MD Anderson Cancer Center, Houston.

Investigators led by Philip Thompson, MD, a hematologist/oncologist at the center, explained that CLL patients receiving ibrutinib, a Bruton’s kinase inhibitor, “rarely achieve complete remission with undetectable measurable residual disease,” so they stay on the costly treatment indefinitely or until disease progression or accumulating adverse events force a switch to venetoclax.

Using the two agents together, instead of consecutively, may allow strong responders to stop treatment altogether and suboptimal responders to have longer remissions, they said.

“We would not advocate prolonged Bruton’s kinase inhibitor use prior to starting venetoclax in treatment-naive patients, as the safety and efficacy of commencing venetoclax after a 3-month ibrutinib monotherapy phase has been repeatedly demonstrated,” the team said.

However, the investigators noted that their “study was not intended to directly answer the question of whether combination therapy is superior to the current paradigm of sequential monotherapy.” Randomized trials are looking into the matter. The study was published recently as a preprint on ResearchSquare.com and has not been peer reviewed.
 

Complete remission in over half

The 45 adult subjects had one or more high-risk features for CLL progression and had received at least 1 year of ibrutinib at 140-420 mg once daily, depending on tolerance. They had bone marrow detectable disease at study entry but did not meet criteria for progression. Median duration of ibrutinib at baseline was 32 months, and about half the subjects were on it as their initial therapy.

Venetoclax, a BCL2 inhibitor with a completely different mechanisms of action, was added to ibrutinib for up to 2 years, escalated up to a target dose of 400 mg once daily.

On intention-to-treat analysis, venetoclax add-on improved ibrutinib response to complete remission in 55% of patients; complete remission was defined as less than 1 CLL cell per 10,000 leukocytes in bone marrow on two consecutive occasions 6 months apart.

The rate of undetectable bone marrow disease was 57% after 1 year of combined treatment and 71% after venetoclax completion, at which point 23 patients with undetectable disease stopped ibrutinib along with venetoclax.

Five patients had disease progression at a median of 41 months after venetoclax initiation, one during combined therapy, three during ibrutinib maintenance afterward, and one with Richter transformation after complete remission and discontinuation of all treatment. No patient had died from CLL.

“There has so far been no significant difference noted in” time to residual disease re-emergence, the team said, based on whether or not patients continued ibrutinib after venetoclax add-on.

There was no significant difference in the rate of bone marrow clearance according to the presence or absence of TP53 abnormalities, complex karyotypes, or prior treatment status.

The most common grade 3/4 adverse event was neutropenia in 20% of patients. Nine patients developed nonmelanoma skin cancer during the trial; six were diagnosed with other solid tumors; three came down with grade 3 infections, and two developed myelodysplastic syndrome, both with a prior history of chemotherapy.

No one stopped venetoclax because of toxicity, but about a third of subjects required dose reductions, most often because of neutropenia.

The study was funded by AbbVie, which is commercializing venetoclax along with Genentech. Investigators disclosed ties to both companies and many others. Dr. Thompson disclosed ties to AbbVie, Pharmacyclics, Lilly, Adaptive Biotechnologies, Janssen, Beigene, and Genentech.