ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are essentially different manifestations of the same disease that are similarly managed. A number of molecular and cytogenetic variables with prognostic implications have been identified. Undetectable minimal residual disease at the end of treatment with chemoimmunotherapy or venetoclax-based combination regimens is an independent predictor of improved survival among patients with previously untreated or relapsed/refractory CLL/SLL. The selection of treatment is based on the disease stage, presence or absence of del(17p) or TP53 mutation, immunoglobulin heavy chain variable region mutation status, patient age, performance status, comorbid conditions, and the agent's toxicity profile. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Prognosis , ImmunotherapyABSTRACT
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.
Subject(s)
Agammaglobulinaemia Tyrosine Kinase , Drug Resistance, Neoplasm , Ikaros Transcription Factor , Leukemia, Lymphocytic, Chronic, B-Cell , Protein Kinase Inhibitors , Proteolysis , Humans , Agammaglobulinaemia Tyrosine Kinase/genetics , Agammaglobulinaemia Tyrosine Kinase/metabolism , Ikaros Transcription Factor/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Mutation , Phosphorylation , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Signal Transduction , Proteolysis/drug effects , Drug Resistance, Neoplasm/drug effectsABSTRACT
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.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Lymphoma, B-Cell, Marginal Zone , Humans , Caspases , Lymphoma, B-Cell, Marginal Zone/pathology , Translocation, Genetic , Prognosis , Chromosomes, Human, Pair 14 , Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 ProteinABSTRACT
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.
ABSTRACT
Introduction: An estimated 15% of community-dwelling older adults have depressive symptoms in the U.S. The Program to Encourage Active, Rewarding Lives (PEARLS) is an evidence-based program for managing late-life depression. PEARLS is a home/community-based collaborative care model delivered by community-based organizations to improve access to quality depression care. Trained staff actively screen for depression to improve recognition, teach problem-solving and activity planning skills for self-management, and connect participants to other supports and services as needed. Methods: This study examined 2015-2021 data from 1,155 PEARLS participants across four states to assess PEARLS effectiveness to reduce depressive symptoms. The clinical outcomes were measured by the self-reported PHQ-9 instrument to assess changes in depressive symptoms scored as depression-related severity, clinical remission, and clinical response. A generalized estimating equation (GEE) model was fitted to examine changes in composite PHQ-9 scores from baseline to the final session. The model adjusted for participants' age, gender, race/ethnicity, education level, income level, marital status, number of chronic conditions, and number of PEARLS sessions attended. Cox proportional hazards regression models were conducted to estimate the hazard ratio for improvement of depressive symptoms (i.e., remission or response), while adjusting for the covariates. Results: PHQ-9 scale scores significantly improved from baseline to their final sessions (mean difference = -5.67, SEM = 0.16, p < 0.001). About 35% of participants achieved remission with PHQ-9 score < 5. Compared to participants with mild depression, patients with moderate depression (HR = 0.43, 95%CI = 0.35-0.55), moderately severe depression (HR = 0.28, 95%CI = 0.21-0.38), and severe depression (HR = 0.22 95%CI = 0.14-0.34) were less likely to experience clinical remission with PHQ-9 score < 5, while adjusting for the covariates. About 73% achieved remission based on no longer having one or both cardinal symptoms. Compared to participants with mild depression, patients with moderate depression (HR = 0.66, 95%CI = 0.56-0.78), moderately severe depression (HR = 0.46, 95%CI = 0.38-0.56), and severe depression (HR = 0.38, 95%CI = 0.29-0.51) were less likely to experience clinical remission, while adjusting for the covariates. Nearly 49% of participants had a clinical response or a ≥ 50% decrease in PHQ-9 scores over time. There were no differences between the severity of depression groups based on the time to clinical response. Discussion: Findings confirm that PEARLS is an effective program to improve depressive symptoms among older adults in diverse real-world community settings and can be a more accessible option for depressive older adults who are traditionally underserved by clinical care.
Subject(s)
Depressive Disorder , Home Care Services , Humans , Aged , Depression/therapy , Depression/diagnosisABSTRACT
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.
