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The accurate diagnosis and classification of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) are challenging due to the overlapping pathological and molecular features of myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). We investigated the genomic landscape in different MDS/MPN subtypes, including chronic myelomonocytic leukemia (CMML; n = 97), atypical chronic myeloid leukemia (aCML; n = 8), MDS/MPN-unclassified (MDS/MPN-U; n = 44), and MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T; n = 12). Our study indicated that MDS/MPN is characterized by mutations commonly identified in myeloid neoplasms, with TET2 (52%) being the most frequently mutated gene, followed by ASXL1 (38.7%), SRSF2 (34.7%), and JAK2 (19.7%), among others. However, the distribution of recurrent mutations differs across the MDS/MPN subtypes. We confirmed that specific gene combinations correlate with specific MDS/MPN subtypes (e.g., TET2/SRSF2 in CMML, ASXL1/SETBP1 in aCML, and SF3B1/JAK2 in MDS/MPN-RS-T), with MDS/MPN-U being the most heterogeneous. Furthermore, we found that older age (≥65 years) and mutations in RUNX1 and TP53 were associated with poorer clinical outcomes in CMML (p < 0.05) by multivariate analysis. In MDS/MPN-U, CBL mutations (p < 0.05) were the sole negative prognostic factors identified in our study by multivariate analysis (p < 0.05). Overall, our study provides genetic insights into various MDS/MPN subtypes, which may aid in diagnosis and clinical decision-making for patients with MDS/MPN.

Abstract Introduction In November 2020, the FDA issued an emergency use authorization (EUA) for monoclonal antibody (mAb) therapy in patients with mild‐to‐moderate COVID‐19 at high risk for disease progression. Methods We retrospectively reviewed 38 adult hematology patients who received mAbs from 11/2020 to 2/2021. Results Thirty (79%) patients received bamlanivimab and 8 (21%) casirivimab‐imdevimab. Four (11%) patients were hospitalized due to COVID‐19, two (5%) progressed to severe disease and one patient (3%) died within 30 days from COVID‐19 disease. Most patients (n = 34, 89%) ultimately tested negative for SARS‐CoV‐2, with 34% (n = 13) clearing the virus within 14 days after mAb infusion. The median time to clearance of viral shedding was 25.5 days (range: 7–138). After mAb infusion, most patients with hematological malignancies (HM) (n = 10/15; 67%) resumed therapy for underlying disease with a median delay of 21.5 days (range: 12–42). We observed a significant difference in hospitalization among patients who received a HCT versus non‐HCT (0% n = 0/26 and 36% n = 4/11, respectively; p

Abstract: Busulfan combined with cyclophosphamide (BuCy) has long been considered a standard myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation (HCT), including both nonmalignant conditions and myeloid diseases. Substituting fludarabine for cyclophosphamide (BuFlu) to reduce toxicity without an increase in relapse has been increasingly performed in children, but without comparison with BuCy. We retrospectively analyzed 1781 children transplanted from 2008 to 2014 to compare the effectiveness of BuCy with BuFlu. Nonmalignant and malignant disease populations were analyzed separately. Overall mortality was comparable for children with nonmalignant conditions who received BuFlu or BuCy (relative risk [RR], 1.14, P = .52). Lower incidences of sinusoidal obstruction syndrome (P = .04), hemorrhagic cystitis (P = .04), and chronic graft-versus-host disease (P = .02) were observed after BuFlu, but the influence of the conditioning regimen could not be assessed by multivariate analysis because of the low frequency of these complications. Children transplanted for malignancies were more likely to receive BuFlu if they had higher hematopoietic cell transplantation-comorbidity index scores (P < .001) or their donor was unrelated and HLA-mismatched (P = .004). Nevertheless, there were no differences in transplant toxicities and comparable transplant-related mortality (RR, 1.2; P = .46), relapse (RR, 1.2; P = .15), and treatment failure (RR, 1.2; P = .12). BuFlu was associated with higher overall mortality (RR, 1.4; P = .008) related to inferior postrelapse survival (P = .001). Our findings demonstrated that outcomes after BuFlu are similar to those for BuCy for children, but for unclear reasons, those receiving BuFlu for malignancy may be at risk for shorter postrelapse survival.

