Are we closer to a standard of care for Richter's syndrome? Novel treatments on the horizon.

INTRODUCTION: The therapeutic landscape for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has significantly evolved over the past decade with dramatically improved outcomes with the introduction of targeted therapies. This unfortunately has not been the case for Richter transformation (RT), the histologic transformation to a more aggressive lymphoma, most typically diffuse large B-cell lymphoma (DLBCL). As such, RT continues to be one of the most challenging complications of CLL/SLL. Historically, RT has a poor response to treatment, with a minority reaching complete remission (CR) and overall survival (OS) being less than a year. AREAS COVERED: The focus of this review is to discuss the effectiveness of commonly used regimens, and review existing data for emerging regimens being examined in ongoing clinical trials to improve prognosis and outcomes in patients with RT. Despite extensive efforts to optimize therapies for RT, there is still no generalized consensus on either first-line treatment regimens or regimens in the relapsed/refractory setting. RT continues to carry a high mortality rate without durable response to current therapeutic agents. EXPERT OPINION: Ongoing and future research may identify novel treatment approaches that will eventually improve outcomes for patients with RT. The optimal care for RT patients is a clinical trial, when feasible.

Frontline Therapy of CLL-Changing Treatment Paradigms.

PURPOSE OF REVIEW: The therapeutic landscape for chronic lymphocytic leukemia (CLL) has undergone a complete makeover following the introduction of highly effective targeted therapies, beginning with ibrutinib which first attained regulatory approval for CLL in 2014. RECENT FINDINGS: In recent years, we have seen further refinement of therapeutic options with the development of newer-generation Bruton's tyrosine kinase inhibitors (BTKi) including acalabrutinib and zanubrutinib that improve upon the safety of ibrutinib. Additionally, venetoclax-based approaches, combined with anti-CD20 antibodies, have allowed for time-limited targeted therapeutic strategies which are particularly attractive for certain subsets of patients though have demonstrated efficacy across all subgroups. Lastly, there is an ongoing movement toward the development of time-limited strategies inclusive of both a BTKi and venetoclax that may further widen potential options. CLL patients requiring frontline therapy have a unique burden of choice between highly effective therapies that differ substantially with respect to side effect profiles and schedules. This review will focus on the frontline management of CLL in the setting of these rapidly changing options.

Comprehensive genomic profiling reveals molecular subsets of ASXL1-mutated myeloid neoplasms.

A large-scale genomic analysis of patients with ASXL1-mutated myeloid disease has not been performed to date. We reviewed comprehensive genomic profiling results from 6043 adults to characterize clinicopathologic features and co-mutation patterns by ASXL1 mutation status. ASXL1 mutations occurred in 1414 patients (23%). Mutation co-occurrence testing revealed strong co-occurrence (p < 0.01) between mutations in ASXL1 and nine genes (SRSF2, U2AF1, RUNX1, SETBP1, EZH2, STAG2, CUX1, CSF3R, CBL). Further analysis of patients with these co-mutations yielded several novel findings. Co-mutation patterns supported that ASXL1/SF3B1 co-mutation may be biologically distinct from ASXL1/non-SF3B1 spliceosome co-mutation. In AML, ASXL1/SRSF2 co-mutated patients frequently harbored STAG2 mutations (42%), which were dependent on the presence of both ASXL1 and SRSF2 mutation (p < 0.05). STAG2 and SETBP1 mutations were also exclusive in ASXL1/SRSF2 co-mutated patients and associated with divergent chronic myeloid phenotypes. Our findings support that certain multi-mutant genotypes may be biologically relevant in ASXL1-mutated myeloid disease.

SOHO State of the Art Updates and Next Questions: Updates on BTK Inhibitors for the Treatment of Chronic Lymphocytic Leukemia.

