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The number of HLA-haploidentical hematopoietic cell transplants continues to increase worldwide due to recent improvements in outcomes, allowing more patients with hematological malignancies and non-malignant disorders to benefit from this procedure and have a chance to cure their disease. Despite these encouraging results, questions remain as multiple donors are usually available for transplantation, and choosing the best HLA-haploidentical donor for transplantation remains a challenge. Several approaches to haploidentical transplantation have been developed over time and, based on the graft received, can be grouped as follows: T-cell depleted haploidentical transplants, either complete or partial, or with T-cell replete grafts, performed with post-transplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis, or G-CSF-primed bone marrow graft and enhanced GVHD prophylaxis. Carefully selecting the donor can help optimize transplant outcomes for recipients of haploidentical donor transplants. Variables usually considered in the donor selection include presence of donor-specific antibodies in the recipient, donor age, donor/recipient gender and ABO combinations, and immunogenic variables, such as natural killer cell alloreactivity or KIR haplotype. Here we provide a comprehensive review of available evidence for selecting haploidentical donors for transplantation, and summarize the recommendations from the European Society for Blood and Marrow Transplantation (EBMT) on donor selection for different transplant platforms.

Hematologic cancers that recur after allogeneic hematopoietic stem-cell transplantation are often difficult to treat. A small pilot study suggests that ipilimumab may induce durable responses in a subgroup of patients with these cancers. Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only cure for many patients who have advanced hematologic cancers, principally through the induction of a graft-versus-tumor effect. 1 Unfortunately, more than one third of patients who have undergone transplantation have a relapse of disease. 2 The prognosis for these patients is poor; the majority die within 1 year after relapse despite salvage chemotherapy, donor-lymphocyte infusion, or retransplantation. 3 – 5 Immune escape (i.e., tumor evasion of the donor immune system) contributes to relapse after allogeneic HSCT, and immune checkpoint inhibitory pathways probably play an important role. 6 The engagement of cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and programmed . . .

Haploidentical donors are now increasingly considered for transplantation in the absence of HLA-matched donors or when an urgent transplant is needed. Donor-specific anti-HLA antibodies (DSA) have been recently recognized as an important barrier against successful engraftment of donor cells, which can affect transplant survival. DSA appear more prevalent in this type of transplant due to higher likelihood of alloimmunization of multiparous females against offspring’s HLA antigens, and the degree of mismatch. Here we summarize the evidence for the role of DSA in the development of primary graft failure in haploidentical transplantation and provide consensus recommendations from the European Society for Blood and Marrow Transplant Group on testing, monitoring, and treatment of patients with DSA receiving haploidentical hematopoietic progenitor cell transplantation.

We report the results from a multicenter retrospective study of 69 adult patients who underwent haploidentical blood or marrow transplantation (haplo-BMT) with post-transplantation cyclophosphamide (PTCy) for chronic phase myelofibrosis. The median age at BMT was 63 years (range, 41–74). Conditioning regimens were reduced intensity in 54% and nonmyeloablative in 39%. Peripheral blood grafts were used in 86%. The median follow-up was 23.1 months (range, 1.6–75.7). At 3 years, the overall survival, relapse-free survival (RFS), and graft-versus-host-disease (GVHD)-free-RFS were 72% (95% CI 59–81), 44% (95% CI 29–59), and 30% (95% CI 17–43). Cumulative incidences of non-relapse mortality and relapse were 23% (95% CI 14–34) and 31% (95% CI 17–47) at 3 years. Spleen size ≥22 cm or prior splenectomy (HR 6.37, 95% CI 2.02–20.1, P = 0.002), and bone marrow grafts (HR 4.92, 95% CI 1.68–14.4, P = 0.004) were associated with increased incidence of relapse. Cumulative incidence of acute GVHD grade 3–4 was 10% at 3 months and extensive chronic GVHD was 8%. Neutrophil engraftment was reported in 94% patients, at a median of 20 days (range, 14–70). In conclusion, haplo-BMT with PTCy is feasible in patients with myelofibrosis. Splenomegaly ≥22 cm and bone marrow grafts were associated with a higher incidence of relapse in this study.

