The introduction of tyrosine kinase inhibitors (TKIs) has proved to be a major advance in the management of patients with chronic myeloid leukemia in chronic phase (CML-CP) although the clinical benefit seems to be limited to those patients who achieve complete cytogenetic remission (CCyR). Patients who achieve CCyR are believed to have an excellent prognosis, but a very small proportion of those patients may lose the response and progress to blastic phase. In this work we studied a cohort of 210 patients who achieved CCyR (142 of them were in MMR) on imatinib as first line therapy in order to identify the incidence of blastic transformation in this population.
Between June 2000 and December 2010, 282 consecutive adult patients with CML-CP were seen at our institution, of whom, 210 achieved CCyR on imatinib 400 mg daily as first-line therapy. The median follow-up was 69 months. Of the 210 patients in CCyR, 5 (2.3%) progressed to blastic transformation (BT) (3 myeloid and 2 lymphoid). The Sokal risk was low in 3 patients and intermediate in two. The median time to achievement of CCyR in these 5 patients was 18 months (range 9–20 months). Two of these patients also achieved a major molecular response (MR3), one achieved a 4 log reduction on the international scale and two patients had a CCyR with no MR3. The median time to achievement of MR3 (or better) in the three patients was 24 months (range 18–28 months). After achieving CCyR all 5 patients had progressive increases in their BCR-ABL1 transcript levels over a period of a few months leading to BT without an intervening accelerated phase. None of the patients had a ABL1 kinase domain mutation prior to transformation to advanced phase, but two patients subsequently developed a new mutation at the time of BT (M244V and T315I, respectively). The 8-year cumulative incidence (CI) of BT after reaching CCyR was 2.3% and was 2.8% when calculated from diagnosis (Figure 1). The median time from achieving CCyR to BT, was 18 months (range 12–40 months). The median time from the onset of an increase in BCR-ABL1 transcripts to BT was 6 months (range 4–7 months). All 5 patients had good compliance with TKIs.
All 5 patients were treated by allogeneic stem cell transplantation after BT in their second chronic phase. One patient proceeded to a transplant after combination chemotherapy and TKI, but 4 others only received a TKI prior to transplant (3 dasatinib and 1 nilotinib). All 5 patients subsequently died due to transplant related causes. The 8-year CI of BT after attaining CCyR was 2.3%. MR3 does not appear to completely protect against BT as 3 of the 5 patients with MR3 lost the response and progressed to BT. In our series we could not identify a time point beyond which patients may be safe from blastic transformation, which continues to be a rare but catastrophic event in responding patients.
Goldman:Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Marin:Novartis: Research Funding; BMS: Research Funding.
Asterisk with author names denotes non-ASH members.