Management of patients with concurrent clonal plasma cell and myeloid disorders: A single center descriptive case series.

Both clonal plasma cell and myeloid disorders occur more frequently with age. Patients with concurrent clonal plasma cell and myeloid disorders (CPCMD) can present clinical and therapeutic challenges. In this single-institution cohort of patients with CPCMD (n = 18), we abstracted clinically relevant themes. A majority of patients (12/18) were treated with clone-directed therapies and three received treatment targeting both clones. Treatment of clones with targetable genetic lesions or those causing end-organ complications should be prioritized. Simultaneous treatment of both clones can be safe but is best done in a stepwise manner. Further study of patients with dual clonal processes is warranted.

1q jumping translocation as a biomarker in myeloid malignancy: frequently mutated genes associated with bad prognosis and low survival.

1q jumping translocation (JT) is rare and its molecular profiles in myeloid malignancies are not well-known. This study evaluated gene mutations in 1q-JT cohorts (0.38%) from hematological malignant specimens that underwent genetic analysis at the Johns Hopkins Hospital (n = 11,908) and the MD Anderson Cancer Center. 1q-JT had frequent mutations in eleven genes, most of which are associated with worse prognosis. BCOR mutations significantly co-occurred with others. Patients tended to have mutations in DNA-repair, spliceosome, and epigenetic modification pathways, though genes utilized within each of these pathways were not randomly distributed. Multi-, albeit overlapping, pathway interruptions tended to manifest in mutations of two gene sets. One gene set consisted of SF3B1 (spliceosome) and TET2 (epigenetic modification), while the other consisted of STAG2 (DNA repair), SRSF2, U2AF (spliceosome), ASXL1, KMT2D (epigenetic modification), BCOR, and GATA2 (transcription factors). An "intermediate" JT-like rearrangement may represent an early sign of occurring 1q-JT. Treatments (hypomethylating agents) and unique structures of the short arms of acrocentric chromosomes may contribute to 1q-JT formation in myeloid malignancies. The median overall survival after identification of a JT was 10 months (95% confidence interval, 5-15 months). Our cohort represents the largest number of myeloid malignancies from multi-centers with before and after the 1q-JT event analyzed to date. Overall, this study identified specific molecular profiles that are associated with 1q-JT in myeloid malignancies. 1q-JT could serve as a poor prognosis biomarker in myeloid malignancies, which could be important in making well-informed clinical decisions and treatment strategies.

The E592K variant of SF3B1 creates unique RNA missplicing and associates with high-risk MDS without ring sideroblasts.

ABSTRACT: Among the most common genetic alterations in myelodysplastic syndromes (MDS) are mutations in the spliceosome gene SF3B1. Such mutations induce specific RNA missplicing events, directly promote ring sideroblast (RS) formation, and generally associate with a more favorable prognosis. However, not all SF3B1 mutations are the same, and little is known about how distinct hotspots influence disease. Here, we report that the E592K variant of SF3B1 associates with high-risk disease features in MDS, including a lack of RS, increased myeloblasts, a distinct comutation pattern, and a lack of favorable survival seen with other SF3B1 mutations. Moreover, compared with other hot spot SF3B1 mutations, E592K induces a unique RNA missplicing pattern, retains an interaction with the splicing factor SUGP1, and preserves normal RNA splicing of the sideroblastic anemia genes TMEM14C and ABCB7. These data have implications for our understanding of the functional diversity of spliceosome mutations, as well as the pathobiology, classification, prognosis, and management of SF3B1-mutant MDS.

Toward a more patient-centered drug development process in clinical trials for patients with myelodysplastic syndromes/neoplasms (MDS): Practical considerations from the International Consortium for MDS (icMDS).

Notable treatment advances have been made in recent years for patients with myelodysplastic syndromes/neoplasms (MDS), and several new drugs are under development. For example, the emerging availability of oral MDS therapies holds the promise of improving patients' health-related quality of life (HRQoL). Within this rapidly evolving landscape, the inclusion of HRQoL and other patient-reported outcomes (PROs) is critical to inform the benefit/risk assessment of new therapies or to assess whether patients live longer and better, for what will likely remain a largely incurable disease. We provide practical considerations to support investigators in generating high-quality PRO data in future MDS trials. We first describe several challenges that are to be thoughtfully considered when designing an MDS-focused clinical trial with a PRO endpoint. We then discuss aspects related to the design of the study, including PRO assessment strategies. We also discuss statistical approaches illustrating the potential value of time-to-event analyses and their implications within the estimand framework. Finally, based on a literature review of MDS randomized controlled trials with a PRO endpoint, we note the PRO items that deserve special attention when reporting future MDS trial results. We hope these practical considerations will facilitate the generation of rigorous PRO data that can robustly inform MDS patient care and support treatment decision-making for this patient population.

