Post-Transplantation Cyclophosphamide for Graft-Versus-Host Disease Prophylaxis in Allogeneic Hematopoietic Cell Transplantation for Higher-Risk Myelodysplastic Syndrome

Introduction: Allogeneic hematopoietic cell transplantation is an only potentially curative option for patients with higher-risk myelodysplastic syndrome (MDS). Owing to the advances in treatment strategies including reduced intensity conditioning, graft-versus-host disease (GVHD) prevention and supportive care, more elderly patients or those with comorbidities can proceed to allogeneic HCT. However, the long-term survival rate following allogeneic HCT is reported to be less than 50%, and non-relapse mortality (NRM) rate is still high reaching upto 30%. In this study, we aimed to evaluate the feasibility of using post-transplantation cyclophosphamide (PTCy) as a GVHD prophylaxis in allogeneic HCT for higher-risk MDS patients. We also compared the post-transplantation outcomes of PTCy group and those of historical control who received HCT using anti-thymocyte globulin (ATG). Methods: Patients with higher-risk MDS or MDS/myeloproliferative neoplasm (MPN) with bone marrow blast ≥ 5% were included in this study. Higher-risk MDS was defined by MDS with International Prognostic Scoring System >1.0 or bone marrow blast ≥ 5% at any time points before HCT. Conditioning regimen consists of busulfan (4-days for patients aged <55 years, 2-days for 55 years), fludarabine. For GVHD prophylaxis, PTCy (50 mg/kg on days 3 and 4), cyclosporine, and mycophenolate mofetil were administered. In historical group, patients received 2- or 4-days of busulfan, fludarabine, and ATG with short course of methotrexate and cyclosporine. Results: Ninety-two and 144 patients received allogeneic HCT using PTCy and ATG, respectively. The median overall survival were 47.9 and 44.0 months, respectively (P=.383). Cumulative incidence of total and grade II-IV acute GVHD in PTCy and ATG group were 19.6% vs. 37.5% (P=.002), and 2.6% vs. 21.7% (P<.001), respectively. Incidence of total and extensive chronic GVHD (50.0% vs. 49.1%, P=.567; 32.5% vs. 33.4%, P=.581), 1-year NRM (20.8% vs. 22.9%, P=.702), and 2-year relapse (16.0% vs. 18.1%, P=.605) were not different between two groups. Neutrophil and platelet engraftment was significantly faster with ATG than PTCy (median 12 vs. 15 for neutrophil; median 15 vs. 24 days for platelet). Conclusion: Allogeneic HCT using PTCy as GVHD prophylaxis in higher-risk MDS seems feasible in terms of low rate of acute GVHD and relapse incidence. Disclosures Choi: Ingenium Therapeutics, Daejeon, Korea: Consultancy, Current holder of individual stocks in a privately-held company. Lee: Ingenium Therapeutics, Daejeon, Korea: Consultancy, Current holder of individual stocks in a privately-held company. Lee: Korean Society of Hematology: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board; AbbVie: Honoraria, Other: Advisory board.

Blast Cells Count Influences Bleeding Incidence in Acute Leukemia: Preliminary Study in South Kalimantan, Indonesia

Background: Acute leukemia is a malignant disease involving hematopoietic tissue, characterized by abnormal blood cells in bone marrow or called blast cells. The most common complications of acute leukemia is bleeding. A high percentage of blasts has been reported to increase the risk of bleeding in acute leukemia. Preliminary study was needed to investigate relationship between blast cells count and bleeding incidence in acute leukemia. Methods: Crosssectional study with observasional analytic in 18 adult subjects was conducted from November 2019 to March 2020 in Ulin Hospital Banjarmasin South Kalimantan. The data were taken from medical records of acute leukemia patients who met inclusion and exclusion criterias. Data analysis was using Fisher’s exact test. Results: There were 7 men and 11 women in this study. Blast cells count in peripheral with cut off <50% was 9 (50%) and ≥50% was 9 (50%). It was same for blast cells count in bone marrow. Both of women and men mostly have bleeding in acute leukemia, and bleeding incidence in women is higher than men. Bleeding condition was happened both in peripheral and bone marrow blast cells count with cut of <50% and ≥50%. Significancy of relationship between blast cells count and bleeding incidence was 0.637. Conclusion: There is no significant between blast cells count and the bleeding incidence in acute leukemia. Another parameters that could be influenced bleeding inceidence need to be investigate in acute leukemia.

