Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2024.

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are essentially different manifestations of the same disease that are similarly managed. A number of molecular and cytogenetic variables with prognostic implications have been identified. Undetectable minimal residual disease at the end of treatment with chemoimmunotherapy or venetoclax-based combination regimens is an independent predictor of improved survival among patients with previously untreated or relapsed/refractory CLL/SLL. The selection of treatment is based on the disease stage, presence or absence of del(17p) or TP53 mutation, immunoglobulin heavy chain variable region mutation status, patient age, performance status, comorbid conditions, and the agent's toxicity profile. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.

Mosunetuzumab with polatuzumab vedotin in relapsed or refractory aggressive large B cell lymphoma: a phase 1b/2 trial.

Relapsed/refractory aggressive large B cell lymphoma (LBCL) remains an area of unmet need. Here we report the primary analysis of a phase 1b/2 trial of outpatient mosunetuzumab (a CD20xCD3 T-cell-engaging bispecific antibody) plus polatuzumab vedotin (an anti-CD79B antibody-drug conjugate) in relapsed/refractory LBCL. The phase 2 component is a single arm of an ongoing multi-arm trial. The primary endpoint during dose expansion was independent review committee (IRC)-assessed best overall response rate. Secondary endpoints included investigator-assessed overall response rate, complete response, duration of response, progression-free survival and overall survival. At data cutoff, 120 patients were enrolled (22 dose escalation, 98 dose expansion). The primary endpoint was met during dose expansion, with IRC-assessed best overall response rate and complete response rates of 59.2% (58/98; 95% confidence interval (CI): 48.8-69.0) and 45.9% (45/98; 95% CI: 35.8-56.3), respectively (median follow-up, 23.9 months). Median duration of complete was not reached (95% CI: 20.5-not estimable (NE)). Median progression-free survival was 11.4 months (95% CI: 6.2-18.7). Median overall survival was 23.3 months (95% CI: 14.8-NE). Across dose escalation and expansion, the most common grade 3 or higher adverse events were neutropenia (25.0%, 30/120) and fatigue (6.7%, 8/120). Any-grade cytokine release syndrome occurred in 16.7% of patients. These data demonstrate that mosunetuzumab plus polatuzumab vedotin has a favorable safety profile with highly durable responses suitable as second-line therapy in transplant-ineligible relapsed/refractory LBCL. ClinicalTrials.gov identifier: NCT03671018 .

Leukemic presentation and progressive genomic alterations of MCD/C5 diffuse large B-cell lymphoma (DLBCL).

Diffuse large B-cell lymphoma (DLBCL) is a heterogenous group of lymphoid malignancies. Based on gene expression profiling, it has been subdivided into germinal center (GC)-derived and activated B-cell (ABC) types. Advances in molecular methodologies have further refined the subclassification of DLBCL, based on recurrent genetic abnormalities. Here, we describe a distinct case of DLBCL that presented in leukemic form. DNA sequencing targeting 275 genes revealed pathogenically relevant mutations of CD79B, MyD88, TP53, TBL1XR1, and PIM1 genes, indicating that this lymphoma would be best classified as MCD/C5 DLBCL, an ABC subtype. Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. Specifically, the recurrent tumor developed loss of TP53 heterozygosity (LOH) and additional chromosomal changes central to ABC DLBCL pathogenesis, such as PRDM1 loss. Acquired resistance to ibrutinib and rituxan was indicated by the emergence of BTK and FOXO1 mutations, respectively, as well as apparent activation of alternative cell-activation pathways, through copy-number alterations (CNAs), detected by high-resolution chromosomal microarrays. In vitro, studies of relapsed lymphoma cells confirmed resistance to standard BTK inhibitors but sensitivity to vecabrutinib, a noncovalent inhibitor active against both wild-type as well as mutated BTK. In summary, we provide in-depth molecular characterization of a de novo leukemic DLBCL and discuss mechanisms that may have contributed to the lymphoma establishment, progression, and development of drug resistance.

SHP1 loss augments DLBCL cellular response to ibrutinib: a candidate predictive biomarker.

