Development of BCR-ABL positive acute lymphoblastic leukemia in donor cells after allogeneic hematopoietic cell transplantation for Philadelphia-positive acute lymphoblastic leukemia

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The most frequent cause of treatment failure after allogeneic hematopoietic cell transplantation (allo-HCT) for leukemia is relapse of the underlying host leukemia. However, occasionally, cytogenetic analysis, alone or in combination with molecular analysis, has indicated that the new leukemia originated in donor cells (DC).1 Leukemic transformation of DC was first described in 1971; 19 further cases have been reported since, of which 13 were acute lymphoblastic leukemia (ALL).1, 2, 3

We report the first case of DC BCR-ABL(+) ALL developing after allo-HCT for Ph(+) ALL. A 37-year-old female was diagnosed with common-ALL (CD10+CD19+CD20+CD22+CD34+CD38+TdT+CD13+MPO−) in November 2001; she had hyperdiploid karyotype with trisomies of chromosomes 2,6,8, and t(9;22) and carried BCR-ABL (e1a2) transcripts. The patient attained complete hematological and cytogenetic remission after one course of the HyperCVAD regimen and was consolidated with one course each of adriamycin–vincristine–high dose cytarabine–prednisone and BiCNU–etoposide–cyclophosphamide–prednisone. She was referred to our Department with the prospect of allo-HCT; then she was tested negative for either BCR-ABL chimeric transcripts or clonal immunoglobulin heavy-chain gene (IgH) rearrangements. In March 2002, after BuCy conditioning she received peripheral blood stem cells (6.32 × 106 CD34+cells/kg) from an HLA-identical male sibling donor. Cyclosporin A and methotrexate were given for GVHD prophylaxis. Molecular remission was maintained in a setting of extensive chronic GVHD until 6 months post-transplant; 4 months later, the patient had overt relapse with CD10+CD19+TdT+MPO−ALL. She attained complete hematological/molecular remission after one course of the C-VAD regimen. Six months after relapse, she maintains complete donor chimerism (CDC) and is scheduled for a second allo-HCT from another HLA-matched sibling.

Starting from day 14 post-transplantation, repeated FISH studies on 500 bone marrow cells, including the study of the relapse sample, demonstrated complete donor (male) chimerism. The relapse sample was positive for the BCR-ABL gene (FISH), BCR-ABL (e1a2) transcripts and a clonal IgH gene rearrangement using the VH3-23 gene (100% homologous to germline). VNTR and STR analysis demonstrated allelic disparities in patient samples pre- and post-transplantation at the VW1 locus; in contrast, allelic identity was identified between donor DNA and patient DNA post-transplantation (Figure 1). Segregation analysis demonstrated that pretransplantation the patient was heterozygous at the HA-2 minor histocompatibility locus (HA-2M/V), whereas post-transplantation she was homozygous for the V allele and thus identical with the donor (also homozygous for the HA-2V allele) (Figure 2).

Figure 1
figure1

OpenGene electropherograms of the STR profiles at the VWA locus, pre- and post-HCT (performed with fluorescent-labeled (Cy5.5) oligonucleotide primers, as described in Gopcsa et al,4 followed by analysis using the Visible Genetics Inc. Open Gene system). Retention time (minutes) is shown at the top of each panel, while 100 and 200 bp DNA markers are shown at left and right, respectively. The size of the PCR product is shown on each peak. (a) Patient's profile pre-HCT; (b) donor's profile; (c) patient's profile post-HCT; (d) patient's profile at relapse.

Figure 2
figure2

Segregation analysis for HA-2 minor histocompatibility antigen alleles, performed as described in Pierce et al8 (HA-2M, lanes 1–5; HA-2V, lanes 7–11). Lanes 1, 7: patient DNA pre-transplantation; lanes 2, 8: patient DNA post-transplantation; lanes 3, 9: donor DNA; lanes 4, 10: positive control; lanes 5, 11: PCR negative (no DNA); lane 6: molecular weight marker (ϕX174 Hae III).

Leukemic transformation of DC was first described in 1971; since then, 19 further cases have been reported, of which 13 were ALL.1, 3, 6 ALL of donor cell origin has developed after allo-HCT for ALL (seven cases), chronic myelogenous leukemia (CML; four cases), acute myeloid leukemia (one case) or thalassemia (one case). Most reported cases (8/13) had normal karyotype; there were only two cases of donor-derived Philadelphia-positive ALL occurring 39 and 6 months, respectively, after bone marrow transplantation for CML.3, 7 Generally, donor cell leukemia tends to be a late event, with only 4/20 reported cases presenting within the first year after transplantation. Importantly, as in our case, one of the two previously reported cases of Ph (+) ALL of donor origin developed less than a year (at 6 months) post-HCT for Ph (+) CML.7

In the present study, we report the first case of BCR-ABL (+) ALL of donor cell origin after allogeneic HCT for Ph (+) ALL. FISH analysis of the ‘relapse’ sample demonstrated complete donor (male) chimerism as well as the presence of the BCR-ABL chimeric gene. We further confirmed the donor origin of the leukemic blasts by molecular evaluation of hematopoietic chimerism at various polymorphic loci.

In the past, the incidence of DCL post-allogeneic HCT may actually have been underestimated. Lack of adequate diagnostic tools has hindered the unequivocal assignment of leukemic clone origin in several cases; in the same context, molecular studies were available to confirm the cytogenetic assignment of DCL in only 9/20 reported cases. It should be emphasized that even with molecular analysis great caution is warranted so as to avoid misdiagnosis of DCL, as evidenced by the case described by Spinelli et al.6 In that case of leukemia relapse occurring in a man who received allogeneic hematopoietic cells from his HLA-identical sister cytogenetic analysis and PCR studies with Y-chromosome-specific markers were strongly suggestive of DCL; nevertheless, it was shown that CDRIII regions of leukemic blasts at diagnosis and relapse were identical, thus proving the patient origin of both leukemic clones. The authors interpreted their results by a postulated loss of the Y chromosome along with duplication of an X-chromosome. The possibility of a similar pitfall in our female patient is effectively ruled out by the persistent detection of complete donor (male) chimerism in all samples after allo-HCT, including the ‘relapse’ sample.

It has been proposed that the study of DCL might provide important insight into the processes of leukemogenesis.1, 7, 8 Postulated mechanisms for development of DCL include: (1) occult leukemia in the donor: this was effectively ruled out for all reported cases since none of the donors later developed leukemia; (2) transfection of DC with chimeric gene sequences associated with specific leukemia subtypes: this has been proposed to occur either via release of oncogenic genetic material (viral or nonviral) from host leukemic cells (mediated by the conditioning therapy) and transfection of DC infused shortly thereafter or via fusion of residual host leukemic cells with donor hematopoietic progenitors; (3) immune dysfunction due to the presence and treatment of graft-versus-host disease. Nevertheless, it has never been possible to prove the exact mechanism responsible for donor cell leukemia development on an individual basis; thus, the full delineation of the underlying processes requires further extensive research.

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