Donor cell leukemia is a rare complication of allogeneic BMT, and many hypotheses about the underlying mechanisms have been put forth.1, 2 Since donor cell leukemia is such a rare phenomenon, treatment of these patients has not been standardized. In this report, we present a child with pre-B ALL who developed a secondary AML of donor origin with Mixed-lineage leukemia (MLL) gene rearrangement after treatment for a relapse of his ALL after allogeneic BMT. A second allogeneic BMT with marrow from the same donor was performed and the patient is in ongoing complete remission now for 4 years. Our data show that long-lasting remission can be achieved after donor-derived, therapy-related AML by a second transplant with marrow from the same donor.
A 1-year-old, Caucasian boy with recurrent infections was diagnosed with ALL FAB L1 in 1988 and he was treated according to the ALL-BFM-86 regimen. In a period of 10 years, he relapsed twice (Figures 1a and b). Flow cytometric analysis on bone marrow aspirates of the initial ALL and the two relapses revealed similar blasts positive for TdT, CD10, CD19, CD22, CD34 and HLA-DR. This immunophenotype is consistent with ALL FAB L1 (pre-B ALL). Classical cytogenetic analysis and real time (RT)-PCR revealed a normal male karyotype and no translocations involving BCR-ABL1, ETV6-RUNX1 (TEL-AML1) or MLL-AF4 fusion genes. In third remission, the child was treated with an allogeneic BMT with marrow from an HLA-identical sibling after conditioning with etoposide, BU and CY. Prophylaxis for GVHD consisted of CsA and methotrexate. Two-and-a-half years after the BMT, he developed a third relapse of his ALL (Figure 1b), characterized by the same immunophenotype. The boy was treated with dexamethasone, vincristine, L-asparaginase, cytarabine, CY, methotrexate, 6-mercaptopurine, teniposide (1000 mg/m2) and etoposide (1200 mg/m2). A fourth complete remission was achieved and donor lymphocyte infusions (5 × 107 T cells/kg) were administered twice to induce a GVL effect.
One-and-a-half years after the third relapse, 4 years after the BMT, the patient developed an AML (Figure 1b). Flow cytometric analysis revealed that the blasts were positive for CD33, CD34, CD13, CD45, CD117 and HLA-DR. Karyotyping of the leukemic blasts showed a t(9;11)(p22;q23) translocation in all analyzed cells. Subsequent FISH analysis revealed that this translocation caused a disruption of the MLL gene (Figure 1c). Quantitative assessment of hematopoietic chimerism using polymorphism RT-PCR3 demonstrated complete donor chimerism of both peripheral blood and bone marrow at the time of AML diagnosis (data not shown). This demonstrates that the secondary AML is of donor origin.
The patient achieved complete remission after two blocks of FLAG (fludarabine, cytarabine and G-CSF). Four months after the diagnosis of the AML of donor origin, a second BMT was performed with non T-cell-depleted marrow cells from the same HLA-matched brother. Persistent complete chimerism and a fast hematological and immunological recovery were achieved. The patient is in complete remission now for 4 years. The brother has not developed any hematological disease.
The identification of the translocation disrupting the MLL gene may be relevant, as the MLL gene is frequently rearranged in therapy-related leukemia following treatment with inhibitors of topoisomerase II.4, 5, 6 The topoisomerase II inhibitors etoposide and teniposide were given to the patient at his third ALL relapse. The direct encounter of the transplanted donor cells with this chemotherapeutic agent therefore most likely caused the MLL gene rearrangement that led to the AML of donor origin. In their review, Reichard et al.1 report three cases of donor cell leukemia with an 11q23-associated abnormality. None of these three patients received chemotherapy after the BMT. To our knowledge, we describe the first case report that links donor-derived leukemia to treatment with DNA topoisomerase II inhibitors given after the first transplant. In a retrospective study of 14 patients, the European Group for Blood and Marrow Transplantation concludes that neither a certain conditioning nor any type of GVHD prophylaxis regimen after transplants represents a special risk for the occurrence of donor cell leukemia.2
Secondary neoplasms after treatment for ALL represent a serious late complication. The clinical outcome of patients with secondary AML is especially dismal, with a median survival time of only 6 months. Treatment generally consists of induction therapy followed by either allogeneic BMT, autologous BMT or further chemotherapy.7 In our case, the AML was therapy-related and of donor origin. We performed a second allogeneic BMT with non T-cell-depleted marrow from the same donor. We chose this ‘semi-autologous’ graft because graft rejection is unlikely, but GVL reactions may occur.8 This treatment option has the additional advantage that the ‘autograft’ from the unaffected donor is not contaminated with leukemic cells. In conclusion, we demonstrate that a second BMT from the same donor may be a curative treatment option for these patients, as our patient is in ongoing complete remission for 4 years.
Reichard KK, Zhang QY, Sanchez L, Hozier J, Viswanatha D, Foucar K . Acute myeloid leukemia of donor origin after allogeneic bone marrow transplantation for precursor T-cell acute lymphoblastic leukemia: case report and review of the literature. Am J Hematol 2006; 81: 178–185.
Hertenstein B, Hambach L, Bacigalupo A, Schmitz N, McCann S, Slavin S et al. Development of leukemia in donor cells after allogeneic stem cell transplantation – a survey of the European Group for Blood and Marrow Transplantation (EBMT). Haematologica 2005; 90: 969–975.
Maas F, Schaap N, Kolen S, Zoetbrood A, Buno I, Dolstra H et al. Quantification of donor and recipient hemopoietic cells by real-time PCR of single nucleotide polymorphisms. Leukemia 2003; 17: 621–629.
Ng A, Taylor GM, Wynn RF, Eden OB . Effects of topoisomerase 2 inhibitors on the MLL gene in children receiving chemotherapy: a prospective study. Leukemia 2005; 19: 253–259.
Sung PA, Libura J, Richardson C . Etoposide and illegitimate DNA double-strand break repair in the generation of MLL translocations: new insights and new questions. DNA Repair (Amst) 2006; 5: 1109–1118.
Felix CA . Leukemias related to treatment with DNA topoisomerase II inhibitors. Med Pediatr Oncol 2001; 36: 525–535.
Lowenberg B, Downing JR, Burnett A . Acute myeloid leukemia. N Engl J Med 1999; 341: 1051–1062.
Komrokji R, Ifthikharuddin JJ, Felgar RE, Abboud CN, Wedow LA, Connaughton A et al. Donor cell myelodysplastic syndrome after allogeneic stem cell transplantation responding to donor lymphocyte infusion: case report and literature review. Am J Hematol 2004; 76: 389–394.
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