SHP1, a tyrosine phosphatase, negatively regulates B-cell receptor (BCR) signaling. Ibrutinib selectively inhibits BTK and has been approved for the treatment of several types of B-cell lymphomas, but not yet in diffuse large B-cell lymphoma (DLBCL). A phase 3 clinical trial of ibrutinib-containing regimen has been completed to evaluate its activity in subtypes or subsets of DLBCL patients. Although the subtype of activated B-cell like (ABC) DLBCL is characterized by chronic active BCR signaling, only a fraction of ABC-DLBCL patients seem to benefit from ibrutinib-containing regimen. New alternative predictive biomarkers are needed to identify patients who better respond. We investigated if SHP1 plays a role in defining the level of the BCR activity and impacts the response to ibrutinib. A meta-analysis revealed that lack of SHP1 protein expression as well as SHP1 promoter hypermethylation is strongly associated with NHL including DLBCL. On a tissue microarray of 95 DLBCL samples, no substantial difference in SHP1 expression was found between the GCB and non-GCB subtypes of DLBCL. However, we identified a strong reverse correlation between SHP1 expression and promoter methylation suggesting that promoter hypermethylation is responsible for SHP1 loss. SHP1 knockout in BCR-dependent GCB and ABC cell lines increased BCR signaling activities and sensitize lymphoma cells to the action of ibrutinib. Rescue of SHP1 in the knockout clones, on the other hand, restored BCR signaling and ibrutinib resistance. Further, pharmacological inhibition of SHP1 in both cell lines and patient-derived primary cells demonstrate that SHP1 inhibition synergized with ibrutinib in suppressing tumor cell growth. Thus, SHP1 loss may serve as an alternative biomarker to cell-of-origin to identify patients who potentially benefit from ibrutinib treatment. Our results further suggest that reducing SHP1 pharmacologically may represent a new strategy to augment tumor response to BCR-directed therapies. Schematic diagram summarizing the major findings. Left panel. When SHP1 is present and functional, it negatively regulates the activity of the BCR pathway. Right pane. When SHP1 is diminished or lost, cells depend more on the increased BCR signaling and making them vulnerable to BTK inhibitor, ibrutinib. Diagram was generated using BioRender.

Resistance to Bruton tyrosine kinase inhibition in chronic lymphocytic leukaemia and non-Hodgkin lymphoma.

Bruton tyrosine kinase inhibitors (BTKi) have transformed the therapeutic landscape of chronic lymphocytic leukaemia (CLL) and non-Hodgkin lymphoma. However, primary and acquired resistance to BTKi can be seen due to a variety of mechanisms including tumour intrinsic and extrinsic mechanisms such as gene mutations, activation of bypass signalling pathways and tumour microenvironment. Herein, we provide an updated review of the key clinical data of BTKi treatment in CLL, mantle cell lymphoma, and diffuse large B-cell lymphoma (DLBCL). We incorporate the most recent findings regarding mechanisms of resistance to covalent and non-covalent inhibitors, including ibrutinib, acalabrutinib, zanubrutinib and pirtobrutinib. We also cover the clinical sensitivity of certain molecular subtypes of DLBCL to an ibrutinib-containing regimen. Lastly, we summarise ongoing clinical investigations aimed at overcoming resistance via use of BTKi-containing combined therapies or the novel non-covalent BTKi. The review article targets an audience of clinical practitioners, clinical investigators and translational researchers.

Assessing Oncologists' Adoption of Biomarker Testing in Metastatic Colorectal Cancer Using Real-World Data.

BACKGROUND: Despite national guideline recommendations for universal biomarker testing (KRAS, NRAS, BRAF, and mismatch repair and microsatellite instability [MMR/MSI]) in all patients with metastatic colorectal cancer (mCRC), little is known regarding adherence to these recommendations in routine practice. METHODS: We retrospectively reviewed patients with mCRC diagnosed between January 1, 2013, and December 27, 2018, from a de-identified electronic health record-derived database. We analyzed disparities in KRAS, NRAS, BRAF, and MMR/MSI testing by race, age, sex, and insurance status using χ2 tests and t tests. We evaluated changes in biomarker testing over time with attention to changes around dates of landmark publications and guideline updates using χ2 tests and Cochran-Armitage tests. RESULTS: A total of 20 333 patients were identified of which 66.6% had test results for any biomarker. Rates of test results for all 4 biomarkers statistically significantly increased over time (P < .001). However, as of June 30, 2018, the rate of test results was only 46% for NRAS, 56% for KRAS, and 46% for BRAF. As of December 31, 2017, the rate of MMR/MSI testing was 59%. Higher documented testing rates were associated with younger age, lower Eastern Cooperative Oncology Group performance status, and commercial insurance. There were no clinically meaningful and/or statistically significant differences in documented testing rates by tumor sidedness, race, sex, or initial stage. CONCLUSIONS: Increased rates of documented testing for NRAS, BRAF, and MMR/MSI in mCRC was seen between 2013 and 2018 reflecting adoption of guideline recommendations. However, the rate of documented testing remains lower than expected and warrants additional research to understand the extent to which this may represent a clinical practice quality concern.

