B Cell Lymphoma

Key clinical point: Idelalisib demonstrated long-term efficacy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia (CLL), and despite having a relatively higher toxicity profile than other targeted therapeutics, can be used in such patients in the absence of alternative therapies.

Major finding: The overall response rate was 65%, with 1 patient achieving complete remission. At a median follow-up of 33.6 months, the median progression-free survival was 16.4 months (95% CI 10.4-26.3), whereas the median overall survival was not reached. Grade ≥ 3 adverse events occurred in 10 patients. The most common serious adverse event was grade ≥ 3 infection (65%).

Study details: This real-world observational retrospective study included 37 patients with CLL (for up to 2.5 years after idelalisib approval in 2014) who had relapsed after or were refractory to ≥ 1 prior lines of therapy and received idelalisib with or without concomitant rituximab.

Disclosures: This study was supported by grants from AFA Insurance (Australia), the Swedish Cancer Society, and others. Three authors declared receiving research grants or honoraria from various sources. The other authors did not have any conflicts of interest to disclose.

Source: Mattsson A et al. Idelalisib (PI3Kδ inhibitor) therapy for patients with relapsed/refractory chronic lymphocytic leukemia: A Swedish nation-wide real-world report on consecutively identified patients. Eur J Haematol. 2023 (Jul 27). doi: 10.1111/ejh.14065

Key clinical point: Idelalisib demonstrated long-term efficacy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia (CLL), and despite having a relatively higher toxicity profile than other targeted therapeutics, can be used in such patients in the absence of alternative therapies.

Major finding: The overall response rate was 65%, with 1 patient achieving complete remission. At a median follow-up of 33.6 months, the median progression-free survival was 16.4 months (95% CI 10.4-26.3), whereas the median overall survival was not reached. Grade ≥ 3 adverse events occurred in 10 patients. The most common serious adverse event was grade ≥ 3 infection (65%).

Study details: This real-world observational retrospective study included 37 patients with CLL (for up to 2.5 years after idelalisib approval in 2014) who had relapsed after or were refractory to ≥ 1 prior lines of therapy and received idelalisib with or without concomitant rituximab.

Disclosures: This study was supported by grants from AFA Insurance (Australia), the Swedish Cancer Society, and others. Three authors declared receiving research grants or honoraria from various sources. The other authors did not have any conflicts of interest to disclose.

Source: Mattsson A et al. Idelalisib (PI3Kδ inhibitor) therapy for patients with relapsed/refractory chronic lymphocytic leukemia: A Swedish nation-wide real-world report on consecutively identified patients. Eur J Haematol. 2023 (Jul 27). doi: 10.1111/ejh.14065

Key clinical point: Idelalisib demonstrated long-term efficacy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia (CLL), and despite having a relatively higher toxicity profile than other targeted therapeutics, can be used in such patients in the absence of alternative therapies.

Major finding: The overall response rate was 65%, with 1 patient achieving complete remission. At a median follow-up of 33.6 months, the median progression-free survival was 16.4 months (95% CI 10.4-26.3), whereas the median overall survival was not reached. Grade ≥ 3 adverse events occurred in 10 patients. The most common serious adverse event was grade ≥ 3 infection (65%).

Study details: This real-world observational retrospective study included 37 patients with CLL (for up to 2.5 years after idelalisib approval in 2014) who had relapsed after or were refractory to ≥ 1 prior lines of therapy and received idelalisib with or without concomitant rituximab.

Disclosures: This study was supported by grants from AFA Insurance (Australia), the Swedish Cancer Society, and others. Three authors declared receiving research grants or honoraria from various sources. The other authors did not have any conflicts of interest to disclose.

Source: Mattsson A et al. Idelalisib (PI3Kδ inhibitor) therapy for patients with relapsed/refractory chronic lymphocytic leukemia: A Swedish nation-wide real-world report on consecutively identified patients. Eur J Haematol. 2023 (Jul 27). doi: 10.1111/ejh.14065

Key clinical point: Compared with obinutuzumab alone, obinutuzumab combined with zanubrutinib significantly improved outcomes in patients with relapsed or refractory follicular lymphoma (FL) without causing safety concerns.

Major finding: At a median follow-up of 20.2 months, patients receiving zanubrutinib + obinutuzumab vs single-agent obinutuzumab had a significantly higher overall response rate (69% vs 46%; P = .001) and longer median progression-free survival (28.0 vs 10.4 months; hazard ratio 0.50; P < .001). The safety profile of zanubrutinib + obinutuzumab was consistent with the known safety profile of the individual drugs.

Study details: Findings are from the phase 2 ROSEWOOD study including 217 patients with FL who were refractory to or had relapsed after ≥ 2 prior systemic treatments, including an anti-CD20 antibody and alkylating agent, and were randomly assigned to receive zanubrutinib + obinutuzumab (n = 145) or Obinutuzumab alone (n = 72).

Disclosures: This study was sponsored by BeiGene. No information on conflicts of interest was provided.

Source: Zinzani PL et al. ROSEWOOD: A phase II randomized study of zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy in patients with relapsed or refractory follicular lymphoma. J Clin Oncol. 2023 (Jul 28). doi: 10.1200/JCO.23.00775

Key clinical point: Compared with obinutuzumab alone, obinutuzumab combined with zanubrutinib significantly improved outcomes in patients with relapsed or refractory follicular lymphoma (FL) without causing safety concerns.

Major finding: At a median follow-up of 20.2 months, patients receiving zanubrutinib + obinutuzumab vs single-agent obinutuzumab had a significantly higher overall response rate (69% vs 46%; P = .001) and longer median progression-free survival (28.0 vs 10.4 months; hazard ratio 0.50; P < .001). The safety profile of zanubrutinib + obinutuzumab was consistent with the known safety profile of the individual drugs.

Study details: Findings are from the phase 2 ROSEWOOD study including 217 patients with FL who were refractory to or had relapsed after ≥ 2 prior systemic treatments, including an anti-CD20 antibody and alkylating agent, and were randomly assigned to receive zanubrutinib + obinutuzumab (n = 145) or Obinutuzumab alone (n = 72).

Disclosures: This study was sponsored by BeiGene. No information on conflicts of interest was provided.

Source: Zinzani PL et al. ROSEWOOD: A phase II randomized study of zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy in patients with relapsed or refractory follicular lymphoma. J Clin Oncol. 2023 (Jul 28). doi: 10.1200/JCO.23.00775

Key clinical point: Compared with obinutuzumab alone, obinutuzumab combined with zanubrutinib significantly improved outcomes in patients with relapsed or refractory follicular lymphoma (FL) without causing safety concerns.

Major finding: At a median follow-up of 20.2 months, patients receiving zanubrutinib + obinutuzumab vs single-agent obinutuzumab had a significantly higher overall response rate (69% vs 46%; P = .001) and longer median progression-free survival (28.0 vs 10.4 months; hazard ratio 0.50; P < .001). The safety profile of zanubrutinib + obinutuzumab was consistent with the known safety profile of the individual drugs.

Study details: Findings are from the phase 2 ROSEWOOD study including 217 patients with FL who were refractory to or had relapsed after ≥ 2 prior systemic treatments, including an anti-CD20 antibody and alkylating agent, and were randomly assigned to receive zanubrutinib + obinutuzumab (n = 145) or Obinutuzumab alone (n = 72).

Disclosures: This study was sponsored by BeiGene. No information on conflicts of interest was provided.

Source: Zinzani PL et al. ROSEWOOD: A phase II randomized study of zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy in patients with relapsed or refractory follicular lymphoma. J Clin Oncol. 2023 (Jul 28). doi: 10.1200/JCO.23.00775

Key clinical point: The addition of rituximab (R) to standard cyclophosphamide, doxorubicine, vincristine, and prednisone (CHOP) first-line therapy significantly prolongs failure-free survival (FFS), overall survival (OS), and the duration of response (DOR) in patients with previously untreated, advanced-stage mantle cell lymphoma (MCL).

