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.

Predictors of SARS-CoV-2 Omicron breakthrough infection after receipt of AZD7442 (tixagevimab-cilgavimab) for pre-exposure prophylaxis among hematologic malignancy patients.

AZD7442 (tixagevimab-cilgavimab) is a combination of two human monoclonal antibodies for pre-exposure prophylaxis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among high-risk patients who do not mount a reliable vaccine response. Foremost among these are hematologic malignancy patients with limited clinical trial or realworld experience to assess the effectiveness of this combination treatment since the emergence of Omicron and its subvariants. We performed a retrospective study of 892 high-risk hematologic malignancy patients who received AZD7442 at Memorial Sloan Kettering Cancer Center in New York City from January 1, 2022 to July 31, 2022. We evaluated demographic, clinical, and laboratory characteristics and performed regression analyses to evaluate risk factors for breakthrough infection. We also evaluated the impact of updated AZD7442 dosing regimens on the risk of breakthrough infection. Among 892 patients, 98 (10.9%) had a breakthrough infection during the study period. A majority received early outpatient treatment (82%) and eventually eight (8.2%) required hospitalization for management of Coronavirus Disease 2019 (COVID-19), with a single instance of severe COVID-19 and death. Patients who received a repeat dose or a higher firsttime dose of AZD7442 had a lower incidence of breakthrough infection. Univariate analyses did not reveal any significant predictors of breakthrough infection. While AZD7442 is effective at reducing SARS-CoV-2 breakthrough infection in patients with hematologic malignancies, no risk factors reliably predicted risk of infection. Patients who received updated dosing regimens as per Food and Drug Administration guidelines had better protection against breakthrough infection.

Real-world comparative effectiveness of acalabrutinib and ibrutinib in patients with chronic lymphocytic leukemia.

Novel agents, including Bruton tyrosine kinase inhibitors (BTKis), have become the standard of care for patients with chronic lymphocytic leukemia (CLL). We conducted a real-world retrospective analysis of patients with CLL treated with acalabrutinib vs ibrutinib using the Flatiron Health database. Patients with CLL were included if they initiated acalabrutinib or ibrutinib between 1 January 2018 and 28 February 2021. The primary outcome of interest was time to treatment discontinuation (TTD). Kaplan-Meier analysis was used to estimate unweighted and weighted median TTD. A weighted Cox proportional hazards model was used to compare the TTD between cohorts. Of the 2509 patients included in the analysis, 89.6% received ibrutinib, and 14.1% received acalabrutinib. TTD was not significantly different between cohorts in the unweighted analysis. After weighting, the cohorts were balanced on all baseline characteristics except cardiovascular risk factors and baseline medications use. The median (95% confidence interval [CI]) TTD was not reached (NR; 95% CI, 25.1 to NR) for the acalabrutinib cohort and was 23.4 months (95% CI, 18.1-28.7) for the ibrutinib cohort. The discontinuation rate at 12 months was 22% for the weighted acalabrutinib cohort vs 31% for the weighted ibrutinib cohort (P = .005). After additional adjustment for prior BTKi use, the acalabrutinib cohort had a 41% lower risk of discontinuation vs ibrutinib (hazard ratio, 0.59; 95% CI, 0.43-0.81; P = .001). In the largest available study comparing BTKis, patients with CLL receiving acalabrutinib demonstrated lower rates of discontinuation and a prolonged time to discontinuation vs those receiving ibrutinib.

Treatment Discontinuation Patterns for Patients With Chronic Lymphocytic Leukemia in Real-World Settings: Results From a Multi-Center International Study.

