Seven-year outcomes of venetoclax-ibrutinib therapy in mantle cell lymphoma: durable responses and treatment-free remissions.

In the phase-2 clinical trial (AIM) of venetoclax-ibrutinib, 24 patients with mantle cell lymphoma (MCL; 23 with relapsed/refractory [R/R] disease) received ibrutinib 560mg and venetoclax 400mg both once daily. High complete remission (CR) and measurable residual disease negative (MRD-negative) CR rates were previously reported. With median survivor follow-up now exceeding 7 years, we report long-term results. Treatment was initially continuous, with elective treatment interruption (ETI) allowed after protocol amendment for patients in MRD-negative CR. For R/R MCL, the estimated 7-year progression-free survival (PFS) was 30% [95%CI: 14-49] (median 28 months [95%CI: 13-82]) and overall survival was 43% [95%CI: 23-62] (median 32 months [95%CI: 15-NE]). Eight patients in MRD-negative CR entered ETI for a median of 58 months (95%CI, 37-79), with four experiencing disease recurrence. Two of 3 re-attained CR on retreatment. Time-to-treatment-failure (TTF), which excluded progression in ETI for those reattaining response, was 39% overall and 68% at 7-years for responders. Beyond 56 weeks Grade 3 and serious adverse events were uncommon. Newly emergent or increasing cardiovascular toxicity were not observed beyond 56 weeks. We demonstrate long-term durable responses and acceptable toxicity profile of venetoclax-ibrutinib in R/R MCL and show feasibility of treatment interruption while maintaining ongoing disease control. (NCT02471391).

An unappreciated cell survival-independent role for BAFF initiating chronic lymphocytic leukemia.

Background: Chronic Lymphocytic Leukemia (CLL) is characterized by the expansion of CD19+ CD5+ B cells but its origin remains debated. Mutated CLL may originate from post-germinal center B cells and unmutated CLL from CD5+ mature B cell precursors. Irrespective of precursor types, events initiating CLL remain unknown. The cytokines BAFF and APRIL each play a significant role in CLL cell survival and accumulation, but their involvement in disease initiation remains unclear. Methods: We generated novel CLL models lacking BAFF or APRIL. In vivo experiments were conducted to explore the impact of BAFF or APRIL loss on leukemia initiation, progression, and dissemination. Additionally, RNA-seq and quantitative real-time PCR were performed to unveil the transcriptomic signature influenced by BAFF in CLL. The direct role of BAFF in controlling the expression of tumor-promoting genes was further assessed in patient-derived primary CLL cells ex-vivo. Results: Our findings demonstrate a crucial role for BAFF, but not APRIL, in the initiation and dissemination of CLL cells. In the absence of BAFF or its receptor BAFF-R, the TCL1 transgene only increases CLL cell numbers in the peritoneal cavity, without dissemination into the periphery. While BAFF binding to BAFF-R is dispensable for peritoneal CLL cell survival, it is necessary to activate a tumor-promoting gene program, potentially linked to CLL initiation and progression. This direct role of BAFF in controlling the expression of tumor-promoting genes was confirmed in patient-derived primary CLL cells ex-vivo. Conclusions: Our study, involving both mouse and human CLL cells, suggests that BAFF might initiate CLL through mechanisms independent of cell survival. Combining current CLL therapies with BAFF inhibition could offer a dual benefit by reducing peripheral tumor burden and suppressing transformed CLL cell output.

BTK inhibitors in CLL: second-generation drugs and beyond.

ABSTRACT: BTK inhibitors (BTKis) are established standards of care in multiple B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom macroglobulinemia. The first-generation BTKi ibrutinib demonstrated superiority over standard chemoimmunotherapy regimens in multiple randomized trials but is limited by cardiovascular side effects such as atrial fibrillation and hypertension. Second-generation BTKis have improved selectivity and demonstrate reduced rates of cardiovascular complications in 3 head-to-head ibrutinib studies. The emergence of BTK C481S mutation has led to the development of noncovalent, "reversible" BTKis, such as pirtobrutinib, which are agnostic to the C481S mutation. However, these inhibitors are associated with resistant mutations outside the C481 hot spot. These variant non-C481 mutations are of great clinical interest because some are shared among pirtobrutinib, zanubrutinib, and acalabrutinib, with potential implications for cross resistance and treatment sequencing. Finally, BTK protein degraders with in vitro activity against C481 and non-C481 mutations are currently in clinical development. Here, we review the evolution of therapeutic BTK-targeting and discuss future directions for clinical research.