Major finding: At a median follow-up of 13.4 years, the R-CHOP vs CHOP group had significantly longer median FFS (2.07 vs 1.36 years; adjusted hazard ratio [aHR] 0.62; P < .0001), OS (5.81 vs 4.84 years; aHR 0.78; P = .039), and DOR (2.08 vs 1.48 years; aHR 0.67; P = .0012). No clinically meaningful differences in late toxicities were observed between the groups.

Study details: This long-term pooled trials analysis of two prospective randomized trials included 385 adult patients with untreated advanced-stage MCL who were randomly assigned to receive CHOP (n = 201) or R-CHOP (n = 184).

Disclosures: This study did not receive any specific funding. Some authors declared serving as advisors, consultants, or board members for or receiving research funding, travel support, or honoraria from various sources.

Source: Fischer L et al on behalf of the German Lymphoma Alliance (GLA) and the German Low-Grade Lymphoma Study Group (GLSG). The addition of rituximab to chemotherapy improves overall survival in mantle cell lymphoma-A pooled trials analysis. Ann Hematol. 2023 (Aug 8). doi: 10.1007/s00277-023-05385-1

Key clinical point: The addition of rituximab (R) to standard cyclophosphamide, doxorubicine, vincristine, and prednisone (CHOP) first-line therapy significantly prolongs failure-free survival (FFS), overall survival (OS), and the duration of response (DOR) in patients with previously untreated, advanced-stage mantle cell lymphoma (MCL).

Major finding: At a median follow-up of 13.4 years, the R-CHOP vs CHOP group had significantly longer median FFS (2.07 vs 1.36 years; adjusted hazard ratio [aHR] 0.62; P < .0001), OS (5.81 vs 4.84 years; aHR 0.78; P = .039), and DOR (2.08 vs 1.48 years; aHR 0.67; P = .0012). No clinically meaningful differences in late toxicities were observed between the groups.

Study details: This long-term pooled trials analysis of two prospective randomized trials included 385 adult patients with untreated advanced-stage MCL who were randomly assigned to receive CHOP (n = 201) or R-CHOP (n = 184).

Disclosures: This study did not receive any specific funding. Some authors declared serving as advisors, consultants, or board members for or receiving research funding, travel support, or honoraria from various sources.

Source: Fischer L et al on behalf of the German Lymphoma Alliance (GLA) and the German Low-Grade Lymphoma Study Group (GLSG). The addition of rituximab to chemotherapy improves overall survival in mantle cell lymphoma-A pooled trials analysis. Ann Hematol. 2023 (Aug 8). doi: 10.1007/s00277-023-05385-1

Key clinical point: The addition of rituximab (R) to standard cyclophosphamide, doxorubicine, vincristine, and prednisone (CHOP) first-line therapy significantly prolongs failure-free survival (FFS), overall survival (OS), and the duration of response (DOR) in patients with previously untreated, advanced-stage mantle cell lymphoma (MCL).

Major finding: At a median follow-up of 13.4 years, the R-CHOP vs CHOP group had significantly longer median FFS (2.07 vs 1.36 years; adjusted hazard ratio [aHR] 0.62; P < .0001), OS (5.81 vs 4.84 years; aHR 0.78; P = .039), and DOR (2.08 vs 1.48 years; aHR 0.67; P = .0012). No clinically meaningful differences in late toxicities were observed between the groups.

Study details: This long-term pooled trials analysis of two prospective randomized trials included 385 adult patients with untreated advanced-stage MCL who were randomly assigned to receive CHOP (n = 201) or R-CHOP (n = 184).

Disclosures: This study did not receive any specific funding. Some authors declared serving as advisors, consultants, or board members for or receiving research funding, travel support, or honoraria from various sources.

Source: Fischer L et al on behalf of the German Lymphoma Alliance (GLA) and the German Low-Grade Lymphoma Study Group (GLSG). The addition of rituximab to chemotherapy improves overall survival in mantle cell lymphoma-A pooled trials analysis. Ann Hematol. 2023 (Aug 8). doi: 10.1007/s00277-023-05385-1

Key clinical point: Allogeneic stem cell transplantation (alloSCT) results in long-term disease control in patients with mantle cell lymphoma (MCL), including those with TP53-mutated disease, and should be considered for earlier use in these high-risk patients who are unresponsive to conventional chemoimmunotherapy.

Major finding: The estimated overall survival rates were 56% (95% CI 36%-72%) at 10 years for the overall cohort and 59% (95% CI 21%-75%) at 4 years for patients with TP53-mutated disease at median follow-ups of 10.8 and 4.2 years, respectively. No relapses were observed in the TP53-mutated subset beyond 6 months after transplantation.

Study details: This retrospective study included 36 patients who underwent alloSCT for MCL, including 13 patients with TP53-mutated disease.

Disclosures: This study did not receive any funding. Some authors declared serving as advisory board members for or receiving honoraria, research funding, or speaker fees from various sources.

Source: Lew TE et al. Allogeneic stem cell transplantation achieves long-term remissions in mantle cell lymphoma, including in TP53-mutated disease. Leuk Lymphoma. 2023 (Aug 2). doi: 10.1080/10428194.2023.2241095

Key clinical point: Allogeneic stem cell transplantation (alloSCT) results in long-term disease control in patients with mantle cell lymphoma (MCL), including those with TP53-mutated disease, and should be considered for earlier use in these high-risk patients who are unresponsive to conventional chemoimmunotherapy.

Major finding: The estimated overall survival rates were 56% (95% CI 36%-72%) at 10 years for the overall cohort and 59% (95% CI 21%-75%) at 4 years for patients with TP53-mutated disease at median follow-ups of 10.8 and 4.2 years, respectively. No relapses were observed in the TP53-mutated subset beyond 6 months after transplantation.

Study details: This retrospective study included 36 patients who underwent alloSCT for MCL, including 13 patients with TP53-mutated disease.

Disclosures: This study did not receive any funding. Some authors declared serving as advisory board members for or receiving honoraria, research funding, or speaker fees from various sources.

Source: Lew TE et al. Allogeneic stem cell transplantation achieves long-term remissions in mantle cell lymphoma, including in TP53-mutated disease. Leuk Lymphoma. 2023 (Aug 2). doi: 10.1080/10428194.2023.2241095

Key clinical point: Allogeneic stem cell transplantation (alloSCT) results in long-term disease control in patients with mantle cell lymphoma (MCL), including those with TP53-mutated disease, and should be considered for earlier use in these high-risk patients who are unresponsive to conventional chemoimmunotherapy.

Major finding: The estimated overall survival rates were 56% (95% CI 36%-72%) at 10 years for the overall cohort and 59% (95% CI 21%-75%) at 4 years for patients with TP53-mutated disease at median follow-ups of 10.8 and 4.2 years, respectively. No relapses were observed in the TP53-mutated subset beyond 6 months after transplantation.

Study details: This retrospective study included 36 patients who underwent alloSCT for MCL, including 13 patients with TP53-mutated disease.

Disclosures: This study did not receive any funding. Some authors declared serving as advisory board members for or receiving honoraria, research funding, or speaker fees from various sources.

Source: Lew TE et al. Allogeneic stem cell transplantation achieves long-term remissions in mantle cell lymphoma, including in TP53-mutated disease. Leuk Lymphoma. 2023 (Aug 2). doi: 10.1080/10428194.2023.2241095

Key clinical point: The combination of the prognostic mantle cell lymphoma (MCL) International Prognostic Index (MIPI) with biological risk factors Ki-67 and p53 expression identifies a subset of patients with MCL having poor prognosis.

