Pirtobrutinib monotherapy in Bruton tyrosine kinase inhibitor-intolerant patients with B-cell malignancies: results of the phase I/II BRUIN trial.

Bruton tyrosine kinase inhibitors (BTKi) have transformed the treatment of B-cell malignancies, but intolerance has often led to their discontinuation. The phase 1/2 BRUIN study evaluated pirtobrutinib, a highly selective non-covalent (reversible) BTKi, in patients with R/R B-cell malignancies (NCT03740529). Pirtobrutinib was investigated in 127 patients with intolerance to at least one prior BTKi therapy in the absence of progressive disease. The most common adverse event (AE) leading to BTKi discontinuation was cardiac disorders (n=40, 31.5%), specifically atrial fibrillation (n=30, 23.6%). The median follow-up was 17.4 months and the median time on pirtobrutinib was 15.3 months. The most common reasons for pirtobrutinib discontinuation were progressive disease (26.8%), AE (10.2%), or death (5.5%). The most frequent treatment-emergent AEs were fatigue (39.4%) and neutropenia (37.0%). Among patients who discontinued a prior BTKi for a cardiac issue, 75% had no recurrence of their cardiac AE. No patient discontinued pirtobrutinib for the same AE that led to discontinuation of the prior BTKi. In 78 CLL/SLL and 21 MCL patients intolerant to prior BTKi, ORR to pirtobrutinib was 76.9% and 81.0%, respectively. Median PFS for CLL/SLL was 28.4 months and was not estimable for MCL. These results suggest that pirtobrutinib was safe, well-tolerated, and an efficacious option in patients with prior BTKi-intolerance.

Real-world incidence and prevention of tumor lysis syndrome in chronic lymphocytic leukemia treated with venetoclax.

Venetoclax is a BCL2 inhibitor used in chronic lymphocytic leukemia (CLL) which can cause tumor lysis syndrome (TLS). We aimed to determine the incidence of and risk factors for TLS among patients with CLL/small lymphocytic lymphoma (SLL) who received treatment with venetoclax at our institution from 1/1/2016 to 12/31/2020. We included 616 venetoclax escalations among 136 pts with CLL. 74 pts (54%) underwent escalation exclusively outpatient, 35 (26%) had at least one planned hospitalization and 27 (20%) were escalated exclusively inpatient. During venetoclax initiation, 86% of pts received allopurinol, 71% intravenous hydration, 18% phosphate binders, and 10% prophylactic rasburicase. Among the entire cohort, 7 pts (5.1%) developed laboratory TLS by modified Cairo Bishop criteria and none developed clinical TLS. Incidence of laboratory TLS was 15% for those escalated exclusively inpatient, 2.9% for those with any prophylactic hospitalization and 2.7% for those escalated exclusively outpatient. Those who developed TLS were more likely to have higher TLS risk, and no additional risk factors were identified. In this single institution retrospective cohort study, laboratory TLS was observed, though clinical TLS was not. Prophylactic measures, including use of IV hydration, may have contributed to low rates of observed TLS in the outpatient setting.

Safety of Extended Pirtobrutinib Exposure in Relapsed and/or Refractory B-Cell Malignancies.

INTRODUCTION: Pirtobrutinib, a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor, has demonstrated promising efficacy in B-cell malignancies and is associated with low rates of discontinuation and dose reduction. Pirtobrutinib is administered until disease progression or toxicity, necessitating an understanding of the safety profile in patients with extended treatment. METHODS: Here we report the safety of pirtobrutinib in patients with relapsed/refractory B-cell malignancies with extended (≥12 months) drug exposure from the BRUIN trial. Assessments included median time-to-first-occurrence of adverse events (AEs), dose reductions, and discontinuations due to treatment-emergent AEs (TEAEs) and select AEs of interest (AESIs). RESULTS: Of 773 patients enrolled, 326 (42%) received treatment for ≥12 months. In the extended exposure cohort, the median time-on-treatment was 19 months. The most common all-cause TEAEs were fatigue (32%) and diarrhea (31%). TEAEs leading to dose reduction occurred in 23 (7%) and discontinuations in 11 (3%) extended exposure patients. One patient had a fatal treatment-related AE (COVID-19 pneumonia). Infections (73.0%) were the most common AESI with a median time-to-first-occurrence of 7.4 months. Majority of TEAEs and AESIs occurred during the first year of therapy. CONCLUSIONS: Pirtobrutinib therapy continues to demonstrate an excellent safety profile amenable to long-term administration without evidence of new or worsening toxicity signals.

Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127.

Increasing use of covalent and noncovalent inhibitors of Bruton's tyrosine kinase (BTK) has elucidated a series of acquired drug-resistant BTK mutations in patients with B cell malignancies. Here we identify inhibitor resistance mutations in BTK with distinct enzymatic activities, including some that impair BTK enzymatic activity while imparting novel protein-protein interactions that sustain B cell receptor (BCR) signaling. Furthermore, we describe a clinical-stage BTK and IKZF1/3 degrader, NX-2127, that can bind and proteasomally degrade each mutant BTK proteoform, resulting in potent blockade of BCR signaling. Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients.

Novel identification of t(14;18)(q32;q21)/IGH::MALT1 in chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is a clonal B-cell malignancy and remains a chronic disease despite improvements in clinical outcomes since the use of targeted therapies. Both clinical and biological parameters are important for determining prognosis. Unlike other mature B-cell lymphomas, translocations involving the immunoglobulin heavy chain (IGH) locus are uncommon in CLL. There have been few case reports of CLL harbouring t(14;18)/IGH::BCL2 and t(14;19)/IGH::BCL3. Here we describe the first two cases of patients with CLL with documented t(14;18)(q32;q21)/IGH::MALT1. Both cases in this report were associated with lower-risk biological parameters. Thus, FISH testing for MALT1 in cases with unknown IGH translocation partners in the setting of CLL should be implemented in clinical practice to better define such cases.

Non-Covalent Bruton's Tyrosine Kinase Inhibitors in the Treatment of Chronic Lymphocytic Leukemia.

Covalent Bruton's tyrosine kinase inhibitors (cBTKi) have led to a paradigm shift in the treatment of chronic lymphocytic leukemia (CLL). These targeted oral therapies are administered as standard treatments in both the front-line and relapsed and/or refractory settings. Given their administration as a continuous therapy with a "treat-to-progression" strategy, limitations of their use include discontinuation due to toxicity or from progression of the disease. Non-covalent Bruton's tyrosine kinase inhibitors (ncBTKi) distinguish themselves by binding reversibly to the BTK target, which may address the limitations of toxicity and acquired resistance seen with cBTKi. Several ncBTKis have been studied preclinically and in clinical trials, including pirtobrutinib and nemtabrutinib. Pirtobrutinib, which is now FDA approved for relapsed and/or refractory mantle cell lymphoma (MCL), has shown outstanding safety and preliminary efficacy in CLL in phase 1 and 2 clinical trials, with phase 3 trials underway. This agent may fill an unmet medical need for CLL patients requiring treatment after a cBTKi. Pirtobrutinib is particularly promising for the treatment of "double exposed" CLL, defined as CLL requiring treatment after both a cBTKi and venetoclax. Some patients have now developedacquired resistance to pirtobrutinib, and resistance mechanisms (including novel acquired mutations in BTK outside of the C481 position) have been recently described. Further study regarding the mechanisms of resistance to pirtobrutinib in patients without prior cBTKi exposure, as well as the potential for cross-resistance between cBTKi and ncBTKis, may be important to help inform where ncBTKis will ultimately fit in the treatment sequencing paradigm for CLL. An emerging clinical challenge is the treatment of CLL after ncBTKi discontinuation. Novel therapeutic strategies are being investigated to address the treatment of patients following disease progression on ncBTKis. Such strategies include novel agents (BTK degraders, bispecific antibody therapy, CAR T-cell therapy, PKC-beta inhibitors) as well as combination approaches incorporating a ncBTKi (e.g., pirtobrutinib and venetoclax) that may help overcome this acquired resistance.