INTRODUCTION: This study assessed treatment discontinuation patterns and reasons among chronic lymphocytic leukemia (CLL) patients initiating first-line (1L) and second-line (2L) treatments in real-world settings. MATERIALS AND METHODS: Using deidentified electronic medical records from the CLL Collaborative Study of Real-World Evidence, premature treatment discontinuation was assessed among FCR, BR, BTKi-based, and BCL-2-based regimen cohorts. RESULTS: Of 1364 1L patients (initiated in 1997-2021), 190/13.9% received FCR (23.7% discontinued prematurely); 255/18.7% received BR (34.5% discontinued prematurely); 473/34.7% received BTKi-based regimens, of whom 28.1% discontinued prematurely; and 43/3.2% received venetoclax-based regimens, of whom 16.3% discontinued prematurely (venetoclax monotherapy: 7/0.5%, of whom 42.9% discontinued; VG/VR: 36/2.6%, of whom 11.1% discontinued). The most common reasons for treatment discontinuation were adverse events (FCR: 25/13.2%; BR: 36/14.1%; BTKi-based regimens: 75/15.9%) and disease progression (venetoclax-based: 3/7.0%). Of 626 2L patients, 20/3.2% received FCR (50.0% discontinued); 62/9.9% received BR (35.5% discontinued); 303/48.4% received BTKi-based regimens, of whom 38.0% discontinued; and 73/11.7% received venetoclax-based regimens, of whom 30.1% discontinued (venetoclax monotherapy: 27/4.3%, of whom 29.6% discontinued; VG/VR: 43/6.9%, of whom 27.9% discontinued). The most common reasons for treatment discontinuation were adverse events (FCR: 6/30.0%; BR: 11/17.7%; BTKi-based regimens: 60/19.8%; venetoclax-based: 6/8.2%). CONCLUSION: The findings of this study highlight the continued need for tolerable therapies in CLL, with finite therapy offering a better tolerated option for patients who are newly diagnosed or relapsed/refractory to prior treatments.

Clinical outcomes among patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who received treatment with a covalent BTK and BCL2 inhibitor in the United States: a real-world database study.

This retrospective study using the nationwide de-identified Flatiron Health electronic health record-derived database was designed to evaluate clinical outcomes among patients with chronic lymphocytic leukemia (CLL) who previously received both a covalent Bruton's tyrosine kinase inhibitor (cBTKi) and B-cell lymphoma 2 inhibitor (BCL2i) in a real-world setting. Outcomes for the immediate next line of therapy following the latter of the cBTKi or BCL2i treatment included: real-world response rate of 34.4% (using methods most consistent with clinical trials); median duration of real-world response of 13.3 months; and median real-world progression-free survival of 9.2 months. Median overall survival was 25.5 months from the start of the immediate next line of therapy. There remains a need for more effective therapies after cBTKi and BCL2i therapy for patients with CLL.

Clonal Characterization and Somatic Hypermutation Assessment by Next-Generation Sequencing in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Detailed Description of the Technical Performance, Clinical Utility, and Platform Comparison.

Somatic hypermutation status of the IGHV gene is essential for treating patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. Unlike the conventional low-throughput method, assessment of somatic hypermutation by next-generation sequencing (NGS) has potential for uniformity and scalability. However, it lacks standardization or guidelines for routine clinical use. We critically assessed the performance of an amplicon-based NGS assay across 458 samples. Using a validation cohort (35 samples), the comparison of two platforms (Ion Torrent versus Illumina) and two primer sets [leader versus framework region 1 (FR1)] in their ability to identify clonotypic IGHV rearrangement(s) revealed 97% concordance. The mutation rates were identical by both platforms when using the same primer set (FR1), whereas a slight overestimation bias (+0.326%) was found when comparing FR1 with leader primers. However, for nearly all patients this did not affect the stratification into mutated or unmutated categories, suggesting that use of FR1 may provide comparable results if leader sequencing is not available and allowing for a simpler NGS laboratory workflow. In routine clinical practice (423 samples), the productive rearrangement was successfully detected by either primer set (leader, 97.7%; FR1, 94.7%), and a combination of both in problematic cases reduced the failure rate to 1.2%. Higher sensitivity of the NGS-based analysis also detected a higher frequency of double IGHV rearrangements (19.1%) compared with traditional approaches.