Major finding: Patients with high combined MIPI (MIPI-c) or p53 expression > 50% (high-risk disease) vs low, low-intermediate, or high-intermediate MIPI-c and p53 expression ≤ 50% (low-risk disease) had significantly shorter median failure-free survival (hazard ratio [HR] 2.97) and overall survival (HR 3.69) at median follow-ups of 9.6 and 9.4 years, respectively (both P < .0001). The results were confirmed in validation cohorts.

Study details: The training cohort included 684 patients with MCL from the MCL-Younger and MCL-Elderly trials with evaluable data for Ki-67 or p53; patients were classified as having high-risk or low-risk disease. The validation cohorts included 230 and 44 patients from the MCL0208 and Nordic-MCL4 trials, respectively.

Disclosures: This study did not receive any funding. Some authors declared serving on advisory boards or speakers’ bureaus of or receiving research funding, consultancy fees, or honoraria from various sources.

Source: Scheubeck G et al. Clinical outcome of mantle cell lymphoma patients with high-risk disease (high-risk MIPI-c or high p53 expression). Leukemia. 2023;37(9):1887-1894 (Jul 26). doi: 10.1038/s41375-023-01977-y

Key clinical point: The combination of the prognostic mantle cell lymphoma (MCL) International Prognostic Index (MIPI) with biological risk factors Ki-67 and p53 expression identifies a subset of patients with MCL having poor prognosis.

Major finding: Patients with high combined MIPI (MIPI-c) or p53 expression > 50% (high-risk disease) vs low, low-intermediate, or high-intermediate MIPI-c and p53 expression ≤ 50% (low-risk disease) had significantly shorter median failure-free survival (hazard ratio [HR] 2.97) and overall survival (HR 3.69) at median follow-ups of 9.6 and 9.4 years, respectively (both P < .0001). The results were confirmed in validation cohorts.

Study details: The training cohort included 684 patients with MCL from the MCL-Younger and MCL-Elderly trials with evaluable data for Ki-67 or p53; patients were classified as having high-risk or low-risk disease. The validation cohorts included 230 and 44 patients from the MCL0208 and Nordic-MCL4 trials, respectively.

Disclosures: This study did not receive any funding. Some authors declared serving on advisory boards or speakers’ bureaus of or receiving research funding, consultancy fees, or honoraria from various sources.

Source: Scheubeck G et al. Clinical outcome of mantle cell lymphoma patients with high-risk disease (high-risk MIPI-c or high p53 expression). Leukemia. 2023;37(9):1887-1894 (Jul 26). doi: 10.1038/s41375-023-01977-y

Key clinical point: The combination of the prognostic mantle cell lymphoma (MCL) International Prognostic Index (MIPI) with biological risk factors Ki-67 and p53 expression identifies a subset of patients with MCL having poor prognosis.

Major finding: Patients with high combined MIPI (MIPI-c) or p53 expression > 50% (high-risk disease) vs low, low-intermediate, or high-intermediate MIPI-c and p53 expression ≤ 50% (low-risk disease) had significantly shorter median failure-free survival (hazard ratio [HR] 2.97) and overall survival (HR 3.69) at median follow-ups of 9.6 and 9.4 years, respectively (both P < .0001). The results were confirmed in validation cohorts.

Study details: The training cohort included 684 patients with MCL from the MCL-Younger and MCL-Elderly trials with evaluable data for Ki-67 or p53; patients were classified as having high-risk or low-risk disease. The validation cohorts included 230 and 44 patients from the MCL0208 and Nordic-MCL4 trials, respectively.

Disclosures: This study did not receive any funding. Some authors declared serving on advisory boards or speakers’ bureaus of or receiving research funding, consultancy fees, or honoraria from various sources.

Source: Scheubeck G et al. Clinical outcome of mantle cell lymphoma patients with high-risk disease (high-risk MIPI-c or high p53 expression). Leukemia. 2023;37(9):1887-1894 (Jul 26). doi: 10.1038/s41375-023-01977-y

Key clinical point: Acalabrutinib demonstrates favorable long-term efficacy and safety in patients with relapsed or refractory mantle cell lymphoma (MCL), including those with poor prognostic factors.

Major finding: The overall and complete response rates were 81.5% (95% CI 73.5%-87.9%) and 47.6% (95% CI 38.5%-56.7%), respectively. After a 38.1-month median follow-up, median duration of response and progression-free survival were 28.6 (95% CI 17.5-39.1) and 22.0 (95% CI 16.6-33.3) months, respectively. No new safety signals were observed.

Study details: The data represent the final results of the phase 2 ACE-LY-004 study of 124 adult patients with MCL, including those with poor prognostic factors, such as blastoid or pleomorphic morphology and Ki-67 index of >30%, who relapsed after or were refractory to ≤ 5 previous therapies and received acalabrutinib twice daily.

Disclosures: This study was funded by AstraZeneca. Some authors declared serving as consultants, advisors, or speakers for and receiving research funds or travel or accommodation expenses from various sources, including AstraZeneca. Two authors declared being employees or equity holders of AstraZeneca.

Source: Le Gouill S et al. Final results and overall survival data from a phase II study of acalabrutinib monotherapy in patients with relapsed/refractory mantle cell lymphoma, including those with poor prognostic factors. Haematologica. 2023 (Jul 20). doi: 10.3324/haematol.2022.282469

Key clinical point: Acalabrutinib demonstrates favorable long-term efficacy and safety in patients with relapsed or refractory mantle cell lymphoma (MCL), including those with poor prognostic factors.

Major finding: The overall and complete response rates were 81.5% (95% CI 73.5%-87.9%) and 47.6% (95% CI 38.5%-56.7%), respectively. After a 38.1-month median follow-up, median duration of response and progression-free survival were 28.6 (95% CI 17.5-39.1) and 22.0 (95% CI 16.6-33.3) months, respectively. No new safety signals were observed.

Study details: The data represent the final results of the phase 2 ACE-LY-004 study of 124 adult patients with MCL, including those with poor prognostic factors, such as blastoid or pleomorphic morphology and Ki-67 index of >30%, who relapsed after or were refractory to ≤ 5 previous therapies and received acalabrutinib twice daily.

Disclosures: This study was funded by AstraZeneca. Some authors declared serving as consultants, advisors, or speakers for and receiving research funds or travel or accommodation expenses from various sources, including AstraZeneca. Two authors declared being employees or equity holders of AstraZeneca.

Source: Le Gouill S et al. Final results and overall survival data from a phase II study of acalabrutinib monotherapy in patients with relapsed/refractory mantle cell lymphoma, including those with poor prognostic factors. Haematologica. 2023 (Jul 20). doi: 10.3324/haematol.2022.282469

Key clinical point: Acalabrutinib demonstrates favorable long-term efficacy and safety in patients with relapsed or refractory mantle cell lymphoma (MCL), including those with poor prognostic factors.

Major finding: The overall and complete response rates were 81.5% (95% CI 73.5%-87.9%) and 47.6% (95% CI 38.5%-56.7%), respectively. After a 38.1-month median follow-up, median duration of response and progression-free survival were 28.6 (95% CI 17.5-39.1) and 22.0 (95% CI 16.6-33.3) months, respectively. No new safety signals were observed.

Study details: The data represent the final results of the phase 2 ACE-LY-004 study of 124 adult patients with MCL, including those with poor prognostic factors, such as blastoid or pleomorphic morphology and Ki-67 index of >30%, who relapsed after or were refractory to ≤ 5 previous therapies and received acalabrutinib twice daily.

Disclosures: This study was funded by AstraZeneca. Some authors declared serving as consultants, advisors, or speakers for and receiving research funds or travel or accommodation expenses from various sources, including AstraZeneca. Two authors declared being employees or equity holders of AstraZeneca.

