Publications by authors named "Nicole Lamanna"

61 Publications

Smudge Cells in Chronic Lymphocytic Leukemia: Pathophysiology, Laboratory Considerations, and Clinical Significance.

Lab Med 2021 Feb 2. Epub 2021 Feb 2.

Clinical Laboratory and Medical Imaging Sciences, School of Health Professions, Rutgers University, Newark, New Jersey, USA.

Chronic lymphocytic leukemia (CLL) is the most commonly encountered leukemia in the clinical laboratory. Cytoskeletal defects in CLL lymphocytes can result in the formation of up to 75% smudge cells (SCs) during blood film preparation. Failure to account for these damaged lymphocytes in the white blood cell (WBC) differential diminishes the accuracy and reproducibility of the results. Lacking clear practice standards on handling SCs in CLL, different laboratories may employ different methods to mitigate SC-induced errors. This review explores the pathophysiology of SCs, their effect on WBC differentials in CLL, and how these results can impact clinical decisions. The pros and cons of various SC corrective methods are described to assist laboratories in developing an optimized protocol to reduce errors and inconsistencies in WBC differentials. Finally, the potential utility of SC enumeration as an indicator of CLL prognosis is discussed in terms of laboratories with differing access to technology.
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http://dx.doi.org/10.1093/labmed/lmaa119DOI Listing
February 2021

Managing toxicities of Bruton tyrosine kinase inhibitors.

Hematology Am Soc Hematol Educ Program 2020 12;2020(1):336-345

Columbia University Medical Center, New York, NY.

Inhibition of Bruton's tyrosine kinase (BTK) has revolutionized the treatment landscape for patients with chronic lymphocytic leukemia (CLL). By targeting this critical kinase in proximal B-cell receptor signaling, BTK inhibitors (BTKis) impair cell proliferation, migration, and activation of NF-κB. Clinically, because indefinite inhibition is a mainstay of therapy, there is an extended period of exposure in which adverse effects can develop. Given the impressive efficacy and activity of BTKis in the treatment of patients with CLL, appropriate management of treatment-emergent adverse events (AEs) is of paramount importance. Here we review the BTKi landscape and present the available toxicity and safety data for each agent. The long-term toxicity profile of ibrutinib, a first-in-class inhibitor, is well characterized and includes a clinically significant incidence of cardiac arrhythmias, bleeding, infection, diarrhea, arthralgias, and hypertension. Acalabrutinib, the initial second-generation BTKi to earn approval from the US Food and Drug Administration, demonstrates improved kinase selectivity for BTK, with commonly observed adverse reactions including infection, headache, and diarrhea. Mediated by both on-target inhibition of BTK and variable off-target inhibition of other kinases including interleukin-2-inducible T-cell kinase (ITK), tyrosine-protein kinase (TEC), and endothelial growth factor receptor (EGFR), the toxicity profile of BTKis is closely linked to their pattern of kinase binding. Other emerging BTKis include second-generation agents with variable degrees of kinase selectivity and third-generation agents that exhibit reversible noncovalent binding to BTK. We also highlight critical considerations for the prevention and monitoring of AEs and offer practical management strategies for treatment-emergent toxicities.
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http://dx.doi.org/10.1182/hematology.2020000118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727553PMC
December 2020

Phase 2 Study of the Safety and Efficacy of Umbralisib in Patients with CLL Who Are Intolerant to BTK or PI3Kδ Inhibitor Therapy.

Blood 2020 Dec 1. Epub 2020 Dec 1.

Duke University Health System, Durham, North Carolina, United States.

Purpose: Intolerance is the most common reason for kinase inhibitor (KI) discontinuation in CLL. Umbralisib a novel, highly selective PI3Kδ/CK1ε inhibitor, is active and well tolerated in CLL patients. This phase 2 trial evaluated umbralisib in CLL patients who are intolerant to prior BTK or PI3K inhibitor therapy.

Patients And Methods: In this phase 2 trial (NCT02742090), umbralisib was initiated at 800 mg oral daily in CLL patients requiring therapy per investigator discretion who were intolerant to prior BTK or PI3K inhibitor therapy, until progression or toxicity. Primary endpoint was progression-free survival (PFS). Secondary endpoints included time to treatment failure and umbralisib safety profile. DNA isolated from buccal swabs was genotyped for polymorphisms in CYP3A4, CYP3A5 and CYP2D6.

Results: Fifty-one patients were enrolled (44 BTKi and 7 PI3Kδi intolerant). Median age was 70 years (range 48-96), median of 2 prior lines of therapy (1-7), 24% had del17p and/or TP53 mutation, and 65% were IGHV unmutated. Most common AEs leading to prior KI discontinuation were rash (27%), arthralgia (18%), and atrial fibrillation (16%). Median progression free survival (PFS) was 23.5 months (95% CI 13.1-not estimable). 58% of patients were on umbralisib for a longer duration than prior KI. Most common (≥5%) grade ≥3 AEs on umbralisib (all causality) were neutropenia (18%), leukocytosis (14%), thrombocytopenia (12%), pneumonia (12%), and diarrhea (8%). Six patients (12%) discontinued umbralisib due to an AE. Eight patients (16%) had dose reductions and were successfully re-challenged.

Conclusions: Umbralisib is safe and effective in this BTK and alternate PI3K inhibitor intolerant CLL population. These are the first prospective data to confirm that switching from a BTK or alternate PI3K inhibitor to umbralisib can result in durable, well tolerated responses.
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http://dx.doi.org/10.1182/blood.2020007376DOI Listing
December 2020

Duvelisib, a new PI3K inhibitor for lymphoid malignancies.

Authors:
Nicole Lamanna

Clin Adv Hematol Oncol 2020 Oct;18(10):606-608

Hematologic Malignancies Section, Herbert Irving Comprehensive Cancer Center, New York-Presbyterian/Columbia University Medical Center, New York, New York.

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October 2020

Efficacy of bendamustine and rituximab in unfit patients with previously untreated chronic lymphocytic leukemia. Indirect comparison with ibrutinib in a real-world setting. A GIMEMA-ERIC and US study.

Cancer Med 2020 Nov 24;9(22):8468-8479. Epub 2020 Sep 24.

