The phase III DUO trial of PI3K inhibitor duvelisib versus ofatumumab in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: final analysis including overall survival.

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LP-118 is a novel B-cell lymphoma 2 / extra-large inhibitor that demonstrates efficacy in models of venetoclax-resistant chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia (CLL) respond well to initial treatment with the Bcell lymphoma 2 (BCL2) inhibitor venetoclax. Upon relapse, they often retain sensitivity to BCL2 targeting, but durability of response remains a concern. We hypothesize that targeting both BCL2 and B-cell lymphoma-extra large (BCLXL) will be a successful strategy to treat CLL, including for patients who relapse on venetoclax. To test this hypothesis, we conducted a pre-clinical investigation of LP-118, a highly potent inhibitor of BCL2 with moderate BCLXL inhibition to minimize platelet toxicity. This study demonstrated that LP-118 induces efficient BAK activation, cytochrome C release, and apoptosis in both venetoclax naïve and resistant CLL cells. Significantly, LP-118 is effective in cell lines expressing the BCL2 G101V mutation and in cells expressing BCLXL but lacking BCL2 dependence. Using an immunocompetent mouse model, Eµ-TCL1, LP-118 demonstrates low platelet toxicity, which hampered earlier BCLXL inhibitors. Finally, LP-118 in the RS4;11 and OSU-CLL xenograft models results in decreases in tumor burden and survival advantage, respectively. These results provide a mechanistic rationale for the evaluation of LP-118 for the treatment of venetoclax responsive and relapsed CLL.

Therapeutic targeting of apoptosis in chronic lymphocytic leukemia.

Therapeutic targeting of apoptosis with small molecule B-cell lymphoma 2 (BCL-2) inhibition with venetoclax is highly efficacious in CLL, leading to sustained deep responses, particularly among patients with treatment-naïve disease with favorable prognostic markers. Patients with unfavorable genetic characteristics such as TP53 aberration and unmutated IGHV may also derive durable benefits, but their remission duration after time-limited venetoclax-containing combination therapy is shorter, particularly in patients with relapsed/refractory disease. Emerging data indicate that the context of disease progression after initial treatment with venetoclax may define the success of re-treatment with venetoclax. Specifically, continuous venetoclax exposure may select for resistant disease due to genetic mechanisms such as BCL2 mutations and functional resistance mechanisms such as hyperphosphorylation of BCL-2 family proteins, which decrease the affinity of venetoclax binding to the target or lead to increased MCL-1 dependence and concomitant decrease in BCL-2 dependence. These patients may be best served by switching to a different class of targeted agents at the time of progression. In contrast, relapsed CLL that arises while being off therapy after a period of time-limited venetoclax-based regimens maintains sensitivity to re-treatment with venetoclax for the majority of patients. Novel strategies related to therapeutic targeting of apoptosis include next-generation BCL-2 inhibitors with improved potency and pharmacokinetic profiles, direct targeting of anti-apoptotic BH3 family proteins beyond BCL-2 such as MCL-1, and indirect targeting of MCL-1 through mechanisms such as small molecule cyclin-dependent kinase 9 inhibitors.

PI3K inhibitors in hematology: When one door closes .

The phosphatidylinositol 3-kinase (PI3K) signaling pathway regulates key cellular processes and is one of the most aberrantly activated pathways in cancer. The class I PI3K catalytic subunits p110g and p110d are highly enriched in leukocytes, providing additional rationale for targeting these PI3Ks in hematologic malignancies. In 2014, the PI3Kd inhibitor idelalisib was the first of four PI3K inhibitors to receive regulatory approval for relapsed B-cell malignancies. This was followed by approvals of the pan-class I inhibitor copanlisib (2017), the dual PI3Kg/d inhibitor duvelisib (2018), and the PI3Kd and casein kinase-1e inhibitor umbralisib (2021). Copanlisib and umbralisib received accelerated approvals, while idelalisib and duvelisib received initial accelerated approvals followed by full approvals. The accelerated approvals were based on overall response rates, however follow-up studies showed increased risk of death and serious side effects. Furthermore, the confirmatory trial with copanlisib failed to show an improvement in progression free survival when compared to chemoimmunotherapy. These developments led to black box warnings for idelalisib and duvelisib, and withdrawal of copanlisib and umbralisib from the market by their manufacturers. Given the uncertain future of this drug class, additional manufacturers terminated ongoing phase III trials with novel PI3K inhibitors. Here, we review the development and current status of PI3K inhibitors in hematology, limitations to their use, and our perspective on whether there is a future for PI3K inhibitors in hematology.