Time to second treatment can be used to predict overall survival in chronic lymphocytic leukemia: identifying risk factors to help guide treatment selection.

Targeted therapies have largely replaced chemoimmunotherapy (CIT) in first-line treatment of chronic lymphocytic leukemia (CLL). We aimed to develop a prognostic model to determine who would benefit from first-line CIT vs target therapy. In follicular lymphoma, time from diagnosis to second treatment (TT2T) correlates better with overall survival (OS) than time from diagnosis to first treatment (TT1T). We hypothesized that TT2T is a potential surrogate for OS in CLL. In a model-building cohort (n = 298), we evaluated potential predictors for TT2T and derived a risk score, which we validated in an external cohort (n = 1141). Our data demonstrated that TT2T and OS were more strongly correlated than TT1T and OS. Our risk score model consisted of three predictors (unmutated IGHV, ß2-microglobulin >297 nmol/L, and Rai stage I-IV), and was prognostic for TT2T and OS. TT2T is a promising surrogate for OS in CLL, but further validation is needed to establish this association.

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.

MAJIC: a phase III trial of acalabrutinib + venetoclax versus venetoclax + obinutuzumab in previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma.

Here we describe the rationale and design of MAJIC, a phase III, prospective, multicenter, randomized trial comparing the combination of the BTK inhibitor acalabrutinib plus the BCL2 inhibitor venetoclax versus the combination of venetoclax plus obinutuzumab as frontline treatment for chronic lymphocytic leukemia or small lymphocytic lymphoma. In both treatment arms, disease response (assessed by International Workshop on Chronic Lymphocytic Leukemia criteria) and minimal residual disease will be used to guide therapy duration, with all patients ultimately discontinuing treatment after a maximum of 2 years. The primary end point is progression-free survival. Key secondary end points include rates of undetectable minimal residual disease, overall response and overall survival. This study will address key unanswered questions in frontline chronic lymphocytic leukemia/small lymphocytic lymphoma therapy by investigating the optimal duration of finite treatment and identifying the optimal venetoclax doublet regimen.

This article describes the design of the MAJIC clinical trial, which investigates two different treatment combinations for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have not received treatment for their disease previously. Patients will be randomized (put into a group by chance) to receive either acalabrutinib + venetoclax (AV) or venetoclax + obinutuzumab (VO). VO is already an approved initial treatment option for CLL/SLL. Acalabrutinib is also an approved initial treatment option when given by itself, but the AV combination is not yet approved. We are doing this study to better understand and directly compare how well AV and VO work when used for the treatment of CLL/SLL. A test done on the blood and bone marrow called 'minimal residual disease' will be used to help guide the length of time that patients receive treatment. Clinical Trial Registration: NCT05057494 (ClinicalTrials.gov).

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.

The potential of pirtobrutinib in multiple B-cell malignancies.

Bruton's tyrosine kinase (BTK) is a critical downstream signaling element from the B-cell receptor (BCR) that has been effectively inhibited in B-cell cancers by irreversible, covalent inhibitors including ibrutinib and acalabrutinib. All FDA-approved covalent BTK inhibitors rely on binding to the cysteine 481 (C481) amino acid within the active site of BTK, thus rendering it inert. While covalent BTK inhibitors have been very successful in multiple B-cell malignancies, improving both overall survival and progression-free survival relative to chemoimmunotherapy in phase 3 trials, they can be limited by intolerance and disease progression. Pirtobrutinib is a novel, highly selective, and non-covalent BTK inhibitor that binds independently of C481, and in a recent, first-in-human phase 1/2 clinical trial was shown to be extremely well tolerated and lead to remissions in relapsed/refractory patients with multiple B-cell malignancies. Here, we review the pharmacologic rationale for pursuing non-covalent BTK inhibitors, the clinical need for such inhibitors, existing safety, and resistance mechanism data for pirtobrutinib, and the forthcoming clinical trials that seek to define the clinical utility of pirtobrutinib, which has the potential to fulfill multiple areas of unmet clinical need for patients with B-cell malignancies.