Strategic Research Program on CLL, Division of Experimental Oncology, IRCCS Ospedale San Raffaele, Università Vita-Salute San Raffaele, Milan, Italy.

Limited information is available on the efficacy of front-line bendamustine and rituximab (BR) in chronic lymphocytic leukemia (CLL) with reduced renal function or coexisting conditions. We therefore analyzed a cohort of real-world patients and performed a matched adjusted indirect comparison with a cohort of patients treated with ibrutinib. One hundred and fifty-seven patients with creatinine clearance (CrCl) <70 mL/min and/or CIRS score >6 were treated with BR. The median age was 72 years; 69% of patients had ≥2 comorbidities and the median CrCl was 59.8 mL/min. 17.6% of patients carried TP53 disruption. The median progression-free survival (PFS) was 45 months; TP53 disruption was associated with a shorter PFS (P = 0.05). The overall survival (OS) at 12, 24, and 36 months was 96.2%, 90.1%, and 79.5%, respectively. TP53 disruption was associated with an increased risk of death (P = 0.01). Data on 162 patients ≥65 years treated with ibrutinib were analyzed and compared with 165 patients ≥65 years treated with BR. Factors predicting for a longer PFS at multivariable analysis in the total patient population treated with BR and ibrutinib were age (HR 1.06, 95% CI 1.02-1.10, P < 0.01) and treatment with ibrutinib (HR 0.55, 95% CI 0.33-0.93, P = 0.03). In a post hoc analysis of patients in advanced stage, a significant PFS advantage was observed in patient who had received ibrutinib (P = 0.03), who showed a trend for OS advantage (P = 0.08). We arrived at the following conclusions: (a) BR is a relatively effective first-line regimen in a real-world population of unfit patients without TP53 disruption, (b) ibrutinib provided longer disease control than BR in patients with advanced disease stage.
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http://dx.doi.org/10.1002/cam4.3470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666748PMC
November 2020

The Impact of Age on Survival in CLL Patients Receiving Ibrutinib as Initial Therapy.

Blood Lymphat Cancer 2020 24;10:1-5. Epub 2020 Aug 24.

Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Introduction: Recent randomized trials have demonstrated the efficacy of ibrutinib-based therapy in the treatment of patients with CLL. In Alliance A041202, a higher than expected number of unexplained deaths were reported with front-line ibrutinib in a patient population aged at least 65 years compared to ECOG 1912, which included patients up to 70 years of age.

Methods: Therefore, we conducted a retrospective analysis to investigate whether ibrutinib was associated with a greater mortality in older patients outside of a clinical trial setting. This multicenter analysis was performed by investigators at 20 academic and community practices.

Results: Amongst the 391 patients included, there was no correlation between age and response rate, PFS, or OS. However, there was a trend to higher rate of deaths in patients >65-years-old (8.7% vs 3.8%, p=0.097), with an increased number of early deaths (13 vs 4, p=0.3).

Conclusion: These data suggest greater intolerance, and possibly mortality, with ibrutinib in an older population. Patients should be educated regarding the potential complications related to ibrutinib and symptoms of concern to report.
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http://dx.doi.org/10.2147/BLCTT.S262592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473982PMC
August 2020

Outcomes of COVID-19 in patients with CLL: a multicenter international experience.

Blood 2020 09;136(10):1134-1143

Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.

Given advanced age, comorbidities, and immune dysfunction, chronic lymphocytic leukemia (CLL) patients may be at particularly high risk of infection and poor outcomes related to coronavirus disease 2019 (COVID-19). Robust analysis of outcomes for CLL patients, particularly examining effects of baseline characteristics and CLL-directed therapy, is critical to optimally manage CLL patients through this evolving pandemic. CLL patients diagnosed with symptomatic COVID-19 across 43 international centers (n = 198) were included. Hospital admission occurred in 90%. Median age at COVID-19 diagnosis was 70.5 years. Median Cumulative Illness Rating Scale score was 8 (range, 4-32). Thirty-nine percent were treatment naive ("watch and wait"), while 61% had received ≥1 CLL-directed therapy (median, 2; range, 1-8). Ninety patients (45%) were receiving active CLL therapy at COVID-19 diagnosis, most commonly Bruton tyrosine kinase inhibitors (BTKi's; n = 68/90 [76%]). At a median follow-up of 16 days, the overall case fatality rate was 33%, though 25% remain admitted. Watch-and-wait and treated cohorts had similar rates of admission (89% vs 90%), intensive care unit admission (35% vs 36%), intubation (33% vs 25%), and mortality (37% vs 32%). CLL-directed treatment with BTKi's at COVID-19 diagnosis did not impact survival (case fatality rate, 34% vs 35%), though the BTKi was held during the COVID-19 course for most patients. These data suggest that the subgroup of CLL patients admitted with COVID-19, regardless of disease phase or treatment status, are at high risk of death. Future epidemiologic studies are needed to assess severe acute respiratory syndrome coronavirus 2 infection risk, these data should be validated independently, and randomized studies of BTKi's in COVID-19 are needed to provide definitive evidence of benefit.
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http://dx.doi.org/10.1182/blood.2020006965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472711PMC
September 2020

Targeting CD38 is lethal to Breg-like chronic lymphocytic leukemia cells and Tregs, but restores CD8+ T-cell responses.

Blood Adv 2020 05;4(10):2143-2157

Department of Cancer Biology, Mayo Clinic, Jacksonville, FL.