Updates in the Role of Checkpoint Inhibitor Immunotherapy in Classical Hodgkin's Lymphoma.

Classical Hodgkin's lymphoma is a highly curable disease, but 10-25% of patients with higher-risk disease relapse. The introduction of checkpoint inhibitors (CPIs) targeting PD-1 have changed the landscape of treatment for patients with relapsed/refractory disease to multiple lines of therapy. The depth of response to CPI as a monotherapy is highest in the first relapse as salvage therapy based on outcomes reported in several phase II studies. With earlier use of CPI and brentuximab vedotin, the optimal sequencing of therapy is evolving. In this review, we will summarize clinical investigation of anti-PD-1 mAb in earlier line settings to provide insights on utilizing these agents as chemotherapy- and radiation-sparing approaches, increasing depth of response, and as part of combination regimens.

Autologous stem cell transplantation after anti-PD-1 therapy for multiply relapsed or refractory Hodgkin lymphoma.

Autologous stem cell transplantation (ASCT) can be curative for patients with relapsed/refractory Hodgkin lymphoma (HL). Based on studies suggesting that anti-PD-1 monoclonal antibodies (mAbs) can sensitize patients to subsequent chemotherapy, we hypothesized that anti-PD-1 therapy before ASCT would result in acceptable outcomes among high-risk patients who progressed on or responded insufficiently to ≥1 salvage regimen, including chemorefractory patients who are traditionally considered poor ASCT candidates. We retrospectively identified 78 HL patients who underwent ASCT after receiving an anti-PD-1 mAb (alone or in combination) as third-line or later therapy across 22 centers. Chemorefractory disease was common, including 42 patients (54%) refractory to ≥2 consecutive systemic therapies immediately before anti-PD-1 treatment. Fifty-eight (74%) patients underwent ASCT after anti-PD-1 treatment, while 20 patients (26%) received additional therapy after PD-1 blockade and before ASCT. Patients received a median of 4 systemic therapies (range, 3-7) before ASCT, and 31 patients (41%) had a positive pre-ASCT positron emission tomography (PET) result. After a median post-ASCT follow-up of 19.6 months, the 18-month progression-free survival (PFS) and overall survival were 81% (95% CI, 69-89) and 96% (95% confidence interval [CI], 87-99), respectively. Favorable outcomes were observed for patients who were refractory to 2 consecutive therapies immediately before PD-1 blockade (18-month PFS, 78%), had a positive pre-ASCT PET (18-month PFS, 75%), or received ≥4 systemic therapies before ASCT (18-month PFS, 73%), while PD-1 nonresponders had inferior outcomes (18-month PFS, 51%). In this high-risk cohort, ASCT after anti-PD-1 therapy was associated with excellent outcomes, even among heavily pretreated, previously chemorefractory patients.

COVID-19 Vaccine-Related Local FDG Uptake.

ABSTRACT: We present a case of increased FDG uptake in the lymph nodes after COVID-19 vaccine administration. Restaging PET/CT scan of a 70-year-old woman with a history of multiple relapsed Hodgkin lymphoma showed muscle activity in the left upper arm laterally, which is in the deep musculature of the left deltoid muscle. There was also increased activity in several normal-sized left axillary nodes as well. On further review of the patient's history, she had received her second shot of the Pfizer-BioNTech COVID-19 vaccine approximately 2 days before the restaging PET/CT scan.

Addressing Recent Failures in Immuno-Oncology Trials to Guide Novel Immunotherapeutic Treatment Strategies.

