I would be very grateful if you could give some advice on management of a patient, aged 62 and previously well, who presented earlier this year with CML. At diagnosis she had evidence of blast crisis with ~ 24% blasts in the BM/PB, although CG analysis did not reveal evidence of clonal evolution with isolated Ph + in all metaphases. She responded promptly to imatinib with predictable pancytopenia requiring initial red cell and platelet transfusion support. A progress BCR-ABL after only 6 weeks of therapy revealed a level of 0.67% (35% at diagnosis) and she has subsequently switched to Dasatinib 70 mg PO BD with mild LFT abnormalities. She is now tranfusion independent with mild – moderate cytopenias.

I was interested in your thoughts on the timing of allogeneic stem cell transplantation considering the rapid response she has had to date. Is it reasonable to continue the TKI and reevaluate her response at 3 mo or based on longer term results should we simply move to a RIC allo Tx? There is unfortunately no available sibling ( deceased) but I think we have a MUD donor. The patient has no significant comorbidities but obviously age (now 63) remains a major concern in terms of risk of Allo Tx.

Many thanks for any thoughts you may have regarding this case.

It is indeed an interesting case. There are two issues here worth considering which affect what you would do. The first is whether you consider this accelerated phase or blast phase. To me this is accelerated phase. The data we have with TKI comes from studies that have used the standard definition rather than the WHO thus it is somewhat easier to know what to expect. Next is what to do with such patients. For patients with blast phase at any time I would unquestionably advocate SCT even with a good early response. For a patient with blast accelerated phase at the time of diagnosis, we recently published our experience and they do actually quite well, particularly when treated with 2nd generation TKI at the time of diagnosis, with most of our experience coming from nilotinib (only because of administrative reasons where one sponsor allowed us to include AP patients in our frontline studies). So in such a setting, a patient like this I would monitor very closely and see that they meet goals as required. The other side of the equation is the local experience with SCT in this setting. If the expected mortality is low, then SCT makes more sense; if not too low, then clos emonitoring is appropriate. One other thing I would add is that for a patient in blast phase, particularly if I am not going to transplant, I prefer to use TKI in combination with chemo. Currently we are doing combination with decitabine in a clinical trial but outside of the trial I would consider ara-C (low dose if concerned about co-morbidities/age) ± idarubicin.

I hope this helps.

JC

I tend to agree with Jorge’s assessment. I am quite impressed by the fall in BCR-ABL over the first 6 weeks. Going from 35% to 0.67% is a remarkable fall. Sue Branford has recently shown that this sort of fall (admittedly in CP patients) was predictive of a very good long response. I think I would reassess carefully at 3 months . I would do a marrow and check RQ-PCR for BCR-ABL on both blood and marrow. I would also do flow on the marrow to look very carefully for any blast cells with a similar immunophenotype to the one you saw at diagnosis.

I substantially agree with my collegues. It is a very challenging case. I am not surprised by the rapid molecular response, that is frequently observed in many of these cases, but the big question, as Jorge said, is if to move the patient to transplant or not. Because of the age, I would take in great consideration the general performance status of the patient. If reasonably good I would trasplant as soon as possible. If not I would postpone the transplant to a second moment, if and when signs of resistance will arise. Ponatinib and intensive chemotherapy could induce a second remission phase after which the alloSCT would still be possible.