Over the last decade, targeted inhibition of Bruton's tyrosine kinase (BTK) has led to a paradigm shift in the way chronic lymphocytic leukemia (CLL) is managed. BTK inhibitors (BTKi) are broadly classified as covalent BTKI and noncovalent BTKi (cBTKi and ncBTK) Ibrutinib, as the first approved cBTKi, vastly improved outcomes for patients with CLL over prior chemoimmunotherapy regimens. However, long-term use is limited by both intolerance and resistance. The second generation of more selective BTKi were developed to improve tolerability. While these agents have led to an improved safety profile in comparison to Ibrutinib (both acalabrutinib and zanubrutinib), and improved efficacy (zanubrutinib), intolerance occasionally occurs, and resistance remains a challenge. The third generation of BTKi, which noncovalently or reversibly inhibits BTK, has shown promising results in early phase trials and are being evaluated in the phase 3 setting. These drugs could be an effective treatment option in patients with either resistance and intolerance to cBTKi. The most recent development in therapeutic agents targeting BTK is the development of BTK degraders. By removing BTK, as opposed to inhibiting it, these drugs could remain efficacious irrespective of BTK resistance mutations, however clinical data are limited at this time. This review summarizes the evolution and ongoing development of newer BTKi and BTK degraders in the management of CLL, with a focus of future directions in this field, including how emerging clinical data could inform therapeutic sequencing in CLL management.

Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia.

BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have poor outcomes after the failure of covalent Bruton's tyrosine kinase (BTK) inhibitor treatment, and new therapeutic options are needed. Pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor, was designed to reestablish BTK inhibition. METHODS: We conducted a phase 1-2 trial in which patients with relapsed or refractory B-cell cancers received pirtobrutinib. Here, we report efficacy results among patients with CLL or SLL who had previously received a BTK inhibitor as well as safety results among all the patients with CLL or SLL. The primary end point was an overall response (partial response or better) as assessed by independent review. Secondary end points included progression-free survival and safety. RESULTS: A total of 317 patients with CLL or SLL received pirtobrutinib, including 247 who had previously received a BTK inhibitor. Among these 247 patients, the median number of previous lines of therapy was 3 (range, 1 to 11), and 100 patients (40.5%) had also received a B-cell lymphoma 2 (BCL2) inhibitor such as venetoclax. The percentage of patients with an overall response to pirtobrutinib was 73.3% (95% confidence interval [CI], 67.3 to 78.7), and the percentage was 82.2% (95% CI, 76.8 to 86.7) when partial response with lymphocytosis was included. The median progression-free survival was 19.6 months (95% CI, 16.9 to 22.1). Among all 317 patients with CLL or SLL who received pirtobrutinib, the most common adverse events were infections (in 71.0%), bleeding (in 42.6%), and neutropenia (in 32.5%). At a median duration of treatment of 16.5 months (range, 0.2 to 39.9), some adverse events that are typically associated with BTK inhibitors occurred relatively infrequently, including hypertension (in 14.2% of patients), atrial fibrillation or flutter (in 3.8%), and major hemorrhage (in 2.2%). Only 9 of 317 patients (2.8%) discontinued pirtobrutinib owing to a treatment-related adverse event. CONCLUSIONS: In this trial, pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL who had received a covalent BTK inhibitor. The most common adverse events were infections, bleeding, and neutropenia. (Funded by Loxo Oncology; BRUIN ClinicalTrials.gov number, NCT03740529.).

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.

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.

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.

Clonal Hematopoiesis and the Heart: a Toxic Relationship.

PURPOSE OF REVIEW: Clonal hematopoiesis (CH) refers to the expansion of hematopoietic stem cell clones and their cellular progeny due to somatic mutations, mosaic chromosomal alterations (mCAs), or copy number variants which naturally accumulate with age. CH has been linked to increased risk of blood cancers, but CH has also been linked to adverse cardiovascular outcomes. RECENT FINDINGS: A combination of clinical outcome studies and mouse models have offered strong evidence that CH mutations either correlate with or cause atherosclerosis, diabetes mellitus, chronic kidney disease, heart failure, pulmonary hypertension, aortic aneurysm, myocardial infarction, stroke, aortic stenosis, poor outcomes following transcatheter aortic valve replacement (TAVR) or orthotopic heart transplant, death or need of renal replacement therapy secondary to cardiogenic shock, death from cardiovascular causes at large, and enhance anthracycline cardiac toxicity. Mechanistically, some adverse outcomes are caused by macrophage secretion of IL-1ß and IL-6, neutrophil invasion of injured myocardium, and T-cell skewing towards inflammatory phenotypes. CH mutations lead to harmful inflammation and arterial wall invasion by bone marrow-derived cells resulting in poor cardiovascular health and outcomes. Blockade of IL-1ß or JAK2 signaling are potential avenues for preventing CH-caused cardiovascular morbidity and mortality.