PRC2 loss of function confers a targetable vulnerability to BET proteins in T-ALL

T-cell acute lymphoblastic leukemia (T-ALL) are aggressive hematological cancers with dismal outcomes, and are in need of new therapeutic options. Polycomb Repressor Complex 2 (PRC2) loss-of-function alterations were reported in pediatric T-ALL; yet their clinical relevance and functional consequences remain elusive. Here, we extensively analyzed PRC2 alterations in a large series of 218 adult T-ALL patients. We found that PRC2 genetic lesions are frequent events in T-ALL and are not restricted to ETP-ALL. PRC2 loss of function associates with activating mutations of the IL7R/JAK/STAT pathway. PRC2-altered T-ALL patients poorly respond to prednisone, have low bone marrow blast clearance, and persistent minimal residual disease. Furthermore, we identified that PRC2 loss of function profoundly reshapes the genetic and epigenetic landscapes, leading to the reactivation of stem cell programs that cooperate with Bromodomain and Extraterminal (BET) proteins to sustain T-ALL. This study identifies BET proteins as key mediators of the PRC2 loss of function-induced remodeling. Our data has uncovered a targetable vulnerability to BET inhibition that can be exploited to treat PRC2-altered T-ALL patients.

Elevated mature monocytes in bone marrow accompanied with a higher IPSS-R score predicts a poor prognosis in myelodysplastic syndromes

Background Myelodysplastic syndromes (MDS) is a group of heterogeneous myeloid clonal diseases originating from hematopoietic stem cells. Clinically, elevated mature monocyte in bone marrow is often observed, but its clinical value still remains unclear. Methods We retrospectively analyzed a cohort of 216 MDS patients to explore the prognostic value of the percentage of mature monocyte in bone marrow (PMMBM). All patients were divided into elevated PMMBM group and the normal group by 6% PMMBM as the cut-off value. Results Our results showed that PMMBM> 6% was associated with inferior overall survival (OS) (P = 0.026) along with higher-risk IPSS-R (P = 0.025) and higher frequency of IDH2 mutation (P = 0.007). Multivariate analyses showed that besides older age (> 60 years) for OS, gender (male) for OS, lower neutrophil count (< 0.8 × 109/L) for OS, higher bone marrow blast percentage (> 5%) for OS and LFS, poorer karyotype for OS, elevated PMMBM was also an independent adverse prognostic factor for OS in MDS (P < 0.0001) but not for LFS (P = 0.736). Conclusions These findings indicate that increased PMMBM may assists Revised International Prognostic Scoring System (IPSS-R) to predict a poor outcome and provide a novel evaluation factor for MDS patients especially when their karyotype analyses fail.

Integration Analysis of JAK2 or RUNX1 Mutation With Bone Marrow Blast Can Improve Risk Stratification in the Patients With Lower Risk Myelodysplastic Syndrome

Despite the improvements in prognostication of the revised International Prognostic Scoring System (IPSS-R) in myelodysplastic syndrome (MDS), there remain a portion of patients with lower risk (low/intermediate risk, LR) but poor prognostics. This study aimed to evaluate the relative contribution of mutational status when added to the IPSS-R, for estimating overall survival (OS) and progression-free survival (PFS) in patients with LR-MDS. We retrospectively analyzed clinical and laboratory variables of 328 patients diagnosed with MDS according to the FAB criteria. Twenty-nine-gene NGS assay was applied to bone marrow samples obtained at diagnosis. 233 (71.04%) patients were classified as LR-MDS. Univariate analysis showed association between inferior outcome (OS and PFS) and presence of JAK2 (p = 0.0177, p = 0.0002), RUNX1 (p = 0.0250, p = 0.0387), and U2AF1 (p = 0.0227, p = 0.7995) mutations. Multivariable survival analysis revealed JAK2 (p &lt; 0.0001) and RUNX1 (p = 0.0215) mutations were independently prognostic for PFS in LR-MDS. Interestingly, bone marrow blast &gt;1.5% could further predict disease progression of patients with LR-MDS (HR 8.06, 95%CI 2.95–22.04, p &lt; 0.0001). Incorporation of JAK2, RUNX1 mutation and bone marrow blast in the IPSS-R can improve risk stratification in patients with LR-MDS. In summary, our result provided new risk factors for LR-MDS prognostics to identify candidates for early therapeutic intervention.

Elevated mature monocytes in bone marrow accompanied with a higher IPSS-R score predicts a poor prognosis in myelodysplastic syndromes

Background: Myelodysplastic syndromes (MDS) is a group of heterogeneousmyeloid clonal diseases originating from hematopoietic stem cells. Clinically, elevated mature monocyte is often observed, but its clinical value still remains unclear.Methods: We retrospectively analyzed a cohort of 235 MDS patients to explore the prognostic value of the percentage of mature monocyte in bone marrow (PMMBM). All patients were divided into elevated PMMBM group and the normal group by 6% PMMBM as the cut-off value. Results: Our results showed that PMMBM>6% was associated with inferior overall survival (OS) (P=0.007) and leukemia-free survival (LFS) (P=0.016) along with higher Revised International Prognostic Scoring System (IPSS-R) score (P<0.0001) and higher frequency of IDH2 mutation (P=0.001). Multivariate analyses showed that besides older age (>60 years), lower hemoglobin level (<10 g/dl), higher bone marrow blast percentage (>5%), poorer karyotype, elevated PMMBM was also an independent adverse prognostic factor for OS in MDS (P=0.049). Conclusions: These findings indicate that increased PMMBM accompanied with a higher IPSS-R score may predict a poor outcome and provide a novel evaluation factor for MDS patients especially when their karyotype analyses fail.