The incorporation of checkpoint inhibitors into the treatment armamentarium of oncologic therapeutics has revolutionized the course of disease in many cancers. This has spurred the evaluation of other novel immunotherapy agents in clinical trials with varying levels of success. This review explores possible explanations for differences in efficacy in clinical outcomes among currently US FDA-approved immunotherapy agents, lessons learned from clinical trial failures of investigational immunotherapies, and methods to improve success in the future. An inherent challenge of early phase immunotherapy trials is identifying the maximum tolerated dose and improving understanding of the pharmacokinetics/pharmacodynamics of immunotherapies as they exert their effects indirectly via T cells rather than directly via dose-dependent cytotoxic activity. The wide heterogeneity of the immune system among patients and within an individual patient over time largely affects the results of optimal dose- and toxicity-finding studies as well as the effectiveness of immunotherapy. Therefore, optimization of phase I/II study design is crucial for clinical trial success. These differences may also help elucidate the lack of immunotherapy benefit in certain disease subtypes despite the presence of specific biomarkers. Broader investigation of the tumor microenvironment and its dynamic nature can help in the identification of alternative pathways for targeted therapies, mechanisms of immunotherapy resistance, and more correlative biomarkers. Finally, manipulation of the tumor microenvironment via a single agonist or antagonist may be inadequate, so combination therapies and sequencing of agents must be further assessed while balancing cumulative toxicity risk.

Use of the APACHE II score to assess impact of therapeutic plasma exchange for critically ill patients with hypertriglyceride-induced pancreatitis.

OBJECTIVES: Hypertriglyceridemic (HTG) pancreatitis carries significant morbidity and mortality and often requires intensive care unit (ICU) admission. Therapeutic plasma exchange (TPE) rapidly lowers serum triglyceride (TG) levels. However, evidence supporting TPE for HTG pancreatitis is lacking. METHODS: Ten patients admitted to the ICU for HTG pancreatitis underwent TPE at our institution from 2005-2015. We retrospectively calculated the Acute Physiology and Chronic Health Examination II (APACHE II) score at the time of initial TPE and again after the final TPE session to assess the impact of triglyceride apheresis on morbidity and mortality associated with HTG pancreatitis. RESULTS: All 10 patients had rapid reduction in TG level after TPE, but only 5 had improvement in their APACHE II score. The median APACHE II score decreased from 19% to 17% after TPE, correlating with an 8% and 9% decrease in median predicted non-operative and post-operative mortality, respectively. The APACHE II score did not differ statistically before and after TPE implementation in our patient group (p=0.39). CONCLUSION: TPE is a clinically useful tool to rapidly lower TG levels, but its impact on mortality of HTG pancreatitis as assessed by the APACHE II score remains uncertain.

Iris nevus growth into melanoma: analysis of 1611 consecutive eyes: the ABCDEF guide.

PURPOSE: To determine clinical features predictive of growth of iris nevus into melanoma. DESIGN: Retrospective, comparative case series. PARTICIPANTS: A total of 1611 consecutive patients referred to an ocular oncology center with iris nevus. INTERVENTION: Observation and photographic documentation. MAIN OUTCOME MEASURES: Growth into melanoma. RESULTS: The mean age at referral for iris nevus was 51 years (median, 54; range, <1-94 years). At presentation, the mean tumor basal diameter was 3 mm (median, 3 mm; range, <1-12 mm) and mean tumor thickness was 0.8 mm (median, 0.5 mm; range, 0-5 mm). All patients were initially diagnosed with benign iris nevus. Growth of iris nevus to melanoma was confirmed in 2% of eyes (n = 27) over a mean follow-up of 68 months (median, 46 months; range, 3-465 months). By Kaplan-Meier estimates, iris nevus growth to melanoma occurred in <1%, 3%, 4%, 8%, and 11% at 1, 5, 10, 15, and 20 years, respectively. Factors predictive of iris nevus growth to melanoma by multivariable analysis included age ≤ 40 years at presentation (hazard ratio [HR], 3), episode of hyphema (HR, 9), 4:00 to 9:00 clock hour location of tumor (HR, 9), diffuse tumor (involving entire iris surface) (HR, 14), ectropion uveae (HR, 4), and feathery tumor margins (HR, 3). Additional important factors by univariable analysis included tumor seeding on the iris or in the anterior chamber angle, feeder vessels, and nodule formation. These factors can be remembered using the mnemonic ABCDEF, representing A = age young, B = blood, C = clock hour inferior, D = diffuse, E = ectropion, and F = feathery margin. CONCLUSIONS: In an analysis of 1611 cases of iris nevus referred for evaluation at an ocular oncology center, growth into melanoma occurred in 8% by 15 years. Risk factors for growth, identified by ABCDEF included Age young, Blood (hyphema), Clock hour inferior, Diffuse configuration, Ectropion uveae, and Feathery tumor margin.