Real-World Treatment Patterns and Outcomes by Line of Therapy and Race in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Treated in the United States: Results From the Final Analysis of the Prospective, Observational, informCLL Registry.

BACKGROUND: informCLL is the largest US-based prospective, observational registry of patients with chronic lymphocytic leukemia (CLL) initiating FDA-approved treatment in the era of targeted therapy. PATIENTS AND METHODS: Patients were enrolled between October 2015 and June 2019. Data were collected for baseline characteristics, treatment patterns, outcomes, and safety. RESULTS: In total, 1459 eligible patients were enrolled (first line, n = 854; relapsed/refractory, n = 605). The most common index treatments were ibrutinib (first line, 45%; relapsed/refractory, 49%) and chemoimmunotherapy (first line, 43%; relapsed/refractory, 20%). With median follow-up of 31.8 and 30.9 months in first-line and relapsed/refractory cohorts, respectively, median time to next treatment (TTNT) in patients who received any index treatment was not reached (NR) and 48.6 months; estimated proportions without next-line therapy at 48 months were 64% and 50%. Median overall survival (OS) was NR for both cohorts; estimated 48-month OS rates were 81% and 64% in first-line and relapsed/refractory cohorts, respectively. In match-adjusted analyses, TTNT was improved with first-line ibrutinib versus chemoimmunotherapy (median NR vs. 56.5 months; hazard ratio, 0.74; 95% CI, 0.56-0.98). Exposure-adjusted rates of AEs leading to discontinuation and serious AEs were lower with ibrutinib versus chemoimmunotherapy. Estimated 36-month OS rates were similar in Black versus White patients who received any index treatment (first line, 87% vs. 83%; relapsed/refractory, 74% vs. 74%) or ibrutinib (first line, 97% vs. 85%; relapsed/refractory, 81% vs. 77%). CONCLUSION: In this prospective, large, real-world CLL registry, first-line ibrutinib was associated with longer TTNT than chemoimmunotherapy, with sustained benefit up to 4 years of follow-up.

Pitfalls of Current Diagnostic Criteria of Tumor Lysis Syndrome.

BACKGROUND: Tumor Lysis syndrome (TLS) is a well-recognized medical emergency in patients with cancer diagnosis. The diagnostic criteria of TLS have been revised many times since it was recognized, but still have many drawbacks limit diagnosis accuracy. SUMMARY: Autopsy studies in patients with perimortem diagnoses of TLS have shown that they may not have actually had TLS. Therefore, many cancer patients who are at risk for TLS, clinical and laboratory criteria may be fulfilled due to other causes of acute kidney injury. In this review, we aim to cast a spotlight on the shortcomings and pitfalls of the current diagnostic criteria for TLS, and propose a roadmap for developing a more rigorous criteria that improve on the diagnostic accuracy. KEY MESSAGES: Causes of AKI in patients with cancer other than TLS should be considered. Because current diagnostic criteria may miss those differential diagnosis, specific biomarkers that can tell when TLS is the underlying process is an important need, besides appropriate criteria that can jump over the pitfalls in the current criteria and enhance the recognition of TLS among other causes.

Racial disparities in chronic lymphocytic leukemia/small lymphocytic lymphoma accounting for small molecule inhibitors: A real-world cohort analysis.

Kaplan-Meier curve depicting overall survival from CLL treatment start by race. For patients with CLL, no overall survival difference was observed between races in this real-world US database.

MRD-directed therapy in CLL: ready for prime time?

In recent years, the treatment paradigm for patients with chronic lymphocytic leukemia (CLL) has moved away from chemoimmunotherapy (CIT) toward the use of novel targeted agents. Commercially available drugs, including Bruton's tyrosine kinase inhibitors and the BCL2 inhibitor venetoclax, often used in combination with anti-CD20 monoclonal antibodies, are now the mainstay of therapy both in the frontline and in relapsed settings. As the landscape for CLL management evolves, therapeutic endpoints need to be redefined. Detection of measurable residual disease (MRD) is a sensitive tool to identify disease burden following treatment with several therapeutic regimens in CLL (including CIT, venetoclax-based regimens, and cellular therapies), and it has demonstrated prognostic value. Despite recent advances, the utility of MRD-directed therapy and attempts to eradicate it in routine clinical practice remain debated. There is little comparative data from clinical trials on the best assay to determine undetectable MRD (U-MRD) and whether its monitoring can lead to changes in treatment strategies. Our review discusses the definitions of MRD, assays for its detection, and its impact on long-term survival outcomes for patients with a CLL diagnosis.

