Improved outcome of allogeneic haemopoietic stem cell transplantation for children with philadelphia positive acute lymphoblastic leukaemia

Although the prognosis for children and young adults with acute lymphoblastic leukaemia (ALL) is excellent after modern intensive treatment, there are several small subgroups who have a high risk of relapse with conventional chemotherapy and are candidates for allogeneic haemopoietic stem cell transplant (allo-HSCT) in first complete remission. One such group is Philadelphia positive (Ph+ve) ALL, which has a poor prognosis in both children and adults. It forms <5% of ALL cases in children but the frequency increases with age to 20– 30% in adults. Although conventional chemotherapy can induce remission in >90% of cases, the risk of relapse is exceptionally high if the remission is not consolidated by an allo-HSCT (Arico et al, 2000). Therefore, first complete remission (CR1) allo-HSCT is currently recommended as definitive treatment for all children with Ph+ ALL by the major childhood ALL study groups. Recently, however, a US Children’s Oncology Group trial obtained an excellent early outcome, comparable to that after allo-HSCT, following treatment with a combination of the tyrosine kinase inhibitor (TKI), imatinib, and conventional chemotherapy(Schultz et al, 2009). It is therefore likely that CR1 allo-HSCT will in future be restricted to sub-groups who show evidence of resistance to chemotherapy and TKIs. Essential to identifying a sub-group in whom the benefit of allo-HSCT might outweigh its risks is availability of data on current outcomes after allo-HSCT using a related or alternative donor. We report our experience of transplanting an unselected group of consecutive patients with Ph+ acute leukaemia diagnosed at our centre over a 12-year period with a minimum of 12 months follow-up post-transplant. Twelve patients with Ph +ve acute leukaemia (six boys and six girls) were diagnosed and transplanted at our centre between May 1998 and April 2010. Individual patient characteristics are described in Table I. Ten patients had ALL, one had acute myeloid leukaemia (AML) and one mixed phenotype acute leukaemia. Nine patients were in CR1 and three were in CR2. Median age at diagnosis was 10 years (2Æ9– 13Æ4 years) and median white blood cell count at presentation was 27Æ2 · 10/l (5Æ0–394Æ4). The median interval between diagnosis and CR1 was 28 d (range 28–75 d). All the patients received first-line treatment on the then current UK national trial protocol. In addition, seven patients received imatinib (six) or dasatinib (one) pre-transplant. Of the three children who received transplant in CR2, two did not receive a CR1 transplant because of lack of a suitable donor and, in the remaining patient, the Ph-status was determined only at relapse because the diagnostic karyotype and fluorescent in situ hybridization failed. The relapses occurred at 32, 38 and 48 months from diagnosis. All three achieved CR2 after reinduction. One received chemotherapy, one single agent imatinib and one a combination of both. Table II shows individual patient details for the transplant procedure and outcomes. The median interval between remission and transplant was 6 months (range 1Æ7– 54 months). Three children received transplant from matched related donors and nine from unrelated donors. No patient died of regimen-related toxicity. Eleven children developed steroid-responsive acute graft-versus-host disease (GVHD) and one had limited chronic GVHD. Two patients experienced a relapse post transplant. Patient 5 had an isolated pelvic relapse 21 months after a matched related donor transplant and is in a molecular remission 50 months following a second transplant from a matched unrelated cord blood donor. She received imatinib before and for 1 year after the second transplant. Patient 3 relapsed 44 months after matched unrelated donor transplant and subsequently received donor lymphocyte infusion (DLI) and imatinib. He remains in CR3 more than 3 years from second relapse on maintenance imatinib. All 12 patients are in CR at a median follow up of 3.6 years post-transplant (1Æ2–9 years). As reported recently by St Jude’s, outcomes of transplant for children with high risk leukaemia have improved significantly in the last decade (Leung et al, 2011). We have witnessed a similar improvement in outcome at our relatively small paediatric transplant centre as a result of a decrease in transplant-related mortality (TRM) to 0% after related donor and <10% after alternative donor transplants (Sorour et al, 2009). For Ph+ ALL, the results reported here are substantially better than that reported in a similar number of patients who received an unrelated donor transplant at a UK centre over a decade ago (Marks et al, 1998). The improvement in outcome may partly be a result of all our patients receiving TKIs at some stage, although the influence of TKIs on transplant outcomes has been inconsistent (Kebriaei et al, 2011; Rives et al, 2011). With treatment-related mortality comparable to that associated with intensive chemotherapy (Arico et al, 2000), CR1 transplant, therefore, remains a legitimate option for sub-groups of Ph+ ALL who have a high risk of relapse due to resistance or intolerance to chemotherapy and TKIs. If so, should the eligibility for alternative donor transplant be restricted to a Correspondence