Background
An increased incidence of subsequent solid cancers (SSCs) has been reported in long‐term survivors of allogeneic hematopoietic stem cell transplantation (allo‐HSCT), and SSC is associated ...with inferior mortality and morbidity. Previous studies showed that the incidence of SSC is significantly higher in those who underwent allo‐HSCT from HLA‐mismatched donors, suggesting that persistent alloimmunity may predispose patients to SSCs. It was recently reported that, in a cohort of patients who received allo‐HSCT from an unrelated donor matched at HLA‐A, ‐B, ‐C, ‐DRB1/3/4/5, and ‐DQB1 loci, HLA‐DPB1 alloimmunity determined by high mismatched eplets (MEs) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) score (PS), was associated with relapse protection and increased risk of acute graft‐versus‐host disease (GVHD).
Methods
In the present study, the impact of HLA‐DPB1 alloimmunity assessed by molecular mismatch algorithms on the development of SSCs in a cohort of 1514 patients who underwent allo‐HSCT for hematologic malignancies was further investigated. ME load at the HLA‐DPB1 locus was measured using the HLAMatchmaker module incorporated in HLA Fusion software, and the PS for mismatched HLA‐DPB1 was calculated using the HSCT module from the PIRCHE online matching service.
Results
In multivariable analysis after adjusting for baseline risk factors, higher ME, PS‐I, and PS‐II in the GVH direction, but not in the HVG direction, were associated with an increased risk of SSCs (ME: subdistribution hazard ratio SHR 1.58, p = .01; PS‐I: SHR 1.59, p = .009; PS‐II: SHR 1.71, p = .003). In contrast, nonpermissive HLA‐DPB1 mismatches defined by the conventional T‐cell epitope algorithm were not predictive of the risk of SSCs. Moreover, posttransplant cyclophosphamide‐based GVHD prophylaxis was associated with a reduced risk of subsequent solid cancer (SHR 0.34, p = .021).
Conclusions
These results indicate for the first time that increased GVH alloreactivity could contribute to the development of SSCs in allo‐HSCT survivors.
HLA‐DPB1 graft‐versus‐host (GVH) alloreactivity assessed by molecular mismatch methods is significantly associated with the higher risk of subsequent solid cancer in survivors of allogeneic hematopoietic stem cell transplantation (allo‐HSCT). Posttransplant cyclophosphamide–based GVH disease prophylaxis that downregulates the GVH alloresponse is associated with a lower risk of SSC after allo‐HSCT.
There have been conflicting results regarding the impact of minimal/measurable disease at transplant on acute myeloid leukemia (AML) outcomes after haploidentical transplantation (haplo‐SCT). We ...assessed the impact of pre‐transplant disease status on post‐transplant outcomes of 143 patients treated with haplo‐SCT using fludarabine‐melphalan (FM) conditioning and post‐transplant cyclophosphamide (PTCy). With a median follow‐up of 29 months, the two‐year PFS for all patients was 41%. Compared to patients in complete remission (CR) at transplant, those with active disease (n = 29) and CR with incomplete count recovery (CRi) (n = 39) had worse PFS. They had hazard ratios (HR) of 3.5 (95% CI: 2.05‐6.1; P < .001) and 2.3 (95% CI: 1.3‐3.9; P = .002), respectively. Among patients who were in CR at transplant, there were no differences in PFS between those who had minimal residual disease (MRD) positive (n = 24), and MRD negative (n = 41) (HR 1.85, 95%CI: 0.9‐4.0; P = .1). In multivariable analysis for patients in CR, only age was predictive for outcomes, while MRD status at transplant did not influence the treatment outcomes. Our findings suggest that haplo‐SCT with FM conditioning regimen and PTCy‐based GVHD prophylaxis has a protective effect, and may potentially abrogate the inferior outcomes of MRD positivity for patients with AML. Patients with positive MRD may benefit from proceeding urgently to a haplo‐SCT, as this does not appear to negatively impact transplant outcomes.