Fever is a common early complication after infusion of stem cells in patients undergoing T-replete HLA haploidentical transplantation using post-transplant cyclophosphamide (PTCY). We analyzed the records of 172 haploidentical transplant patients to identify risk factors and to assess the impact of such fevers on transplant morbidity and mortality. One hundred and seventy-two patients received haploidential hematopoietic stem cell transplantation (haplo-HSCT) using PBSC (n = 103) or marrow (n = 69) grafts. One hundred and forty patients (81%) experienced fever (T ≥ 100.5 °F or >38 °C) with median onset on d + 2. Compared to patients who did not develop fevers, patients with fevers received higher median CD34+ cell dose (5.00 vs. 3.08 × 106/kg, p < 0.001), CD3+ cell dose (12.8 vs. 4.5 × 107/kg), were more likely to have received a myeloablative regimen (50% vs. 9%, p < 0.001), and PBSC source (71% vs. 9%, p < 0.001). Cox model showed that fever had no impact on TRM, GVHD, OS, and DFS. In the logistic regression to identify correlation with fevers, higher degree of HLA mismatches and use of PBSC were all predictors of developing fever. Fevers between infusion of the T-Cell replete graft and administration of PTCY are very common in Haplo-HSCT. This complication is transient and had no impact on post-transplant morbidity and mortality.

Due to perceived intolerance, many elderly AML patients do not receive therapy, and few are considered for hematopoietic cell transplantation (HCT). To better understand “real-world” outcomes, 323 consecutive AML patients ≥ 60 years referred from 2009 to 2017 were evaluated (median age 70 [60–88] years); favorable (fav) in 48 (15%), intermediate (int) in 112 (35%) and poor risk in 161 (50%). Remission induction therapy, either intensive chemotherapy (IC, n = 205) or hypomethylating agents (HMA, n = 57), was given to all but 61 (19%) patients. With median f/u of 34 months, 2-year overall survival (OS) for the whole cohort was 31%; 40 and 33% for IC- and HMA-treated vs. 0% for untreated patients. Early mortality was 14%. Remission (CR/CRi) was achieved in 60% of patients, with approximately half of these surviving 2 years. In transplant-eligible patients (60–75-year-old, int/poor risk, achieving remission), 54 (46%) of 118 received HCT. Transplanted patients had improved 2- and 3-year post-remission survival of 59% and 40% compared to 26% and 18% in similar patients not receiving HCT (HR = 0.59, 95% CI 0.37–0.93, p = 0.023). These results suggest that survival of elderly AML patients may be improved through a coordinated approach of remission induction therapy for most patients followed by HCT when feasible.

Allogeneic hematopoietic cell transplantation (HCT) is associated with significant morbidity and mortality especially in the first year after HCT. In this study, we examine the long-term outcomes of patients who survived at least one year post HCT without evidence of relapse. We analyzed the records for 389 consecutive patients receiving an allogeneic transplant from 2005 to 2016 from a MRD, MUD, or haploidentical donor, who were alive and disease free at one year post-transplant. Patient characteristics and outcome parameters were extracted from our institutional database where they had been prospectively entered. A total of 389 patients met the selection criteria with donor graft including MRD 37%, MUD 39%, and Haploidenitcal relative 24%. The median follow-up of survivors from time of HCT was 48.2 months. The median overall survival and disease-free survival at 5 years after the first anniversary post HCT was 78 and 74%, respectively. The most common causes of late mortality were disease relapse, chronic GVHD and infections. The major risk factors for late mortality included chronic GVHD requiring immunosuppression, being transplanted between 2005 and 2009 compared to later years and male sex. Patients with high risk disease risk index (DRI) had worse OS compared to low risk DRI. The risk factors for late relapse included male sex and high/very high disease risk index. The projected long-term survival of 1-year survivors following allogeneic HCT is excellent. However, some patients remain at high risk of late relapse and late mortality. Early referral to transplant, adopting post-transplant consolidation strategies for high risk patients, and implementing newer GVHD prevention methods are potential interventions to help minimize the risk of late relapse and death.