Umbilical cord blood stem cell transplants are commonly used in adults lacking HLA-identical donors. Delays in hematopoietic recovery contribute to mortality and morbidity. To hasten recovery, we used co-infusion of progenitor cells from a partially matched related donor and from an umbilical cord blood graft (haplo-cord transplant). Here we compared the outcomes of haplo-cord and double-cord transplants. A total of 97 adults underwent reduced intensity conditioning followed by haplo-cord transplant and 193 patients received reduced intensity conditioning followed by double umbilical cord blood transplantation. Patients in the haplo-cord group were more often from minority groups and had more advanced malignancy. Haplo-cord recipients received fludarabine-melphalan-anti-thymocyte globulin. Double umbilical cord blood recipients received fludarabine-cyclophosphamide and low-dose total body irradiation. In a multivariate analysis, haplo-cord had faster neutrophil (HR=1.42, P=0.007) and platelet (HR=2.54, P

Summary  A phase I study was performed to determine the safety and pharmacokinetics of XK469R in patients with refractory acute leukemia. The study aimed to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of XK469R given intravenously over 30 to 60 min on days 1, 3, and 5 of a 21 day cycle. Patients were treated in successive cohorts of six until DLT was observed. Once the MTD was determined, an additional cohort of six patients was enrolled at the previous dose level and that dose was considered the recommended phase 2 dose (RPTD). Forty-six patients were treated at dose levels of 1,400, 1,750, 2,200, and 2,750 mg. The DLTs were: mucositis, colitis and hyperbilirubinemia. Reversible myelosuppression was noted at all dose levels. One (2%) of 42 patients achieved a complete remission and five patients (11%) had hematologic improvement. The half-life of the drug was long with a mean value of 48 h. The mean clearance was 206 mL/h with a coefficient of variation of 32%. No correlation was observed between the development of DLT and pharmacokinetics. The RTPD is 1,750 mg. XK469R induced hematological responses in patients with refractory leukemia at tolerable doses. [ABSTRACT FROM AUTHOR]

We conducted a retrospective analysis of WT1-mutated acute myeloid leukemia (AML) patients who underwent allogeneic stem cell transplant. Thirty-seven patients with WT1-mutated AML were identified. Primary induction failure (40%) and early relapse rate (18%) after idarubicin/cytarabine (7 + 3) chemotherapy were observed. All patients with induction failure subsequently achieved CR with additional chemotherapy. There was no significant difference between outcomes after myeloablative vs. reduced intensity (Fludarabine/Melphalan [Flu/Mel]) conditioning regimens. RFS but not OS was significantly better in patients who received FLAG-IDA prior to transplant and/or a fludarabine-containing conditioning. In an independent ex vivo study, WT1-mutated AML samples exhibited greater sensitivity to fludarabine (p = 0.026) and melphalan (p = 0.0005) than non-WT1-mutated AML samples while there was no difference between sensitivity to cytarabine. Our data favor using a fludarabine-based induction for AML with WT1 mutation instead of 7 + 3. Fludarabine conditioning regimens for alloHCT showed better RFS but not OS. [ABSTRACT FROM AUTHOR]

Introduction: In November 2020, the FDA issued an emergency use authorization (EUA) for monoclonal antibody (mAb) therapy in patients with mild-to-moderate COVID-19 at high risk for disease progression. Methods: We retrospectively reviewed 38 adult hematology patients who received mAbs from 11/2020 to 2/2021. Results: Thirty (79%) patients received bamlanivimab and 8 (21%) casirivimab-imdevimab. Four (11%) patients were hospitalized due to COVID-19, two (5%) progressed to severe disease and one patient (3%) died within 30 days from COVID-19 disease. Most patients (n = 34, 89%) ultimately tested negative for SARS-CoV-2, with 34% (n = 13) clearing the virus within 14 days after mAb infusion. The median time to clearance of viral shedding was 25.5 days (range: 7-138). After mAb infusion, most patients with hematological malignancies (HM) (n = 10/15; 67%) resumed therapy for underlying disease with a median delay of 21.5 days (range: 12-42). We observed a significant difference in hospitalization among patients who received a HCT versus non-HCT (0% n = 0/26 and 36% n = 4/11, respectively; p < 0.01). Conclusions: This study demonstrates that SARS-CoV-2 specific mAb was safe and may reduce hospitalization compared to what is reported in malignant hematology patients at high risk for disease progression. Our HCT cohort patients had less hospitalization rate compared with HM cohort patients. [ABSTRACT FROM AUTHOR]

Rearrangements of I lysine [K] methyltransferase 2 A i ( I KMT2A i ) gene, previously known as the I MLL i gene, occur in 3 to 7% of adult patients with de novo AML and are enriched in therapy-related disease, particularly after treatment with topoisomerase II inhibitors [[1]]. Response and survival of patients with KMT2A rearranged acute myeloid leukemia (AML) receiving venetoclax in combination with hypomethylating agent therapy (HMA). The inferior prognosis of KMT2A rearranged AML patients undergoing alloSCT presents an opportunity for post-transplant maintenance trials with therapies targeting KMT2A. [Extracted from the article]