Cardiovascular events reported in patients with B-cell malignancies treated with zanubrutinib.

ABSTRACT: First-generation Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, has been associated with an increased risk of cardiovascular toxicities. Zanubrutinib is a more selective, next-generation BTK inhibitor. In this analysis, incidence rates of atrial fibrillation, symptomatic (grade ≥2) ventricular arrhythmia, and hypertension were evaluated in a pooled analysis of 10 clinical studies with zanubrutinib monotherapy in patients (N = 1550) with B-cell malignancies and a pooled analysis of head-to-head studies comparing zanubrutinib with ibrutinib (ASPEN cohort 1; ALPINE). Among the 10 studies, most patients (median age, 67 years) were male (66.3%) and had CLL/SLL (60.5%). Overall incidence and exposure-adjusted incidence rates (EAIR) for atrial fibrillation, symptomatic ventricular arrhythmia, and hypertension were lower with zanubrutinib than ibrutinib. Despite a similar prevalence of preexisting cardiovascular events in ASPEN and ALPINE, atrial fibrillation/flutter incidence rates (6.1% vs 15.6%) and EAIR (0.2 vs 0.64 persons per 100 person-months; P < .0001) were lower with zanubrutinib than with ibrutinib. Symptomatic ventricular arrhythmia incidence was low for both zanubrutinib (0.7%) and ibrutinib (1.7%) with numerically lower EAIR (0.02 vs 0.06 persons per 100 person-months, respectively) for zanubrutinib. The hypertension EAIR was lower with zanubrutinib than ibrutinib in ASPEN but similar between treatment arms in ALPINE. The higher hypertension EAIR in ALPINE was inconsistent with other zanubrutinib studies. However, fewer discontinuations (1 vs 14) and deaths (0 vs 6) due to cardiac disorders occurred with zanubrutinib versus ibrutinib in ALPINE. These data support zanubrutinib as a treatment option with improved cardiovascular tolerability compared with ibrutinib for patients with B-cell malignancies in need of BTK inhibitors. These trials were registered at www.ClinicalTrials.gov as # NCT03053440, NCT03336333, NCT03734016, NCT04170283, NCT03206918, NCT03206970, NCT03332173, NCT03846427, NCT02343120, and NCT03189524.

Biomarker analysis of the ASPEN study comparing zanubrutinib with ibrutinib for patients with Waldenström macroglobulinemia.

ABSTRACT: The phase 3 ASPEN trial (NCT03053440) compared Bruton tyrosine kinase inhibitors (BTKis), zanubrutinib and ibrutinib, in patients with Waldenström macroglobulinemia (WM). Post-hoc biomarker analysis was performed using next-generation sequencing on pretreatment bone marrow samples from 98 patients treated with zanubrutinib and 92 patients treated with ibrutinib with mutated (MUT) MYD88 and 20 patients with wild-type (WT) MYD88 treated with zanubrutinib. Of 329 mutations in 52 genes, mutations in CXCR4 (25.7%), TP53 (24.8%), ARID1A (15.7%), and TERT (9.0%) were most common. TP53MUT, ARID1AMUT, and TERTMUT were associated with higher rates of CXCR4MUT (P < .05). Patients with CXCR4MUT (frameshift or nonsense [NS] mutations) had lower very good partial response (VGPR) and complete response rates (CR; 17.0% vs 37.2%, P = .020) and longer time to response (11.1 vs 8.4 months) than patients with CXCR4WT treated with BTKis. CXCR4NS was associated with inferior progression-free survival (PFS; hazard ratio [HR], 3.39; P = .017) in patients treated with ibrutinib but not in those treated with zanubrutinib (HR, 0.67; P = .598), but VGPR + CR rates were similar between treatment groups (14.3% vs 15.4%). Compared with ibrutinib, patients with CXCR4NS treated with zanubrutinib had a favorable major response rate (MRR; 85.7% vs 53.8%; P = .09) and PFS (HR, 0.30; P = .093). In patients with TP53MUT, significantly lower MRRs were observed for patients treated with ibrutinib (63.6% vs 85.7%; P = .04) but not for those treated with zanubrutinib (80.8% vs 81.9%; P = .978). In TP53MUT, compared with ibrutinib, patients treated with zanubrutinib had higher VGPR and CR (34.6% vs 13.6%; P < .05), numerically improved MRR (80.8% vs 63.6%; P = .11), and longer PFS (not reached vs 44.2 months; HR, 0.66; P = .37). Collectively, patients with WM with CXCR4MUT or TP53MUT had worse prognosis compared with patients with WT alleles, and zanubrutinib led to better clinical outcomes.

