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Ibrutinib has been shown to have immunomodulatory effects by inhibiting Bruton's tyrosine kinase (BTK) and IL-2-inducible T cell kinase (ITK). The relative importance of inhibiting these 2 kinases has not been examined despite its relevance to immune-based therapies. Peripheral blood mononuclear cells from chronic lymphocytic leukemia (CLL) patients on clinical trials of ibrutinib (BTK/ITK inhibitor; n = 19) or acalabrutinib (selective BTK inhibitor; n = 13) were collected serially. T cell phenotype, immune function, and CLL cell immunosuppressive capacity were evaluated. Ibrutinib markedly increased CD4+ and CD8+ T cell numbers in CLL patients. This effect was more prominent in effector/effector memory subsets and was not observed with acalabrutinib. Ex vivo studies demonstrated that this may be due to diminished activation-induced cell death through ITK inhibition. PD-1 and CTLA-4 expression was significantly markedly reduced in T cells by both agents. While the number of Treg cells remained unchanged, the ratio of these to conventional CD4+ T cells was reduced with ibrutinib, but not acalabrutinib. Both agents reduced expression of the immunosuppressive molecules CD200 and BTLA as well as IL-10 production by CLL cells. Ibrutinib treatment increased the in vivo persistence of activated T cells, decreased the Treg/CD4+ T cell ratio, and diminished the immune-suppressive properties of CLL cells through BTK-dependent and -independent mechanisms. These features provide a strong rationale for combination immunotherapy approaches with ibrutinib in CLL and other cancers. ClinicalTrials.gov NCT01589302 and NCT02029443. Samples described here were collected per OSU-0025. The National Cancer Institute.

Purpose of ReviewThis article summarizes the current state of knowledge of hairy cell leukemia (HCL) regarding presentation, diagnosis, therapy, and monitoring, including perspectives on emergent therapies.Recent FindingsOver the past decade, there has been enormous progress in the understanding of the biology of HCL which has led to the development of novel therapeutic strategies. The maturation of data regarding existing management strategies has also lent considerable insight into therapeutic outcomes and prognosis of patients treated with chemo- or chemoimmunotherapy. Purine nucleoside analogs remain the cornerstone of treatment, and the addition of rituximab has deepened and prolonged responses in the upfront and relapsed setting. Targeted therapies now have a more defined role in the management of HCL, with BRAF inhibitors now having a potential in the first-line setting in selected cases as well as in relapse. Next-generation sequencing for the identification of targetable mutations, evaluation of measurable residual disease, and risk stratification continue to be areas of active investigation.SummaryRecent advances in HCL have led to more effective therapeutics in the upfront and relapsed setting. Future efforts will focus on identifying patients with high-risk disease who require intensified regimens. Multicenter collaborations are the key to improving overall survival and quality of life in this rare disease.

Hairy cell leukemia variant (HCL-v) is a rare B-cell lymphoproliferative disorder with distinct immunophenotypic and molecular characteristics when compared to classical hairy cell leukemia (HCL-c). In contrast to the enormous progress in therapeutic options for HCL-c, HCL-v remains a therapeutic challenge due to inferior outcomes with standard chemoimmunotherapy and BCR signaling pathway inhibitors, and due to the fact that HCL-v has limited molecular therapeutic targets. In addition, because of the rarity of the disease, there is a paucity of later phase studies or multicenter trials to guide treatment decisions. In this article, we briefly review the diagnostic criteria and clinical characteristics of HCL-v and present a comprehensive overview of current therapeutic options in HCL-v.

Background Hairy Cell Leukemia (HCL) is a B‐cell lymphoproliferative disorder that predominantly affects males, yet recent evidence suggests a notable gender participation gap in HCL clinical trials. This study aims to characterize that disparity and explore potential factors contributing to the under‐enrollment of females. Methods In this descriptive, retrospective study, we searched EMBASE, PUBMED, Cochrane Central, and ClinicalTrials.gov from January 1983 to December 2023 for publications on clinical trials (CT) in HCL, descriptive statistical analysis of all the sociodemographic variables was performed. Results We analyzed 57 clinical trials totaling 4595 HCL patients, with 79.1% male and 20.9% female participants. The male‐to‐female ratio declined from 5.91 (1983–1993) to 4.19 (2014–2023). Although the gender gap narrowed over time, female participation slightly decreased to 19.2% in the most recent period (2014–2023). Conclusions Female enrollment in HCL clinical trials remains disproportionately low compared to incidence rates, underscoring the need to address underlying barriers to improve equity in clinical research and treatment outcomes. Trial Registration The authors have confirmed clinical trial registration is not needed for this submission.

