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Traditional response criteria in MDS and AML are based on bone marrow morphology and may not accurately reflect clonal tumor burden in patients treated with non-cytotoxic chemotherapy. We used next-generation sequencing of serial bone marrow samples to monitor MDS and AML tumor burden during treatment with epigenetic therapy (decitabine and panobinostat). Serial bone marrow samples (and skin as a source of normal DNA) from 25 MDS and AML patients were sequenced (exome or 285 gene panel). We observed that responders, including those in complete remission (CR), can have persistent measurable tumor burden (i.e., mutations) for at least one year without disease progression. Using an ultra-sensitive sequencing approach, we detected extremely rare mutations (equivalent to 1 heterozygous mutant cell in 2000 non-mutant cells) months to years prior to their expansion at disease relapse. While patients can live with persistent clonal hematopoiesis in a CR or stable disease, ultimately we find evidence that expansion of a rare subclone occurs at relapse or progression. Here we demonstrate that sequencing of serial samples provides an alternative measure of tumor burden in MDS or AML patients and augments traditional response criteria that rely on bone marrow blast percentage.

A letter to the editor is presented on the study regarding the effectiveness of carfilzomib drug for acute lymphoblastic leukemia (ALL) and myeloid leukemia (AML) treatment.

Purpose: Persistent molecular disease (PMD) after induction chemotherapy predicts relapse in AML. In this study, we used whole-exome sequencing (WES) and targeted error-corrected sequencing to assess the frequency and mutational patterns of PMD in 30 patients with AML., Materials and Methods: The study cohort included 30 patients with adult AML younger than 65 years who were uniformly treated with standard induction chemotherapy. Tumor/normal WES was performed for all patients at presentation. PMD analysis was evaluated in bone marrow samples obtained during clinicopathologic remission using repeat WES and analysis of patient-specific mutations and error-corrected sequencing of 40 recurrently mutated AML genes (MyeloSeq)., Results: WES for patient-specific mutations detected PMD in 63% of patients (19/30) using a minimum variant allele fraction (VAF) of 2.5%. In comparison, MyeloSeq identified persistent mutations above 0.1% VAF in 77% of patients (23/30). PMD was usually present at relatively high levels (>2.5% VAFs), such that WES and MyeloSeq agreed for 73% of patients despite differences in detection limits. Mutations in DNMT3A , ASXL1 , and TET2 (ie, DTA mutations) were persistent in 16 of 17 patients, but WES also detected non-DTA mutations in 14 of these patients, which for some patients distinguished residual AML cells from clonal hematopoiesis. Surprisingly, MyeloSeq detected additional variants not identified at presentation in 73% of patients that were consistent with new clonal cell populations after chemotherapy., Conclusion: PMD and clonal hematopoiesis are both common in patients with AML in first remission. These findings demonstrate the importance of baseline testing for accurate interpretation of mutation-based tumor monitoring assays for patients with AML and highlight the need for clinical trials to determine whether these complex mutation patterns correlate with clinical outcomes in AML.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN aged ≥2 years. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and outcomes in patients with relapsed/refractory BPDCN remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. To begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts, which includes a multidisciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC's inaugural meetings are presented herein., (© 2023 by The American Society of Hematology.)