Patients with chronic lymphocytic leukemia (CLL) are characterized by monoclonal expansion of CD5+CD23+CD27+CD19+κ/λ+ B lymphocytes and are clinically noted to have profound immune suppression. In these patients, it has been recently shown that a subset of B cells possesses regulatory functions and secretes high levels of interleukin 10 (IL-10). Our investigation identified that CLL cells with a CD19+CD24+CD38hi immunophenotype (B regulatory cell [Breg]-like CLL cells) produce high amounts of IL-10 and transforming growth factor β (TGF-β) and are capable of transforming naive T helper cells into CD4+CD25+FoxP3+ T regulatory cells (Tregs) in an IL-10/TGF-β-dependent manner. A strong correlation between the percentage of CD38+ CLL cells and Tregs was observed. CD38hi Tregs comprised more than 50% of Tregs in peripheral blood mononuclear cells (PBMCs) in patients with CLL. Anti-CD38 targeting agents resulted in lethality of both Breg-like CLL and Treg cells via apoptosis. Ex vivo, use of anti-CD38 monoclonal antibody (mAb) therapy was associated with a reduction in IL-10 and CLL patient-derived Tregs, but an increase in interferon-γ and proliferation of cytotoxic CD8+ T cells with an activated phenotype, which showed an improved ability to lyse patient-autologous CLL cells. Finally, effects of anti-CD38 mAb therapy were validated in a CLL-patient-derived xenograft model in vivo, which showed decreased percentage of Bregs, Tregs, and PD1+CD38hiCD8+ T cells, but increased Th17 and CD8+ T cells (vs vehicle). Altogether, our results demonstrate that targeting CD38 in CLL can modulate the tumor microenvironment; skewing T-cell populations from an immunosuppressive to immune-reactive milieu, thus promoting immune reconstitution for enhanced anti-CLL response.
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http://dx.doi.org/10.1182/bloodadvances.2019001091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252547PMC
May 2020

The Connect CLL Registry: final analysis of 1494 patients with chronic lymphocytic leukemia across 199 US sites.

Blood Adv 2020 04;4(7):1407-1418

Willamette Valley Cancer Institute, US Oncology, Eugene, OR.

Optimal treatment of chronic lymphocytic leukemia (CLL) remains unclear. The Connect CLL Registry, a United States-based multicenter prospective observational cohort study, enrolled 1494 patients between 2010 and 2014 from predominantly community-based settings. Patients were grouped by line of therapy (LOT) at enrollment. With a median follow-up of 46.6 months (range, 0-63.0 months), median overall survival (OS) was not reached in LOT1, 63.0 months (95% confidence interval [CI], 46.0-63.0 months) in LOT2, and 38.0 months (95% CI, 33.0-47.0 months) in LOT≥3. Bendamustine and rituximab (BR; 33.5%); fludarabine, cyclophosphamide, and rituximab (FCR; 21.4%); and rituximab monotherapy (18.5%) were the most common regimens across LOTs. Median event-free survival (EFS) was similar in patients treated with BR (59.0 months) and FCR (55.0 months) in LOT1; median OS was not reached. In multivariable analysis, BR or FCR vs other treatments in LOT1 was associated with improved EFS (hazard ratio [HR], 0.60; P < .0001) and OS (0.67; P = .0162). Using the Kaplan-Meier product limit, ibrutinib vs other treatments improved OS in LOT2 (HR, 0.279; P = .009), LOT3 (0.441; P = .011), and LOT≥4 (0.578; P = .043). Prognostic modeling of death at 2 years postenrollment identified 3 risk groups: low (mortality rate, 6.2%), medium (14.5%), and high (27.4%). The most frequent adverse events across LOTs were pneumonia (11.6%) and febrile neutropenia (6.2%). These data suggest that advantages of LOT1 FCR over BR seen in clinical trials may not translate to community practice, whereas receiving novel LOT2 agents improved outcomes. This trial was registered at www.clinicaltrials.gov as NCT01081015.
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http://dx.doi.org/10.1182/bloodadvances.2019001145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160291PMC
April 2020

ALPINE: zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma.

Future Oncol 2020 Apr 24;16(10):517-523. Epub 2020 Mar 24.

Peter MacCallum Cancer Centre, St Vincent's Hospital, University of Melbourne, Melbourne, Victoria 3000, Australia and University of Melbourne, Parkville, Victoria 3052, Australia.

Treatment standards for chronic lymphocytic leukemia (CLL) have been transformed with the advent of effective inhibitors of B-cell receptor signaling such as ibrutinib - a first-in-class inhibitor of BTK. Off-target kinase inhibitions by ibrutinib are thought to contribute to its adverse events. Zanubrutinib is a next-generation BTK inhibitor with minimal off-target effects, sustained BTK occupancy in peripheral blood mononuclear cells and lymph nodes from patients with B-cell malignancies and promising responses in patients with CLL. Described here is a head-to-head Phase III study comparing the efficacy and safety of zanubrutinib with those of ibrutinib in patients with CLL/small lymphocytic lymphoma in the relapsed/refractory setting.
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http://dx.doi.org/10.2217/fon-2019-0844DOI Listing
April 2020

Assessment of the Efficacy of Therapies Following Venetoclax Discontinuation in CLL Reveals BTK Inhibition as an Effective Strategy.

Clin Cancer Res 2020 Jul 20;26(14):3589-3596. Epub 2020 Mar 20.

Department of Haematology, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.

Purpose: Venetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains nonstandard and poorly understood.

Experimental Design: To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type [Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies].

Results: We identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve ( = 130), and 81% were idelalisib naïve ( = 263). ORR to BTKi was 84% ( = 44) in BTKi-naïve patients versus 54% ( = 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons.

Conclusions: For BTKi-naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3815DOI Listing
July 2020

Is There a Role for Chemotherapy in the Era of Targeted Therapies?

Curr Hematol Malig Rep 2020 04;15(2):72-82

Columbia University Medical Center, NY, USA.

Purpose Of Review: The treatment landscape of chronic lymphocytic leukemia has been rapidly evolving over the past few years. The prior standard of care, chemoimmunotherapy, is being replaced by targeted agents, and the utility of chemotherapy has come under question. In this review, we examine recent data comparing chemoimmunotherapy to targeted agents, how these data impact clinical management, and whether there are potential future roles for cytotoxic chemotherapy.

Recent Findings: Clinical trials have shown improved clinical outcomes with targeted agents compared to traditional chemoimmunotherapy. Based on these data, the current treatment paradigm primarily favors targeted agents over chemoimmunotherapy, with a few exceptions. However, targeted agents have notable limitations, and thus, there may be a future role of cytotoxic chemotherapy when administered in combination with targeted agents. Although targeted agents have nearly replaced chemoimmunotherapy in the treatment of chronic lymphocytic leukemia, novel combinations utilizing chemotherapy are being developed that may lead to better outcomes.
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http://dx.doi.org/10.1007/s11899-020-00563-8DOI Listing
April 2020

Efficacy and Safety of Duvelisib Following Disease Progression on Ofatumumab in Patients with Relapsed/Refractory CLL or SLL in the DUO Crossover Extension Study.

