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.

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

Recent years have seen significant improvement in chronic lymphocytic leukemia (CLL) management. Targeting B-cell lymphoma (BCL-2) and Bruton’s kinase (BTK) have become the main strategies to restrain CLL activity. These agents are generally well tolerated, but the discontinuation of these therapies happens due to resistance, adverse effects, and Richter’s transformation. A growing population of patients who have previously used both BTK inhibitors and BCL2 suffer from the constriction of the following regimens. This review explores the resistance mechanisms for both ibrutinib and venetoclax. Moreover, we present innovative approaches evaluated for treating double-refractory CLL.

Treatment of Double-Refractory Chronic Lymphocytic Leukemia—An Unmet Clinical Need

Bruton's tyrosine kinase (BTK) inhibitors have recently been approved for clinical use against several B-cell indolent lymphoid malignancies, both as single agents or in combination. One second-generation BTK inhibitor that is being developed for the treatment of B-cell hematological malignancies, as well as for autoimmune disorders, is orelabrutinib.This paper reviews recent developments in the use of orelabrutinib against B-cell indolent lymphoid malignancies such as chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, Waldenstrom macroglobulinemia and central nervous system lymphoma. Google Scholar and PubMed were initially searched for articles, and the corpus of articles was broadened by reviewing the references of the identified papers. All were in English. The corpus comprised papers from 2016 to April 2023. In addition, a manual search was performed of conference proceedings from the last five years of The American Society of Hematology, American Society of Clinical Oncology and the European Hematology Association.Orelabrutinib is an active drug in indolent and aggressive B-cell lymphoid malignancies. It demonstrates high selectivity, good efficacy and an excellent safety profile. Nevertheless, further clinical trials are required to optimize its use. In addition, several other highly selective BTK inhibitors are being examined in early-phase studies. 

The preclinical discovery and development of orelabrutinib as a novel treatment option for B-cell lymphoid malignancies

While the past decade has witnessed unprecedented progress for patients with chronic lymphocytic leukemia (CLL), outcomes for patients with Richter transformation (RT) remain dismal. Multiagent chemoimmunotherapy regimens, such as rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, are commonly used, although outcomes are far poorer than observed with the same regimens used in de novo diffuse large B-cell lymphoma. The revolutionary targeted therapies approved for CLL, such as inhibitors of Bruton tyrosine kinase and B-cell leukemia/lymphoma-2, have limited activity in RT as monotherapy, and initial promising activity of checkpoint blockade antibodies was also eventually found to be ineffective as monotherapy for most patients. Over the past few years, as outcomes for patients with CLL improved, there has been a growing focus of the research community on improving our biological understanding of the underlying pathophysiology of RT and on translating these new insights into rational combination strategies that are poised to improve therapeutic outcomes. Here, we present a brief overview of the biology and diagnosis of RT, as well as prognostic considerations, before providing a summary of the data supporting various therapies that have been recently studied in RT. We then turn our attention to the horizon and describe several of the promising novel approaches under investigation to treat this challenging disease. 

Practical Management of Richter Transformation in 2023 and Beyond

Simple Summary Here, we present a review of cellular therapies that have been used in both chronic lymphocytic leukemia and Richter’s transformation. We will review the data behind allogeneic hematopoietic stem cell transplantation in the modern era. Subsequently, we will discuss existing and emerging strategies for chimeric antigen receptor-based approaches. Abstract Cellular therapies can be viewed as both the newest and oldest techniques for treating chronic lymphocytic leukemia (CLL) and Richter’s transformation (RT). On one hand, allogeneic hematopoietic stem cell transplantation (alloHSCT) has been available for decades, though its use is diminishing with the increasing availability of effective novel targeted agents, especially in CLL. Among newer techniques, chimeric antigen receptor T-cells (CAR-T) have demonstrated astounding efficacy in several hematologic malignancies, leading to FDA approval and use in clinical practice. However, though CLL is the earliest disease type for which CAR-T were studied, development has been slower and has yet to lead to regulatory approval. Owing partially to its rarity but also due to the aggressive behavior of RT, CAR-T in RT have only been minimally explored. Here, we will focus on the applications of cellular therapies in CLL and RT, specifically reviewing more recent data related to alloHSCT in the novel-agent era and CAR-T cell development in CLL/RT, focusing on safety and efficacy successes and limitations. We will review strategies to improve upon CAR-T efficacy and discuss ongoing trials utilizing CAR-T in CLL/RT, as well as emerging technologies, such as allogeneic CAR-T and natural killer CAR (CAR NK) cells.

