Haploidentical bone marrow transplantation in patients with advanced myelodysplastic syndrome
Authors: Riccardo Varaldo, Anna Maria Raiola, Carmen Di Grazia, Sara Aquino, Germana Beltrami, Stefania Bregante, Fabio Cruciani, Alida Dominietto, Anna Ghiso, Livia Giannoni, Francesca Gualandi, Adalberto Ibatici, Teresa Lamparelli, Carlo Marani, Maria Teresa Van Lint, Valeria Santini, Andrea Bacigalupo, Emanuele Angelucci
Journal: American Journal of Hematology (2017)

Myelodysplastic syndromes (MDS) are a heterogeneous and complex group of hematopoietic stem cell disorders, primarily found within the elderly population, characterized by ineffective hematopoiesis with a variable risk to progression to acute myeloid leukemia. Despite innovative drug developments, allogeneic hemopoietic cell transplantation (HCT) is, to date, the only available curative option for myelodysplastic syndrome patients.1, 2 Indication and timing of the procedure have been widely discussed in the literature.3-5 However, HCT is broadly underutilized: older patients' age, age-related comorbidities, lack of appropriate donor are factors involved into the limited application of HCT to MDS.6, 7 Over the last decade, the emerging role of reduced-intensity conditioning and the use of alternative donors (ie, haplotransplant, cord blood transplant) have expanded the eligibility and feasibility of this procedure to several patients and to those who are not eligible for a standard myeloablative conditioning regimen. Because a haploidentical donor is available in most families recent implementation of haploidentical HCT in transplant centers program has offered to many patients the opportunity to undergo this potentially curative approach. From August 2011 until March 2016, 30 consecutive patients with median age of 60 years (range 43-70) and a median comorbidity index8 of 3 (range 0-7), underwent T cell replete haplotransplant.9 All but one presented advanced disease characteristics: 16 very high risk, 8 high risk, 5 intermediate, 1 low risk according to the revised international prognostic scoring system (r-IPSS).10 Median diagnosis–transplant interval was 9.5 months. Fifteen patients had received de-methylating agents before transplant, no complete response was observed. Haplo donors/recipients were typed at the HLA-A, HLA-B,HLA-C, HLA-DRB1 at high resolution level. The donor/recipient pairs exhibited a median of four mismatches (range 0 to 4) on the unshared haplotype. Conditioning regimen was assigned on the basis of age and comorbidity index8: 10 patients received myeloablative conditioning regimen and 20 a reduced intensity conditioning regimen as previously reported.9 All patients received un-manipulated marrow derived hemopoietic cells. Marrow harvest was done as previously described.11 The median of infused nucleated cell dose was 3.1 × 108/kg (range 1.1-6). Graft versus host prophylaxis was performed by post transplant high doses of cyclophosphamide.9 Overall survival, disease-free survival rate, non-relapse mortality, acute and chronic graft versus host disease (GvHD) rates were calculated using the method of Kaplan and Meier with relapse and death as competitive events. The cumulative incidence of grade II-IV acute GvHD was 15%. Chronic GvHD developed in six patients and was extensive in five. Two patients experienced graft failure and were successfully re-transplanted with the same haploidentical donor after non myeloablative-conditioning regimen. Cumulative incidence of non-relapse mortality was 4% and 18% at 1 and 4 years, respectively. Two patients died in complete remission at 389 (chronic GvHD+ sepsis) and 1123 (interstitial pneumonitis) days after transplant, respectively. Seven patients relapsed at a median time from transplant of 188 days (range 139-560 days). Cumulative risk of relapse was 27%. All relapsed patients subsequently died by disease progression despite best supportive care (n = 4), salvage therapy with donor lymphocytes infusion (n = 1), de-methylating agents and donor lymphocytes infusion (n = 1), or acute leukemia like chemotherapy plus de-methylating agent and donor lymphocytes infusion (n = 1). At the time of this writing of the 21 surviving patients (all in remission) two were receiving chronic GvHD treatment. With a median follow-up of 20.5 months (range 4-54) the 3 years overall survival and disease-free survival were 72% (95% CI 63-81) and 69% (95% CI 60-78), respectively. Figure 1 reports the 3 years overall (a) and disease free survival (b). Relapse remains a major challenge in this setting of patients with extremely poor prognosis despite post transplant treatment therapy. No significant risk factor for death or relapse was identified in our limited transplant series however mutation analysis was not carried out. A dismal outcome has been recently reported in several research articles according to somatic mutational status.12, 13 A better relapse risk stratification before HCT could help identify subgroups of patients who are more likely to benefit from an adapted conditioning regimen or from early post transplant therapeutic strategies such as preemptive/prophylactic donor lymphocytes infusion and/or hypo-methylating agents. Three years overall (a) and disease-free survival (b) of the 30 MDS patients submitted to haploidentical HCT. Because of the limited number of patients in follow-up after the third year no survival data have been calculated after these limit despite e single late death (day + 1123) was registered. This analysis is hampered by the limited number of patients analyzed and by the usual limitations related to its retrospective nature. However these data, considering very high-risk features of disease in more than 50% of patients and elevated median comorbidity index are encouraging and deserve further studies. A larger prospective trial of haploidentical transplant in higher risk MDS patients fitting with the procedure and lacking an HLA identical donor is warranted. This article was supported by FA-RI.T.M.O. Nothing to report.