Clin Cancer Res 2020 05 21;26(9):2096-2103. Epub 2020 Jan 21.

Department of Medicine I, Division of Hematology and Hemostaseology, and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Purpose: In the phase III DUO trial, duvelisib, an oral dual PI3K-δ,γ inhibitor, demonstrated significantly improved efficacy versus ofatumumab [median (m) progression-free survival (PFS), 13.3 vs. 9.9 months (HR, 0.52; < 0.0001); overall response rate [ORR], 74% vs. 45% ( < 0.0001)], with a manageable safety profile in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). We report results from patients with progressive disease (PD) after ofatumumab who crossed over to duvelisib in the DUO trial.

Patients And Methods: Patients with radiographically confirmed PD after ofatumumab received duvelisib 25 mg twice daily in 28-day cycles until PD, intolerance, death, or study withdrawal. The primary endpoint was ORR per investigator. Secondary endpoints included duration of response (DOR), PFS, and safety.

Results: As of December 14, 2018, 90 ofatumumab-treated patients in the DUO trial prior to crossover had an ORR of 29%, mDOR of 10.4 months, and mPFS of 9.4 months. After crossover, 77% of patients (69/90) achieved a response, with an mDOR of 14.9 months and mPFS of 15.7 months. Patients with del(17p) and/or mutations had similar outcomes [ORR, 77% (20/26); mPFS, 14.7 months]. Notably, 73% of patients (47/64) with disease previously refractory to ofatumumab achieved a response. The most frequent any-grade/grade 3/4 treatment-emergent adverse events were diarrhea (47%/23%), neutropenia (26%/23%), pyrexia (24%/4%), cutaneous reactions (23%/4%), and thrombocytopenia (10%/6%).

Conclusions: Duvelisib demonstrated high response rates with good durability and a manageable safety profile in patients with R/R CLL/SLL who progressed on ofatumumab, including patients with high-risk disease and disease previously refractory to ofatumumab.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3061DOI Listing
May 2020

The efficacy and safety of venetoclax therapy in elderly patients with relapsed, refractory chronic lymphocytic leukaemia.

Br J Haematol 2020 03 4;188(6):918-923. Epub 2019 Nov 4.

Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton's tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and <75 years treated in the relapsed, refractory non-trial setting. We demonstrate that venetoclax has equivalent efficacy and safety in relapsed/refractory CLL patients who are elderly, the majority of whom are previous ibrutinib-exposed and therefore may otherwise have few clear therapeutic options.
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http://dx.doi.org/10.1111/bjh.16271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528953PMC
March 2020

A retrospective comparison of venetoclax alone or in combination with an anti-CD20 monoclonal antibody in R/R CLL.

Blood Adv 2019 05;3(10):1568-1573

Nottingham University Hospitals, NHS Foundation Trust, Nottingham, United Kingdom.

Venetoclax (VEN) is approved for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) as monotherapy (VENmono) or in combination with rituximab. Whether VEN plus anti-CD20 (VENcombo) is superior to VENmono is unknown. We conducted a multicenter, retrospective cohort analysis comparing 321 CLL patients treated with VENmono vs VENcombo across the United States and the United Kingdom. We examined demographics, baseline characteristics, dosing, adverse events, response rates, and outcomes. The primary endpoints were progression-free survival (PFS) and overall survival (OS), estimated by Kaplan-Meier method, in patients treated with VENmono vs VENcombo. Univariate and bivariate analyses were performed with COX regression. Three hundred twenty-one CLL patients were included (3 median prior treatments, 78% prior ibrutinib). The overall response rates (ORRs) were similar (VENmono, 81% ORR, 34% complete remission [CR] vs VENcombo, 84% ORR, 32% CR). With a median follow-up of 13.4 months, no differences in PFS and OS were observed between the groups. In unadjusted analyses, the hazard ratios (HRs) for PFS and OS for VENmono vs VENcombo were HR 1.0 (95% confidence interval [CI], 0.6-1.8; = .7) and HR 1.2 (95% CI, 0.6-2.3; = .5), respectively. When adjusting for differences between the cohorts, the addition of an anti-CD20 antibody in combination with VEN did not impact PFS (HR, 1.0; 95% CI, 0.5-2.0; = .9) or OS (HR, 1.1; 95% CI, 0.4-2.6; = .8). We demonstrate comparable efficacy between VENmono and VENcombo in a heavily pretreated, high-risk, retrospective cohort, in terms of both response data and survival outcomes. Prospective studies are needed to validate these findings.
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http://dx.doi.org/10.1182/bloodadvances.2019000180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538868PMC
May 2019

Tumor Lysis, Adverse Events, and Dose Adjustments in 297 Venetoclax-Treated CLL Patients in Routine Clinical Practice.

Clin Cancer Res 2019 07 19;25(14):4264-4270. Epub 2019 Apr 19.

Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, New York.

Purpose: Clinical trials of venetoclax reported negligible rates of clinical tumor lysis syndrome (TLS) in patients with chronic lymphocytic leukemia (CLL) when using an extended dose escalation schedule. We aimed to understand TLS prophylaxis, rates of select adverse events (AE), and impact of dosing modifications in routine clinical practice.

Experimental Design: This retrospective cohort study included 297 CLL venetoclax-treated patients outside of clinical trials in academic and community centers. Demographics, baseline disease characteristics, venetoclax dosing, TLS risk and prophylaxis, and AEs were collected.

Results: The group was 69% male, 96% had relapsed/refractory CLL, 45% had deletion chromosome 17p, 84% had unmutated , 80% received venetoclax monotherapy, and median age was 67. TLS risk was categorized as low (40%), intermediate (32%), or high (28%), and 62% had imaging prior to venetoclax initiation. Clinical TLS occurred in 2.7% of patients and laboratory TLS occurred in 5.7%. Pre-venetoclax TLS risk group and creatinine clearance independently predict TLS development in multivariable analysis. Grade 3/4 AEs included neutropenia (39.6%), thrombocytopenia (29.2%), infection (25%), neutropenic fever (7.9%), and diarrhea (6.9%). Twenty-two patients (7.4%) discontinued venetoclax due to an AE. Progression-free survival was similar regardless of number of dose interruptions, length of dose interruption, and stable venetoclax dose.