Leukemia stem cells utilize cell adhesion molecules like CXCR4/CXCL12 to home to bone marrow stromal niches where they are maintained in a dormant, protected state. Dociparstat sodium (DSTAT, CX-01) is a low anticoagulant heparin with multiple mechanisms of action, including inhibition of the CXCR4/CXCL12 axis, blocking HMGB1, and binding platelet factor 4 (PF-4). We conducted a pilot study adding DSTAT to azacitidine for patients with AML or MDS unresponsive to or relapsed after prior hypomethylating agent therapy, hypothesizing that DSTAT may improve response rates. Twenty patients were enrolled, with a median of 2 prior lines of therapy and 6 cycles of prior hypomethylating agents. Among fifteen patients evaluable for response, there was 1 complete remission, and 3 marrow complete remissions, for a response rate of 27 % among evaluable patients (20 % overall). Hematologic improvement was observed in 5 additional patients. The median overall survival for all enrolled patients was 205 days (95 % CI 119-302). While cytopenias and infections were common, these were not out of proportion to what would be expected in this population of patients undergoing treatment with azacitidine alone. In summary, this trial demonstrated the feasibility of combining DSTAT with azacitidine, with several responses observed, suggesting this combination warrants further study., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The hypomethylating agent azacitidine can prolong overall survival (OS) in patients with higher risk-myelodysplastic syndromes (HR-MDS) compared to conventional regimens. However, outcomes differ largely between studies, making it challenging to determine the contribution of novel therapies added to azacitidine. Further, a discrepancy is seen between complete (CR) or partial (PR) response rates and OS improvement with azacitidine, making it challenging to rely on earlier endpoints than OS. We conducted a systematic literature search and study-level systematic review of 237 clinical studies to better understand outcomes for HR-MDS patients treated with azacitidine. Pooled marrow CR was 9% (N = 2654; 95% CI: 6-13 %), CR rate was 17 % (N = 6943; 95% CI: 15-20 %), and median OS (mOS) was 18.6 months (N = 2820; 95% CI: 15.3-21.9). A weak correlation to mOS was detected with CR rate (207 patient cohorts, Pearson's r = 0.315; P < 0.0005), and a much stronger correlation with median progression-free survival (mPFS) (r=0.88, P = 3 × 10 -14 ). Six-months progression-free survival rates correlated with 1-year OS rates but were only infrequently reported (N = 41 patient cohorts) therefore not allowing a robust recommendation for a surrogate to the established OS endpoint. Larger patient numbers and patient-level data appear necessary, especially for designing future clinical trials using azacitidine combinations., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Physicians treating hematologic malignancies increasingly order targeted sequencing panels to interrogate recurrently mutated genes. The precise impact of these panels on clinical decision making is not well understood., Methods: Here, we report our institutional experience with a targeted 40-gene panel (MyeloSeq) that is used to generate a report for both genetic variants and variant allele frequencies for the treating physician (the limit of mutation detection is approximately one AML cell in 50)., Results: In total, 346 sequencing reports were generated for 325 patients with suspected hematologic malignancies over an 8-month period (August 2018 to April 2019). To determine the influence of genomic data on clinical care for patients with acute myeloid leukemia (AML), we analyzed 122 consecutive reports from 109 patients diagnosed with AML and surveyed the treating physicians with a standardized questionnaire. The panel was ordered most commonly at diagnosis (61.5%), but was also used to assess response to therapy (22.9%) and to detect suspected relapse (15.6%). The panel was ordered at multiple timepoints during the disease course for 11% of patients. Physicians self-reported that 50 of 114 sequencing reports (44%) influenced clinical care decisions in 44 individual patients. Influences were often nuanced and extended beyond identifying actionable genetic variants with US Food and Drug Administration-approved drugs., Conclusion: This study provides insights into how physicians are currently using multigene panels capable of detecting relatively rare AML cells. The most influential way to integrate these tools into clinical practice will be to perform prospective clinical trials that assess patient outcomes in response to genomically driven