Characterization of the Intraclonal Complexity of Chronic Lymphocytic Leukemia B Cells: Potential Influences of B-Cell Receptor Crosstalk with Other Stimuli.

Chronic lymphocytic leukemia (CLL) clones contain subpopulations differing in time since the last cell division ("age"): recently born, proliferative (PF; CXCR4DimCD5Bright), intermediate (IF; CXCR4IntCD5Int), and resting (RF; CXCR4BrightCD5Dim) fractions. Herein, we used deuterium (2H) incorporation into newly synthesized DNA in patients to refine the kinetics of CLL subpopulations by characterizing two additional CXCR4/CD5 fractions, i.e., double dim (DDF; CXCR4DimCD5Dim) and double bright (DBF; CXCR4BrightCD5Bright); and intraclonal fractions differing in surface membrane (sm) IgM and IgD densities. Although DDF was enriched in recently divided cells and DBF in older cells, PF and RF remained the most enriched in youngest and oldest cells, respectively. Similarly, smIgMHigh and smIgDHigh cells were the youngest, and smIgMLow and smIgDLow were the oldest, when using smIG levels as discriminator. Surprisingly, the cells closest to the last stimulatory event bore high levels of smIG, and stimulating via TLR9 and smIG yielded a phenotype more consistent with the in vivo setting. Finally, older cells were less sensitive to in vivo inhibition by ibrutinib. Collectively, these data define additional intraclonal subpopulations with divergent ages and phenotypes and suggest that BCR engagement alone is not responsible for the smIG levels found in vivo, and the differential sensitivity of distinct fractions to ibrutinib might account, in part, for therapeutic relapse.

Results from a Real-World Multicenter Analysis of 482 Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib: A Look at Racial Differences.

BACKGROUND: Despite recent approvals of lifesaving treatments for chronic lymphocytic leukemia (CLL), real-world data on the tolerability of the Bruton tyrosine kinase inhibitor ibrutinib for CLL treatment are lacking, especially in Black patients. OBJECTIVE: To expand upon a previously reported retrospective chart review of ibrutinib-treated patients with CLL to increase the number of sites and the enrollment period in first-line (1L) and relapsed/refractory (R/R) settings with a subanalysis based on ethnicity. PATIENTS AND METHODS: Adults with CLL who initiated ibrutinib treatment from five centers were followed for ≥ 6 months. RESULTS: We identified 482 patients with CLL [405 White (153 1L, 252 R/R), 37 Black (17 1L, 20 R/R), 40 other/unidentified]. At baseline, 58.5% of all patients (68.8% of Black patients) had hypertension. At a median follow-up of 28.2 months, 31.1% of patients overall discontinued ibrutinib, 16.2% due to adverse events (12.2% 1L, 18.8% R/R). Overall, 46.0% of patients experienced ≥ 1 dose hold (40.2% 1L, 49.8% R/R), and 28.8% of patients experienced ≥ 1 dose reduction (24.9% 1L, 31.4% R/R). Among Black patients, ibrutinib was discontinued in 24.3% of patients (17.6% 1L, 30.0% R/R), 8.1% due to disease progression and 5.4% due to adverse events; 40.5% of patients experienced ≥ 1 dose hold (35.3% 1L, 45.0% R/R), and 32.4% of patients experienced ≥ 1 dose reduction (23.5% 1L, 40.0% R/R). CONCLUSIONS: Toxicity and disease progression were the most common reasons for ibrutinib discontinuations in the overall population and among Black patients, respectively. Encouraging research participation of underrepresented patient groups will help clinicians better understand treatment outcomes.