Conclusions: These data provide insights into current use of venetoclax in clinical practice, including TLS rates observed in clinical practice. We identified opportunities for improved adherence to TLS risk stratification and prophylaxis, which may improve safety.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0361DOI Listing
July 2019

Final Results of a Randomized, Phase III Study of Rituximab With or Without Idelalisib Followed by Open-Label Idelalisib in Patients With Relapsed Chronic Lymphocytic Leukemia.

J Clin Oncol 2019 06 17;37(16):1391-1402. Epub 2019 Apr 17.

18 Ulm University, Ulm, Germany.

Purpose: A randomized, double-blind, phase III study of idelalisib (IDELA) plus rituximab versus placebo plus rituximab in patients with relapsed chronic lymphocytic leukemia (CLL) was terminated early because of superior efficacy of the IDELA-plus-rituximab (IDELA/R) arm. Patients in either arm could then enroll in an extension study to receive IDELA monotherapy. Here, we report the long-term efficacy and safety data for IDELA-treated patients across the primary and extension studies.

Patients And Methods: Patients were randomly assigned to receive rituximab in combination with either IDELA 150 mg twice daily (IDELA/R; n = 110) or placebo (placebo/R; n = 110). Key end points were progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and safety.

Results: The long-term efficacy and safety of treatment with IDELA was assessed in 110 patients who received at least one dose of IDELA in the primary study, 75 of whom enrolled in the extension study. The IDELA/R-to-IDELA group had a median PFS of 20.3 months (95% CI, 17.3 to 26.3 months) after a median follow-up time of 18 months (range, 0.3 to 67.6 months). The ORR was 85.5% (94 of 110 patients; n = 1 complete response). The median OS was 40.6 months (95% CI, 28.5 to 57.3 months) and 34.6 months (95% CI, 16.0 months to not reached) for patients randomly assigned to the IDELA/R and placebo/R groups, respectively. Prolonged exposure to IDELA increased the incidence of all-grade, grade 2, and grade 3 or greater diarrhea (46.4%, 17.3%, and 16.4%, respectively), all-grade and grade 3 or greater colitis (10.9% and 8.2%, respectively) and all-grade and grade 3 or greater pneumonitis (10.0% and 6.4%, respectively) but did not increase the incidence of elevated hepatic aminotransferases.

Conclusion: IDELA improved PFS and OS compared with rituximab alone in patients with relapsed CLL. Long-term IDELA was effective and had an expected safety profile. No new IDELA-related adverse events were identified with longer exposure.
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http://dx.doi.org/10.1200/JCO.18.01460DOI Listing
June 2019

The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL.

Blood 2018 12 4;132(23):2446-2455. Epub 2018 Oct 4.

Department III of Internal Medicine, University Hospital Ulm, Ulm, Germany; and.

Duvelisib (also known as IPI-145) is an oral, dual inhibitor of phosphatidylinositol 3-kinase δ and γ (PI3K-δ,γ) being developed for treatment of hematologic malignancies. PI3K-δ,γ signaling can promote B-cell proliferation and survival in clonal B-cell malignancies, such as chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). In a phase 1 study, duvelisib showed clinically meaningful activity and acceptable safety in CLL/SLL patients. We report here the results of DUO, a global phase 3 randomized study of duvelisib vs ofatumumab monotherapy for patients with relapsed or refractory (RR) CLL/SLL. Patients were randomized 1:1 to oral duvelisib 25 mg twice daily (n = 160) or ofatumumab IV (n = 159). The study met the primary study end point by significantly improving progression-free survival per independent review committee assessment compared with ofatumumab for all patients (median, 13.3 months vs 9.9 months; hazard ratio [HR] = 0.52; < .0001), including those with high-risk chromosome 17p13.1 deletions [del(17p)] and/or mutations (HR = 0.40; = .0002). The overall response rate was significantly higher with duvelisib (74% vs 45%; < .0001) regardless of del(17p) status. The most common adverse events were diarrhea, neutropenia, pyrexia, nausea, anemia, and cough on the duvelisib arm, and neutropenia and infusion reactions on the ofatumumab arm. The DUO trial data support duvelisib as a potentially effective treatment option for patients with RR CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02004522.
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http://dx.doi.org/10.1182/blood-2018-05-850461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284216PMC
December 2018

Outcomes of front-line ibrutinib treated CLL patients excluded from landmark clinical trial.

Am J Hematol 2018 11 26;93(11):1394-1401. Epub 2018 Sep 26.

Cardinal Health, Dublin, Ohio.

Ibrutinib demonstrated superior response rates and survival for treatment-naïve chronic lymphocytic leukemia (CLL) patients in a pivotal study that excluded patients younger than 65 (<65) and/or with chromosome 17p13 deletion (del[17p13]). We examined outcomes and toxicities of CLL patients who would have been excluded from the pivotal study, specifically <65 and/or those with del[17p13]. This multicenter, retrospective cohort study examined CLL patients treated with front-line ibrutinib at 20 community and academic centers, categorizing them based on key inclusion criteria for the RESONATE-2 trial: <65 vs ≥65 and present vs absent del[17p13]. Of 391 included patients, 57% would have been excluded from the pivotal study. Forty-one percent of our cohort was <65, and 30% had del(17p13). Patients <65 were more likely to start 420 mg of ibrutinib daily; those who started at reduced doses had inferior PFS. The most common adverse events were arthralgias, fatigue, rash, bruising, and diarrhea. Twenty-four percent discontinued ibrutinib at 13.8 months median follow-up; toxicity was the most common reason for discontinuation, though progression and/or transformation accounted for a larger proportion of discontinuations in <65 and those with del(17p13). Response rates were similar for <65 and those with del(17p13). However, patients with del(17p13) had inferior PFS and OS. Ibrutinib in the front-line setting has extended beyond the population in which it was initially studied and approved. This study highlights and compares important differences in ibrutinib dosing, treatment interruptions, toxicities, reasons for discontinuation, and survival outcomes in two important patient populations not studied in RESONATE-2.
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http://dx.doi.org/10.1002/ajh.25261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552812PMC
November 2018

Clonal diversity predicts adverse outcome in chronic lymphocytic leukemia.