Burden of Infection in Patients With and Without Secondary Immunodeficiency Disease Following Diagnosis of a Mature B Cell Malignancy.

BACKGROUND: This retrospective cohort study compared patient characteristics and burden of infection in patients with mature B cell malignancies with and without secondary immunodeficiency disease (SID). PATIENTS AND METHODS: Data were extracted from the Humedica database (H-DB) and Guardian Research Network (GRN) database from October 1, 2015 to March 10, 2020, including a 6-month pre-index period (PIP) and 12-month follow-up. Patients aged ≥18 years diagnosed with chronic lymphocytic leukemia/small lymphocytic lymphoma, multiple myeloma, or non-Hodgkin's lymphoma in the PIP were stratified into 2 cohorts: SID (hypogammaglobulinemia [using ICD-10-CM codes] or serum IgG levels <5.0 g/L, both with signs and symptoms of SID or at least 1 infection) and no-SID. Patients with SID or primary immunodeficiency diseases in the PIP were excluded. RESULTS: Overall, 2221 patients with SID (H-DB/GRN: n = 1959/262), and 19,141 patients without SID (n = 17,598/1543) were included. Baseline characteristics were similar across cohorts. At 12-month follow-up, significantly more patients with SID had experienced ≥1 infection and ≥1 severe bacterial infection than those without SID (both P < .001). H-DB/GRN mean (standard deviation) number of severe bacterial infections was 7.6 (9.9)/2.9 (2.7) for the SID cohort versus 5.2 (6.8)/2.4 (2.2) for the no-SID cohort. CONCLUSION: This study confirms that patients with mature B cell malignancies and SID face a significantly higher burden of infections than those without SID.

Acalabrutinib-based regimens in frontline or relapsed/refractory higher-risk CLL: pooled analysis of 5 clinical trials.

ABSTRACT: Before targeted therapies, patients with higher-risk chronic lymphocytic leukemia (CLL), defined as del(17p) and/or TP53 mutation (TP53m), unmutated immunoglobulin heavy chain variable region genes (uIGHV), or complex karyotype (CK), had poorer prognosis with chemoimmunotherapy. Bruton tyrosine kinase inhibitors (BTKis) have demonstrated benefit in higher-risk patient populations with CLL in individual trials. To better understand the impact of the second-generation BTKi acalabrutinib, we pooled data from 5 prospective clinical studies of acalabrutinib as monotherapy or in combination with obinutuzumab (ACE-CL-001, ACE-CL-003, ELEVATE-TN, ELEVATE-RR, and ASCEND) in patients with higher-risk CLL in treatment-naive (TN) or relapsed/refractory (R/R) cohorts. A total of 808 patients were included (TN cohort, n = 320; R/R cohort, n = 488). Median follow-up was 59.1 months (TN cohort) and 44.3 months (R/R cohort); 51.3% and 26.8% of patients in the TN and R/R cohorts, respectively, remained on treatment at last follow-up. In the del(17p)/TP53m, uIGHV, and CK subgroups in the TN cohort, median progression-free survival (PFS) and median overall survival (OS) were not reached (NR). In the del(17p)/TP53m, uIGHV, and CK subgroups in the R/R cohort, median PFS was 38.6 months, 46.9 months, and 38.6 months, respectively, and median OS was 60.6 months, NR, and NR, respectively. The safety profile of acalabrutinib-based therapy in this population was consistent with the known safety profile of acalabrutinib in a broad CLL population. Our analysis demonstrates long-term benefit of acalabrutinib-based regimens in patients with higher-risk CLL, regardless of line of therapy.

An indirect comparison of acalabrutinib with and without obinutuzumab vs zanubrutinib in treatment-naive CLL.