Approach to a patient with "double refractory" chronic lymphocytic leukemia: "Double, double toil and trouble" (Shakespeare).

As patients continue to live longer with chronic lymphocytic leukemia, it has become evident that there is an unmet treatment need for patients who have progressed on multiple lines of therapy. In this article, we attempt to define the "double refractory" patient as resistant to both Bruton's tyrosine kinase inhibitors (BTKi) and venetoclax for which prognosis is poor and there remains no standard of care. We further examine the mechanism of resistance to these targeted agents and discuss the current landscape for managing this patient population. Finally, we explore data supporting promising new agents, including non-covalent BTKi, chimeric antigen receptor T cells, and additional classes of agents currently in development.

Adding Umbralisib and Ublituximab (U2) to Ibrutinib in Patients with CLL: A Phase II Study of an MRD-Driven Approach.

PURPOSE: Ibrutinib has transformed the management of chronic lymphocytic leukemia (CLL), though its use is limited by toxicity and resistance. In this study, we utilized an "add on" approach for patients who had been treated with ibrutinib in the front-line or relapsed/refractory settings with detectable MRD. Umbralisib and ublituximab (U2) were added on to ibrutinib, patients were treated until achieving undetectable-MRD (U-MRD), and then they entered a period of treatment-free observation (TFO). PATIENTS AND METHODS: Patients were eligible if they received ibrutinib in any line of therapy for at least 6 months and had detectable MRD (flow cytometry, <1 cell in 10-4 cutoff for U-MRD). U2 was added to ibrutinib, and patients were monitored serially for MRD. Once U-MRD was achieved or a total of 24 cycles were administered, patients entered a period of TFO. The primary study objective was rate of U-MRD. Secondary endpoints included safety and durability of clinical benefit after treatment discontinuation. RESULTS: Twenty-eight patients were enrolled of whom 27 were evaluable for efficacy. Patients received ibrutinib for a median of 21 months (range 7-67) prior to study enrollment. Fourteen patients (52%) have achieved U-MRD per protocol whereas 78% had at least one U-MRD evaluation. Seventeen patients (63%) have entered TFO after a median of 6.4 months on triplet therapy. Progression-free survival at 12 months was estimated at 95%. Grade ≥3 adverse events were hypertension 7%, diarrhea 4%, and increased ALT/AST 4%. CONCLUSIONS: This triplet approach utilizes the addition of U2 to ibrutinib as an MRD-driven time-limited therapy. This therapy was well tolerated and effective. TFO following this therapy appears durable in ongoing follow-up.

New Directions for Mantle Cell Lymphoma in 2022.

Mantle cell lymphoma is a rare B-cell non-Hodgkin lymphoma that is clinically and biologically heterogeneous. Risk stratification at the time of diagnosis is critical. One of the most powerful prognostic indices is the Mantle Cell Lymphoma International Prognostic Index-Combined, which integrates an estimate of proliferation (Ki67 index) with the standard Mantle Cell Lymphoma International Prognostic Index clinical factors. In addition, the presence of TP53 mutation is associated with suboptimal response to intensive chemoimmunotherapy and particularly dismal survival outcomes. Given their excellent activity in the relapsed/refractory setting, increasingly, biologically targeted therapeutics-such as covalent Bruton tyrosine kinase inhibitors, lenalidomide, and venetoclax-are being incorporated into "chemotherapy-free" regimens and in combination with established chemoimmunotherapy backbones for treatment-naïve mantle cell lymphoma. In addition, risk-adapted treatment programs are increasingly being studied. These programs tailor treatment according to baseline prognostic factors (e.g., presence of TP53 mutation) and may incorporate biomarkers of response such as minimal residual disease assessment. Although still investigational, these studies present an opportunity to move beyond the biology-agnostic, historical fitness-based treatment selection paradigm and toward a more personalized, tailored treatment approach in mantle cell lymphoma. After Bruton tyrosine kinase inhibitor failure, many promising standard or investigational therapies exist, including CAR T-cell therapy (including brexucabtagene autoleucel and lisocabtagene maraleucel), bispecific antibody therapy targeting CD20-CD3, zilovertamab vedotin (an antibody-drug conjugate that targets ROR1), and the noncovalent Bruton tyrosine kinase inhibitor pirtobrutinib. These new therapies show promising efficacy, even among high-risk patients, and will likely translate to improvements in survival outcomes for patients with progressive mantle cell lymphoma following treatment with a Bruton tyrosine kinase inhibitor.

Mechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors.

BACKGROUND: Covalent (irreversible) Bruton's tyrosine kinase (BTK) inhibitors have transformed the treatment of multiple B-cell cancers, especially chronic lymphocytic leukemia (CLL). However, resistance can arise through multiple mechanisms, including acquired mutations in BTK at residue C481, the binding site of covalent BTK inhibitors. Noncovalent (reversible) BTK inhibitors overcome this mechanism and other sources of resistance, but the mechanisms of resistance to these therapies are currently not well understood. METHODS: We performed genomic analyses of pretreatment specimens as well as specimens obtained at the time of disease progression from patients with CLL who had been treated with the noncovalent BTK inhibitor pirtobrutinib. Structural modeling, BTK-binding assays, and cell-based assays were conducted to study mutations that confer resistance to noncovalent BTK inhibitors. RESULTS: Among 55 treated patients, we identified 9 patients with relapsed or refractory CLL and acquired mechanisms of genetic resistance to pirtobrutinib. We found mutations (V416L, A428D, M437R, T474I, and L528W) that were clustered in the kinase domain of BTK and that conferred resistance to both noncovalent BTK inhibitors and certain covalent BTK inhibitors. Mutations in BTK or phospholipase C gamma 2 (PLCγ2), a signaling molecule and downstream substrate of BTK, were found in all 9 patients. Transcriptional activation reflecting B-cell-receptor signaling persisted despite continued therapy with noncovalent BTK inhibitors. CONCLUSIONS: Resistance to noncovalent BTK inhibitors arose through on-target BTK mutations and downstream PLCγ2 mutations that allowed escape from BTK inhibition. A proportion of these mutations also conferred resistance across clinically approved covalent BTK inhibitors. These data suggested new mechanisms of genomic escape from established covalent and novel noncovalent BTK inhibitors. (Funded by the American Society of Hematology and others.).

Recognizing Unmet Need in the Era of Targeted Therapy for CLL/SLL: "What's Past Is Prologue" (Shakespeare).

The management of chronic lymphocytic leukemia (CLL) has undergone unprecedented changes over the last decade. Modern targeted therapies are incorporated into clinical practice. Unfortunately, patients have begun to develop resistance or intolerance to multiple classes. Symptomatic patients previously treated with a BTK inhibitor (BTKi) and venetoclax represent a new and rapidly growing unmet need in CLL. Here, we define unmet needs in a modern treatment context. We also critically review the literature for PI3K inhibitors and chemoimmunotherapy and lack of data to support their utility following BTKis and venetoclax. Finally, we suggest opportunities to ensure the continued innovation for patients with CLL.

Treatment of Chronic Lymphocytic Leukemia After Discontinuation of Bruton's Tyrosine Kinase Inhibitors.

The Bruton's tyrosine kinase inhibitors (BTKis) ibrutinib and acalabrutinib have led to durable responses for patients with both treatment-naïve and relapsed/refractory chronic lymphocytic leukemia (CLL). Many patients, however, ultimately discontinue BTKis due to toxicity or progressive CLL. This article reviews the two most common reasons for ibrutinib and acalabrutinib discontinuation, including adverse events as well as CLL progression. The data for specific CLL-directed therapies following BTKi discontinuation, including venetoclax, phosphatidylinositol 3-kinase inhibitors, cellular therapies, and ongoing clinical trials, are reviewed. An evidence-based sequencing algorithm for treatment of CLL following BTKi discontinuation is proposed.