Hairy cell leukemia is an uncommon B‐cell malignancy with excellent response to purine analogs and to targeted therapies such as ibrutinib and vemurafenib. However, purine analogs are known to be highly immunosuppressive and the infection burden in this patient population with current therapies is unknown. We therefore conducted a retrospective cohort study following 149 patients. Median follow‐up time was 6.9 years. Thirty‐six percent developed an opportunistic or serious infection requiring hospitalization. Most cases were bacterial and most coincided with neutropenia and/or CD4 T‐lymphopenia. No single treatment agent was significantly associated with increased or decreased incidence of infection. Reassuringly, the cumulative incidence of infections plateaued 2 months after initial treatment suggesting clinically significant immune recovery. Only one patient in our cohort passed away due to infection. Estimated 10‐year overall survival was 99% suggesting that infections may not cause as much mortality as was seen prior to current therapies.

Polycythemia vera (PV) is a rare myeloproliferative neoplasm (MPN) associated with significant impairment in quality of life (QoL) due to disease-related symptoms and complications. Assessment of disease burden constitutes standard monitoring of symptoms and response. Conventional treatments for MPN, such as hydroxyurea, phlebotomy, or interferon, have not shown a significant impact in QoL or patient-reported outcomes (PRO). Ruxolitinib (RUX) is a JAK2 inhibitor approved for patients intolerant or resistant to hydroxyurea (HA). We conducted a systematic review of clinical trials of RUX in patients with PV that incorporated PRO measures to evaluate the effects on PRO and QoL. Three randomized Phase 3 studies reported in four publications were relevant for analysis. Although the small number of trials and potential for treatment bias in the review, treatment with RUX was associated with improved QoL and PRO in PV patients intolerant or resistant to hydroxyurea.

Background Purine nucleoside analogs (PNAs) are the recommended first-line treatment for patients with hairy cell leukemia (HCL), but they are associated with adverse events (AEs). Due to a lack of real-world evidence regarding AEs that are associated with PNAs , we used commercial data to assess AE rates, AE-related health care resource utilization (HCRU), and costs among PNA-treated patients with HCL. Adults aged ≥18 years with ≥2 claims for HCL ≥30 days apart from 1 January 2006 through 31 December 2015 were included. Included patients had ≥1 claim for HCL therapy (cladribine ± rituximab or pentostatin ± rituximab [index date: first claim date]) and continuous enrollment for a ≥ 6-month baseline and ≥ 12-month follow-up period. Patient sub-cohorts were based on the occurrence of myelosuppression and opportunistic infections (OIs). Generalized linear models were used to compare HCRU and costs. Results In total, 647 PNA-treated patients were identified (mean age: 57.1 years). Myelosuppression and OI incidence were 461 and 42 per 1000 patient-years, respectively. Adjusted results indicated that those with myelosuppression had higher rates of hospitalization (47.4% vs 12.4%; P  < .0001) and incurred higher mean inpatient costs ($23,517 vs $12,729; P  = .011) and total costs ($57,325 vs $34,733; P  = .001) as compared with those without myelosuppression. Similarly, patients with OIs had higher rates of hospitalization (53.8% vs 30.8%; P  = .025) and incurred higher mean inpatient costs ($21,494 vs $11,229; P  < .0001) as compared with those without OIs. Conclusions PNA therapy is highly effective but associated with significant toxicities that increase costs; these findings indicate a need for therapies with improved toxicity profiles and better risk stratification of patients at risk of developing myelosuppression and OIs.

Patients with chronic lymphocytic leukemia (CLL) who receive chemoimmunotherapy and do not achieve complete remission experience significantly shortened progression-free interval (PFS). Additionally, the majority of patients treated for relapsed disease demonstrate evidence of measurable disease. Eradication of minimal residual disease (MRD) results in improved PFS and overall survival. Maintenance therapy might result in eradication of MRD and improve response duration but might be associated with an increase in incidence of infectious complications. Flavopiridol is a broad cyclin-dependent kinase (CDK) inhibitor with established safety and efficacy in patients with relapsed CLL, particularly patients with high-risk cytogenetic features. A pharmacologically derived schedule was utilized as consolidation therapy in this phase I study to assess the safety and feasibility of outpatient therapy with flavopiridol in patients with low tumor burden. Flavopiridol was administered as a 30-min loading dose of 30 mg/m 2 followed by a 4-h infusion of 30 mg/m 2 once weekly for 3 weeks every 5 weeks (1 cycle) for planned 2 cycles in ten patients. Therapy was extremely well tolerated and no patient developed acute tumor lysis syndrome. The most common toxicities were gastrointestinal. Of the patients, 22 % improved their response from a PR to CR. Eighty-eight percent experienced a reduction in tumor burden as measured by extent of bone marrow involvement including patients with del17p and complex karyotype. The study establishes the safety and efficacy of flavopiridol as consolidation therapy after chemoimmunotherapy for patients with CLL. Further evaluation is required in larger trials for the utility of CDK inhibitors as consolidation or maintenance strategies. Registration number at ClinicalTrials.gov: NCT00377104.