Plain language summary of zanubrutinib or ibrutinib in chronic lymphocytic leukemia that is resistant to treatment or has come back after treatment.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a research study called ALPINE. The study involved people who had been diagnosed with, and previously treated at least once for, relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Lymphocytes help to find and fight off viruses and infections in the body, but when someone has CLL or SLL, the body creates abnormal lymphocytes, leaving the patient with a weakened immune system and susceptible to illness. In CLL, these lymphocytes are in the bone marrow and bloodstream, whereas for SLL, they are mostly found in the lymph nodes, such as those in the neck. HOW WAS THE RESEARCH DONE?: The ALPINE study was designed to directly compare the cancer-fighting effects and side effects of zanubrutinib and ibrutinib as treatment for patients with relapsed or refractory CLL/SLL. WHAT WERE THE RESULTS?: After 30 months, zanubrutinib was more effective than ibrutinib at reducing and keeping the cancer from coming back. Clinical Trial Registration: NCT03734016 (ClinicalTrials.gov).

CAR T cells and time-limited ibrutinib as treatment for relapsed/refractory mantle cell lymphoma: the phase 2 TARMAC study.

ABSTRACT: CD19-directed chimeric antigen receptor T cells (CAR-T) achieve high response rates in patients with relapsed/refractory mantle cell lymphoma (MCL). However, their use is associated with significant toxicity, relapse concern, and unclear broad tractability. Preclinical and clinical data support a beneficial synergistic effect of ibrutinib on apheresis product fitness, CAR-T expansion, and toxicity. We evaluated the combination of time-limited ibrutinib and CTL019 CAR-T in 20 patients with MCL in the phase 2 TARMAC study. Ibrutinib commenced before leukapheresis and continued through CAR-T manufacture for a minimum of 6 months after CAR-T administration. The median prior lines of therapy was 2; 50% of patients were previously exposed to a Bruton tyrosine kinase inhibitor (BTKi). The primary end point was 4-month postinfusion complete response (CR) rate, and secondary end points included safety and subgroup analysis based on TP53 aberrancy. The primary end point was met; 80% of patients demonstrated CR, with 70% and 40% demonstrating measurable residual disease negativity by flow cytometry and molecular methods, respectively. At 13-month median follow-up, the estimated 12-month progression-free survival was 75% and overall survival 100%. Fifteen patients (75%) developed cytokine release syndrome; 12 (55%) with grade 1 to 2 and 3 (20%) with grade 3. Reversible grade 1 to 2 neurotoxicity was observed in 2 patients (10%). Efficacy was preserved irrespective of prior BTKi exposure or TP53 mutation. Deep responses correlated with robust CAR-T expansion and a less exhausted baseline T-cell phenotype. Overall, the safety and efficacy of the combination of BTKi and T-cell redirecting immunotherapy appears promising and merits further exploration. This trial was registered at www.ClinicalTrials.gov as #NCT04234061.

Targeting TP53 disruption in chronic lymphocytic leukemia: Current strategies and future directions.

In the modern era of Chronic Lymphocytic Leukemia (CLL) targeted therapy, the loss of p53 function due to genetic abnormalities remains a significant challenge. This is because even targeted agents, which are currently the mainstay of treatment for CLL, do not directly target p53 or restore its disrupted pathway. Consequently, resistance to therapy and unfavorable clinical outcomes often accompany these p53-related abnormalities. An essential goal of future clinical research should be to address the ostensibly "undruggable" p53 pathway. Currently, multiple therapeutic approaches are being explored to tackle TP53 dysfunction and improve outcomes in high-risk CLL. These approaches include the use of oncoprotein murine double minute 2 inhibitors, small-molecule p53 reactivators, exportin 1 (XPO1) inhibitors, and ataxia-telangiectasia mutated and Rad3-related (ATR) inhibitors. Combinations of these p53-targeting strategies, along with established novel therapies such as B-cell receptor or B-cell lymphoma-2 (BCL-2) inhibitors, may shape the future of therapeutic trials in this challenging-to-treat disease.

Australia and New Zealand consensus position statement: use of COVID-19 therapeutics in patients with haematological malignancies.

