Page 149 - 2019_06-Haematologica-web

ATG in myelofibrosis patients
Introduction
Primary myelofibrosis and myelofibrosis secondary to polycythemia vera or essential thrombocythemia are myeloproliferative neoplasms characterized by progres- sive fibrosis of the bone marrow and myeloid metaplasia in the spleen and liver. Disease severity can be assessed by a number of different prognostic scoring systems, which are able to predict survival without treatment in patients with primary and secondary myelofibrosis.1–5 The risk factors usually taken into account in these scores are disease-related symptoms, the degree of cytopenia or hyperleukocytosis, peripheral or bone marrow blast excess and age. Moreover, cytogenetics and somatic mutations provide additional prognostic power to these scoring instruments.3,6–9 According to the number of risk factors, the expected median survival from diagnosis can range from more than 10 years to less than 18 months. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment in patients with myelofibrosis. One registry-based study demon- strated that patients with intermediate-2- or high-risk dis- ease according to the Dynamic International Prognostic Scoring System (DIPSS) have an advantage in overall sur- vival following transplantation and international expert consensus guidelines are in favor of transplantation in such patients.10,11 Cumulatively, overall survival after HSCT can range between 40% and 65% according to risk factors related to the disease, patient and type of donor.12– 18 Results have been considered better with transplant from an HLA-matched sibling donor than an unrelated donor. However, acute and chronic graft-versus-host dis- ease (GvHD) remain frequent causes of death in patients with myelofibrosis undergoing HSCT, often contributing to a relatively high transplant-related mortality of around 30%.12–18 The optimal conditioning regimen and GvHD prophylaxis in these patients remain unknown. Two prospective studies of HSCT in myelofibrosis, in which the conditioning regimen and GvHD prophylaxis strate- gies were homogeneous, can be considered to compare GvHD rates and outcomes. In 2009, Kröger et al. reported on 103 myelofibrosis patients given conditioning with fludarabine, busulfan and the antihuman T-lymphocyte immune globulin Grafalon® at a dose of 30 mg/kg when the graft was from a matched related donor and 60 mg/kg when the donor was unrelated, combined with cyclosporine and a short course of methotrexate. With this regimen, including in vivo T-cell depletion, the rate of acute grade II-IV GvHD was relatively low (27%) and the incidence of chronic GvHD was 49%. The relapse inci- dence was 32% in the setting of a matched related donor and 20% with an unrelated donor; these incidences were not statistically significantly different. Rondelli et al. sub- sequently reported a second prospective trial regarding HSCT in myelofibrosis using a fludarabine and melpha- lan platform in patients transplanted from a matched related donor, with the addition of Thymoglobulin® in patients with an unrelated donor.17 Acute GvHD rates were substantial, being 38% and 41% in the sibling donor group and unrelated donor group, respectively. Chronic GvHD rates did not differ significantly between the sibling donor (36%) and unrelated donor (38%) groups. Of particular note, mortality was dramatically higher (68%) in the group of patients who underwent unrelated donor HSCT but the effect of antilymphocyte
globulin (ATG) on this higher mortality risk remains undetermined. Collectively, from these two studies, it cannot be concluded unambiguously that ATG is benefi- cial in the setting of transplantation from a matched relat- ed donor. Recently, a randomized trial showed that ATG prevents chronic GvHD in patients with acute lymphoid leukemia or acute myeloid leukemia undergoing trans- plantation from an HLA-matched sibling donor following myeloablative conditioning regimens.19 Indeed, while acute GvHD was non-significantly lowered, the cumula- tive incidence of chronic GvHD dropped from 69% with- out ATG to 32% with Grafalon® without increasing the risk of relapse. In this large European Society for Blood and Marrow Transplantation (EBMT) cohort, we aimed to determine the effect of ATG in the setting of HSCT for myelofibrosis using an HLA-matched sibling donor, which is of particular importance as data remain scarce given the rarity of the disease.
Methods
Consecutive patients transplanted from a matched sibling donor without ex vivo graft manipulation between 2007 and 2015 for myelofibrosis and registered in the EBMT registry were included in this study. Patients who received post-transplant treatment with cyclophosphamide or alemtuzumab as GvHD prophylaxis and those without sufficient information regarding blood cell counts prior to transplantation were excluded. A total of 287 patients were selected for the final analysis, among whom 135 received in vivo T-cell depletion while 152 did not.
The DIPSS was calculated according to the original definition.1 For some patients the data on peripheral blast count at the time of transplantation were missing; in these cases, the diagnostic blast count was used. General symptoms were either weight loss or sweating (only 2 patients had fever); data on constitution- al symptoms were missing for 50 patients. Because information on the brand of drug used for T-cell depletion was not available in the registry, a stepwise hypothetical strategy was formulated to identify patients who received Thymoglobulin® and those who had received Grafalon®: ATG doses of 10 mg/kg or lower were considered as Thymoglobulin® whereas doses of 20 mg/kg or higher were considered as Grafalon® based on usual doses of each brand. This strategy was also checked by country in which the HSCT was performed, as some countries used only Grafalon®, others used only Thymoglobulin® and some used both products.
Disease-free survival was defined as survival without disease relapse or progression documented in the registry. GvHD-free, relapse-free survival (GRFS) was defined as survival without dis- ease relapse or progression, without grade III-IV acute GvHD and without chronic extensive GvHD documented in the reg- istry.
Failure time data were analyzed used Kaplan-Meier estimates, log-rank tests and Cox modeling unless competing risks existed, when cumulative incidence curves, the Gray test and cause-spe- cific Cox models were used.20 When estimating the cumulative incidence of chronic GvHD, patients were censored at the time of donor lymphocyte infusion, as previously reported. Based on frailty models,21 we tested whether there was a center effect on each outcome.
The study complied with regulatory requirements, the decla- ration of Helsinki and Good Practice standards. Independent review boards approved the study. Patients gave written informed consent.
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