Donor Cell Derived Leukemia: Description Of 38 Cases and a Case Control Study
Authors: Engel Nicole , Duarte Rafael F. , Labopin Myriam , Schroeder Thomas , Tischer Johanna , Ljungman Per T. , Schaap Nicolaas PM , Guyotat Denis , Beguin Yves , Nagler Arnon , Schroyens Wilfried A. , Basak Grzegorz Wladyslaw , Kolb Hans Jochem , Badoglio Manuela , Tichelli Andre , Rovo Alicia 
Published: October 2019

Abstract

Introduction
The development of leukemia in donor cells (DCL) in the recipient after an allogeneic hematopoietic transplantation is a rare but severe complication and has been suggested as a model for leukemogenesis. Due to a low incidence, very little is known about the pathogenesis and management, although different pathogenetic factors e.g. immunoregulatory dysfunction, replicative stress and damaged host environment have already been postulated. Apart from a few small case series most of the patients have been reported in single case reports. Therefore we aim to evaluate the incidence and outcome of DCL within the EBMT centers and to identify potential risk factors for DCL.

Methods
Identification of cases and controls was done using a survey sent to all EBMT centers. An additional questionnaire was sent in order to get complete specific information for DCL cases.
Prognostic factors were studied with a matched pair analysis comparing cases and controls confirmed not having developed DCL. Matching factors were age, gender, diagnosis, disease status at transplantation, year of transplantation, donor, stem cell source and length of follow-up (control’s follow-up was equivalent to, or exceeded that, of time to DCL in cases).

Results

Incidence of DCL
Out of 47,186 allogeneic transplantations performed from 1985 to 2013 in fifty-nine participating EBMT centers, thirty-eight DCL cases were identified. The cumulative incidence of DCL was 0.127 % at 10 years and 0.270 % at 25 years after transplantation.

Case description
Donor origin of leukemia was confirmed by STR/VNTR analysis (21), by FISH/conventional cytogenetics (14) and by HLA-typing (3). Patients were transplanted for AML/MDS (13), ALL (5), CML (8), CLL (3), lymphoma (3), multiple myeloma (1), granulocytic sarcoma (1) and non-malignant diseases (4). Graft source was bone marrow (14), G-CSF mobilized peripheral blood stem cells (20) and cord blood units (4). Donors were HLA-identical siblings in most cases (22), matched unrelated donors in 12 and mismatched related and unrelated donors in 2 cases each. Donor age was a median of 37 years [0-72]. DCL was diagnosed as AML (22), MDS (7), ALL (2), CML (2) and CLL (5). Interestingly, apart from monosomy 7 (5/38), trisomy 8 (3/38), RUNX1 mutation (2/38) and BCR-ABL translocation (2/38) no cytogenetic or molecular aberrations were detected repeatedly. Median time from allogeneic transplantation to DCL diagnosis was 44.13 months [1.57-279.15]. Most of the patients were treated intensively prior to allogeneic transplantation including previous allogeneic (4) and autologous (4) transplantation. Conditioning regimen tended to be myeloablative in 26 out of 38 cases, 20 patients received growth factor within the first 100 days after transplantation. Acute GvHD has been observed in 20/38 patients and 17/38 suffered from chronic GvHD. Viral complications have been reported for CMV (26/38), VZV (6/38), HBV (3/38), Parvovirus (3/38), HSV (2/38), BKV (2/38), HHV6 (2/38), and HCV, Parainfluenza, RSV, EBV and Adenovirus in 1 patient each. Donor follow-up was available for 25/38 donors: 7 donors developed the same disease as DCL (4 CLL, 2 MDS, 1 CML) suggesting the transfer of (pre-) malignant clones by transplantation.
For DCL treatment 12 patients received chemotherapy only, 17 patients were transplanted subsequently (HSCT), 1 patient is planned for subsequent HSCT, 2 patients were treated but not with chemotherapy, 4 patients were not treated and for 2 patients DCL treatment is unknown. After a median follow up of 32 months 12 patients are alive (5 chemotherapy only, 4 HSCT, 3 no treatment).

Prognostic factors for DCL
We were able to match 34 DCL cases with 67 controls. Three factors were significantly associated with an increased risk for DCL development: the use of growth factor within the first 100 days after transplantation (p .02; HR 2.43), in vivo T-cell depletion by either alemtuzumab or anti-thymocyte globulin (p .014; HR 2.59) and previous allograft (p .012; HR 4.08). Donor age, type of conditioning, CMV status, immunosuppression, and GVHD were not identified as risk factors for DCL development.

Conclusion
This study for the first time characterizes a case series of 38 patients with DCL and provides data for further discussion of pathogenesis and management of DCL.

Disclosures:
No relevant conflicts of interest to declare.