Leukemia 2019 02 23;33(2):390-402. Epub 2018 Jul 23.

Department of Hematology and Lymphoma and Myeloma Center Amsterdam, Academic Medical Center Amsterdam, University of Amsterdam, Amsterdam, The Netherlands.

Genomic analyses of chronic lymphocytic leukemia (CLL) identified somatic mutations and associations of clonal diversity with adverse outcomes. Clonal evolution likely has therapeutic implications but its dynamic is less well studied. We studied clonal composition and prognostic value of seven recurrently mutated driver genes using targeted next-generation sequencing in 643 CLL patients and found higher frequencies of mutations in TP53 (35 vs. 12%, p < 0.001) and SF3B1 (20 vs. 11%, p < 0.05) and increased number of (sub)clonal (p < 0.0001) mutations in treated patients. We next performed an in-depth evaluation of clonal evolution on untreated CLL patients (50 "progressors" and 17 matched "non-progressors") using a 404 gene-sequencing panel and identified novel mutated genes such as AXIN1, SDHA, SUZ12, and FOXO3. Progressors carried more mutations at initial presentation (2.5 vs. 1, p < 0.0001). Mutations in specific genes were associated with increased (SF3B1, ATM, and FBXW7) or decreased progression risk (AXIN1 and MYD88). Mutations affecting specific signaling pathways, such as Notch and MAP kinase pathway were enriched in progressive relative to non-progressive patients. These data extend earlier findings that specific genomic alterations and diversity of subclones are associated with disease progression and persistence of disease in CLL and identify novel recurrently mutated genes and associated outcomes.
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http://dx.doi.org/10.1038/s41375-018-0215-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718955PMC
February 2019

Autologous CD19-Targeted CAR T Cells in Patients with Residual CLL following Initial Purine Analog-Based Therapy.

Mol Ther 2018 08 15;26(8):1896-1905. Epub 2018 Jun 15.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Patients with residual chronic lymphocytic leukemia (CLL) following initial purine analog-based chemoimmunotherapy exhibit a shorter duration of response and may benefit from novel therapeutic strategies. We and others have previously described the safety and efficacy of autologous T cells modified to express anti-CD19 chimeric antigen receptors (CARs) in patients with relapsed or refractory B cell acute lymphoblastic leukemia and CLL. Here we report the use of CD19-targeted CAR T cells incorporating the intracellular signaling domain of CD28 (19-28z) as a consolidative therapy in 8 patients with residual CLL following first-line chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab. Outpatients received low-dose conditioning therapy with cyclophosphamide (600 mg/m), followed by escalating doses of 3 × 10, 1 × 10, or 3 × 10 19-28z CAR T cells/kg. An objective response was observed in 3 of 8 patients (38%), with a clinically complete response lasting more than 28 months observed in two patients. Self-limited fevers were observed post-CAR T cell infusion in 4 patients, contemporaneous with elevations in interleukin-6 (IL-6), IL-10, IL-2, and TGF-α. None developed severe cytokine release syndrome or neurotoxicity. CAR T cells were detectable post-infusion in 4 patients, with a longest observed persistence of 48 days by qPCR. Further strategies to enhance CAR T cell efficacy in CLL are under investigation.
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http://dx.doi.org/10.1016/j.ymthe.2018.05.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6094824PMC
August 2018

Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States.

Haematologica 2018 09 7;103(9):1511-1517. Epub 2018 Jun 7.

Cardinal Health, Dublin, OH, USA.

Venetoclax is a BCL2 inhibitor approved for 17p-deleted relapsed/refractory chronic lymphocytic leukemia with activity following kinase inhibitors. We conducted a multicenter retrospective cohort analysis of patients with chronic lymphocytic leukemia treated with venetoclax to describe outcomes, toxicities, and treatment selection following venetoclax discontinuation. A total of 141 chronic lymphocytic leukemia patients were included (98% relapsed/refractory). Median age at venetoclax initiation was 67 years (range 37-91), median prior therapies was 3 (0-11), 81% unmutated , 45% del(17p), and 26.8% complex karyotype (≥ 3 abnormalities). Prior to venetoclax initiation, 89% received a B-cell receptor antagonist. For tumor lysis syndrome prophylaxis, 93% received allopurinol, 92% normal saline, and 45% rasburicase. Dose escalation to the maximum recommended dose of 400 mg daily was achieved in 85% of patients. Adverse events of interest included neutropenia in 47.4%, thrombocytopenia in 36%, tumor lysis syndrome in 13.4%, neutropenic fever in 11.6%, and diarrhea in 7.3%. The overall response rate to venetoclax was 72% (19.4% complete remission). With a median follow up of 7 months, median progression free survival and overall survival for the entire cohort have not been reached. To date, 41 venetoclax treated patients have discontinued therapy and 24 have received a subsequent therapy, most commonly ibrutinib. In the largest clinical experience of venetoclax-treated chronic lymphocytic leukemia patients, the majority successfully completed and maintained a maximum recommended dose. Response rates and duration of response appear comparable to clinical trial data. Venetoclax was active in patients with mutations known to confer ibrutinib resistance. Optimal sequencing of newer chronic lymphocytic leukemia therapies requires further study.
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http://dx.doi.org/10.3324/haematol.2018.193615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119152PMC
September 2018

Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis.

Haematologica 2018 05 1;103(5):874-879. Epub 2018 Feb 1.

Hematology/Oncology, Georgetown University Hospital, Washington DC, USA.