Source: Le Gouill S et al. Final results and overall survival data from a phase II study of acalabrutinib monotherapy in patients with relapsed/refractory mantle cell lymphoma, including those with poor prognostic factors. Haematologica. 2023 (Jul 20). doi: 10.3324/haematol.2022.282469

Early, intriguing research suggests that preventing acute graft-versus-host disease (GVHD) in the gut – a potentially life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) – could be accomplished by the administration of a single antibody that targets the anti-DLL4 Notch signaling pathway, without compromising the stem cell transplant.

“The major surprise was that none of the anti–DLL4-treated animals developed acute gastrointestinal GVHD for the entire duration of the study. This was a remarkable finding, given that intestinal GVHD is otherwise seen in the vast majority of nonhuman primate transplant recipients that receive either no prophylaxis, or prophylaxis with agents other than anti-DLL4 antibodies,” co–senior author Ivan Maillard, MD, PhD, a professor of medicine and vice chief for research in hematology-oncology at the University of Pennsylvania, Philadelphia, said in an interview.

“The timing was critical,” the authors noted in the study, recently published in Science Translational Medicine. “Intervening before any symptoms of GvHD appear made the long-term protection possible.”

While GVHD may be mild to moderate in chronic forms, acute cases can be serious, if not fatal, and nearly all severe acute GVHD prominently involves the gastrointestinal tract, which can drive activation of pathogenic T cells and potentially lead to tissue damage following allo-HCT.

Systemic corticosteroids are standard first-line treatment for acute GVHD. However, response rates generally range only from 40% to 60%, and there are concerns of side effects. Meanwhile, second-line treatments are of inconsistent benefit.

With previous studies on mice showing benefits of targeting Notch pathway inhibition, particularly DLL4, Dr. Maillard and colleagues further investigated the effects in nonhuman primates that were allo-HCT recipients, using the anti-DLL4 antibody REGN421, which has pharmacokinetic and toxicity information available from previous studies.

The nonhuman primates were treated with one of two dosing regimens: a single dose of REGN421 3 mg/kg at baseline, post HCT, (n = 7) or three weekly doses at days 0, 7 and 14, post transplant (n = 4). Those primates were compared with 11 primates receiving allo-HCT transplants that received supportive care only.

Primates receiving three weekly doses of REGN421 showed antibody concentrations of greater than 2 mcg/mL for more than 30 days post HCT. A single dose of REGN421 was associated with protection from acute GVHD at day 0, while three weekly doses showed protection at day 0, 7, and 14, consistent with an impact of REGN421 during the early phases of T-cell activation.

Compared with animals receiving only supportive care, prophylaxis with REGN421 was associated with delayed acute GVHD onset and lengthened survival.

Of the 11 primates treated with REGN421, none developed clinical signs of gastrointestinal acute GVHD, whereas the majority of those receiving standard care or other preventive interventions did.

“Detailed analysis of acute GVHD clinical presentations in REGN421-treated animals in comparison to no treatment controls revealed near complete protection from GI-acute GvHD with REGN421,” the authors reported.

Furthermore, pathology scores in the gastrointestinal tract were lower with REGN421 treatment, compared with the no-treatment cohort, and the scores matched those of healthy nontransplanted nonhuman primates.

The primates treated with REGN421 did ultimately develop other clinical and pathologic signs of skin, hepatic or pulmonary acute GVHD, but without gastrointestinal disease.

The treatment was not associated with any adverse effects on the allo-HCT, with primates receiving either a single dose or three weekly doses of REGN421 showing rapid donor engraftment after allo-HCT, including high bone marrow, whole blood, and T-cell donor chimerism.

“Reassuringly, short-term systemic DLL4 blockade with REGN421 did not trigger unexpected side effects in our nonhuman primate model, while preserving rapid engraftment as well hematopoietic and immune reconstitution.”

The mechanism preserving the engraftment, described as a “major surprise,” specifically involved DLL4 inhibition blocking the homing of pathogenic T cells to the gut while preserving homing of regulatory T cells that dampen the immune response, Dr. Maillard explained.

“This effect turned out to be at least in part through a posttranslational effect of DLL4/Notch blockade on integrin pairing at the T-cell surface,” he explained. “This was a novel and quite unexpected mechanism of action conserved from mice to nonhuman primates.”

The results are encouraging in terms of translating to humans because of their closer similarities in various physiological factors, Dr. Maillard said.

“The nonhuman primate model of transplantation [offers] a transplantation model very close to what is being performed in humans, as well as the opportunity to study an immune system very similar to that of humans in nonhuman primates,” he said.

Dr. Maillard noted that, while trials in humans are not underway yet, “we are in active discussions about it,” and the team is indeed interested in testing REGN421 itself, with the effects likely to be as a prophylactic strategy.

There are currently no approved anti-DLL4 antibody drugs for use in humans.

“Our approach is mostly promising as a preventive treatment, rather than as a secondary treatment for GVHD, because DLL4/Notch blockade seems most active when applied early after transplantation during the time of initial seeding of the gut by T cells (in mice, we had observed the critical time window for a successful intervention to be within 48 hours of transplantation),” Dr. Maillard said.“There remain questions about which other prophylactic treatments we should ideally combine anti-DLL4 antibodies with.”

Dr. Maillard has received research funding from Regeneron and Genentech and is a member of Garuda Therapeutics’s scientific advisory board.

Early, intriguing research suggests that preventing acute graft-versus-host disease (GVHD) in the gut – a potentially life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) – could be accomplished by the administration of a single antibody that targets the anti-DLL4 Notch signaling pathway, without compromising the stem cell transplant.

“The major surprise was that none of the anti–DLL4-treated animals developed acute gastrointestinal GVHD for the entire duration of the study. This was a remarkable finding, given that intestinal GVHD is otherwise seen in the vast majority of nonhuman primate transplant recipients that receive either no prophylaxis, or prophylaxis with agents other than anti-DLL4 antibodies,” co–senior author Ivan Maillard, MD, PhD, a professor of medicine and vice chief for research in hematology-oncology at the University of Pennsylvania, Philadelphia, said in an interview.

“The timing was critical,” the authors noted in the study, recently published in Science Translational Medicine. “Intervening before any symptoms of GvHD appear made the long-term protection possible.”

While GVHD may be mild to moderate in chronic forms, acute cases can be serious, if not fatal, and nearly all severe acute GVHD prominently involves the gastrointestinal tract, which can drive activation of pathogenic T cells and potentially lead to tissue damage following allo-HCT.

Systemic corticosteroids are standard first-line treatment for acute GVHD. However, response rates generally range only from 40% to 60%, and there are concerns of side effects. Meanwhile, second-line treatments are of inconsistent benefit.

With previous studies on mice showing benefits of targeting Notch pathway inhibition, particularly DLL4, Dr. Maillard and colleagues further investigated the effects in nonhuman primates that were allo-HCT recipients, using the anti-DLL4 antibody REGN421, which has pharmacokinetic and toxicity information available from previous studies.

The nonhuman primates were treated with one of two dosing regimens: a single dose of REGN421 3 mg/kg at baseline, post HCT, (n = 7) or three weekly doses at days 0, 7 and 14, post transplant (n = 4). Those primates were compared with 11 primates receiving allo-HCT transplants that received supportive care only.

Primates receiving three weekly doses of REGN421 showed antibody concentrations of greater than 2 mcg/mL for more than 30 days post HCT. A single dose of REGN421 was associated with protection from acute GVHD at day 0, while three weekly doses showed protection at day 0, 7, and 14, consistent with an impact of REGN421 during the early phases of T-cell activation.

Compared with animals receiving only supportive care, prophylaxis with REGN421 was associated with delayed acute GVHD onset and lengthened survival.

Of the 11 primates treated with REGN421, none developed clinical signs of gastrointestinal acute GVHD, whereas the majority of those receiving standard care or other preventive interventions did.

“Detailed analysis of acute GVHD clinical presentations in REGN421-treated animals in comparison to no treatment controls revealed near complete protection from GI-acute GvHD with REGN421,” the authors reported.