/pdf/cellular-therapies-in-chronic-lymphocytic-leukemia-and-1qf4x5j7.pdf

Cellular Therapies in Chronic Lymphocytic Leukemia and Richter’s Transformation: Recent Developments in Chimeric Antigen Receptor T-Cells, Natural Killer Cells, and Allogeneic Stem Cell Transplant

Background: For patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and certain B-cell neoplasms, resistance to Bruton tyrosine kinase inhibitors (BTKi) develops primarily through mutations at the cysteine binding site (C481) or PLCγ2 mutations. Nemtabrutinib (MK-1026, formerly ARQ-531) is a non-covalent, potent inhibitor of both wild type and C481-mutated BTK. Aims: In the phase 1/2 dose-escalation and dose-expansion BELLWAVE-001 study (NCT03162536), the preliminary recommended phase 2 dose (RP2D) of nemtabrutinib was determined to be 65 mg once daily. The efficacy and safety of nemtabrutinib in patients (pts) with CLL/SLL and B-cell non-Hodgkin lymphoma (NHL) were also evaluated at a higher dose during the dose-expansion phase. Methods: In this open-label, single-arm phase 2 study, 9 expansion cohorts were initiated following determination of preliminary nemtabrutinib RP2D. Approximately 10-25 eligible pts were enrolled into Cohort A (relapsed/refractory (r/r) CLL/SLL, with ≥2 prior therapies including covalent BTKi, with documented C481 mutation), Cohort B (r/r CLL/SLL progressed on/intolerant to a BTKi, with ≥2 prior therapies without C481 mutation), Cohort C (Richter transformation with ≥1 prior therapy), Cohort D-H (follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, high-grade B cell lymphoma with known MYC, BCL-2 or BCL-6 translocations, and Waldenström macroglobulinemia [WM], respectively, who received ≥2 prior therapies), Cohort I (food-effect cohort including pts with B-cell NHL, CLL/SLL, and WM). Primary end point was ORR (per iwCLL criteria, by investigator) for participants with CLL/SLL. Secondary end points included DOR and safety and tolerability. Results: Among 118 pts enrolled, 44 had B-cell NHL, 68 CLL/SLL, and 4 WM. Of these, 94 (79.6%) were treated at the preliminary RP2D, including 51 (54.3%) participants with CLL/SLL. Pts with CLL/SLL had a median (range) number of prior therapies of 4 (1-18), 43 (84%) had prior BTKi therapy, 12 (23%) had del17p, 30 (59%) had IGHV unmutated status, and 32 (63%) had C481S BTK mutation. At data cut-off (April 7, 2021), median (range) follow-up was 4.6 mo (0.1-26.7) for all treated pts. ORR was 57.9% (22/38; 1 CR, 21 PR/PRL) per iwCLL criteria in the efficacy-evaluable population of pts with CLL/SLL treated at preliminary RP2D. Median duration of response was not estimable [NE] (range, 8.3 mo-NE). Among all treated participants, 114 (97%) had a treatment-emergent adverse event (TEAE), with 78 (66%) having a drug-related TEAE, and 9 (8%) having a drug-related TEAE that led to discontinuation. Common TEAEs (≥ 20%) included fatigue (33%), constipation (31%), dysgeusia (28%), cough (25%), nausea (25%), pyrexia (25%), dizziness (23%), hypertension (23%), peripheral edema (22%), diarrhea (21%), and arthralgia (20%). Grade ≥3 TEAEs occurred in 80 (68%) participants. Grade 5 TEAEs occurred in 7 (6%) participants and included death following disease progression 3 (3%), sepsis 1 (1%), dyspnea 1 (1%), and respiratory failure 2 (2%). Common drug-related TEAEs (≥10%) included dysgeusia (15%), nausea (11%), fatigue (11%), and decreased neutrophil count (10%). Grade 3-4 drug-related TEAEs occurred in 31 (26%) participants. No drug-related TEAEs led to death. Summary/Conclusion: Nemtabrutinib has promising antitumor activity with a manageable safety profile in pts with CLL/SLL exposed to multiple lines of therapy, including in those who had progression of disease on prior covalent BTKi. Further evaluation of nemtabrutinib in B-cell malignancies is ongoing. 

P682: nemtabrutinib (mk-1026), a non-covalent inhibitor of wild-type and c481s mutated bruton tyrosine kinase for b-cell malignancies: efficacy and safety of the phase 2 dose-expansion bellwave-001 study

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P682: nemtabrutinib (mk-1026), a non-covalent inhibitor of wild-type and c481s mutated bruton tyrosine kinase for b-cell malignancies: efficacy and safety of the phase 2 dose-expansion bellwave-001 study