Clinical trials that led to ibrutinib's approval for the treatment of chronic lymphocytic leukemia showed that its side effects differ from those of traditional chemotherapy. Reasons for discontinuation in clinical practice have not been adequately studied. We conducted a retrospective analysis of chronic lymphocytic leukemia patients treated with ibrutinib either commercially or on clinical trials. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. This multicenter, retrospective analysis included ibrutinib-treated chronic lymphocytic leukemia patients at nine United States cancer centers or from the Connect® Chronic Lymphocytic Leukemia Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival. Six hundred sixteen ibrutinib-treated patients were identified. A total of 546 (88%) patients were treated with the commercial drug. Clinical trial patients were younger (mean age 58 61 years, =0.01) and had a similar time from diagnosis to treatment with ibrutinib (mean 85 87 months, =0.8). With a median follow-up of 17 months, an estimated 41% of patients discontinued ibrutinib (median time to ibrutinib discontinuation was 7 months). Notably, ibrutinib toxicity was the most common reason for discontinuation in all settings. The median progression-free survival and overall survival for the entire cohort were 35 months and not reached (median follow-up 17 months), respectively. In the largest reported series on ibrutinib- treated chronic lymphocytic leukemia patients, we show that 41% of patients discontinued ibrutinib. Intolerance as opposed to chronic lymphocytic leukemia progression was the most common reason for discontinuation. Outcomes remain excellent and were not affected by line of therapy or whether patients were treated on clinical studies or commercially. These data strongly argue in favor of finding strategies to minimize ibrutinib intolerance so that efficacy can be further maximized. Future clinical trials should consider time-limited therapy approaches, particularly in patients achieving a complete response, in order to minimize ibrutinib exposure.
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http://dx.doi.org/10.3324/haematol.2017.182907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927982PMC
May 2018

Reasons for initiation of treatment and predictors of response for patients with Rai stage 0/1 chronic lymphocytic leukemia (CLL) receiving first-line therapy: an analysis of the Connect CLL cohort study.

Leuk Lymphoma 2018 10 7;59(10):2327-2335. Epub 2018 Feb 7.

k Willamette Valley Cancer Institute, US Oncology , Springfield , OR , USA.

A 'watch-and-wait' strategy is recommended for most patients with early-stage chronic lymphocytic leukemia (CLL) prior to treatment initiation. In the Connect CLL registry, a prospective observational cohort study of 1494 patients treated in 199 US centers, median time to first-line treatment initiation was 3.8, 1.5, and 0.6 years for patients with Rai stage 0, 1, and ≥2, respectively. Only 60% of patients with Rai stage 0/1 underwent FISH/cytogenetic testing prior to initiation of a new line of therapy. Lymphocytosis and lymphadenopathy were the most common reasons for treatment initiation. Lymphocytosis as a reason for treatment initiation was associated with inferior event-free survival at Rai stage 0/1. Short treatment duration was associated with inferior overall survival regardless of Rai stage; sensitivity analyses confirmed the association. The Connect CLL registry provides valuable information on a real-world population of patients with CLL, clarifying both the timing and rationale for initiating therapy.
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http://dx.doi.org/10.1080/10428194.2018.1427860DOI Listing
October 2018

Prognostic Testing Patterns and Outcomes of Chronic Lymphocytic Leukemia Patients Stratified by Fluorescence In Situ Hybridization/Cytogenetics: A Real-world Clinical Experience in the Connect CLL Registry.

Clin Lymphoma Myeloma Leuk 2018 02 6;18(2):114-124.e2. Epub 2017 Dec 6.

Willamette Valley Cancer Institute, US Oncology, Springfield, OR.

Introduction: Prognostic genetic testing is recommended for patients with chronic lymphocytic leukemia (CLL) to guide clinical management. Specific abnormalities, such as del(17p), del(11q), and unmutated IgHV, can predict the depth and durability of the response to CLL therapy.

Patients And Methods: In the present analysis of the Connect CLL Registry (ClinicalTrials.gov identifier, NCT01081015), a prospective observational cohort study of patients treated across 199 centers, the patterns of prognostic testing and outcomes of patients with unfavorable-risk genetics were analyzed. From 2010 to 2014, 1494 treated patients were enrolled in the registry by line of therapy (LOT), and stratified by the results of cytogenetic/fluorescence in situ hybridization (FISH) testing into 3 risk levels: unfavorable (presence of del[17p] or del[11q]), favorable (absence of del[17p] and del[11q]), and unknown.

Results: Cytogenetic/FISH testing was performed in 861 patients (58%) at enrollment; only 40% of these patients were retested before starting a subsequent LOT. Of those enrolled at the first LOT, unfavorable-risk patients had inferior event-free survival compared with favorable-risk patients (hazard ratio, 1.60; P = .001). Event-free survival was inferior with bendamustine-containing regimens (P < .0001). Event-free survival did not differ significantly between risk groups for patients treated with ibrutinib or idelalisib in the relapse/refractory setting. The predictors of reduced event-free survival included unfavorable-risk genetics, age ≥ 75 years, race, and treatment choice at enrollment.

Conclusion: The present study has shown that prognostic cytogenetic/FISH testing is infrequently performed and that patients with unfavorable-risk genetics treated with immunochemotherapy combinations have worse outcomes. This underscores the importance of performing prognostic genetic testing for all CLL patients to guide treatment.
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http://dx.doi.org/10.1016/j.clml.2017.11.010DOI Listing
February 2018

Early progression of disease as a predictor of survival in chronic lymphocytic leukemia.

Blood Adv 2017 Nov 28;1(25):2433-2443. Epub 2017 Nov 28.

Winship Cancer Institute, Emory University, Atlanta, GA.

Chemoimmunotherapy for chronic lymphocytic leukemia (CLL) promotes clonal evolution of aggressive clones, which in some patients may lead to early progression of disease (POD). We studied the prognostic value of early POD in a cohort of patients with CLL enrolled between 2010 and 2014 in the Connect CLL Registry. Overall, 829 eligible patients receiving first-line therapy were categorized into 3 groups: early POD (progression <2 years after treatment initiation), late POD (progression ≥2 years after treatment initiation), and no POD as of 1 May 2017. Baseline demographics, treatment characteristics, and overall survival (OS) were analyzed. Logistic regression models identified independent predictors of early POD; Cox regression models were used to evaluate the risk of early POD. With a median follow-up of 48.8 months, 209 (25.2%), 162 (19.5%), and 458 (55.3%) patients had early, late, and no POD, respectively. Patients with early POD were older and had inferior response to similar first-line treatment regimens vs late and no POD groups (overall response rate: 53% vs 80% vs 84%). Patients with early POD were more likely to have unfavorable-risk cytogenetics (del[11q]/del[17p]) than patients with no POD (34% vs 20%; = .04). Early POD was associated with an inferior OS across all patients (hazard ratio, 3.6; 95% confidence interval, 2.6-5.1; < .01) and in patients treated with fludarabine, cyclophosphamide plus rituximab, and bendamustine plus rituximab ( < .05). Early POD within 2 years of first-line therapy is a robust clinical prognostic factor for inferior OS in patients with CLL. The Connect CLL Registry was registered at www.clinicaltrials.gov as #NCT01081015.
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http://dx.doi.org/10.1182/bloodadvances.2017011262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729627PMC
November 2017

Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial.