Subject(s)
Antineoplastic Agents , Leukemia, Lymphocytic, Chronic, B-Cell , Receptors, Chimeric Antigen , Antineoplastic Agents/therapeutic use , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Prognosis , Protein Kinase Inhibitors/therapeutic use , Receptors, Chimeric Antigen/therapeutic useABSTRACT
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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Leukemia, Lymphocytic, Chronic, B-Cell , Adenine/analogs & derivatives , Antibodies, Monoclonal , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Heterocyclic Compounds, 4 or More Rings , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Neoplasm, Residual/drug therapy , PiperidinesABSTRACT
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.
Subject(s)
Immunoconjugates , Lymphoma, Mantle-Cell , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Humans , Immunoconjugates/therapeutic use , Immunotherapy , Immunotherapy, Adoptive , Lymphoma, Mantle-Cell/diagnosis , Lymphoma, Mantle-Cell/genetics , Lymphoma, Mantle-Cell/therapy , Protein Kinase Inhibitors/therapeutic useABSTRACT
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.).
Subject(s)
Agammaglobulinaemia Tyrosine Kinase , Drug Resistance, Neoplasm , Leukemia, Lymphocytic, Chronic, B-Cell , Mutation , Phospholipase C gamma , Protein Kinase Inhibitors , Humans , Middle Aged , Adenine/analogs & derivatives , Adenine/pharmacology , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Agammaglobulinaemia Tyrosine Kinase/genetics , Agammaglobulinaemia Tyrosine Kinase/ultrastructure , Drug Resistance, Neoplasm/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Phospholipase C gamma/genetics , Piperidines/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Receptors, Antigen, B-Cell/metabolism , Sequence Analysis, RNA , Signal Transduction/drug effectsABSTRACT
In this review, we examine the literature supporting treatment decision making in the front-line and relapsed/refractory settings for patients with chronic lymphocytic leukemia (CLL). In the front-line setting, novel-agent-based approaches, including continuous Bruton tyrosine kinase (BTK) inhibitor-based therapy and time-limited venetoclax with obinutuzumab, have demonstrated survival benefit over chemoimmunotherapy. While novel-agent-based front-line approaches are appropriate for most patients, fludarabine, cyclophosphamide, and rituximab (FCR) remains a consideration for a selected population of young patients with immunoglobulin heavy chain variable region gene (IGHV)-mutated disease because of the possibility of a prolonged remission following FCR. As front-line novel-agent-based approaches have not been compared directly, decision making regarding which novel-agent-based approach to use in the front-line setting is often based on comorbidities and shared decision making. In the relapsed/refractory setting, BTK inhibitors, venetoclax-based therapy, and phosphoinositide 3-kinase (PI3K) inhibitors have demonstrated survival benefit when compared with chemoimmunotherapy regimens. Data to support various treatment sequences are limited, which highlights the need for prospective data to examine the optimal treatment sequence. Finally, we examine therapies with combinations of novel agents, and novel agents in development, including covalent and noncovalent BTK inhibitors, PI3K inhibitors, B-cell lymphoma 2 (BCL2) inhibitors, immunotherapies, and cellular therapies. With effective approved options and new agents in development, the role of chemoimmunotherapy in the management of CLL has diminished.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Antineoplastic Agents/therapeutic use , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Agents, Immunological/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Phosphoinositide-3 Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins/antagonists & inhibitors , Randomized Controlled Trials as Topic , RecurrenceABSTRACT
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.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Humans , Immunotherapy , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Phosphatidylinositol 3-Kinases , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic useABSTRACT