Despite widespread vaccination rates, we are living with high transmission rates of SARS-CoV-2. Although overall hospitalisation rates are falling, the risk of serious infection remains high for patients who are immunocompromised because of haematological malignancies. In light of the ongoing pandemic and the development of multiple agents for treatment, representatives from the Haematology Society of Australia and New Zealand and infectious diseases specialists have collaborated on this consensus position statement regarding COVID-19 management in patients with haematological disorders. It is our recommendation that both patients with haematological malignancies and treating specialists be educated regarding the preventive and treatment options available and that patients continue to receive adequate vaccinations, keeping in mind the suboptimal vaccine responses that occur in haematology patients, in particular, those with B-cell malignancies and on B-cell-targeting or depleting therapy. Patients with haematological malignancies should receive treatment for COVID-19 in accordance with the severity of their symptoms, but even mild infections should prompt early treatment with antiviral agents. The issue of de-isolation following COVID-19 infection and optimal time to treatment for haematological malignancies is discussed but remains an area with evolving data. This position statement is to be used in conjunction with advice from infectious disease, respiratory and intensive care specialists, and current guidelines from the National COVID-19 Clinical Evidence Taskforce and the New Zealand Ministry of Health and Cancer Agency Te Aho o Te Kahu COVID-19 Guidelines.

T-Cell Engaging Antibodies in Diffuse Large B Cell Lymphoma-An Update.

Novel cellular immunotherapies such as T-cell engaging antibodies (TCEAbs) are changing the landscape of treatment for diffuse large B cell lymphoma (DLBCL), especially in the relapsed/refractory (R/R) setting. TCEAbs harness the power of the host immune system to induce killing of tumor cells by binding to both the tumor antigen and the T-cell receptor. Since the approval of blinatumomab for R/R acute lymphoblastic leukemia, there has been significant development in novel TCEAbs. Many of these novel TCEAbs have shown promising effectiveness in R/R DLBCL, with favorable response rates including complete remissions, even in heavily pretreated patients. There are unique therapy-related toxicities with TCEAbs, namely cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS), and it is important to both recognize and manage these side effects appropriately. This review examines the development and mechanism of action of these TCEAbs, and the available published data from clinical trials. Their role in the treatment of DLBCL, the management of therapy-related adverse events, and the mechanisms of resistance will also be discussed.

Cognition following chimeric antigen receptor T-cell therapy: A systematic review.

BACKGROUND: This systematic review aimed to characterise the cognitive outcomes of patients who received chimeric antigen receptor T-cell therapy. METHODS: A systematic search of the literature was performed using PubMed, PsycINFO, SCOPUS, EMBASE, Medline, and CINAHL (February 2023). Risk of bias was assessed using the JBI Checklist for Case Reports and the Risk of Bias Assessment Tool for Non-randomised Studies. RESULTS: Twenty-two studies met inclusion criteria with a total of 1104 participants. There was considerable methodological heterogeneity with differing study designs (e.g., cohort studies, clinical trials, case studies, a qualitative interview, and a focus group), measures of cognition (e.g., self-report, neuropsychological measures, clinician assessed/neurological examinations), and longest follow-up time points (i.e., five days to five years). DISCUSSION: Results of the studies were heterogenous with studies demonstrating stable, improved, or reduced cognition across differing time points. Overall, cognitive symptoms are common particularly in the acute stage (<2 weeks) post-infusion. Most deficits that arise in the acute stage resolve within one to two weeks, however, there is a subset of patients who continue to experience and self-report persistent deficits in the subacute and chronic stages. Future studies are needed to comprehensively analyse cognition using a combination of self-report and psychometric measures following chimeric antigen receptor T-cell therapy in the acute, subacute, and chronic settings.

Long-term outcomes of second-line versus later-line zanubrutinib treatment in patients with relapsed/refractory mantle cell lymphoma: An updated pooled analysis.

