All patients engrafted patient Patient developed secondary g
All patients engrafted; 1 patient (Patient 6) developed secondary graft rejection following an A antigen mismatched graft from a male sibling and went on to receive a VUD HSCT with a female donor. There were no major conditioning related toxicities. Bacterial infections occurred in 6 patients prior to engraftment, and all responded to antibiotics. Seven out of 9 patients are alive at a median follow up of 46 months post HSCT (range 6–82 months). Patient 6 presented in chronic phase and progressed to lymphoid blast crisis with CNS disease on imatinib. She was subsequently treated with vincristine and prednisolone and 1 mu opioid receptor antagonist of high dose methotrexate combined with dasatinib and obtained a complete morphological remission. She died of sepsis and chronic GVHD, in complete molecular remission (CMR), following her second allograft. Patient 8 was transplanted post second myeloid blast crisis (in 3rd responsive phase), and relapsed back into blast crisis 3 months post HSCT and died 5 months post-HSCT. The median times to engraftment, complications of HSCT, use of donor lymphocyte infusions (DLI) and outcomes are summarised in Table 2. By definition, patients intolerant or resistant to TKIs will have higher EBMT scores than historical controls. In 2008 our centre published a case series of 14 patients who had achieved a CCyR with imatinib and then went on to have a reduced intensity conditioned allograft followed by DLI to eradicate minimal residual disease in patients with a BCR-ABL:ABL >0.02%. Despite this group of patients having an inherently better risk profile (median EBMT score 2.5 versus 5 in this cohort)—engraftment times, toxicities from HSCT and outcomes from HSCT were similar. Engraftment in the imatinib only group was a median of 10 days to neutrophils >0.5×109, versus 14 days in the second generation TKI group, and time to platelets >20×109 was 10 days and 11 days respectively. GVHD was more frequent in the imatinib only group (57% of patients) compared with the second-generation TKI cohort (44%; not significant). In the imatinib only group all patients had at least a major molecular response (MMR) with 8 out of 14 patients achieving a complete molecular response (CMR). In the second generation TKI group 1 patient died of relapsed blast crisis and a second has incurred cytogenetic relapse at least in part due to poor compliance. The other surviving patients all achieved at least a MMR, with 4 patients obtaining a CMR. There was 1 treatment related death in each group. The role of second generation TKIs post HSCT remains undefined. Relapse is the principal cause of treatment failure post HSCT. CML is exquisitely sensitive to DLI and this can be an effective means of treating molecular or cytogenetic relapse, but carries with it incumbent risks of GVHD. Imatinib has previously been shown to be an effective therapy for post transplant relapse and there is therefore a rationale for use of a TKI in high-risk patients post HSCT in a prophylactic setting. It is intuitive that in these imatinib resistant/intolerant patients a second generation TKI would be more effective but we have found them to be åpoorly tolerated post HSCT with frequent haematologic and gastrointestinal toxicities. In addition, drug interactions can be a significant problem in the post HSCT period with the majority of patients on multiple medications including antibiotics and immunosuppressants. In this cohort a second generation TKI post HSCT was attempted post HSCT in 7 patients (see Table 2). It was intended to commence TKIs approximately 4 weeks post engraftment routinely, regardless of BCR-ABL transcript number. TKI selection was based on previous response to TKI pre-HSCT and commenced post HSCT at a median of +65 days (range +38 to +88 days) for a median of 14 weeks (range 2–32 weeks) but all ultimately were stopped owing to toxicities, predominantly cytopenias. Patient 9 received bosutinib (having proven refractory to all other second generation TKIs pre-HSCT) for increasing BCR-ABL transcript numbers post HSCT and initially achieved a MMR (not a candidate for DLI owing to concurrent grade II GVHD) but has since suffered a cytogenetic relapse owing to poor compliance not caused by toxicities. In the context of our high rates of MMRs without successful use of prophylactic second generation TKIs post HSCT, we have now abandoned prophylactic second generation TKI usage. At our centre, post transplant TKIs are now considered for mixed chimerism and increasing BCR-ABL transcripts as a bridge to DLI or in patients with GVHD for whom DLI is inappropriate.