Increased thromboembolic events occur in women with mechanical prosthetic valves during pregnancy, and selecting an effective and safe anticoagulant is still a challenge. Low molecular weight heparin ...(LMWH) is a promising alternative, but a recent warning and label change about its use in patients with mechanical prosthetic valves has caused confusion among physicians. The aim of the present study was to review the risks of maternal and fetal complications with mechanical heart valves treated with LMWH during pregnancy. We performed a review of the current medical literature through MEDLINE and EMBASE (1989 to 2004). Additional data sources included abstract proceedings, and reference lists of selected articles. Among 81 pregnancies in 75 women, the proportion of valve thrombosis was 8.64% (7/81; 95% CI, 2.52%-14.76%). The frequency of overall thromboembolic complication (TEC) was 12.35% (10/81; 95% CI, 5.19%-19.51%). Nine of ten patients with TEC received a fixed dose of LMWH and two of these received a fixed low dose of LMWH. Among 51 pregnancies whose anti-factor Xa levels were monitored, only one patient was reported to have a thromboembolic complication. The frequency of live births with LMWH was 87.65% (95%CI, 80.49%-94.81%). In pregnant women with mechanical heart valves, LMWH appears to be a suitable option to a vitamin K antagonist. The use of LMWH warrants monitoring and appropriate dose adjustments to maintain a 4-6 hr post-injection anti-factor Xa level at a minimum of 1.0 U/ml to decrease the incidence of TEC.
Treated secondary acute myeloid leukemia (ts-AML)-i.e., AML arising from a previously treated antecedent hematologic disorder-is associated with very poor outcomes. The optimal frontline treatment ...regimen for these patients is uncertain.
We retrospectively analyzed 562 patients who developed AML from preceding myelodysplastic syndrome or chronic myelomonocytic leukemia for which they had received a hypomethylating agent (HMA). Patients with ts-AML were stratified by frontline AML treatment with intensive chemotherapy (IC, n = 271), low-intensity therapy (LIT) without venetoclax (n = 237), or HMA plus venetoclax (n = 54).
Compared with IC or LIT without venetoclax, HMA plus venetoclax resulted in higher CR/CRi rates (39% and 25%, respectively; P = 0.02) and superior OS (1-year OS 34% and 17%, respectively; P = 0.05). The benefit of HMA plus venetoclax was restricted to patients with non-adverse risk karyotype, where HMA plus venetoclax resulted in a median OS of 13.7 months and 1-year OS rate of 54%; in contrast, for patients with adverse risk karyotype, OS was similarly dismal regardless of treatment approach (median OS 3-5 months). A propensity score analysis accounting for relevant clinical variables confirmed the significant OS benefit of HMA plus venetoclax, as compared with other frontline treatment approaches. In a landmark analysis, patients with ts-AML who underwent subsequent hematopoietic stem cell transplantation (HSCT) had superior 3-year OS compared to non-transplanted patients (33% vs. 8%, respectively; P = 0.003).
The outcomes of ts-AML are poor but may be improved with use of an HMA plus venetoclax-based regimen, followed by HSCT, particularly in those with a non-adverse risk karyotype.
Summary
Major ABO mismatching is not considered a contraindication to allogeneic haematopoietic stem cell transplantation (HSCT). Modern reduced‐intensity conditioning and reduced‐toxicity regimens ...cause much less myeloablation than conventional myeloablative regimens, such as cyclophosphamide with busulfan or total body irradiation, which may affect the incidence of pure red cell aplasia (PRCA). We estimated the incidence and described the natural history of PRCA in patients with major ABO‐mismatched donor stem cells. Between 2007 and 2008, 161 (27% of all patients undergoing HSCT) underwent allogeneic HSCT with major ABO‐mismatched stem cells and 12 (7·5%) of these patients developed PRCA. Thirty and ninety day T‐cell and myeloid cell chimerism and neutrophil and platelet engraftment did not differ between patients who developed PRCA and those who did not. The only risk factor associated with PRCA was the use of a fludarabine/busulfan conditioning regimen. All patients with PRCA needed red cell transfusion for several months after HSCT resulting in significant iron overload. Pure red cell aplasia resolved spontaneously in the majority (seven patients) but only resolved after stopping tacrolimus in three patients. Hence, after major ABO‐mismatched HSCT, the incidence of PRCA was 7·5% and it resolved spontaneously or after withdrawal of immunosuppression in the majority of patients.
PDF