Furthermore, pathology scores in the gastrointestinal tract were lower with REGN421 treatment, compared with the no-treatment cohort, and the scores matched those of healthy nontransplanted nonhuman primates.

The primates treated with REGN421 did ultimately develop other clinical and pathologic signs of skin, hepatic or pulmonary acute GVHD, but without gastrointestinal disease.

The treatment was not associated with any adverse effects on the allo-HCT, with primates receiving either a single dose or three weekly doses of REGN421 showing rapid donor engraftment after allo-HCT, including high bone marrow, whole blood, and T-cell donor chimerism.

“Reassuringly, short-term systemic DLL4 blockade with REGN421 did not trigger unexpected side effects in our nonhuman primate model, while preserving rapid engraftment as well hematopoietic and immune reconstitution.”

The mechanism preserving the engraftment, described as a “major surprise,” specifically involved DLL4 inhibition blocking the homing of pathogenic T cells to the gut while preserving homing of regulatory T cells that dampen the immune response, Dr. Maillard explained.

“This effect turned out to be at least in part through a posttranslational effect of DLL4/Notch blockade on integrin pairing at the T-cell surface,” he explained. “This was a novel and quite unexpected mechanism of action conserved from mice to nonhuman primates.”

The results are encouraging in terms of translating to humans because of their closer similarities in various physiological factors, Dr. Maillard said.

“The nonhuman primate model of transplantation [offers] a transplantation model very close to what is being performed in humans, as well as the opportunity to study an immune system very similar to that of humans in nonhuman primates,” he said.

Dr. Maillard noted that, while trials in humans are not underway yet, “we are in active discussions about it,” and the team is indeed interested in testing REGN421 itself, with the effects likely to be as a prophylactic strategy.

There are currently no approved anti-DLL4 antibody drugs for use in humans.

“Our approach is mostly promising as a preventive treatment, rather than as a secondary treatment for GVHD, because DLL4/Notch blockade seems most active when applied early after transplantation during the time of initial seeding of the gut by T cells (in mice, we had observed the critical time window for a successful intervention to be within 48 hours of transplantation),” Dr. Maillard said.“There remain questions about which other prophylactic treatments we should ideally combine anti-DLL4 antibodies with.”

Dr. Maillard has received research funding from Regeneron and Genentech and is a member of Garuda Therapeutics’s scientific advisory board.

Early, intriguing research suggests that preventing acute graft-versus-host disease (GVHD) in the gut – a potentially life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) – could be accomplished by the administration of a single antibody that targets the anti-DLL4 Notch signaling pathway, without compromising the stem cell transplant.

“The major surprise was that none of the anti–DLL4-treated animals developed acute gastrointestinal GVHD for the entire duration of the study. This was a remarkable finding, given that intestinal GVHD is otherwise seen in the vast majority of nonhuman primate transplant recipients that receive either no prophylaxis, or prophylaxis with agents other than anti-DLL4 antibodies,” co–senior author Ivan Maillard, MD, PhD, a professor of medicine and vice chief for research in hematology-oncology at the University of Pennsylvania, Philadelphia, said in an interview.

“The timing was critical,” the authors noted in the study, recently published in Science Translational Medicine. “Intervening before any symptoms of GvHD appear made the long-term protection possible.”

While GVHD may be mild to moderate in chronic forms, acute cases can be serious, if not fatal, and nearly all severe acute GVHD prominently involves the gastrointestinal tract, which can drive activation of pathogenic T cells and potentially lead to tissue damage following allo-HCT.

Systemic corticosteroids are standard first-line treatment for acute GVHD. However, response rates generally range only from 40% to 60%, and there are concerns of side effects. Meanwhile, second-line treatments are of inconsistent benefit.

With previous studies on mice showing benefits of targeting Notch pathway inhibition, particularly DLL4, Dr. Maillard and colleagues further investigated the effects in nonhuman primates that were allo-HCT recipients, using the anti-DLL4 antibody REGN421, which has pharmacokinetic and toxicity information available from previous studies.

The nonhuman primates were treated with one of two dosing regimens: a single dose of REGN421 3 mg/kg at baseline, post HCT, (n = 7) or three weekly doses at days 0, 7 and 14, post transplant (n = 4). Those primates were compared with 11 primates receiving allo-HCT transplants that received supportive care only.

Primates receiving three weekly doses of REGN421 showed antibody concentrations of greater than 2 mcg/mL for more than 30 days post HCT. A single dose of REGN421 was associated with protection from acute GVHD at day 0, while three weekly doses showed protection at day 0, 7, and 14, consistent with an impact of REGN421 during the early phases of T-cell activation.

Compared with animals receiving only supportive care, prophylaxis with REGN421 was associated with delayed acute GVHD onset and lengthened survival.

Of the 11 primates treated with REGN421, none developed clinical signs of gastrointestinal acute GVHD, whereas the majority of those receiving standard care or other preventive interventions did.

“Detailed analysis of acute GVHD clinical presentations in REGN421-treated animals in comparison to no treatment controls revealed near complete protection from GI-acute GvHD with REGN421,” the authors reported.

Furthermore, pathology scores in the gastrointestinal tract were lower with REGN421 treatment, compared with the no-treatment cohort, and the scores matched those of healthy nontransplanted nonhuman primates.

The primates treated with REGN421 did ultimately develop other clinical and pathologic signs of skin, hepatic or pulmonary acute GVHD, but without gastrointestinal disease.

The treatment was not associated with any adverse effects on the allo-HCT, with primates receiving either a single dose or three weekly doses of REGN421 showing rapid donor engraftment after allo-HCT, including high bone marrow, whole blood, and T-cell donor chimerism.

“Reassuringly, short-term systemic DLL4 blockade with REGN421 did not trigger unexpected side effects in our nonhuman primate model, while preserving rapid engraftment as well hematopoietic and immune reconstitution.”

The mechanism preserving the engraftment, described as a “major surprise,” specifically involved DLL4 inhibition blocking the homing of pathogenic T cells to the gut while preserving homing of regulatory T cells that dampen the immune response, Dr. Maillard explained.

“This effect turned out to be at least in part through a posttranslational effect of DLL4/Notch blockade on integrin pairing at the T-cell surface,” he explained. “This was a novel and quite unexpected mechanism of action conserved from mice to nonhuman primates.”

The results are encouraging in terms of translating to humans because of their closer similarities in various physiological factors, Dr. Maillard said.

“The nonhuman primate model of transplantation [offers] a transplantation model very close to what is being performed in humans, as well as the opportunity to study an immune system very similar to that of humans in nonhuman primates,” he said.

Dr. Maillard noted that, while trials in humans are not underway yet, “we are in active discussions about it,” and the team is indeed interested in testing REGN421 itself, with the effects likely to be as a prophylactic strategy.

There are currently no approved anti-DLL4 antibody drugs for use in humans.

“Our approach is mostly promising as a preventive treatment, rather than as a secondary treatment for GVHD, because DLL4/Notch blockade seems most active when applied early after transplantation during the time of initial seeding of the gut by T cells (in mice, we had observed the critical time window for a successful intervention to be within 48 hours of transplantation),” Dr. Maillard said.“There remain questions about which other prophylactic treatments we should ideally combine anti-DLL4 antibodies with.”

Dr. Maillard has received research funding from Regeneron and Genentech and is a member of Garuda Therapeutics’s scientific advisory board.