T-replete haploidentical donor transplants using posttransplant cyclophosphamide (haplo) have greatly expanded donor availability and are increasingly utilized. Haplo were originally performed using truly nonmyeloablative conditioning and a bone marrow graft. We have also developed myeloablative conditioning and peripheral blood stem cell (PBSC) grafts for use with haplo. However, some patients may not tolerate myeloablative conditioning but may still benefit from a more dose-intensified preparative regimen to control malignancy and diminish graft rejection. To this end, we enrolled 25 patients on a prospective phase II trial utilizing a regimen of fludarabine 30 mg/m2/day × 5 days and Melphalan 140 mg/m2 on day -1 (flu/Mel) followed by infusion of unmanipulated PBSC graft from a haploidentical donor. GVHD prophylaxis included cyclophosphamide 50 mg/kg/day on days 3 and 4, mycophenolate mofetil on day 35, and tacrolimus on day 180. Median age was 57 years (range from 35 to 68). Transplantation diagnosis included AML (n = 11), ALL (n = 4), MDS/MPD (n = 6), NHL/CLL (n = 3), and MM (n = 1). Using the refined Disease Risk Index (DRI), patients were low (n = 1), intermediate (n = 13), and high/very high (n = 11). 22 out of 25 patients engrafted with a median time to neutrophil and platelet engraftment of 18 days and 36 days, respectively. All engrafting patients achieved full peripheral blood T-lymphocyte and myeloid donor chimerism at day 30. The 180-day cumulative incidence for acute GVHD grades II–IV and III-IV was seen in 20% (95% CI 8%–37%) and 8% (95% CI 2%–22%), respectively. The 2-year cumulative incidence of chronic GVHD was 16% (95% CI 5%–33%) (moderate-severe 12% (95% CI 3%–27%)). After a median follow-up of 28.3 months, the estimated 2-year OS, DFS, NRM, and relapse were 56% (95%CI 33–74%), 44% (95%CI 23%–64%), 20% (95% CI 8%–37%), and 36% (95% CI 17%–55%), respectively. Among patients with high/very high risk DRI, 2-year OS was 53% compared to 69% for low/intermediate DRI. When compared with a contemporaneous cohort of patients at our center receiving haploidentical transplant with nonablative fludarabine, Cytoxan, and total body irradiation flu/Cy/TBI regimen, the outcomes were statistically similar to the 2-year OS at 56% vs. 63% p=0.75 and DFS at 44% vs. 46% p=0.65.

Relapse is the main cause of treatment failure after nonmyeloablative haploidentical transplant (haplo-HSCT). In an attempt to reduce relapse, we have developed a myeloablative (MA) haplo-HSCT approach utilizing posttransplant cyclophosphamide (PT/Cy) and peripheral blood stem cells as the stem cell source. We summarize the results of two consecutive clinical trials, using a busulfan-based ( n = 20 ) and a TBI-based MA preparative regimen ( n = 30 ), and analyze a larger cohort of 64 patients receiving MA haplo-HSCT. All patients have engrafted with full donor chimerism and no late graft failures. Grade III-IV acute GVHD and moderate-severe chronic GVHD occurred in 23% and 30%, respectively. One-year NRM was 10%. Predicted three-year overall survival, disease-free survival, and relapse were 53%, 53%, and 26%, respectively, in all patients and 79%, 74%, and 9%, respectively, in patients with a low/intermediate disease risk index (DRI). In multivariate analysis, DRI was the most significant predictor of survival and relapse. Use of TBI (versus busulfan) had no significant impact on survival but was associated with significantly less BK virus-associated hemorrhagic cystitis. We contrast our results with other published reports of MA haplo-HSCT PT/Cy in the literature and attempt to define the comparative utility of MA haplo-HSCT to other methods of transplantation.