Reduced post-transplant cyclophosphamide doses in haploidentical hematopoietic cell transplantation for elderly patients with hematological malignancies.

Although post-transplant cyclophosphamide (PT-Cy) is effective for graft-versus-host disease (GVHD) prophylaxis, it is associated with toxicities, which might be dose-dependent. We compared the outcomes with PT-Cy at 80 mg/kg to those with PT-Cy at 100 mg/kg in elderly patients undergoing haploidentical hematopoietic cell transplantation (HCT). Inclusion criteria included peripheral blood stem cells, hematological malignancy, and age>65 years (or age>60 years if cardiac event history). Thirty-eight patients received PT-Cy at 80 mg/kg and 55 100 mg/kg, divided in two doses. The cumulative incidences (CI) of acute grade II-IV, acute grade III-IV, and moderate/severe chronic GVHD were 32%, 16%, and 13% with PT-Cy at 80 mg/kg compared to 33%, 13%, and 16% with 100 mg/kg, respectively. In multivariable analysis, reducing PT-Cy dose had no significant impact on GVHD. Neutrophil and platelet engraftments were significantly improved, and CI of BK virus-associated hemorrhagic cystitis was reduced with 80 mg/kg of PT-Cy compared to 100 mg/kg. At 2 years, non-relapse mortality was 16% and 31%, progression-free survival 65% and 49%, overall survival 70% and 56%, and GVHD-free, relapse-free survival 52% and 36% with 80 mg/kg and 100 mg/kg, respectively. Reducing PT-Cy dose to 80 mg/kg is safe and associated with improved hematological recovery and lower CI of hemorrhagic cystitis in elderly patients undergoing haploidentical HCT.

Stable pulmonary function after haploidentical stem cell transplantation with post-transplant cyclophosphamide: a single center experience.

Prior studies have reported pulmonary function tests (PFT) before and after related and unrelated allogeneic hematopoietic stem cell transplantation (HSCT). However, limited data exist on the evaluation of lung function after haploidentical stem cell transplantation (HAPLO) with post-transplant cyclophosphamide (PTCY). We retrospectively reported the evaluation of PFTs at screening before HAPLO in 80 patients at 100 days and 1 year of follow-up. The proportion of surviving patients with available PFTs at 100 days and 1 year were 86% and 68%, respectively. During the follow-up period, four patients met the criteria for bronchiolitis obliterans syndrome and two for interstitial lung disease. Overall survival was 73% (95% CI 62-82%) at 2 years. We observed a significant reduction in diffusing capacity of the lungs for carbon monoxide (DLCO) corrected for the most recent hemoglobin concentration (DLCOc) at 100 days after HAPLO. However, an overall substantial stable pulmonary function was observed at 1 year.

Thiotepa-busulfan-fludarabine as a conditioning regimen for patients with myelofibrosis undergoing allogeneic hematopoietic transplantation: a single center experience.

We assessed the outcomes associated with thiotepa, busulfan and fludarabine (TBF) conditioning regimen in a cohort of 29 consecutive patients allografted for myelofibrosis (MF). The median age was 56 (range 42-70) years. According to the refined Dynamic International Prognostic Scoring System (DIPSS-plus), 15 (52%) patients were classified as high risk. Graft source was peripheral blood stem cells in 27 patients. Donor type was HLA-matched related (n = 5), matched unrelated (n = 16), mismatched unrelated (n = 1), and haploidentical (n = 7). All but 2 patients engrafted. The cumulative incidence (CI) of grade II-IV acute graft-versus-host disease (GVHD) was 21% (95% CI, 10-42) at day 100. The CI of chronic GVHD was 39% (95% CI, 23-65) at 3 years. The median follow-up period was 39 (range 14-60) months. Overall survival was 69% (95% CI, 50-83) at 3 years. No relapse was observed. TBF is a valid conditioning strategy in patients with MF.

Clinical, histopathological and molecular characterization of hypoplastic myelodysplastic syndrome.

Diagnostic criteria for hypoplastic myelodysplasic syndrome (h-MDS) have not been clearly established, making the differential diagnosis from other bone marrow failure syndromes (BMF) challenging. In this study, we aimed to delineate clinical, histopathological, and molecular features of h-MDS, based on a large and well-annotated cohort of patients with bone marrow (BM) hypocellularity. The study included 534 consecutive adult patients with hypocellular BM (278 h-MDS and 136 aplastic anemia), and 727 with normo- or hypercellular MDS (n-MDS). Comparison of clinical features of patients with h-MDS as defined by BM cellularity ≤25% (n = 204) or reduced age-adjusted cellularity (n = 74) did not reveal significant differences. We developed a diagnostic score to discriminate h-MDS from non-malignant BMF based on histological and cytological variables with the highest specificity for MDS (h-score). The information from chromosomal abnormalities and somatic mutation patterns was then integrated into a cyto-histological/genetic score (hg-score). This score was able to segregate two groups of h-MDS with a significantly different risk of blast progression (P < 0.001). The integration of cyto-histological and genetic features in adult patients with hypocellular BM facilitated segregation into two distinct groups, one with clinical and genetic features highly consistent with myeloid neoplasm, and one with features more consistent with non-malignant BMF.

Clinical significance of somatic mutation in unexplained blood cytopenia.

Unexplained blood cytopenias, in particular anemia, are often found in older persons. The relationship between these cytopenias and myeloid neoplasms like myelodysplastic syndromes is currently poorly defined. We studied a prospective cohort of patients with unexplained cytopenia with the aim to estimate the predictive value of somatic mutations for identifying subjects with, or at risk of, developing a myeloid neoplasm. The study included a learning cohort of 683 consecutive patients investigated for unexplained cytopenia, and a validation cohort of 190 patients referred for suspected myeloid neoplasm. Using granulocyte DNA, we looked for somatic mutations in 40 genes that are recurrently mutated in myeloid malignancies. Overall, 435/683 patients carried a somatic mutation in at least 1 of these genes. Carrying a somatic mutation with a variant allele frequency ≥0.10, or carrying 2 or more mutations, had a positive predictive value for diagnosis of myeloid neoplasm equal to 0.86 and 0.88, respectively. Spliceosome gene mutations and comutation patterns involving TET2, DNMT3A, or ASXL1 had positive predictive values for myeloid neoplasm ranging from 0.86 to 1.0. Within subjects with inconclusive diagnostic findings, carrying 1 or more somatic mutations was associated with a high probability of developing a myeloid neoplasm during follow-up (hazard ratio = 13.9, P < .001). The predictive values of mutation analysis were confirmed in the independent validation cohort. The findings of this study indicate that mutation analysis on peripheral blood granulocytes may significantly improve the current diagnostic approach to unexplained cytopenia and more generally the diagnostic accuracy of myeloid neoplasms.