The treatment landscape of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) has been transformed over the past decade with the advent of targeted therapies, including Bruton tyrosine kinase (BTK) inhibitors. Covalent BTK inhibitors, which are available in both the frontline and relapsed/refractory settings, include ibrutinib, acalabrutinib, and zanubrutinib.^1-3

BTK inhibitors have also demonstrated activity in higher-risk subgroups, including patients harboring TP53 aberrations. Clinical trials have shown encouraging outcomes of BTK inhibitors in these patients, and real-world studies have demonstrated similar findings.^4-6 Recently, a real-world Italian registry study similarly showed favorable outcomes in 747 patients with CLL carrying 17p- or TP53 or both mutations treated with first-line ibrutinib. in what appears to be the largest real-world analysis of this patient population (Rigolin et al). At 24 months, the median overall survival was not reached; the estimated treatment persistence and survival rates were 63.4% (95% CI 60.0%-67.0%) and 82.6% (95% CI 79.9%-85.4%), respectively. The median time to treatment discontinuation was 37.4 months (95% CI 34.8-42.2 months). Disease progression or death was the reason for discontinuation in 45.8% of patients. Although ibrutinib is not generally the favored BTK inhibitor given an improved safety profile with next-generation options, these data provide real-world estimates for outcomes with BTK inhibitors in this large dataset of high-risk patients.

Although outcomes have improved for patients with CLL or SLL, it is common for resistance to targeted therapy to eventually occur. Noncovalent BTK inhibitors, such as pirtobrutinib, offer a promising approach for this population. The BRUIN trial was a phase 1/2 trial of pirtobrutinib in patients with relapsed/refractory CLL or SLL (Mato et al). A total of 317 patients were treated, including 247 who had previously received a BTK inhibitor. Patients had been treated with a median of three prior lines of therapy and over 40% had been treated with a BCL-2 inhibitor. The overall response rate was 73.3% (95% CI 67.3%-78.7%) and increased to 82.2% (95% CI 76.8%-86.7%) when partial response with lymphocytosis was included. At a 19.4-month median follow-up, the median progression-free survival was 19.6 (95% CI 16.9-22.1) months. The drug was also well-tolerated, with 2.8% of patients discontinuing therapy owing to treatment-related adverse events. Adverse events that can be seen with BTK inhibition, including hypertension, atrial fibrillation or flutter, and bleeding, were rare. This trial demonstrates that CLL/SLL cells can maintain dependency on the B-cell receptor pathway following treatment with a covalent inhibitor and that ongoing BTK inhibition using a novel mechanism is a feasible strategy. The optimal sequencing of pirtobrutinib with other available therapies, including BCL-2 inhibitors, remains unknown.

BTK inhibitors are also active in mantle cell lymphoma (MCL). They are approved for relapsed/refractory disease and are being studied in earlier lines of therapy. Whereas early progression of disease (POD) has been shown to be an important prognostic marker in MCL, the impact of early relapse on outcome specifically after BTK inhibitor initiation is less clear.⁷ A recent multicente retrospective observational study aimed to determine the impact on time-to-POD between rituximab-containing front-line therapy and second-line BTK inhibitor and overall outcomes (Villa et al). This study included 360 adult patients with relapsed or refractory MCL treated with second-line BTK inhibitor. Not surprisingly, the authors found that patients with POD within 24 months of first-line therapy had significantly shorter median progression-free survival (0.45 year vs 2.3 years; P < .001) and overall survival (0.9 year vs 5.5 years P < .001) compared with patients with relapse beyond 24 months. Furthermore, they found that Ki-67 ≥ 30% and Mantle Cell Lymphoma International Prognostic Index (MIPI) were also associated with progression‐free survival and overall survival from the start of a second-line BTK inhibitor, though to a lesser extent than time-to-POD. These variables were subsequently used to determine a second-line BTK MIPI, which can help inform which patients are most likely to benefit from a BTK inhibitor compared with other available options, such as chimeric antigen receptor (CAR) T-cell therapy or a clinical trial strategy.

BTK inhibitors are an important drug class for the treatment of lymphoid cancers and have changed the treatment paradigms in CLL/SLL and MCL. Additional studies evaluating combination strategies, sequencing approaches, time-limited options, and predictors of response are likely to further refine optimization of use in these diseases.

Additional References

1.         Barr PM, Owen C, Robak T, et al. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022;6:3440-3450. doi:10.1182/bloodadvances.2021006434

2.         Sharman JP, Egyed M, Jurczak W, et al. Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naive chronic lymphocytic leukemia. Leukemia. 2022;36:1171-1175. doi:10.1038/s41375-021-01485-x

3.         Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23:1031-1043. doi:10.1016/S1470-2045(22)00293-5

4.         Ahn IE, Tian X, Wiestner A. Ibrutinib for chronic lymphocytic leukemia with TP53 alterations. N Engl J Med. 2020;383:498-500. doi:10.1056/NEJMc2005943

5.         Allan JN, Shanafelt T, Wiestner A, et al. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations: a pooled analysis from four clinical trials. Br J Haematol. 2022;196:947-953. doi:10.1111/bjh.17984

6.         Mato AR, Tang B, Azmi S, et al. A clinical practice comparison of patients with chronic lymphocytic leukemia with and without deletion 17p receiving first-line treatment with ibrutinib. Haematologica. 2022;107:2630-2640. doi:10.3324/haematol.2021.280376

7.         Bond DA, Switchenko JM, Villa D, et al. Early relapse identifies MCL patients with inferior survival after intensive or less intensive frontline therapy. Blood Adv. 2021;5:5179-5189. doi:10.1182/bloodadvances.2021004765

The treatment landscape of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) has been transformed over the past decade with the advent of targeted therapies, including Bruton tyrosine kinase (BTK) inhibitors. Covalent BTK inhibitors, which are available in both the frontline and relapsed/refractory settings, include ibrutinib, acalabrutinib, and zanubrutinib.^1-3

BTK inhibitors have also demonstrated activity in higher-risk subgroups, including patients harboring TP53 aberrations. Clinical trials have shown encouraging outcomes of BTK inhibitors in these patients, and real-world studies have demonstrated similar findings.^4-6 Recently, a real-world Italian registry study similarly showed favorable outcomes in 747 patients with CLL carrying 17p- or TP53 or both mutations treated with first-line ibrutinib. in what appears to be the largest real-world analysis of this patient population (Rigolin et al). At 24 months, the median overall survival was not reached; the estimated treatment persistence and survival rates were 63.4% (95% CI 60.0%-67.0%) and 82.6% (95% CI 79.9%-85.4%), respectively. The median time to treatment discontinuation was 37.4 months (95% CI 34.8-42.2 months). Disease progression or death was the reason for discontinuation in 45.8% of patients. Although ibrutinib is not generally the favored BTK inhibitor given an improved safety profile with next-generation options, these data provide real-world estimates for outcomes with BTK inhibitors in this large dataset of high-risk patients.

Although outcomes have improved for patients with CLL or SLL, it is common for resistance to targeted therapy to eventually occur. Noncovalent BTK inhibitors, such as pirtobrutinib, offer a promising approach for this population. The BRUIN trial was a phase 1/2 trial of pirtobrutinib in patients with relapsed/refractory CLL or SLL (Mato et al). A total of 317 patients were treated, including 247 who had previously received a BTK inhibitor. Patients had been treated with a median of three prior lines of therapy and over 40% had been treated with a BCL-2 inhibitor. The overall response rate was 73.3% (95% CI 67.3%-78.7%) and increased to 82.2% (95% CI 76.8%-86.7%) when partial response with lymphocytosis was included. At a 19.4-month median follow-up, the median progression-free survival was 19.6 (95% CI 16.9-22.1) months. The drug was also well-tolerated, with 2.8% of patients discontinuing therapy owing to treatment-related adverse events. Adverse events that can be seen with BTK inhibition, including hypertension, atrial fibrillation or flutter, and bleeding, were rare. This trial demonstrates that CLL/SLL cells can maintain dependency on the B-cell receptor pathway following treatment with a covalent inhibitor and that ongoing BTK inhibition using a novel mechanism is a feasible strategy. The optimal sequencing of pirtobrutinib with other available therapies, including BCL-2 inhibitors, remains unknown.

