Eradication of residual bcr-abl-positive clones by inducing graft-versus-host disease after allogeneic stem cell transplantation in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

Abstract

Summary:Persistence of bcr-abl transcripts after marrow grafting is thought to convey a high risk for relapse in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). Donor leukocyte infusion (DLI) is closely associated with development of graftversus-host disease (GVHD) and has well-defined activity against relapsed chronic myelogenous leukemia (CML) but not ALL. We report two patients with Phpositive ALL who remained bcr-abl positive by reverse transcriptase polymerase chain reaction (RT-PCR) after marrow grafting. Residual bcr-abl transcripts in both patients were eliminated following acute GVHD, which was induced by either DLI or rapid reduction of immunosuppression. Both patients have continued in complete molecular remission for 18 months and 8 months following transplantation, respectively. Our observation suggests that induction of GVHD may eliminate minimal residual disease, thereby preventing leukemia relapse in patients transplanted for Ph-positive ALL. Bone Marrow Transplantation (2002) 29, 63-66. DOI: 10.1038/sj/bmt/1703318 Keywords: bcr-abl; MRD; Ph-positive ALL; DLI; stem cell transplantation; GVL The prognosis of Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) is much worse than other types of ALL in both children and adults. 1-3 The Ph chromosome t(9;22)(q34;q11) results from a translocation involving the breakpoint cluster region of the bcr gene on chromosome 22 and the abl gene on chromosome 9. This rearrangement is seen in 20 to 26% of adult

Reduced intensity conditioning and prophylactic DLI can cure patients with high-risk acute leukaemias if complete donor chimerism can be achieved

“…A GvL-effect in ALL has also been demonstrated in two patients with Ph+ALL with persistent bcr-abl transcript, who reached complete molecular remission after either termination of immunosuppression or DLI. 31 DLI was followed by a high rate of severe GvHD, although transplant-related mortality was low in our study, which underlines that toxicity of the conditioning regimen is acceptable. The GvL-effect of DLI did not parallel GvHD, because 2/6 converting patients did not develop GvHD and five patients with persistent MC developed GvHD.…”

High-hyperdiploidy in Philadelphia positive adult acute lymphoblastic leukaemia: case-series and review of literature

“…Post-T x events including time (in days post-SCT) to neutrophil (n) and platelet (Plt) engraftment, acute (Ac) and chronic (ch) GVHD are also described In our report, only one patient relapsed post-SCT, but achieved a sustained molecular remission with DLI. Since successful salvage with DLI of relapsed Ph + ALL postsibling allograft is uncommon, 15,16 the favourable outcome in our patient may be related to the kinetics of Ph + / hyperdiploid cells that facilitate an allogeneic immune response.…”

Loss of the GVL effect by loss of the Y-chromosome as putative mechanism of immune escape in ALL

“…1 Despite dismal results of donor lymphocyte infusions (DLI) in ALL, Philadelphia-positive ALL has been associated with a clinical relevant graft-versus-leukemia (GVL) reaction after allogeneic peripheral blood stem cell transplantation (PBSCT). [2][3][4] Minor histocompatibility antigens on the Ychromosome (HY) have been identified as important targets for the GVL effect as well as the graft-versus-host disease (GVHD). 5 Here we report a patient with Philadelphia-positive ALL, who relapsed with loss of the Ychromosome in the relapsed clone after sex-mismatched allogeneic PBSCT and ongoing chronic GVHD.…”