BACKGROUND: We hypothesised that combining zanubrutinib with obinutuzumab and venetoclax (BOVen) as an initial therapy for chronic lymphocytic leukaemia and small lymphocytic lymphoma would lead to high rates of undetectable minimal residual disease (MRD), and we explored MRD as a biomarker for directing treatment duration. METHODS: This multicenter, investigator-initiated, single-arm, phase 2 trial took place at two two academic medical centres in the USA. Patients were eligible for the primary cohort if they had treatment-naive chronic lymphocytic leukaemia or small lymphocytic lymphoma, required therapy, and were at least 18 years of age with an Eastern Cooperative Oncology Group performance status up to 2. BOVen was administered in 28 day cycles (oral zanubrutinib at 160 mg twice per day starting in cycle 1 on day 1; intravenous obinutuzumab at 1000 mg on day 1 [split over day 1 with 100 mg and day 2 with 900 mg for an absolute lymphocyte count >25â000 cells per µL or lymph nodes >5 cm in diameter], day 8, and day 15 of cycle 1, and day 1 of cycles 2-8; and oral venetoclax ramp up to 400 mg per day starting in cycle 3 on day 1) and discontinued after 8-24 cycles when prespecified undetectable MRD criteria were met in the peripheral blood and bone marrow. The primary endpoint was the proportion of patients that reached undetectable MRD in both the peripheral blood and bone marrow (flow cytometry cutoff less than one chronic lymphocytic leukaemia cell per 10â000 leukocytes [<10-4]) assessed per protocol. This trial is registered at clinicaltrials.gov (NCT03824483). The primary cohort is closed to recruitment, and recruitment continues in the TP53-mutated mantle cell lymphoma cohort. FINDINGS: Between March 14, 2019, and Oct 10, 2019, 47 patients were screened for eligibility, and 39 patients were enrolled and treated. Median age was 62 years (IQR 52-70) with 30 (77%) of 39 male participants and nine (23%) of 39 female participants. 28 (72%) of 39 patients had unmutated immunoglobulin heavy-chain variable-region and five (13%) of 39 had 17p deletion or TP53 mutation. After a median follow-up of 25·8 months (IQR 24·0-27·3), 33 (89%) of 37 patients (95% CI 75-97) had undetectable MRD in both blood and bone marrow, meeting the prespecified undetectable MRD criteria to stop therapy after a median of ten cycles (IQR 8-12), which includes two cycles of zanubrutinib and obinutuzumab before starting venetoclax. After median surveillance after treatment of 15·8 months (IQR 13·0-18·6), 31 (94%) of 33 patients had undetectable MRD. The most common adverse events were thrombocytopenia (23 [59%] of 39), fatigue (21 [54%]), neutropenia (20 [51%]), and bruising (20 [51%]), and the most common adverse event at grade 3 or worse was neutropenia (seven [18%]) in the intention-to-treat population. One death occurred in a patient with intracranial haemorrhage on day 1 of cycle 1 after initiating intravenous heparin for pulmonary emboli. INTERPRETATION: BOVen was well tolerated and met its primary endpoint, with 33 (89%) of 37 previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma reaching undetectable MRD in both peripheral blood and bone marrow despite a median treatment duration of only 10 months, owing to our undetectable MRD-driven treatment discontinuation design. These data support further evaluation of the BOVen regimen in chronic lymphocytic leukaemia and small lymphocytic lymphoma with treatment duration guided by early MRD response kinetics. FUNDING: Beigene, Genentech (Roche), Grais-Cutler Fund, Lymphoma Research Fund, Lymphoma Research Foundation, American Cancer Society, Farmer Family Foundation, and the National Instititutes of Health and National Cancer Institute.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Aged , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bridged Bicyclo Compounds, Heterocyclic , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Male , Middle Aged , Neoplasm, Residual , Piperidines , Pyrazoles , Pyrimidines , SulfonamidesSubject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/mortality , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , SARS-CoV-2/drug effects , Adult , Aged , Aged, 80 and over , COVID-19/complications , COVID-19/therapy , COVID-19/virology , Disease Management , Drug Therapy, Combination , Female , Follow-Up Studies , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/epidemiology , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Leukemia, Lymphocytic, Chronic, B-Cell/virology , Male , Middle Aged , Prognosis , Retrospective Studies , SARS-CoV-2/isolation & purification , Survival Rate , United States/epidemiologyABSTRACT
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.