interventions., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Erica K. BarnellEmployment: Geneoscopy Stock and Other Ownership Interests: Geneoscopy Patents, Royalties, Other Intellectual Property: Inventor of intellectual property in start-up company (Geneoscopy) Travel, Accommodations, Expenses: GeneoscopyKenneth F. NewcomerEmployment: Geneoscopy (I) Stock and Other Ownership Interests: Geneoscopy (I) Patents, Royalties, Other Intellectual Property: Inventor of intellectual property owned by Geneoscopy (I)Zachary L. SkidmoreStock and Other Ownership Interests: Aim Immunotech, Catalyst PharmaceuticalsKilannin KrysiakConsulting or Advisory Role: Gerson Lehrman GroupLukas D. WartmanConsulting or Advisory Role: Novartis, IncyteStephen T. OhConsulting or Advisory Role: Incyte, Novartis, Blueprint Medicines, Celgene, Kartos, CTI BioPharma Corp, PharmaEssentia, Disc Medicine, Constellation Pharmaceuticals Research Funding: Incyte (Inst), Gilead Sciences (Inst), CTI BioPharma Corp (Inst), Kartos (Inst), Celgene (Inst), Sierra Oncology (Inst), Blueprint Medicines (Inst), Constellation Pharmaceuticals (Inst)John S. WelchConsulting or Advisory Role: Archer Biosciences, Agios Research Funding: Janssen Oncology (Inst), Notable Labs (Inst)Keith E. Stockerl-GoldsteinStock and Other Ownership Interests: Abbott Laboratories, AbbVie Consulting or Advisory Role: Celgene Research Funding: GlaxoSmithKline, Takeda, BiolineRx, Janssen Other Relationship: CellerantRavi VijConsulting or Advisory Role: Bristol Myers Squibb, Celgene, Janssen, Sanofi, Karyopharm Therapeutics, Takeda, Genentech, AbbVie, Oncopeptides Research Funding: Takeda, Celgene, Bristol Myers Squibb Travel, Accommodations, Expenses: Celgene, Bristol Myers Squibb, Sanofi, Janssen, DAVAOncology, Karyopharm Therapeutics, Amgen, Takeda, AbbVieAmanda F. CashenConsulting or Advisory Role: Agios Speakers' Bureau: Novartis, CelgeneIskra PusicConsulting or Advisory Role: Kadmon, Incyte, SyndaxCamille N. AbboudStock and Other Ownership Interests: AbbVie (I), Abbott Laboratories (I), Gilead Sciences (I), Bristol Myers Squibb (I), Johnson & Johnson (I) Honoraria: Cardinal Health, Dova Pharmaceuticals, NkartaTherapeutics, Archer Biosciences Research Funding: Actinium Pharmaceuticals, Selvita (Inst), AlloVir (Inst), Forty-Seven (Inst)Armin GhobadiHonoraria: Kite Pharma Consulting or Advisory Role: Kite Pharma, Celgene, Amgen, Wugen Speakers' Bureau: Kite Pharma, AmgenGeoffrey L. UyConsulting or Advisory Role: Astellas Pharma, Genentech, Jazz PharmaceuticalsMark A. SchroederConsulting or Advisory Role: Astellas Pharma, Dova Pharmaceuticals, Flatiron Health, GlaxoSmithKline, Incyte, Partners Therapeutics, Partners Therapeutics, Pfizer Speakers' Bureau: AbbVie, Merck, TakedaJohn F. DiPersioStock and Other Ownership Interests: Magenta Therapeutics, Wugen Honoraria: Incyte Consulting or Advisory Role: Cellworks, Rivervest, Magenta Therapeutics, Incyte Research Funding: Amphivena Therapeutics (Inst), Macrogenics (Inst), Incyte (Inst), Wugen (Inst), BiolineRx (Inst), Maxcyte (Inst), Bigelow Aerospace (Inst) Patents, Royalties, Other Intellectual Property: Patents: CD7 and CD2 knockout for CART to CD7 and CDL; Duvelisib for treatment of cytokine release syndrome; NT-17 to enhance CART survival; Novel WU mobilizing compounds (Inst); Selection of IMPDH mutant stem cells; IFNγ, upregulate MHCII for relapsed AML; Dextran-based molecules to detect CAR-T cells; Combining integrin inhibitor with chemokine binders, 016131; JAK and calcineurin inhibition, solid organ transplant; VLA4, gro-b; Triple combination–CXCR2, VLA-4, gro-b; Targeting IFNR/CSCR3 in GvHD; WU/SLU compounds VLA4 and CXCR2 (Inst) Travel, Accommodations, Expenses: Incyte, Macrogenics, Magenta TherapeuticsMary C. PolitiResearch Funding: MerckDavid H. SpencerConsulting or Advisory Role: Wugen Research Funding: IlluminaEric J. DuncavageStock and Other Ownership Interests: P&V Licensing Consulting or Advisory Role: Cofactor Genomics, Bristol Myers Squibb, Eli Lilly Open Payments Link: https://openpaymentsdata.cms.gov/physician/317379Timothy J. LeyResearch Funding: Rigel Patents, Royalties, Other Intellectual Property: Licenses for monoclonal antibodies and recombinant granzymesMeagan A. JacobyHonoraria: Takeda Research Funding: Geron (Inst), AbbVie (Inst), Jazz Pharmaceuticals (Inst), Aprea AB (Inst), Amphivena (Inst), Janssen (Inst) No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