SOHO State of the Art Updates and Next Questions: An Update on Higher Risk Myelodysplastic Syndromes.

Higher-risk myelodysplastic syndromes (HR-MDS) are clonal myeloid neoplasms that cause life-limiting complications from severe cytopenias and leukemic transformation. Efforts to better classify, prognosticate, and assess therapeutic responses in HR-MDS have resulted in publication of new clinical tools in the last several years. Given limited current treatment options and suboptimal outcomes, HR-MDS stands to benefit from the study of investigational agents.Higher-risk myelodysplastic syndromes (HR-MDS) are a heterogenous group of clonal myeloid-lineage malignancies often characterized by high-risk genetic lesions, increased blood transfusion needs, constitutional symptoms, elevated risk of progression to acute myeloid leukemia (AML), and therapeutic need for allogeneic bone marrow transplantation. Use of blast percentage and other morphologic features to define myelodysplastic neoplasm subtypes is rapidly shifting to incorporate genetics, resulting in a subset of former HR-MDS patients now being considered as AML in presence of leukemia-defining genetic alterations. A proliferation of prognostic tools has further focused use of genetic features to drive decision making in clinical management. Recently, criteria to assess response of HR-MDS to therapy were revised to incorporate more clinically meaningful endpoints and better match AML response criteria. Basic science investigations have resulted in improved understanding of the relationship between MDS genetic lesions, bone marrow stromal changes, germline predispositions, and disease phenotype. However, therapeutic advances have been more limited. There has been import of the IDH1 inhibitor ivosidenib, initially approved for AML; the Bcl-2 inhibitor venetoclax and liposomal daunorubicin/cytarabine (CPX-351) are under active investigation as well. Unfortunately, effective treatment of TP53-mutated disease remains elusive, though preliminary evidence suggests improved outcomes with oral decitabine/cedazuridine over parenteral hypomethylating agent monotherapy. Investigational agents with novel mechanisms of action may help expand the repertoire of treatment options for HR-MDS and trials continue to offer a hopeful therapeutic avenue for suitable patients.

Graft Failure Incidence, Risk Factors, and Outcomes in Patients Undergoing Non-Myeloablative Allogeneic Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide.

Graft failure (GF) is a major complication of allogeneic hematopoietic cell transplantation (alloHCT) that results in significant morbidity and mortality. Post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis has emerged as an effective regimen across the spectrum of donor-match settings, but few studies have investigated the characteristics of GF in the setting of PTCy-based GVHD prophylaxis. The objective was to detail the incidence, clinical features, risk factors, and outcomes for patients with primary graft failure (PGF) and secondary graft failure (SGF). In this retrospective study at a single institution, 958 consecutive patients undergoing first nonmyeloablative (NMA) alloHCT with PTCy-based GVHD prophylaxis were analyzed. PGF was defined as a failure to achieve an ANC ≥ 500 cells/m3 by day 30 of transplant in the absence of residual disease. SGF was defined as complete loss of donor chimerism after initial engraftment. The incidences of PGF and SGF were 3.8% (n = 37) and 1.8% (n = 17), respectively. Neither PGF nor SGF were associated with HLA disparity. In a multivariate analysis, risk factors for PGF in this cohort included age ≥ 65 (OR 2.4, 95% CI 1.2 to 4.8, P = .0120), an underlying diagnosis of MDS, MPN, or MDS/MPN overlap (OR 2.8, 95% CI 1.4 to 5.7, P = .0050), post-transplant viremia with HHV-6 (OR 2.9, 95% CI 1.5 to 5.7, P = .0030), and low CD34+ dose (OR 0.7, 95% CI 0.5 to 0.9, P = .0080). Patients with PGF had poor overall survival, driven primarily by a high rate of nonrelapse mortality (59% at 36 months). SGF was associated with use of a bone marrow graft source and a diagnosis of Hodgkin lymphoma. Patients with SGF had excellent clinical outcomes with only one of seventeen patients experiencing relapse and relapse-related mortality. The incidence of PGF and SGF in patients receiving NMA conditioning and PTCy is low and is not impacted by HLA disparities between donors and recipients. PGF is more common in recipients with age ≥ 65, a diagnosis of MDS, MPN, or MDS/MPN-overlap, post-transplant HHV-6 viremia, and low CD34+ cell dose. Low total nucleated cell dose is also a risk factor for PGF in patients receiving a bone marrow graft source. Patients who experience PGF have poor outcomes due to high rates of nonrelapse mortality, whereas patients who experience SGF have excellent long-term outcomes.