BTK inhibitors are also active in mantle cell lymphoma (MCL). They are approved for relapsed/refractory disease and are being studied in earlier lines of therapy. Whereas early progression of disease (POD) has been shown to be an important prognostic marker in MCL, the impact of early relapse on outcome specifically after BTK inhibitor initiation is less clear.⁷ A recent multicente retrospective observational study aimed to determine the impact on time-to-POD between rituximab-containing front-line therapy and second-line BTK inhibitor and overall outcomes (Villa et al). This study included 360 adult patients with relapsed or refractory MCL treated with second-line BTK inhibitor. Not surprisingly, the authors found that patients with POD within 24 months of first-line therapy had significantly shorter median progression-free survival (0.45 year vs 2.3 years; P < .001) and overall survival (0.9 year vs 5.5 years P < .001) compared with patients with relapse beyond 24 months. Furthermore, they found that Ki-67 ≥ 30% and Mantle Cell Lymphoma International Prognostic Index (MIPI) were also associated with progression‐free survival and overall survival from the start of a second-line BTK inhibitor, though to a lesser extent than time-to-POD. These variables were subsequently used to determine a second-line BTK MIPI, which can help inform which patients are most likely to benefit from a BTK inhibitor compared with other available options, such as chimeric antigen receptor (CAR) T-cell therapy or a clinical trial strategy.

BTK inhibitors are an important drug class for the treatment of lymphoid cancers and have changed the treatment paradigms in CLL/SLL and MCL. Additional studies evaluating combination strategies, sequencing approaches, time-limited options, and predictors of response are likely to further refine optimization of use in these diseases.

Additional References

1.         Barr PM, Owen C, Robak T, et al. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022;6:3440-3450. doi:10.1182/bloodadvances.2021006434

2.         Sharman JP, Egyed M, Jurczak W, et al. Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naive chronic lymphocytic leukemia. Leukemia. 2022;36:1171-1175. doi:10.1038/s41375-021-01485-x

3.         Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23:1031-1043. doi:10.1016/S1470-2045(22)00293-5

4.         Ahn IE, Tian X, Wiestner A. Ibrutinib for chronic lymphocytic leukemia with TP53 alterations. N Engl J Med. 2020;383:498-500. doi:10.1056/NEJMc2005943

5.         Allan JN, Shanafelt T, Wiestner A, et al. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations: a pooled analysis from four clinical trials. Br J Haematol. 2022;196:947-953. doi:10.1111/bjh.17984

6.         Mato AR, Tang B, Azmi S, et al. A clinical practice comparison of patients with chronic lymphocytic leukemia with and without deletion 17p receiving first-line treatment with ibrutinib. Haematologica. 2022;107:2630-2640. doi:10.3324/haematol.2021.280376

7.         Bond DA, Switchenko JM, Villa D, et al. Early relapse identifies MCL patients with inferior survival after intensive or less intensive frontline therapy. Blood Adv. 2021;5:5179-5189. doi:10.1182/bloodadvances.2021004765

The treatment landscape of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) has been transformed over the past decade with the advent of targeted therapies, including Bruton tyrosine kinase (BTK) inhibitors. Covalent BTK inhibitors, which are available in both the frontline and relapsed/refractory settings, include ibrutinib, acalabrutinib, and zanubrutinib.^1-3

BTK inhibitors have also demonstrated activity in higher-risk subgroups, including patients harboring TP53 aberrations. Clinical trials have shown encouraging outcomes of BTK inhibitors in these patients, and real-world studies have demonstrated similar findings.^4-6 Recently, a real-world Italian registry study similarly showed favorable outcomes in 747 patients with CLL carrying 17p- or TP53 or both mutations treated with first-line ibrutinib. in what appears to be the largest real-world analysis of this patient population (Rigolin et al). At 24 months, the median overall survival was not reached; the estimated treatment persistence and survival rates were 63.4% (95% CI 60.0%-67.0%) and 82.6% (95% CI 79.9%-85.4%), respectively. The median time to treatment discontinuation was 37.4 months (95% CI 34.8-42.2 months). Disease progression or death was the reason for discontinuation in 45.8% of patients. Although ibrutinib is not generally the favored BTK inhibitor given an improved safety profile with next-generation options, these data provide real-world estimates for outcomes with BTK inhibitors in this large dataset of high-risk patients.

Although outcomes have improved for patients with CLL or SLL, it is common for resistance to targeted therapy to eventually occur. Noncovalent BTK inhibitors, such as pirtobrutinib, offer a promising approach for this population. The BRUIN trial was a phase 1/2 trial of pirtobrutinib in patients with relapsed/refractory CLL or SLL (Mato et al). A total of 317 patients were treated, including 247 who had previously received a BTK inhibitor. Patients had been treated with a median of three prior lines of therapy and over 40% had been treated with a BCL-2 inhibitor. The overall response rate was 73.3% (95% CI 67.3%-78.7%) and increased to 82.2% (95% CI 76.8%-86.7%) when partial response with lymphocytosis was included. At a 19.4-month median follow-up, the median progression-free survival was 19.6 (95% CI 16.9-22.1) months. The drug was also well-tolerated, with 2.8% of patients discontinuing therapy owing to treatment-related adverse events. Adverse events that can be seen with BTK inhibition, including hypertension, atrial fibrillation or flutter, and bleeding, were rare. This trial demonstrates that CLL/SLL cells can maintain dependency on the B-cell receptor pathway following treatment with a covalent inhibitor and that ongoing BTK inhibition using a novel mechanism is a feasible strategy. The optimal sequencing of pirtobrutinib with other available therapies, including BCL-2 inhibitors, remains unknown.

BTK inhibitors are also active in mantle cell lymphoma (MCL). They are approved for relapsed/refractory disease and are being studied in earlier lines of therapy. Whereas early progression of disease (POD) has been shown to be an important prognostic marker in MCL, the impact of early relapse on outcome specifically after BTK inhibitor initiation is less clear.⁷ A recent multicente retrospective observational study aimed to determine the impact on time-to-POD between rituximab-containing front-line therapy and second-line BTK inhibitor and overall outcomes (Villa et al). This study included 360 adult patients with relapsed or refractory MCL treated with second-line BTK inhibitor. Not surprisingly, the authors found that patients with POD within 24 months of first-line therapy had significantly shorter median progression-free survival (0.45 year vs 2.3 years; P < .001) and overall survival (0.9 year vs 5.5 years P < .001) compared with patients with relapse beyond 24 months. Furthermore, they found that Ki-67 ≥ 30% and Mantle Cell Lymphoma International Prognostic Index (MIPI) were also associated with progression‐free survival and overall survival from the start of a second-line BTK inhibitor, though to a lesser extent than time-to-POD. These variables were subsequently used to determine a second-line BTK MIPI, which can help inform which patients are most likely to benefit from a BTK inhibitor compared with other available options, such as chimeric antigen receptor (CAR) T-cell therapy or a clinical trial strategy.

BTK inhibitors are an important drug class for the treatment of lymphoid cancers and have changed the treatment paradigms in CLL/SLL and MCL. Additional studies evaluating combination strategies, sequencing approaches, time-limited options, and predictors of response are likely to further refine optimization of use in these diseases.