Ibrutinib, a Bruton tyrosine kinase inhibitor, is an approved oral targeted therapy for the treatment of chronic lymphocytic leukemia (CLL). Patients treated with ibrutinib can experience side effects (referred to as adverse events) and may need to reduce the drug dose (referred to as dose reductions) or stop treatment (referred to as discontinuations) for a variety of reasons. A previous study showed that patients who were treated with ibrutinib experienced frequent dose reductions and discontinuations. This study described dose reductions and discontinuations in a larger patient population treated with ibrutinib and also described outcomes in Black patients. Patients with CLL treated with ibrutinib were identified from five medical centers and were followed for a minimum of 6 months. Patients experienced frequent dose reductions and discontinuations in routine clinical practice. The most common cause of discontinuations was adverse events in the overall patient population and disease progression in the Black patient population. Black patients treated with ibrutinib had similar rates of dose reductions and discontinuations as the overall patient population. Rates of dose reductions and discontinuations for patients with CLL treated with ibrutinib were higher in this real-world study than in clinical trials.

Duvelisib Eliminates CLL B Cells, Impairs CLL-Supporting Cells, and Overcomes Ibrutinib Resistance in a Xenograft Model.

PURPOSE: Inhibitors of Bruton's tyrosine kinase (BTKi) and PI3K (PI3Ki) have significantly improved therapy of chronic lymphocytic leukemia (CLL). However, the emergence of resistance to BTKi has introduced an unmet therapeutic need. Hence, we sought evidence for essential roles of PI3K-δi and PI3K-γi in treatment-naïve and BTKi-refractory CLL. EXPERIMENTAL DESIGN: Responses to PI3K-δi, PI3K-γi, and the dual-inhibitor duvelisib in each B, T, and myeloid cell compartments of CLL were studied in vitro, and in a xenograft mouse model using primary cells from treatment-naïve and ibrutinib-resistant patients, and finally, in a patient with ibrutinib-resistant CLL treated with duvelisib. RESULTS: We demonstrate the essential roles of PI3K-δ for CLL B-cell survival and migration, of PI3K-γ for T-cell migration and macrophage polarization, and of dual inhibition of PI3K-δ,γ for efficacious reduction of leukemia burden. We also show that samples from patients whose disease progressed on ibrutinib were responsive to duvelisib therapy in a xenograft model, irrespective of BTK mutations. In support of this, we report a patient with ibrutinib-resistant CLL, bearing a clone with BTK and PLCγ2 mutations, who responded immediately to single-agent duvelisib with redistribution lymphocytosis followed by a partial clinical remission associated with modulation of T and myeloid cells. CONCLUSIONS: Our data define the mechanism of action whereby dual inhibition of PI3K-δ,γ affects CLL B-cell numbers and T and myeloid cell pro-leukemia functions and support the use of duvelisib as a valuable approach for therapeutic interventions, including for patients refractory to BTKi.

Characteristics and Clinical Outcomes of Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Receiving Ibrutinib for ≥5 Years in the RESONATE-2 Study.

Primary results from the phase 3 RESONATE-2 study demonstrated superior efficacy and tolerability with ibrutinib versus chlorambucil in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Here, we describe characteristics and outcomes of patients who received ibrutinib treatment for ≥5 years in RESONATE-2. Patients aged ≥65 years with previously untreated CLL/SLL, without del(17p), were randomly assigned 1:1 to once-daily ibrutinib 420 mg until disease progression/unacceptable toxicity (n = 136) or chlorambucil 0.5−0.8 mg/kg for ≤12 cycles (n = 133). Baseline characteristics in ibrutinib-randomized patients (n = 136) were generally similar between patients on ibrutinib treatment for ≥5 years (n = 79) versus those on treatment for <5 years (n = 57). In patients on ibrutinib treatment for ≥5 years, complete response rates improved over time, reaching 42% by 5 years. Estimated 7-year progression-free survival and overall survival rates were 82% and 94%, respectively. Adverse events (AEs) led to dose reductions in 16/79 patients (20%); these AEs were resolved for 13/16 patients (81%). AEs led to dose holds (≥7 days) in 45/79 patients (57%); these AEs were resolved for 43/45 patients (96%). More than half (58%) of ibrutinib-randomized patients benefitted from ibrutinib treatment for ≥5 years regardless of baseline characteristics. Dose modification resolved AEs for most patients, thereby facilitating continued treatment.