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.

Game of clones: Diverse implications for clonal hematopoiesis in lymphoma and multiple myeloma.

Clonal hematopoiesis (CH) refers to the disproportionate expansion of hematopoietic stem cell clones and their corresponding progeny following the acquisition of somatic mutations. CH is common at the time of diagnosis in patients with blood cancers, including multiple myeloma (MM) and lymphoma. The presence of CH mutations correlates with IL-6 mediated inflammation and may result in lymphoma or MM modulation through microenvironment effects or by manifestations of the mutations themselves within the founding tumor clone. As might be expected with a variety of mutations and multiple potential mechanisms, CH exerts context-dependent effects, being protective in some settings and harmful in others. Though CH is very common in patients with hematologic malignancies, how it intersects with therapy and the natural disease course of these cancers are active areas of investigation. In lymphomas and MM specifically, patients have high rates of CH at diagnosis and are subsequently exposed to therapies, such as cytotoxic chemotherapy, that can cause CH progression to overt hematologic malignancy. The expanding diversity of treatment modalities for these cancers also increases the opportunities for CH to impact clinical outcome and modulate clinical responses. Here we review the basic biology and known health effects of CH, and we focus on the clinical relevance of CH in lymphoma and MM.

Evaluation of an interdisciplinary venetoclax initiation process in minimizing risk of tumor lysis syndrome.

Venetoclax is a BCL-2 inhibitor approved for treatment of adult patients with chronic lymphocytic leukemia (CLL). Due to significant risk of tumor lysis syndrome (TLS) upon treatment initiation, a 5-week dose ramp-up is recommended. University of North Carolina Medical Center (UNCMC) utilizes a novel interdisciplinary model of care involving clinical pharmacists (CPs) who oversee the 5-week ramp-up to minimize treatment-related adverse events. The aim of this study was to investigate the effects of a pharmacist-led venetoclax initiation protocol on patient outcomes. The primary objective was to determine the incidence of venetoclax-induced TLS during dose ramp-up in patients managed by a CP. In this cohort (n = 39), there were no cases of TLS during the venetoclax ramp-up. Reduced TLS rates were observed in CP-managed real-world patients compared to previous real-world reports. This real-world analysis supports the utilization of CPs for intensive monitoring of patients initiated on venetoclax.

Impact of adherence to ibrutinib on clinical outcomes in real-world patients with chronic lymphocytic leukemia.

Ibrutinib is an oral Bruton's tyrosine kinase inhibitor approved for treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Clinical trial data suggest that strict adherence is directly related to clinical outcomes. This retrospective, multicenter study aimed to evaluate ibrutinib adherence and its impact on clinical outcomes in patients with CLL/SLL treated in the real-world setting. The primary outcome was to quantify ibrutinib adherence rates in the real-world setting using the proportion of days covered (PDC) calculation. Secondary outcomes included the association of ibrutinib adherence with progression-free survival (PFS) and overall survival (OS). For the 100 patients in the primary analysis, the mean PDC was 95% (range: 65-100%). Patients who maintained PDC > 95% for each of the first 6 months experienced fewer PFS events (n = 1) compared to those with PDC ≤ 95% (n = 5; p=.03). The correlation between adherence and OS was not assessed due to a low number of events.

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.).

Prostate cancer research in the 21st century; report from the 2021 Coffey-Holden prostate cancer academy meeting.