Current Treatment of Chronic Lymphocytic Leukemia: The Diminishing Role of Chemoimmunotherapy.

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.

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.

Disease- and Therapy-Specific Impact on Humoral Immune Responses to COVID-19 Vaccination in Hematologic Malignancies.

Coronavirus disease-19 (COVID-19) vaccine response data for patients with hematologic malignancy, who carry high risk for severe COVID-19 illness, are incomplete. In a study of 551 hematologic malignancy patients with leukemia, lymphoma, and multiple myeloma, anti-SARS-CoV-2 spike IgG titers and neutralizing activity were measured at 1 and 3 months from initial vaccination. Compared with healthy controls, patients with hematologic malignancy had attenuated antibody titers at 1 and 3 months. Furthermore, patients with hematologic malignancy had markedly diminished neutralizing capacity of 26.3% at 1 month and 43.6% at 3 months, despite positive seroconversion rates of 51.5% and 68.9% at the respective time points. Healthy controls had 93.2% and 100% neutralizing capacity at 1 and 3 months, respectively. Patients with leukemia, lymphoma, and multiple myeloma on observation had uniformly blunted responses. Treatment with Bruton tyrosine kinase inhibitors, venetoclax, phosphoinositide 3-kinase inhibitors, anti-CD19/CD20-directed therapies, and anti-CD38/B-cell maturation antigen-directed therapies substantially hindered responses, but single-agent immunomodulatory agents did not. Significance: Patients with hematologic malignancy have compromised COVID-19 vaccine responses at baseline that are further suppressed by active therapy, with many patients having insufficient neutralizing capacity despite positive antibody titers. Refining vaccine response parameters is critical to guiding clinical care, including the indication for booster vaccines, for this vulnerable population.See related article by Tamari et al., p. 577. This article is highlighted in the In This Issue feature, p. 549.

Zanubrutinib, obinutuzumab, and venetoclax with minimal residual disease-driven discontinuation in previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: a multicentre, single-arm, phase 2 trial.

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 >25 000 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 10 000 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.

Reduced-intensity conditioning hematopoietic stem cell transplantation for chronic lymphocytic leukemia and Richter's transformation.

Allogeneic hematopoietic stem cell transplantation (HSCT) may potentially cure patients with chronic lymphocytic leukemia (CLL) and Richter's transformation (CLL-RT) or CLL without RT, but the impact of novel agents on HSCT is unclear. CLL-RT patients have a grave prognosis, and their outcomes after HSCT are uncertain. We conducted a retrospective analysis of all 58 CLL patients, including 23 CLL-RT patients, who underwent reduced intensity conditioning (RIC) HSCT at Memorial Sloan Kettering Cancer Center (New York, NY) between September 2006 and April 2017. With a median follow-up of 68 months (range, 24-147 months), 5-year progression-free survival (PFS) was 40% (95% confidence interval [CI], 28%-56%), and overall survival (OS) was 58% (95% CI, 48%-74%). The 1-year graft-versus-host disease/relapse-free survival (GRFS) was 38% (95% CI, 25%-50%). Patients with CLL-RT and CLL patients without RT had comparable outcomes. In both cohorts, treatment-sensitive response and ≤3 previous lines of therapy produced superior PFS and OS. Outcomes were agnostic to adverse cytogenetic and molecular features. Novel agents did not have a negative impact on HSCT outcomes. Total body irradiation (TBI)-containing RIC yielded inferior PFS, OS, and GRFS. CLL-RT patients older than age 55 years who had an HSCT Comorbidity Index score of ≥2 demonstrated inferior OS. This study, which is the largest series of RIC-HSCT for patients with CLL-RT, provides evidence supporting RIC-HSCT in early remission courses for patients with CLL-RT and poor-risk CLL patients. TBI-containing RIC should be considered with caution.