Consensus opinion from an international group of experts on measurable residual disease in hairy cell leukemia.

A significant body of literature has been generated related to the detection of measurable residual disease (MRD) at the time of achieving complete remission (CR) in patients with hairy cell leukemia (HCL). However, due to the indolent nature of the disease as well as reports suggesting long-term survival in patients treated with a single course of a nucleoside analog albeit without evidence of cure, the merits of detection of MRD and attempts to eradicate it have been debated. Studies utilizing novel strategies in the relapse setting have demonstrated the utility of achieving CR with undetectable MRD (uMRD) in prolonging the duration of remission. Several assays including immunohistochemical analysis of bone marrow specimens, multi-parameter flow cytometry and molecular assays to detect the mutant BRAF V600E gene or the consensus primer for the immunoglobulin heavy chain gene (IGH) rearrangement have been utilized with few comparative studies. Here we provide a consensus report on the available data, the potential merits of MRD assessment in the front-line and relapse settings and recommendations on future role of MRD assessment in HCL.

How Have Targeted Agents Changed the Treatment Landscape for Elderly Patients with CLL?

PURPOSE OF REVIEW: Chronic lymphocytic leukemia (CLL) is a common hematologic malignancy in elderly patients. At the time of diagnosis, most patients have comorbid medical conditions. Although patients have other competing medical issues, the majority of patients will die from CLL or CLL-related complications. This review will discuss treatment in elderly patients with CLL. RECENT FINDINGS: Recent work has focused on understanding the role comorbid medical conditions play in the management of CLL in elderly patients, including the use of geriatric assessment, Charlson comorbidity index, cumulative illness rating scale, and most recently, the CLL-comorbidity index. The treatment landscape for CLL has shifted from chemoimmunotherapy to the use of targeted agents. Several clinical trials in elderly patients have demonstrated improvement in progression-free survival (PFS) with ibrutinib + / - obinutuzumab, acalabrutinib + / - obinutuzumab, zanubrutinib, venetoclax-obinutuzumab, idelalisib, and duvelisib. The adverse event profile and potential for drug-drug interactions in the treatment of CLL in elderly patients have not been described, and further studies are needed to determine optimal treatment. Treatment of elderly patients with CLL should be made on a case-by-case basis based on a patient's fitness, comorbid medical conditions, and concomitant medications. The use of targeted agents has improved outcomes in this patient population, but further studies are needed to determine the best practice.

Health-related quality of life and treatment satisfaction in Chronic Lymphocytic Leukemia (CLL) patients on ibrutinib compared to other CLL treatments in a real-world US cross sectional study.

The objective of this study was to describe real-world health-related quality of life (HRQoL) and treatment satisfaction of ibrutinib-treated patients with CLL compared to a reference group. This study was completed in two parts. The first portion (Norming Study) was a US online survey conducted to serve as a reference population. The Norming Study included a total of 139 patients with CLL, excluding those treated with ibrutinib: 64 were treatment naive (Tx naive), 36 were 1st line (1L), and 38 were in or had completed ≥2 lines (2L+) patients with CLL. The second portion (CLL Ibrutinib Study) included 1L and 2L+ ibrutinib patients with CLL treated for ≥6 months in which 118 patients (1L n = 88 and 2L+ n = 30) completed the study. Respondents completed demographic and clinical information and the following HRQoL surveys: (Short Form-12v2® Health Survey [SF-12v2], Functional Assessment of Cancer Therapy-General [FACT-G], FACT-Leukemia [FACT-Leu] Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue, and Cancer Therapy Satisfaction Questionnaire [CTSQ]). Higher scores indicate better HRQoL/treatment satisfaction. Differences in effect sizes between the two samples at the group level were calculated using Hedges' g. Medium to large positive effects were seen in the CLL Ibrutinib group on several measures compared to the Reference Study groups. The FACT-G total score was 89.2±11.1 for CLL Ibrutinib Study patients compared to 75.8±22.6 CLL Norming Tx naïve patients, 61.3±21.8 in 1L, and 61.7±20.7 in 2L+. Similar trends were seen with FACT-Leu total score and FACIT-Fatigue. CLL Ibrutinib Study patients scored higher on all CTSQ domain scores compared to the CLL Norming patients treated with other CLL therapies. We found that Ibrutinib-treatment had better HRQoL and treatment satisfaction compared to patients receiving other therapies, irrespective of line of therapy.

