Therapy-related myelodysplastic syndrome after allogeneic BMT: successful treatment by donor lymphocyte infusions

Therapy-related myelodysplastic syndrome (t-MDS)/AML is a well-described complication of autologous BMT (auto-BMT), but it occurs rarely after allogeneic BMT. We report here a case of t-MDS/AML of recipient origin, associated with high-risk karyotypic abnormalities involving chromosome 7 that presented 1 year after allogeneic BMT for B-ALL and was successfully treated with donor lymphocyte infusions (DLIs). In February 2006, a 20-year-old man was diagnosed with pre-B ALL (CD34+, CD19+, CD22+, CD20−, CD10+, Cμ+, sIg−). The karyotype was hyperdiploid (55,XY,+X,+4,+6,+14,+17,+18,+21x2,+mar[5]/46,XY[15]). He was enrolled in the multicentric GRAALL 2003 trial and received induction therapy combining VCR, DNR, CY, L-asparaginase, prednisone and intrathecal chemotherapy. The patient was initially steroid- and chemotherapy resistant, but achieved complete haematological and cytogenetic remission after salvage chemotherapy. Unrelated HLA-B-mismatched BMT from a male donor was performed 7 months after diagnosis. The conditioning regimen consisted of high-dose CY, anti-thymoglobulin and 12 Gy fractionated TBI; GVHD prophylaxis consisted of CsA and short-course MTX. On day 23 post transplant, the patient developed grade II cutaneous and gastrointestinal GVHD that was successfully treated with steroids (2 mg/kg/day). Immunosuppressive treatments were gradually tapered 6 months after BMT. Chimerism was 100% donor on day 30 and remained the same for 10 months after BMT. The patient then presented with neutropenia and thrombocytopenia (the ANC fell from 2.5 to 1 g/l and the plt count from 200 to 100 g/l). Concomitantly, analysis of blood chimerism showed 6% recipient cells, which increased to 27% 1 month later, with 40% of recipient cells in the CD3-negative population. A BM aspirate revealed trilineage dysplasia with 4% blasts. The karyotype did not show the typical abnormalities found at diagnosis in leukaemia; however, the karyotype was complex, with three clones involving chromosome 7, as follows (see Figure 1): 46,XY,t(1;15)(p36;q21),del(7)(q31q35),t(12;16)(q21;p12)[5]/45,XY,t(2;21)(q12;q22),−7,del(8)(p21),add(13)(q33),del(20)(q12q13)[5]/45,XY,add(3)(q24),7,10,add(19)(q13),+mar[3]/ 46,XY[9]. According to the World Health Organization (WHO) classification, the diagnosis of ‘refractory anaemia with multilineage dysplasia and without excess of blasts’ was established. In addition, the presence of cytopenia and complex chromosomal abnormalities made it an intermediate-2 (score=1.5) myelodysplasia, according to the International Prognostic Scoring System (IPSS) prognostic score. These findings were consistent with the diagnosis of t-MDS and the presence of monosomy 7 and t(2;21) (probably involving AML1 gene), suggesting alkylation-induced t-MDS.1 Considering the graft-vs-myelodysplasia effect, previously reported after nonmyeloablative transplant, and the known efficacy of DLI when administered for post transplant MDS relapse,2 the patient was treated with DLI, consisting of 1.5 × 107 CD3+ cells/kg. He did not develop any sign of acute GVHD. At 6 weeks after DLI, he achieved CR, with normal blood cell counts, disappearance of haematological and karyotypic abnormalities on BM aspirate and complete donor chimerism (see Figures 2a and b). At 20 months after DLI, he was still in CR, but had limited chronic GVHD. Therapy-related myelodysplastic syndrome/AML is a frequent long-term complication of auto-BMT performed for both solid and haematological malignancies. The estimated incidence of t-MDS/AML after auto-BMT for lymphoma is between 1 and 14%, occurring from 3 to 15 years after auto-BMT.3 The pre auto-BMT chromosomal abnormalities seen in patients who go on developing t-MDS/AML support the hypothesis that stem cell damage is probably related to previous chemotherapy rather than to the conditioning regimen administered before transplant.4 In contrast to what has been reported for auto-BMT, t-MDS/AML of recipient origin is a very rare occurrence after allogeneic BMT; among more than 8000 transplanted patients, only 6 cases have been reported in large retrospective studies evaluating long-term complications after allogeneic BMT.5 In the allogeneic setting, recipient haematopoietic destruction is achieved not only through the conditioning regimen but also with the assistance of the donor immune system, resulting most likely in risk reduction for the recipient. Nevertheless, t-MDS/AML frequency may be higher in transplants with a higher frequency of recipient stem cell survival, as seen with reduced-intensity conditioning transplant. Reappearance of recipient markers in chimerism analysis, concomitantly with the diagnosis of myelodysplastic syndrome, strongly suggests the recipient origin of this t-MDS/AML. It can be noted that the evolution of the blood counts, karyotype and BM aspiration was strictly correlated to that of recipient chimerism in peripheral blood, emphasizing the critical importance of performing chimerism studies to detect any abnormal reappearance of recipient haematopoietic cells early on. Therapy-related myelodysplastic syndrome/AML after auto-BMT carries a poor prognosis. The median survival time is <1 year, and is only 6 months when the karyotype is unfavourable.1, 6 Usual treatment options consist of supportive care, standard AML chemotherapy or allogeneic BMT,7 but such intensive therapies may lead to high toxicity in these already heavily treated patients. A previous case report showed that the rare occurrence of t-MDS/AML after allogeneic BMT could be effectively treated by another allogeneic BMT from a different HLA-matched donor.8 Recently, the use of a nonmyeloablative conditioning regimen before allogeneic BMT or that of DLI for post transplant MDS relapse has shown promise of long-term remissions and suggests a graft-vs-myelodysplasia effect.2, 9 In the case presented here, the successful treatment of t-MDS/AML with complex karyotype and poor prognosis using DLI alone also points to a strong graft-vs-myelodysplasia effect. Therapy-related myelodysplastic syndrome/AML of recipient origin is a very rare complication of allogeneic BMT; however, it may become more frequent with the recurrent use of nonmyeloablative conditioning regimens. Thus, chimerism analysis might be a useful tool for the early diagnosis of this complication, and early treatment with DLI may represent an effective and well-tolerated therapeutic option, although more case reports and more prolonged follow-ups are warranted. The authors declare no conflict of interest.