Patients with acute leukemia who undergo allogenic hematopoietic cell transplantation with active disease have high rates of relapse and poor overall survival (OS) post-transplant compared to patients undergoing HCT in remission. Here, we report the long-term outcomes in 32 patients who received a high-intensity conditioning regimen comprising fractionated total body irradiation (FTBI; 1200 cGy) with pharmacokinetic (PK) dosing of intravenous Busulfan (IV BU) targeted to first dose area under curve (AUC) of 700–900 µM/min and etoposide (30 mg/kg) in a prospective phase 2 clinical trial. The median age of the patients at the time of HCT was 37 years (range: 18–50) presenting with high-risk (n = 6) and relapsed/refractory(r/r) acute leukemias (n = 26). All but one patient underwent HCT using peripheral blood stem cells from matched sibling donors. At a median follow-up of 17.3 years (range 14.4–19.0), 11 patients remained alive. The disease-free survival and OS at 15 years was 34% (versus 40% at 5-years post-HCT). The 15-year cumulative incidence of relapse was 26% and non-relapse mortality (NRM) was 38% (95% CI: 21–54%) and the cumulative incidence of chronic GVHD at 15 years was 33% using a prophylactic regimen of cyclosporine A and mycophenolate mofetil. The most common life-threatening late effects were secondary malignancies, metabolic, or cardiac complications with a cumulative incidence of 6.6%, 6.6%, and 13.3%, respectively. No unusual late effects or patterns of relapse were noted on longer followed on patients treated with intensified myeloablative condition regimen. Results from this study supports continued development of intensive conditioning regimens in patients with r/r acute leukemias to improve leukemia free (LFS) and OS in this high-risk population. [ABSTRACT FROM AUTHOR]

The 1-year OS for HCT patients (21 patients) was 85% (95% CI 61-95%) compared to 41% (95% CI 16-65%) in non-HCT patients in cCR (14 patients). The 1-year LFS in patients who underwent HCT (21 patients) was 67% (95% CI 41-84%) I versus i 33% (95% CI 10-57%) in non-HCT patients in cCR (14 patients). [Extracted from the article]

Background: Blinatumomab has demonstrated encouraging activity in relapsed/refractory (r/r) and minimal residual disease–positive (MRD+) acute lymphoblastic leukemia (ALL). Extramedullary disease (EMD) relapse or relapse with CD19– disease has been observed after blinatumomab therapy in patients with r/r or MRD+ ALL. However, the pathophysiology and risk factors of treatment failure are not fully understood. Methods: This study retrospectively reviewed the outcomes of adult patients with B‐cell ALL treated with blinatumomab (n = 132) for either r/r (n = 103) or MRD+ disease (n = 29) at the authors' center (2013‐2021) and analyzed factors associated with treatment response and EMD failure. Results: The overall response rate was 64%. A lower marrow blast burden before blinatumomab (P =.049) and no history of previous EMD (P =.019) were significantly associated with a higher response. Among the patients who responded to blinatumomab, 56% underwent consolidation with allogeneic transplantation. Blinatumomab failure was observed in 89 patients; 43% of these patients (n = 38) either progressed or relapsed at extramedullary sites. A history of extramedullary involvement (53% vs 24%; P =.005) and retention of CD19 expression at the time of relapse/progression (97% vs 74%; P =.012) were associated with a higher risk for extramedullary failure. Central nervous system (CNS) failure after blinatumomab was encountered in 39% of the patients with EMD. Conclusions: A history of EMD predicted an inferior response to blinatumomab therapy with a higher risk for relapse/progression at extramedullary sites (particularly CNS). Consolidation with allogenic transplantation in patients who primarily responded to blinatumomab did not abrogate the risk of extramedullary relapse. The incorporation of extramedullary assessment and the intensification of CNS prophylaxis may help in addressing extramedullary failure. Lay Summary: Extramedullary failure is common during blinatumomab therapy for relapsed/refractory acute lymphoblastic leukemia.A history of extramedullary disease predicts an inferior response to blinatumomab therapy and a higher risk for relapse/progression at extramedullary sites.Most extramedullary failure cases retain CD19 expression. Extramedullary failure is common during blinatumomab therapy for relapsed/refractory acute lymphoblastic leukemia. A history of extramedullary disease predicts an inferior response to blinatumomab therapy and a higher risk for relapse/progression at extramedullary sites. [ABSTRACT FROM AUTHOR]

I Cancer i 's reputation is determined by the quality of the manuscripts submitted and the expertise, dedication, and promptness of the individuals who critically review the manuscripts. We here at I Cancer i are therefore pleased to continue our Outstanding Reviewer Recognition Program. [Extracted from the article]