Impact of the Types and Relative Quantities of IGHV Gene Mutations in Predicting Prognosis of Patients With Chronic Lymphocytic Leukemia.

Patients with CLL with mutated IGHV genes (M-CLL) have better outcomes than patients with unmutated IGHVs (U-CLL). Since U-CLL usually express immunoglobulins (IGs) that are more autoreactive and more effectively transduce signals to leukemic B cells, B-cell receptor (BCR) signaling is likely at the heart of the worse outcomes of CLL cases without/few IGHV mutations. A corollary of this conclusion is that M-CLL follow less aggressive clinical courses because somatic IGHV mutations have altered BCR structures and no longer bind stimulatory (auto)antigens and so cannot deliver trophic signals to leukemic B cells. However, the latter assumption has not been confirmed in a large patient cohort. We tried to address the latter by measuring the relative numbers of replacement (R) mutations that lead to non-conservative amino acid changes (Rnc) to the combined numbers of conservative (Rc) and silent (S) amino acid R mutations that likely do not or cannot change amino acids, "(S+Rc) to Rnc IGHV mutation ratio". When comparing time-to-first-treatment (TTFT) of patients with (S+Rc)/Rnc ≤ 1 and >1, TTFTs were similar, even after matching groups for equal numbers of samples and identical numbers of mutations per sample. Thus, BCR structural change might not be the main reason for better outcomes for M-CLL. Since the total number of IGHV mutations associated better with longer TTFT, better clinical courses appear due to the biologic state of a B cell having undergone many stimulatory events leading to IGHV mutations. Analyses of larger patient cohorts will be needed to definitively answer this question.

Activated CLL cells regulate IL-17F-producing Th17 cells in miR155-dependent and outcome-specific manners.

Chronic lymphocytic leukemia (CLL) results from expansion of a CD5+ B cell clone that requires interactions with other cell types, including T cells. Moreover, patients with CLL have elevated levels of circulating IL-17A+ and IL-17F+ CD4+ T (Th17) cells, with higher numbers of IL-17A+ Th17 cells correlating with better outcomes. We report that CLL Th17 cells expressed more miR155, a Th17-differentiation regulator, than control Th17 cells, despite naive CD4+ T (Tn) cell basal miR155 levels being similar in both. We also found that CLL cells directly regulated miR155 levels in Tn cells, thereby affecting Th17 differentiation, by documenting that coculturing Tn cells with resting or activated (Bact) CLL cells altered the magnitude and direction of T cell miR155 levels; CLL Bact cells promoted IL-17A+ and IL-17F+ T cell generation by an miR155-dependent mechanism, confirmed by miR155 inhibition; coculture of Tn cells with CLL Bact cells led to a linear correlation between the degree and direction of T cell miR155 expression changes and production of IL-17F but not IL-17A; and Bact cell-mediated changes in Tn cell miR155 expression correlated with outcome, irrespective of IGHV mutation status, a strong prognostic indicator. These results identify a potentially unrecognized CLL Bact cell-dependent mechanism, upregulation of Tn cell miR155 expression and subsequent enhancement of IL-17F+ Th17 generation, that favors better clinical courses.

Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial.

