Factors affecting outcome of allogeneic stem cell transplantation as salvage in patients with acute myeloid leukemia primary refractory to intensive induction therapy
Authors: Marta Medeot, Mario Tiribelli, Francesca Patriarca, Alessandra Sperotto, Antonella Geromin, Renato Fanin
Journal: American Journal of Hematology (2014)

To the Editor: We read with great interest the manuscript by Jabbour and colleagues entitled “Allogeneic stem cell transplantation (SCT) as initial salvage for patients with acute myeloid leukemia refractory to high-dose cytarabine-based induction chemotherapy” 1. The authors reported that allogeneic SCT was associated with superior overall survival (OS) compared to salvage chemotherapy, with a 3-year OS rate of 39% in the SCT group. Moreover, in the 28 transplanted patients, they found that a higher percentage of bone marrow (BM) blasts at SCT was associated with inferior outcome and that relapse after transplant was the major cause of treatment failure. We reviewed our database and identified 34 patients with AML primary refractory after intensive induction chemotherapy who underwent allogeneic SCT between 2000 and 2013. All patients received induction chemotherapy including high-dose (conventionally defined as ≥2 g/m2/day) cytarabine (HDAC) and idarubicin (10 mg/m2/day), associated in 31 cases with fludarabine (n = 27) or etoposide (n = 4). Twenty-seven patients received at least a second course with HDAC and idarubicin, without achieving complete remission (CR). Median number of chemotherapy courses before SCT was 2 (range, 1–4). Median age at SCT was 55 years (range, 27–69), and SCT was performed at a median of 5.5 months (range, 1.6–10) from diagnosis. Twenty-one patients (62%) received grafts from a sibling donor and 13 (38%) from a matched unrelated donor. In 27 patients (79%), stem cells source was peripheral blood (PB), while BM stem cells were used in seven cases. Patients were conditioned either with myeloablative (n = 18) or reduced-intensity conditioning (n = 16) regimens. OS was defined as time from SCT to death or last follow-up. Thirty patients (88%) died, with a median OS of 4.5 months (95%CI 2.6–8.6) and a 3-year OS of 18% (95%CI 7–32). Cause of death was disease relapse/progression in 23 cases (77%), while the remaining 7 (23%) died of nonrelapse mortality (NRM). Twenty-nine patients were evaluable for response after SCT, as five died of early NRM. Nineteen patients (66%) achieved CR: 13/19 (68%) relapsed after a median of 3.4 months (range 1.7–18.2) and survived for a further 1.4 months (range 0.4–9); among the six patients in sustained CR, four are alive and two died of NRM after 79 and 55 months. Ten patients (34%) had resistant leukemia after SCT and died in a median of 2.5 months (range, 1.4–6.6). Considering pretransplant characteristics, OS was not predicted by gender, karyotype, age at SCT, time to SCT, number of chemotherapy courses, donor type, stem cell source, or conditioning regimen. There was a significant association between OS and WBC count at SCT (<10,000/ml: 20 months [95%CI 4.6-NA] vs. ≥10,000/ml: 3.6 months [95%CI 1.9–4.5], P < 0.0001), platelet (PLT) count at SCT (>30,000/ml: 18.8 months [95%CI 3.6-NA] vs. ≤30,000/ml: 3.7 months [95%C 1.9–10], P = 0.05) and PB blasts at SCT (absent: 79 months [95%CI 2.6-NA] vs. present: 4.5 months [95%CI 3.4–8.6], P = 0.03). Stratifying patients according to WBC, PLT, and circulating blasts, we identified four groups with different survival: median OS for patients with 0, 1, 2, or 3 adverse prognostic factors was 79, 10.1, 4.1, and 3.5 months, respectively (P = 0.004) (Fig. 1). OS according to the number of adverse prognostic factors: WBC ≥10,000/ml, PLT ≤30,000/ml, and circulating blasts. Our data confirm that allogeneic SCT can cure a minority of patients with primary refractory AML, and that relapse is the major cause of treatment failure after SCT. In our experience, 3-year OS was lower than that of the MDACC group (18% compared to 39%) but comparable to that reported by the GITMO (10%) 2 and significantly superior to survival after salvage chemotherapy (2–5%) 1, 3. Jabbour et al. found higher WBC, lower PLT, and higher BM blasts percentage at SCT to be associated with superior OS, but did not define any cutoff value 1. In the setting of unrelated donor transplant for AML primary refractory to various induction strategies (conventional 3 + 7 or HDAC-based regimens), Craddock et al. identified number of chemotherapy courses before SCT (>2) and BM blasts percentage (above a median of 38.5%), along with patient CMV serostatus, as predictive factors for OS 4. We found that WBC count <10,000/ml, PLT count >30,000/ml and absence of circulating blasts predict superior long-term outcome after SCT. If confirmed in larger studies, this finding may help in designing a simple pre-SCT score to identify AML patients primary refractory to intensive induction chemotherapy that could maximally benefit from the transplant procedure. M.M. and M.T. designed the study, collected and analyzed the data, and wrote the manuscript; F.P. A.S., and A.G. contributed to patient care and collection of data; R.F. edited the manuscript. All authors approved the submission of the manuscript. Marta Medeot, Mario Tiribelli,* Francesca Patriarca, Alessandra Sperotto, Antonella Geromin, and Renato Fanin Division of Hematology and Bone Marrow Transplantation, Department of Clinical and Experimental Medical Sciences, AOU Udine, Udine, Italy