ABSTRACT: The efficacy and safety of acalabrutinib plus obinutuzumab and acalabrutinib monotherapy vs zanubrutinib in patients with treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma without del(17p) were compared using an unanchored matching-adjusted indirect comparison. Individual patient-level data from ELEVATE-TN (acalabrutinib plus obinutuzumab, n = 162; acalabrutinib monotherapy, n = 163) were weighted to match published aggregate baseline data from SEQUOIA cohort 1, which excluded patients with del(17p) (zanubrutinib, n = 241), using variables that were prognostic/predictive of investigator-assessed progression-free survival (INV-PFS) in an exploratory Cox regression analysis of ELEVATE-TN. After matching, INV-PFS was longer with acalabrutinib plus obinutuzumab (hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.23-0.74) and comparable with acalabrutinib monotherapy (HR, 0.91; 95% CI, 0.53-1.56) vs zanubrutinib. Acalabrutinib monotherapy had significantly lower odds of any grade hypertension vs zanubrutinib (odds ratio [OR], 0.44; 95% CI, 0.20-0.99), whereas acalabrutinib plus obinutuzumab had significantly higher odds of neutropenia (OR, 2.19; 95% CI, 1.33-3.60) and arthralgia (OR, 2.33; 95% CI, 1.37-3.96) vs zanubrutinib. No other significant differences in safety were observed. In summary, acalabrutinib plus obinutuzumab had longer INV-PFS with increased odds of neutropenia and arthralgia than zanubrutinib, whereas acalabrutinib monotherapy had similar INV-PFS with lower odds of any grade hypertension. These trials were registered at www.ClinicalTrials.gov as #NCT02475681 and #NCT03336333.

Six-year follow-up and subgroup analyses of a phase 2 trial of venetoclax for del(17p) chronic lymphocytic leukemia.

ABSTRACT: Chromosome 17p deletion (del[17p]) is associated with poor prognosis in patients with chronic lymphocytic leukemia (CLL). Venetoclax is approved for treatment of previously untreated and relapsed/refractory (R/R) CLL, including patients with del(17p), based on the open-label, multicenter, phase 2 M13-982 trial (NCT01889186). Here, we detail the 6-year follow-up analysis for M13-982. A total of 158 patients with previously untreated (n = 5) or R/R (n = 153) del(17p) CLL received 400 mg venetoclax daily after initial ramp-up until progressive disease. After a median follow-up of 70 months, the best objective response rate (ORR) was 77% (21% complete remission [CR] and 49% partial remission [PR]), with a median duration of response (DOR) of 39.3 months (95% confidence interval [CI], 31.1-50.5). The median progression-free survival (PFS) was 28.2 months (95% CI, 23.4-37.6), and median overall survival (OS) was 62.5 months (95% CI, 51.7-not reached), with 16% of patients remaining on treatment after 6 years. Multivariable analysis did not identify statistically significant correlation between patient subgroups defined by clinical or laboratory variables and ORR or PFS. The most common grade ≥3 adverse events were neutropenia (42%), infections (33%), anemia (16%), and thrombocytopenia (16%). Post hoc comparative analyses of PFS and OS from treatment initiation, from a 24-month landmark, and by minimal residual disease status were performed between patients with del(17p) in the M13-982 and MURANO studies in the interest of understanding these data in another context. These long-term data show the continued benefits of venetoclax in patients with del(17p) CLL. The trial was registered at www.clinicaltrials.gov as #NCT01889186.

A multicenter study of venetoclax-based treatment for patients with Richter transformation of chronic lymphocytic leukemia.

ABSTRACT: Patients with chronic lymphocytic leukemia (CLL) who develop Richter transformation (RT) have a poor prognosis when treated with chemoimmunotherapy regimens used for de novo diffuse large B-cell lymphoma. Venetoclax, a BCL2 inhibitor, has single-agent efficacy in patients with RT and is potentially synergistic with chemoimmunotherapy. In this multicenter, retrospective study, we evaluated 62 patients with RT who received venetoclax-based treatment outside of a clinical trial, in combination with a Bruton tyrosine kinase inhibitor (BTKi; n=28), rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (n=13), or intensive chemoimmunotherapy other than R-CHOP (n=21). The best overall and complete response rates were 36%/25%, 54%/46%, and 52%/38%, respectively. The median progression-free and overall survival estimates for the same treatment groups were 4.9/14.3 months, 14.9 months/not reached, and 3.3/9 months, respectively. CLL with del(17p) was associated with a lower complete response rate in the total cohort (odds ratio [OR] 0.15; 95% confidence interval [CI] 0.04-0.6; p=0.01) and venetoclax-naïve subgroup (OR 0.13; 95%CI 0.02-0.66; p=0.01). TP53 mutated CLL was associated with a lower complete response rate (OR 0.15; 95%CI 0.03-0.74; p=0.02) and shorter progression-free survival (hazard ratio 3.1; 95%CI 1.21-7.95; p=0.02) only in venetoclax-naïve subgroup. No other clinical or baseline characteristics, including prior venetoclax treatment for CLL, showed statistically significant association with outcomes. Grade 3-4 neutropenia and thrombocytopenia events were most frequent with intensive chemoimmunotherapy + venetoclax; grade 3-4 infection rates were similar across treatment groups. In this difficult-to-treat RT patient population, venetoclax-based combination regimens achieved high response rates, with durable remission and survival observed in a subset of patients.