Oral decitabine-cedazuridine versus intravenous decitabine for myelodysplastic syndromes and chronic myelomonocytic leukaemia (ASCERTAIN): a registrational, randomised, crossover, pharmacokinetics, phase 3 study.

BACKGROUND: The DNA methyltransferase inhibitors azacitidine and decitabine for individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia are available in parenteral form. Oral therapy with similar exposure for these diseases would offer potential treatment benefits. We aimed to compare the safety and pharmacokinetics of oral decitabine plus the cytidine deaminase inhibitor cedazuridine versus intravenous decitabine. METHODS: We did a registrational, multicentre, open-label, crossover, phase 3 trial of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia and individuals with acute myeloid leukaemia, enrolled as separate cohorts; results for only participants with myelodysplastic syndromes or chronic myelomonocytic leukaemia are reported here. In 37 academic and community-based clinics in Canada and the USA, we enrolled individuals aged 18 years or older who were candidates to receive intravenous decitabine, with Eastern Cooperative Oncology Group performance status 0 or 1 and a life expectancy of at least 3 months. Participants were randomly assigned (1:1) to receive 5 days of oral decitabine-cedazuridine (one tablet once daily containing 35 mg decitabine and 100 mg cedazuridine as a fixed-dose combination) or intravenous decitabine (20 mg/m2 per day by continuous 1-h intravenous infusion) in a 28-day treatment cycle, followed by 5 days of the other formulation in the next treatment cycle. Thereafter, all participants received oral decitabine-cedazuridine from the third cycle on until treatment discontinuation. The primary endpoint was total decitabine exposure over 5 days with oral decitabine-cedazuridine versus intravenous decitabine for cycles 1 and 2, measured as area under the curve in participants who received the full treatment dose in cycles 1 and 2 and had decitabine daily AUC0-24 for both oral decitabine-cedazuridine and intravenous decitabine (ie, paired cycles). On completion of the study, all patients were rolled over to a maintenance study. This study is registered with ClinicalTrials.gov, NCT03306264. FINDINGS: Between Feb 8, 2018, and June 7, 2021, 173 individuals were screened, 138 (80%) participants were randomly assigned to a treatment sequence, and 133 (96%) participants (87 [65%] men and 46 [35%] women; 121 [91%] White, four [3%] Black or African-American, three [2%] Asian, and five [4%] not reported) received treatment. Median follow-up was 966 days (IQR 917-1050). Primary endpoint of total exposure of oral decitabine-cedazuridine versus intravenous decitabine was 98·93% (90% CI 92·66-105·60), indicating equivalent pharmacokinetic exposure on the basis of area under the curve. The safety profiles of oral decitabine-cedazuridine and intravenous decitabine were similar. The most frequent adverse events of grade 3 or worse were thrombocytopenia (81 [61%] of 133 participants), neutropenia (76 [57%] participants), and anaemia (67 [50%] participants). The incidence of serious adverse events in cycles 1-2 was 31% (40 of 130 participants) with oral decitabine-cedazuridine and 18% (24 of 132 participants) with intravenous decitabine. There were five treatment-related deaths; two deemed related to oral therapy (sepsis and pneumonia) and three to intravenous treatment (septic shock [n=2] and pneumonia [n=1]). INTERPRETATION: Oral decitabine-cedazuridine was pharmacologically and pharmacodynamically equivalent to intravenous decitabine. The results support use of oral decitabine-cedazuridine as a safe and effective alternative to intravenous decitabine for treatment of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia. FUNDING: Astex Pharmaceuticals.

How Great Is the Threat of Clonal Hematopoiesis? Let This New Risk Score Be Your Guide.

The recent expanding compendium of sequencing analysis has offered insight into the pathobiology of myeloid neoplasms. This molecular evidence of clonal hematopoiesis provides information to allow earlier identification of predisposition states to myeloid neoplasms, such as clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of unknown significance (CCUS). The ability to risk-stratify cases of clonal hematopoiesis that may evolve to frank myeloid neoplasms is essential to manage expectations for patients and providers alike.