BACKGROUND: We previously reported results of a pooled analysis of two zanubrutinib studies in relapsed or refractory (R/R) MCL showing better survival outcomes when zanubrutinib is used in second-line versus later-line. Here, we present an updated pooled analysis with a longer follow-up of 35.2 months. METHODS: Data were pooled from two studies-BGB-3111-AU-003 (NCT02343120) and BGB-3111-206 (NCT03206970) of zanubrutinib in R/R MCL. The patients were divided into two groups based on the treatment line of zanubrutinib: the second-line and the later-line group. The inverse propensity score weighting method was used to balance the baseline covariates between the groups. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), PFS, and OS rates, objective response rate (ORR), duration of response (DOR), and safety. RESULTS: Among 112 pooled patients, 41 (36.6%) patients received zanubrutinib as second-line and 71 (63.4%) patients as later-line therapy. After weighting, OS was significantly improved in the second-line versus later-line group (HR, 0.459 [95% CI: 0.215, 0.98]; p = 0.044) with median OS not estimable in both groups. The PFS was similar between the two groups (HR, 0.78 [95% CI: 0.443, 1.373]; p = 0.389) but with numerically longer median PFS in the second-line versus later-line group (27.8 vs. 22.1 months). ORR was numerically higher in the second-line versus later-line (88.6% vs. 85.7%), and DOR was similar between the two groups (25.2 vs. 25.1 months). Zanubrutinib showed a similar safety profile in both groups. CONCLUSION: Zanubrutinib in second-line treatment was associated with significantly improved OS compared with later-line treatment of R/R MCL.

Zanubrutinib: past, present, and future.

In recent years, Bruton tyrosine kinase (BTK) inhibitors have provided significant advances in the treatment of patients with B-cell malignancies. Ibrutinib was the first BTK inhibitor to be approved, and it changed the standard-of-care treatment for diseases such as chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone lymphoma, and Waldenström macroglobulinemia, improving efficacy outcomes and safety compared to chemotherapy. In this article, we review the development of zanubrutinib, a next-generation BTK inhibitor, from molecular design to patient-related outcomes. We start this journey by providing insights into the discovery of BTK and the physiologic, genetic, and molecular characterization of patients lacking this kinase, together with the brief treatment landscape in the era of chemo-immunotherapies. Zanubrutinib was originally developed by applying a structure-activity strategy to enhance the specificity as well as enzymatic and pharmacokinetic properties. Preclinical studies confirmed greater specificity and better bioavailability of zanubrutinib compared with that of ibrutinib, which supported the initiation of clinical trials in humans. Preliminary clinical results indicated activity in B-cell malignancies together with an improved safety profile, in line with less off-target effects described in the preclinical studies. The clinical program of zanubrutinib has since expanded significantly, with ongoing studies in a wide range of hemato-oncological diseases and in combination with many other therapies. Zanubrutinib currently is approved for various B-cell malignancies in multiple countries. This story highlights the importance of multidisciplinary collaborative research, from bench to bedside, and provides an example of how the commitment to finding improved treatment options should always run parallel to patient care.

ZNF683 marks a CD8+ T cell population associated with anti-tumor immunity following anti-PD-1 therapy for Richter syndrome.

Unlike many other hematologic malignancies, Richter syndrome (RS), an aggressive B cell lymphoma originating from indolent chronic lymphocytic leukemia, is responsive to PD-1 blockade. To discover the determinants of response, we analyze single-cell transcriptome data generated from 17 bone marrow samples longitudinally collected from 6 patients with RS. Response is associated with intermediate exhausted CD8 effector/effector memory T cells marked by high expression of the transcription factor ZNF683, determined to be evolving from stem-like memory cells and divergent from terminally exhausted cells. This signature overlaps with that of tumor-infiltrating populations from anti-PD-1 responsive solid tumors. ZNF683 is found to directly target key T cell genes (TCF7, LMO2, CD69) and impact pathways of T cell cytotoxicity and activation. Analysis of pre-treatment peripheral blood from 10 independent patients with RS treated with anti-PD-1, as well as patients with solid tumors treated with anti-PD-1, supports an association of ZNF683high T cells with response.

Chronic lymphocytic leukaemia Australasian consensus practice statement.

Chronic lymphocytic leukaemia (CLL) is the most common haematological malignancy in Australia and New Zealand (ANZ). Considerable changes to diagnostic and management algorithms have occurred within the last decade. The availability of next-generation sequencing and measurable residual disease assessment by flow cytometry allow for advanced prognostication and response assessments. Novel therapies, including inhibitors of Bruton's tyrosine kinase (BTKi) and B-cell lymphoma 2 (BCL2) inhibitors, have transformed the treatment landscape for both treatment-naïve and relapsed/refractory disease, particularly for patients with high-risk genetic aberrations. Recommendations regarding appropriate supportive management continue to evolve, and special considerations are required for patients with CLL with respect to the global SARS-CoV-2 pandemic. The unique funding and treatment environments in Australasia highlight the need for specific local guidance with respect to the investigation and management of CLL. This consensus practice statement was developed by a broadly representative group of ANZ experts in CLL with endorsement by peak haematology bodies, with a view to providing this standardised guidance.