Lancet Oncol 2018 01 12;19(1):65-75. Epub 2017 Dec 12.

Division of Pharmaceutics, College of Pharmacy, Columbus, OH, USA. Electronic address:

Background: Therapy targeting Bruton's tyrosine kinase (BTK) with ibrutinib has transformed the treatment of chronic lymphocytic leukaemia. However, patients who are refractory to or relapse after ibrutinib therapy have poor outcomes. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 active in previously treated patients with relapsed or refractory chronic lymphocytic leukaemia. In this study, we assessed the activity and safety of venetoclax in patients with chronic lymphocytic leukaemia who are refractory to or relapse during or after ibrutinib therapy.

Methods: In this interim analysis of a multicentre, open-label, non-randomised, phase 2 trial, we enrolled patients aged 18 years or older with a documented diagnosis of chronic lymphocytic leukaemia according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and an Eastern Cooperative Oncology Group performance score of 2 or lower. All patients had relapsed or refractory disease after previous treatment with a BCR signalling pathway inhibitor. All patients were screened for Richter's transformation and cases confirmed by biopsy were excluded. Eligible patients received oral venetoclax, starting at 20 mg per day with stepwise dose ramp-up over 5 weeks to 400 mg per day. Patients with rapidly progressing disease received an accelerated dosing schedule (to 400 mg per day by week 3). The primary endpoint was overall response, defined as the proportion of patients with an overall response per investigator's assessment according to IWCLL criteria. All patients who received at least one dose of venetoclax were included in the activity and safety analyses. This study is ongoing; data for this interim analysis were collected per regulatory agencies' request as of June 30, 2017. This trial is registered with ClinicalTrials.gov, number NCT02141282.

Findings: Between September, 2014, and November, 2016, 127 previously treated patients with relapsed or refractory chronic lymphocytic leukaemia were enrolled from 15 sites across the USA. 91 patients had received ibrutinib as the last BCR inhibitor therapy before enrolment, 43 of whom were enrolled in the main cohort and 48 in the expansion cohort recruited later after a protocol amendment. At the time of analysis, the median follow-up was 14 months (IQR 8-18) for all 91 patients, 19 months (9-27) for the main cohort, and 12 months (8-15) for the expansion cohort. 59 (65%, 95% CI 53-74) of 91 patients had an overall response, including 30 (70%, 54-83) of 43 patients in the main cohort and 29 (60%, 43-72) of 48 patients in the expansion cohort. The most common treatment-emergent grade 3 or 4 adverse events were neutropenia (46 [51%] of 91 patients), thrombocytopenia (26 [29%]), anaemia (26 [29%]), decreased white blood cell count (17 [19%]), and decreased lymphocyte count (14 [15%]). 17 (19%) of 91 patients died, including seven because of disease progression. No treatment-related deaths occurred.

Interpretation: The results of this interim analysis show that venetoclax has durable clinical activity and favourable tolerability in patients with relapsed or refractory chronic lymphocytic leukaemia whose disease progressed during or after discontinutation of ibrutinib therapy. The durability of response to venetoclax will be assessed in the final analysis in 2019.

Funding: AbbVie, Genentech.
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http://dx.doi.org/10.1016/S1470-2045(17)30909-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027999PMC
January 2018

Tumor Lysis Syndrome in Chronic Lymphocytic Leukemia with Novel Targeted Agents.

Oncologist 2017 11 29;22(11):1283-1291. Epub 2017 Aug 29.

St Vincent's Hospital, Melbourne, Australia.

Tumor lysis syndrome (TLS) is an uncommon but potentially life-threatening complication associated with the treatment of some cancers. If left untreated, TLS may result in acute renal failure, cardiac dysrhythmia, neurologic complications, seizures, or death. Tumor lysis syndrome is most commonly observed in patients with hematologic malignancies with a high proliferation rate undergoing treatment with very effective therapies. In chronic lymphocytic leukemia (CLL), historically, TLS has been observed less often, owing to a low proliferation rate and slow response to chemotherapy. New targeted therapies have recently been approved in the treatment of CLL, including the oral kinase inhibitors, idelalisib and ibrutinib, and the B-cell lymphoma-2 protein inhibitor, venetoclax. Several others are also under development, and combination strategies of these agents are being explored. This review examines the diagnosis, prevention, and management of TLS and summarizes the TLS experience in CLL clinical trials with newer targeted agents. Overall, the risk of TLS is small, but the consequences may be fatal; therefore, patients should be monitored carefully. Therapies capable of eliciting rapid response and combination regimens are increasingly being evaluated for treatment of CLL, which may pose a higher risk of TLS. For optimal management, patients at risk for TLS require prophylaxis and close monitoring with appropriate tests and appropriate management to correct laboratory abnormalities, which allows for safe and effective disease control.

Implications For Practice: Tumor lysis syndrome (TLS) is a potentially fatal condition observed with hematologic malignancies, caused by release of cellular components in the bloodstream from rapidly dying tumor cells. The frequency and severity of TLS is partly dependent upon the biology of the disease and type of therapy administered. Novel targeted agents highly effective at inducing rapid cell death in chronic lymphocytic leukemia (CLL) may pose a risk for TLS in patients with tumors characterized by rapid growth, high tumor burden, and/or high sensitivity to treatment. In this review, prevention strategies and management of patients with CLL who develop TLS are described.
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http://dx.doi.org/10.1634/theoncologist.2017-0055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679833PMC
November 2017