For patients with relapsed or refractory classical Hodgkin lymphoma (cHL), salvage chemotherapy followed by consolidation with autologous stem cell transplant (ASCT) remains the standard of care. Even with this aggressive treatment strategy, 5-year progression-free survival is ≤50%, and there remains interest in maintenance strategies to improve long-term disease-free survival. Lenalidomide is an immunomodulatory agent with demonstrated activity in multiple subtypes of lymphoma including cHL, and has also been shown to improve both progression-free and overall survival as maintenance therapy after ASCT in multiple myeloma. This multicenter study evaluated maintenance lenalidomide after ASCT for patients with cHL. Patients were enrolled 60 to 90 days post-transplant and received oral lenalidomide on days 1 to 28 of 28-day cycles for a maximum of 18 cycles. Lenalidomide was started at 15 mg daily and increased to maximum of 25 mg daily if tolerated. The primary objective of this study was to assess the feasibility of this regimen, with a goal <30% rate of discontinuation at or before cycle 12 for drug-related reasons. Twenty-seven patients were enrolled and 26 received at least 1 dose of lenalidomide. With a median follow-up of 51.3 months (range, 12.2 to 76.2 months), 23 of 26 patients were alive. Median event-free survival was 9.4 months and median progression-free survival had not been reached, with 17 of 26 patients (65.4%) remaining in remission at last follow-up. Excluding 4 patients who discontinued therapy for progression and 2 who discontinued due to noncompliance, the discontinuation rate at or before cycle 12 was 52%. Treatment was complicated by a high frequency of hematologic adverse events, with 15 patients (58%) experiencing grade 3 to 4 hematologic toxicity and 5 (19%) experiencing grade 4 hematologic toxicity. We conclude that the regimen of maintenance lenalidomide explored in this study is not feasible for patients with cHL immediately following ASCT. An alternative lenalidomide dose or schedule may be better tolerated following ASCT for patients with relapsed or refractory cHL., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Recent whole-genome sequencing (WGS) studies have demonstrated that tumors typically comprise a founding clone and multiple subclones (i.e., clonal heterogeneity is common). The possible combination of mutations in each tumor clone is enormous, making each tumor genetically unique. Clonal heterogeneity likely has a role in cancer progression, relapse, metastasis, and chemoresistance due to functional differences in genetically unique subclones. In current clinical practice, gene mutations are only classified as being present or absent, ignoring the clonal complexity of cancers. In this review, we address how tumor clonality is measured using next-generation sequencing (NGS) data, highlight that clonal heterogeneity is common across multiple tumor types, and discuss the potential clinical implications of tumor clonal heterogeneity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Human gammaherpesvirus infections are associated with development of lymphoproliferative disease. Understanding of the mechanisms of gammaherpesvirus lymphomagenesis during chronic infection in a natural host has been limited by the exquisite species specificity of human gammaherpesviruses and the expense of primates. Murine gammaherpesvirus gammaHV68 is genetically and biologically related to human gammaherpesviruses and herpesvirus saimiri and has been reported to be associated with lymphoproliferative disease in mice (N. P. Sunil-Chandra, J. Arno, J. Fazakerley, and A. A. Nash, Am. J. Pathol. 145:818-826, 1994). We report the development of an animal model of gammaHV68 lymphomagenesis in BALB/c beta2 microglobulin-deficient mice (BALB beta2m-/-). GammaHV68 infection induced two lymphoproliferative lesions: B-cell lymphoma and atypical lymphoid hyperplasia (ALH). ALH lesion histology resembled lesions of Epstein-Barr virus-associated posttransplant lymphoproliferative disease and was characterized by the abnormal infiltration of the white pulp with cells expressing the plasma cell marker CD138. Lymphomas observed in gammaHV68-infected animals were B220+/CD3- large-cell lymphomas. GammaHV68-infected cells were common in ALH lesions as measured by in situ hybridization with a probe specific for viral tRNAs (vtRNAs), but they were scarce in gammaHV68-infected spleens with normal histology. Unlike ALH lesions, gammaHV68 vtRNA-positive cells were rare in lymphomas. GammaHV68 infection of BALB beta2m-/- mice results in lymphoproliferation and lymphoma, providing a valuable tool for identifying viral and host genes involved in gammaherpesvirus-associated malignancies. Our findings suggest that gammaHV68 induces lymphomas via hit-and-run oncogenesis, paracrine effects, or stimulation of chronic inflammation.