Herein, we present the long-term follow-up of the randomized E1912 trial comparing the long-term efficacy of ibrutinib-rituximab (IR) therapy to fludarabine, cyclophosphamide, and rituximab (FCR) and describe the tolerability of continuous ibrutinib. The E1912 trial enrolled 529 treatment-naïve patients aged ≤70 years with chronic lymphocytic leukemia (CLL). Patients were randomly assigned (2:1 ratio) to receive IR or 6 cycles of FCR. With a median follow-up of 5.8 years, median progression-free survival (PFS) is superior for IR (hazard ratio [HR], 0.37; P < .001). IR improved PFS relative to FCR in patients with both immunoglobulin heavy chain variable region (IGHV) gene mutated CLL (HR: 0.27; P < .001) and IGHV unmutated CLL (HR: 0.27; P < .001). Among the 354 patients randomized to IR, 214 (60.5%) currently remain on ibrutinib. Among the 138 IR-treated patients who discontinued treatment, 37 (10.5% of patients who started IR) discontinued therapy due to disease progression or death, 77 (21.9% of patients who started IR) discontinued therapy for adverse events (AEs)/complications, and 24 (6.8% of patients who started IR) withdrew for other reasons. Progression was uncommon among patients able to remain on ibrutinib. The median time from ibrutinib discontinuation to disease progression or death among those who discontinued treatment for a reason other than progression was 25 months. Sustained improvement in overall survival (OS) was observed for patients in the IR arm (HR, 0.47; P = .018). In conclusion, IR therapy offers superior PFS relative to FCR in patients with IGHV mutated or unmutated CLL, as well as superior OS. Continuous ibrutinib therapy is tolerated beyond 5 years in the majority of CLL patients. This trial was registered at www.clinicaltrials.gov as #NCT02048813.

Haemophagocytic lymphohistiocytosis following COVID-19 mRNA vaccination.

The development of vaccinations has been instrumental in the ongoing effort to combat the COVID-19 pandemic. Although the benefits of vaccination are unquestionable, there have been reports of potentially rare life-threatening complications following vaccination including thrombocytopaenia, haemolytic anaemia, vasculitis and myocarditis. Haemophagocytic lymphohistiocytosis (HLH), a rare but life-threatening inflammatory condition, has also been described postadenoviral vector COVID-19 vaccination but it has never been reported post-messenger RNA (mRNA) COVID-19 vaccination. We report two cases of HLH admitted to our hospital after administration of COVID-19 mRNA vaccines. We also searched the vaccine adverse event reporting system and found 50 reports of suspected HLH following COVID-19 vaccination. Presently, we cannot define a causality between COVID-19 mRNA vaccination and HLH development. However, we hope the reporting of our two cases (and additional cases seen in the adverse event reporting database) will help us determine whether there is a potential relationship. Prompt recognition of this condition is of utmost importance to initiate life-saving therapy.

Zilovertamab Vedotin Targeting of ROR1 as Therapy for Lymphoid Cancers.

BACKGROUND: Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein present on many cancers. Zilovertamab vedotin (ZV) is an antibody­drug conjugate comprising a monoclonal antibody recognizing extracellular ROR1, a cleavable linker, and the anti-microtubule cytotoxin monomethyl auristatin E. METHODS: In this phase 1, first-in-human, dose-escalation study, we accrued patients with previously treated lymphoid cancers to receive ZV every 3 weeks until the occurrence of cancer progression or unacceptable toxicity had occurred. RESULTS: We enrolled 32 patients with tumor histologies of mantle cell lymphoma (MCL) (n=15), chronic lymphocytic leukemia (n=7), diffuse large B-cell lymphoma (DLBCL) (n=5), follicular lymphoma (n=3), Richter transformation lymphoma (n=1), or marginal zone lymphoma (n=1). Patients had received a median of four previous drug and/or cellular therapies. Starting dose levels were 0.5 (n=1), 1.0 (n=3), 1.5 (n=3), 2.25 (n=11), and 2.5 (n=14) mg per kg of body weight (mg/kg). Pharmacokinetic and pharmacodynamic data documented systemic ZV exposure and exposure-dependent ZV targeting of ROR1 on circulating tumor cells. As expected with an monomethyl auristatin E-containing antibody­drug conjugate, adverse events (AEs) included acute neutropenia and cumulative neuropathy resulting in a recommended ZV dosing regimen of 2.5 mg/kg every 3 weeks. No clinically concerning AEs occurred to suggest ROR1-mediated toxicities or nonspecific ZV binding to normal tissues. ZV induced objective tumor responses in 7 of 15 patients with MCL (47%; 4 partial and 3 complete) and in 3 of 5 patients with DLBCL (60%; 1 partial and 2 complete); objective tumor responses were not observed among patients with other tumor types. CONCLUSIONS: In heavily pretreated patients, ZV demonstrated no unexpected toxicities and showed evidence of antitumor activity, providing clinical proof of concept for selective targeting of ROR1 as a potential new approach to cancer therapy. (ClinicalTrials.gov number, NCT03833180.)