Comparative analysis of chromosomal aberrations in children with acute leukemia

Leukemia is a hematopoetic tissue tumor with a primary lesion of the bone marrow, where the morphological substrate is the blast cell. Chromosomal and molecular genetic aberrations play a major role in the acute leukemia pathogenesis, determing the morphological, immunological and clinical features of the disease. Our study was aimed to to analyze retrospectively the structure and frequency of chromosomal aberrations in children with initially diagnosed acute leukemia. Material and methods. Medical histories retrospective analysis of children charged to oncohematology department of the «Scientific Center of Pediatrics and Pediatric Surgery» in Almaty for the period 2015 - 2017 was carried out. 310 histories with primary diagnosed acute leukemia were studied. Results and discussion. Among 310 patients different chromosome aberrations were isolated in 158 patients (51%) during cytogenetic and molecular cytogenetic (in situ hybridization) studies of bone marrow blast cells. A normal karyotype was observed in 102 patients (33%). Conclusion. The lymphoblastic variant of acute leukemia was determined in 75.5%, that indicates its leading role in AL structure among the children of different ages. AML was determined in 22.6% of all OL cases. The most frequent chromosomal rearrangement in ALL patients was blast cell chromosome hyperdiploidy (10,6%) and t(12;21)(p13;q22)/ETV6-RUNX1,which was detected in 37 (16%) patients. The most frequent AML abberation was t (8;21) (q22;q22)/RUNX1-RUNX1T1, identified in 15 (21.4%) patients. Keywords: acute leukemia, bone marrow, blast cells, karyotype, chromosomal aberrations, cytogenetic study.

Therapy for lower-risk MDS

Lower-risk myelodysplastic syndromes (MDS) are characterized by the presence of dysplasia, low bone marrow blast percentage, low number and depth of cytopenia(s), and relatively good-risk karyotpic and molecular abnormalities. A score of ≤3.5 on the Revised International Prognostic Scoring System classifies patients as lower-risk MDS. Information from a mutational profile of the MDS at time of diagnosis (and over serial time points) can be reassuring for predicted behavior of lower-risk MDS compared with one expected to progress more rapidly (higher-risk MDS). Supportive care continues to be the crux of treatment, although the options to reduce transfusion needs have improved in 2020. Erythropoiesis stimulating agents, lenalidomide, and luspatercept address the most frequent (and symptomatic) cytopenia (anemia) and are started only when patients are transfusion dependent. Patients can derive long-term benefits (years) from these approaches but will often progress to higher-risk MDS. Interestingly, some patients with lower-risk MDS can present with an isolated thrombocytopenia for which thrombopoietin receptor analogs such as romiplostim and eltrombopag are options (as long as blast counts are low). The presence of pancytopenia and or intensifying and unremitting clinical symptoms are often treated with hypomethylating agents or (anti–thymocyte globulin if hypocellular MDS is of concern). Targeted therapies are emerging for small subsets of MDS patients with specific somatic mutations (ie, TP53, IDH1/2, FLT3), although currently, there are no approved, mutation-directed medications to treat MDS.

IMMUNOPHENOTYPIC PROFILE OF T ACUTE LYMPHOBLASTIC LEUKAEMIA IN A TERTIARY CARE CENTRE - OUR EXPERIENCE

Background:Studying the immunophenotypic profile of T-ALL patients in Kashmir and correlation of various demographic factors. Methods: 36 patients of all age groups were registered for this study of which 35 were included in the analyses. Result: 82.86% were males and 17.14% were females. 51.43% had common thymocyte T-ALL, 28.57% had pro T-ALL and 20% had mature thymocyte T-ALL. The average age at presentation was 18.60 years. 51.43% were CD1a positive. CD2 was positive in 70.83%. 88.57% were CD5 positive while 100% were positive for CD7. 42.86% were CD34 positive. The average bone marrow blast percentage was 82.43%. The average peripheral blood TLC was 92.73 x 103 cells/cumm. Conclusion: This is the first study to report immunophenotypic and demographic profile of T-ALL in Kashmir with the aim to increase understanding of the disease and contributing to more suitable treatment options.