Additional References

1.         Barr PM, Owen C, Robak T, et al. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022;6:3440-3450. doi:10.1182/bloodadvances.2021006434

2.         Sharman JP, Egyed M, Jurczak W, et al. Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naive chronic lymphocytic leukemia. Leukemia. 2022;36:1171-1175. doi:10.1038/s41375-021-01485-x

3.         Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23:1031-1043. doi:10.1016/S1470-2045(22)00293-5

4.         Ahn IE, Tian X, Wiestner A. Ibrutinib for chronic lymphocytic leukemia with TP53 alterations. N Engl J Med. 2020;383:498-500. doi:10.1056/NEJMc2005943

5.         Allan JN, Shanafelt T, Wiestner A, et al. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations: a pooled analysis from four clinical trials. Br J Haematol. 2022;196:947-953. doi:10.1111/bjh.17984

6.         Mato AR, Tang B, Azmi S, et al. A clinical practice comparison of patients with chronic lymphocytic leukemia with and without deletion 17p receiving first-line treatment with ibrutinib. Haematologica. 2022;107:2630-2640. doi:10.3324/haematol.2021.280376

7.         Bond DA, Switchenko JM, Villa D, et al. Early relapse identifies MCL patients with inferior survival after intensive or less intensive frontline therapy. Blood Adv. 2021;5:5179-5189. doi:10.1182/bloodadvances.2021004765

Key clinical point: Compared with Bruton tyrosine kinase inhibitors (BTKi) alone, BTKi + anti-CD20 monoclonal antibodies (mAb) demonstrated better efficacy in patients with untreated, relapsed, or refractory chronic lymphocytic leukemia (CLL) without causing safety concerns.

Major finding: The BTKi + anti-CD20 mAb therapy vs BTKi monotherapy group had significantly improved progression-free survival (hazard ratio 0.70; 95% CI 0.51-0.97), complete response rate (relative risk [RR] 2.03; 95% CI 1.01-4.06), and undetectable minimal residual disease rate (RR 6.43; 95% CI 3.54-11.67) and a similar risk for grade ≥3 adverse events (RR 1.08; 95% CI 0.80-1.45).

Study details: Findings are from a meta-analysis of 4 randomized controlled trials including 1056 patients who received a BTKi + anti-CD20 mAb or BTKi monotherapy for untreated, relapsed, or refractory CLL.

Disclosures: This study was supported by grants from the National Science and Technology Council in Taiwan and the industry-academia cooperation program. The authors declared no conflicts of interest.

Source: Nguyen TT et al. Efficacy and safety of add-on anti-CD20 monoclonal antibody to Bruton tyrosine kinase inhibitor treatment for chronic lymphocytic leukemia: A meta-analysis. Sci Rep. 2023;13:9775 (Jun 16). Doi: 10.1038/s41598-023-36279-x

Key clinical point: Compared with Bruton tyrosine kinase inhibitors (BTKi) alone, BTKi + anti-CD20 monoclonal antibodies (mAb) demonstrated better efficacy in patients with untreated, relapsed, or refractory chronic lymphocytic leukemia (CLL) without causing safety concerns.

Major finding: The BTKi + anti-CD20 mAb therapy vs BTKi monotherapy group had significantly improved progression-free survival (hazard ratio 0.70; 95% CI 0.51-0.97), complete response rate (relative risk [RR] 2.03; 95% CI 1.01-4.06), and undetectable minimal residual disease rate (RR 6.43; 95% CI 3.54-11.67) and a similar risk for grade ≥3 adverse events (RR 1.08; 95% CI 0.80-1.45).

Study details: Findings are from a meta-analysis of 4 randomized controlled trials including 1056 patients who received a BTKi + anti-CD20 mAb or BTKi monotherapy for untreated, relapsed, or refractory CLL.

Disclosures: This study was supported by grants from the National Science and Technology Council in Taiwan and the industry-academia cooperation program. The authors declared no conflicts of interest.

Source: Nguyen TT et al. Efficacy and safety of add-on anti-CD20 monoclonal antibody to Bruton tyrosine kinase inhibitor treatment for chronic lymphocytic leukemia: A meta-analysis. Sci Rep. 2023;13:9775 (Jun 16). Doi: 10.1038/s41598-023-36279-x

Key clinical point: Compared with Bruton tyrosine kinase inhibitors (BTKi) alone, BTKi + anti-CD20 monoclonal antibodies (mAb) demonstrated better efficacy in patients with untreated, relapsed, or refractory chronic lymphocytic leukemia (CLL) without causing safety concerns.

Major finding: The BTKi + anti-CD20 mAb therapy vs BTKi monotherapy group had significantly improved progression-free survival (hazard ratio 0.70; 95% CI 0.51-0.97), complete response rate (relative risk [RR] 2.03; 95% CI 1.01-4.06), and undetectable minimal residual disease rate (RR 6.43; 95% CI 3.54-11.67) and a similar risk for grade ≥3 adverse events (RR 1.08; 95% CI 0.80-1.45).

Study details: Findings are from a meta-analysis of 4 randomized controlled trials including 1056 patients who received a BTKi + anti-CD20 mAb or BTKi monotherapy for untreated, relapsed, or refractory CLL.

Disclosures: This study was supported by grants from the National Science and Technology Council in Taiwan and the industry-academia cooperation program. The authors declared no conflicts of interest.

Source: Nguyen TT et al. Efficacy and safety of add-on anti-CD20 monoclonal antibody to Bruton tyrosine kinase inhibitor treatment for chronic lymphocytic leukemia: A meta-analysis. Sci Rep. 2023;13:9775 (Jun 16). Doi: 10.1038/s41598-023-36279-x

Key clinical point: The presence of one or more lymph nodes >56.5 mm before starting venetoclax is an independent risk factor for early progression during venetoclax therapy in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Major finding: After a median follow up of 14.3 months, the median progression-free survival (PFS) was not reached and the estimated 3‐year PFS rate was 54%. Multivariable analysis revealed a >56.5 mm diameter of at least one lymph node before therapy initiation to be a significant predictive factor for progression (adjusted hazard ratio 1.01; P =.005).

Study details: Findings are from a multicenter retrospective study including 128 patients with relapsed or refractory CLL treated with ibrutinib, idelalisib, or both who switched to venetoclax due to progression or adverse events, of which 28 patients experienced progressive disease.

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

Source: Autore F et al. Lymphadenopathy as a predictor of progression during venetoclax treatment in chronic lymphocytic leukemia. A campus chronic lymphocytic leukemia study. Hematol Oncol. 2023 (Jul 1). Doi: 10.1002/hon.3199

Key clinical point: The presence of one or more lymph nodes >56.5 mm before starting venetoclax is an independent risk factor for early progression during venetoclax therapy in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Major finding: After a median follow up of 14.3 months, the median progression-free survival (PFS) was not reached and the estimated 3‐year PFS rate was 54%. Multivariable analysis revealed a >56.5 mm diameter of at least one lymph node before therapy initiation to be a significant predictive factor for progression (adjusted hazard ratio 1.01; P =.005).

Study details: Findings are from a multicenter retrospective study including 128 patients with relapsed or refractory CLL treated with ibrutinib, idelalisib, or both who switched to venetoclax due to progression or adverse events, of which 28 patients experienced progressive disease.

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

Source: Autore F et al. Lymphadenopathy as a predictor of progression during venetoclax treatment in chronic lymphocytic leukemia. A campus chronic lymphocytic leukemia study. Hematol Oncol. 2023 (Jul 1). Doi: 10.1002/hon.3199

Key clinical point: The presence of one or more lymph nodes >56.5 mm before starting venetoclax is an independent risk factor for early progression during venetoclax therapy in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Major finding: After a median follow up of 14.3 months, the median progression-free survival (PFS) was not reached and the estimated 3‐year PFS rate was 54%. Multivariable analysis revealed a >56.5 mm diameter of at least one lymph node before therapy initiation to be a significant predictive factor for progression (adjusted hazard ratio 1.01; P =.005).

Study details: Findings are from a multicenter retrospective study including 128 patients with relapsed or refractory CLL treated with ibrutinib, idelalisib, or both who switched to venetoclax due to progression or adverse events, of which 28 patients experienced progressive disease.

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

Source: Autore F et al. Lymphadenopathy as a predictor of progression during venetoclax treatment in chronic lymphocytic leukemia. A campus chronic lymphocytic leukemia study. Hematol Oncol. 2023 (Jul 1). Doi: 10.1002/hon.3199