INTRODUCTION: The 2021 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, "Prostate Cancer Research in the 21st Century," was held virtually, from June 24-25, 2021. METHODS: The CHPCA Meeting is organized by the Prostate Cancer Foundation as a unique discussion-oriented meeting focusing on critical topics in prostate cancer research envisioned to bridge the next major advances in prostate cancer biology and treatment. The 2021 CHPCA Meeting was virtually attended by 89 investigators and included 31 talks over nine sessions. RESULTS: Major topic areas discussed at the meeting included: cancer genomics and sequencing, functional genomic approaches to studying mediators of plasticity, emerging signaling pathways in metastatic castration resistant prostate cancer, Wnt signaling biology and the challenges of targeted therapy, clonal hematopoiesis, neuroendocrine cell plasticity and antitumor immunity, cancer immunotherapy and its synergizers, and imaging the tumor microenvironment and metabolism. DISCUSSION: This meeting report summarizes the research presented at the 2021 CHPCA Meeting. We hope that publication of this knowledge will accelerate new understandings and the development of new biomarkers and treatments for prostate cancer.

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.

Phase II Trial of Pembrolizumab after High-Dose Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia.

Immune suppression, exhaustion, and senescence are frequently seen throughout disease progression in acute myeloid leukemia (AML). We conducted a phase II study of high-dose cytarabine followed by pembrolizumab 200 mg i.v. on day 14 to examine whether PD-1 inhibition improves clinical responses in relapsed/refractory (R/R) AML. Overall responders could receive pembrolizumab maintenance up to 2 years. Among 37 patients enrolled, the overall response rate, composite complete remission (CRc) rate (primary endpoint), and median overall survival (OS) were 46%, 38%, and 11.1 months, respectively. Patients with refractory/early relapse and those receiving treatment as first salvage had encouraging outcomes (median OS, 13.2 and 11.3 months, respectively). Grade ≥3 immune-related adverse events were rare (14%) and self-limiting. Patients who achieved CRc had a higher frequency of progenitor exhausted CD8+ T cells expressing TCF-1 in the bone marrow prior to treatment. A multifaceted correlative approach of genomic, transcriptomic, and immunophenotypic profiling offers insights on molecular correlates of response and resistance to pembrolizumab. SIGNIFICANCE: Immune-checkpoint blockade with pembrolizumab was tolerable and feasible after high-dose cytarabine in R/R AML, with encouraging clinical activity, particularly in refractory AML and those receiving treatment as first salvage regimen. Further study of pembrolizumab and other immune-checkpoint blockade strategies after cytotoxic chemotherapy is warranted in AML.See related commentary by Wei et al., p. 551. This article is highlighted in the In This Issue feature, p. 549.

Safety and Efficacy of Pembrolizumab Prior to Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia.

Programmed death 1 (PD-1) is an integral component of acute myelogenous leukemia (AML) immune evasion, chemotherapy resistance, and disease progression. PD-1 inhibitors are being investigated as treatment for AML in combination with hypomethylating agents and cytotoxic chemotherapy with encouraging findings. Although allogeneic stem cell transplantation (alloSCT) remains the most established curative treatment for patients with relapsed and refractory AML in complete remission, there are limited data on the clinical outcomes and safety of immune checkpoint inhibitors (ICIs) prior to alloSCT in AML. In the present study, we compared clinical outcomes of 9 patients with AML receiving high-dose cytarabine followed by pembrolizumab in a phase II clinical trial (NCT02768792) prior to alloSCT versus a historical control group of 18 AML patients who underwent alloSCT without prior ICI exposure. The nonparametric Jonckheere-Terpstra test was used to test for a difference in the ordered severity categories of acute graft-versus-host disease (GVHD) within 100 days of transplantation. Time-to-event estimates for overall survival and relapse-free survival were calculated using the Kaplan-Meier method and compared using a log-rank test. One-year survival was not significantly different between the treatment groups (67% versus 78%; P = .34). 100-day mortality was 0% in the ICI group versus 17% in the control group, and there was no increase in grade III-IV acute GVHD in patients treated with pembrolizumab prior to alloSCT. No chronic GVHD was seen in patients treated with pembrolizumab prior to alloSCT and who received post-transplantation cyclophosphamide (PTCy) as part of their conditioning regimen. These findings reinforce the safety and feasibility of ICI therapy prior to alloSCT in patients with AML, and suggest that PTCy may abrogate GVHD risk and severity in patients who receive ICI prior to undergoing alloSCT for AML.