Who is the best relative? Optimizing haploidentical donor transplantation in lymphoma

Every so often, the field of cellular therapy bears witness to a scientific advancement that is truly revolutionary; a game changer. Haploidentical-related donor haematopoietic cell transplantation (haplo-HCT), utilising T-cell replete grafts and a platform of post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prevention is one such example. Backed by several publications and wider application of this treatment modality, the past decade has essentially seen a consistent increase in haplo-transplants for the treatment of haematological malignancies (D’Souza & Fretham, 2018). The obvious next challenge for the scientific community is to understand the variables that may make haplo-HCT safer and better. Multiple studies, editorials and algorithms later, this remain an area of active research and debate(Wang et al., 2014; Handgretinger, 2014; Chang et al., 2016; Solomon et al., 2018; McCurdy et al., 2018; Bacigalupo & Laurenti, 2018). In the current edition, the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (Bazarbachi et al, 2019) report the effects of haploidentical donor characteristics, stem cell source and conditioning intensity on post-transplant outcomes specifically in lymphoma patients. The study included 474 patients undergoing haplo-HCT with PTCy between 2010-2016 with a median follow-up of 32 months. The key relevant findings on multivariate analysis include: (i) Lower acute GVHD (aGVHD) IIIV withoffspring donor and bone marrow as graft source; (ii) Higher extensive chronic GVHD (cGVHD) with female donor to male recipient, sister donor and use of donors beyond first degree relations; (iv) Inferior overall survival (OS) with donors beyond first-degree relations and donor and recipient cytomegalovirus seropositivity. Relapse, progression-free survival (PFS) and OS were also affected by lymphoma histology and remission status, while non-relapse mortality (NRM) was affected by remission status and increasing patient age. Conditioning intensity, stratified as myeloablative versus reduced intensity, had no impact on transplant outcomes. Chiefly accounting for the impact on survival, the authors conclude that any first degree haploidentical donor may be appropriate. How does the data presented here compare to other reports? Unlike the prior reports, the current study distinguishes itself as being specific to lymphoma patients in the modern era of haplo-HCT. It reaffirms the general safety and efficacy of this treatment modality. The largest study to date, which included mostly leukaemia and myelodysplasia patients treated uniformly with a Chinese protocol of growth factor mobilized T-cell replete peripheral blood and bone marrow graft with intense immunosuppression, noted a lower incidence of aGVHD, NRM and better OS was noted with offspring donors, age <30 years and male sex (Wang et al., 2014). The study also found that non-inherited maternal antigen (NIMA) mismatched donors were associated with less aGVHD, whereas specific human leucocyte antigen (HLA)-disparities did not correlate with outcomes (Wang et al., 2014). Questions regarding the broad applicability of the Chinese data has been raised owing to the differing treatment protocols compared to the European and North American practice of using PTCy (Handgretinger, 2014). The Center for International Blood and Marrow Transplant Research reported a similar study (n = 928), which included 27% lymphoma patients (McCurdy et al., 2018). Although a higher mortality was noted with donor age >30 years, this effect was negated when stratified by patient age (McCurdy et al., 2018). So, can we incorporate these data to facilitate patient care? Caveats abound. First and foremost, as is the case with most registry databases, the cohort consists of a heterogenous patient population, whose initial treatments and management would have probably differed based on institutional practices. No data regarding the influence of key factors that may potentially influence transplant outcomes such as disparities in human leukocyte (HLA), non-inherited maternal/paternal Correspondence: Professor Bipin N. Savani, Department of Medicine, Division of Hematology-Oncology, Vanderbilt University Medical Center, 2665 TVC, 1301 Medical Center Drive, Nashville, TN 37232, USA. E-mail: bipin.savani@vanderbilt.edu editorial comment