Significance IGHV mutation status is a well established prognostic factor in chronic lymphocytic leukemia, and also provides crucial insights into tumor cell biology and function. Currently, determination of IGHV transcript sequence, from which mutation status is calculated, requires a specialized laboratory procedure. RNA sequencing is a method that provides high resolution, high dynamic range transcriptome data that can be used for differential expression, isoform discovery, and variant determination. In this paper, we demonstrate that unselected next-generation RNA sequencing can accurately determine the IGH@ sequence, including the complete sequence of the complementarity-determining region 3 (CDR3), and mutation status of CLL cells, potentially replacing the current method which is a specialized, single-purpose Sanger-sequencing based test. Immunoglobulins (Ig) are produced by B lymphocytes as secreted antibodies or as part of the B-cell receptor. There is tremendous diversity of potential Ig transcripts (>1 × 10 ¹²) as a result of hundreds of germ-line gene segments, random nucleotide incorporation during joining of gene segments into a complete transcript, and the process of somatic hypermutation at individual nucleotides. This recombination and mutation process takes place in the maturing B cell and is responsible for the diversity of potential epitope recognition. Cancers arising from mature B cells are characterized by clonal production of Ig heavy ( IGH@ ) and light chain transcripts, although whether the sequence has undergone somatic hypermutation is dependent on the maturation stage at which the neoplastic clone arose. Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults and arises from a mature B cell with either mutated or unmutated IGH@ transcripts, the latter having worse prognosis and the assessment of which is routinely performed in the clinic. Currently, IGHV mutation status is assessed by Sanger sequencing and comparing the transcript to known germ-line genes. In this paper, we demonstrate that complete IGH@ V-D-J sequences can be computed from unselected RNA-seq reads with results equal or superior to the clinical procedure: in the only discordant case, the clinical transcript was out-of-frame. Therefore, a single RNA-seq assay can simultaneously yield gene expression profile, SNP and mutation information, as well as IGHV mutation status, and may one day be performed as a general test to capture multidimensional clinically relevant data in CLL.

BackgroundMelanoma has high response rate to immune checkpoint inhibitors. KIT, a driver mutation in melanoma seen in ~10% of the patients.1 However, the role of the KIT mutation in immune microenvironment of melanoma is not well established yet. Here we report a case with KIT mutation and a likely impaired B cell activity with poor response to Immune-checkpoint inhibitor therapy (ICI). We also describe the overall survival of melanoma depending on KIT mutation and MS4A1/CD20 expression, which encodes CD20, B-lymphocyte-specific membrane protein that plays a role in the development, differentiation, and activation of B-lymphocytes.2 MethodsA case with poor response to ICI with KIT mutation and monoclonal B cell lymphocytosis was identified. Clinical and molecular characteristics of melanoma in TCGA was analyzed using cBioPortal web page. TCGA data were analyzed to determine KIT mutation status and MS4A1/CD20 expression in melanoma cohort. Samples in the upper 33 percentile of MS4A1 expression were identified as high expression, and the lower 33 percentile were identified as low expression. Mantel-Cox method was used for overall survival (OS) comparison between the cohorts.Results69-year-old male with initial diagnosis of stage III-B melanoma of the left thumb with local recurrence in the resection site and then lung metastases. Patient was then started on nivolumab/ipilimumab with rapid progression on immunotherapy. He was found to have KIT mutation (exon 13K642EMT), and started on imatinib, but he continued to have progression. He was switched to temozolomide with no response. He also had history of leukopenia, pre-dating the metastatic melanoma and was diagnosed with monoclonal B cell lymphocytosis. With the hypothesis that the patient‘s dysfunctional B cells may have impaired ability of ICI and poor prognosis; we analyzed TCGA database for KIT mutation and MS4A1/CD20 expression- which was used as marker for B cell activity. KIT mutation was seen in 10 of 147 patients with high MS4A1/CD20 expression, and 10 of 135 patients with low MS4A1/CD20 expression. Overall survival was 15 months for the patients with KIT mutation and low MS4A1/CD20 expression, and significantly lower when compared with other groups despite low number of patients. (P<0.0001) (figure 1).Abstract 525 Figure 1KIT mutation and MS41A/CD20 expression - overall survivalLow MS41A/CD20 expression with concurrent KIT mutation is associated with poor overall survivalConclusionsB cells have significant role in immune response to tumor. Lower expression of MS4A1/CD20 is known to be associated with poor prognosis in melanoma and other solid tumors.3 We demonstrated that a concurrent KIT mutation in melanoma with lower expression of MS4A1/CD20 contributes to poor prognosis in melanoma. Therefore, this small subset of aggressive tumors may need combination strategies involving targeting driver pathways with a kinase and immune checkpoint inhibitor.Referencesde Mendonça UB, Cernea CR, Matos LL, de Araujo Lima RR. Analysis of KIT gene mutations in patients with melanoma of the head and neck mucosa: a retrospective clinical report. Oncotarget 2018 May 1;9(33):22886.Tedder TF, Boyd AW, Freedman AS, Nadler LM, Schlossman S. The B cell surface molecule B1 is functionally linked with B cell activation and differentiation. The Journal of Immunology 1985 Aug 1;135(2):973–9.Liu Y, Wang L, Lo KW, Lui VW. Omics-wide quantitative B-cell infiltration analyses identify GPR18 for human cancer prognosis with superiority over CD20. Communications biology 2020 May 12;3(1):1–1.