Five-year follow-up of a phase 2 study of ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial therapy in CLL.

ABSTRACT: We previously reported high rates of undetectable minimal residual disease <10-4 (uMRD4) with ibrutinib plus fludarabine, cyclophosphamide, and rituximab (iFCR) followed by 2-year ibrutinib maintenance (I-M) in treatment-naïve chronic lymphocytic leukemia (CLL). Here, we report updated data from this phase 2 study with a median follow-up of 63 months. Of 85 patients enrolled, including 5 (6%) with deletion 17p or TP53 mutation, 91% completed iFCR and 2-year I-M. Five-year progression-free survival (PFS) and overall survival were 94% (95% confidence interval [CI], 89%-100%) and 99% (95% CI, 96%-100%), respectively. No additional deaths have occurred with this extended follow-up. No difference in PFS was observed by immunoglobulin heavy-chain variable region gene status or duration of I-M. High rates of peripheral blood (PB) uMRD4 were maintained (72% at the end of iFCR, 66% at the end of 2-year I-M, and 44% at 4.5 years from treatment initiation). Thirteen patients developed MRD conversion without clinical progression, mostly (77%) after stopping ibrutinib. None had Bruton tyrosine kinase (BTK) mutations. One patient had PLCG2 mutation. Six of these patients underwent ibrutinib retreatment per protocol. Median time on ibrutinib retreatment was 34 months. The cumulative incidence of atrial fibrillation was 8%. Second malignancy or nonmalignant hematologic disease occurred in 13%, mostly nonmelanoma skin cancer. Overall, iFCR with 2-year I-M achieved durably deep responses in patients with diverse CLL genetic markers. Re-emergent clones lacked BTK mutation and retained sensitivity to ibrutinib upon retreatment. This trial is registered at www.clinicaltrials.gov as #NCT02251548.

Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy for Richter Transformation: An International, Multicenter, Retrospective Study.

PURPOSE: Outcomes for Richter transformation (RT) are poor with current therapies. The efficacy and safety of anti-CD19 chimeric antigen receptor T-cell therapy (CAR-T) for RT are not established. METHODS: We performed an international multicenter retrospective study of patients with RT who received CAR-T. Patient, disease, and treatment characteristics were summarized using descriptive statistics, and modeling analyses were used to determine association with progression-free survival (PFS) and overall survival (OS). PFS and OS were estimated from the date of CAR-T infusion. RESULTS: Sixty-nine patients were identified. The median age at CAR-T infusion was 64 years (range, 27-80). Patients had a median of four (range, 1-15) previous lines of therapy for CLL and/or RT, including previous Bruton tyrosine kinase inhibitor and/or BCL2 inhibitor therapy in 58 (84%) patients. The CAR-T product administered was axicabtagene ciloleucel in 44 patients (64%), tisagenlecleucel in 17 patients (25%), lisocabtagene maraleucel in seven patients (10%), and brexucabtagene autoleucel in one patient (1%). Eleven patients (16%) and 25 patients (37%) experienced grade ≥3 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, respectively. The overall response rate was 63%, with 46% attaining a complete response (CR). After a median follow-up of 24 months, the median PFS was 4.7 months (95% CI, 2.0 to 6.9); the 2-year PFS was 29% (95% CI, 18 to 41). The median OS was 8.5 months (95% CI, 5.1 to 25.4); the 2-year OS was 38% (95% CI, 26 to 50). The median duration of response was 27.6 months (95% CI, 14.5 to not reached) for patients achieving CR. CONCLUSION: CAR-T demonstrates clinical efficacy for patients with RT.