Long‐term outcome of NPM1 mutated acute myeloid leukemia: A single‐institution experience
Authors: Hamid Sayar, Parvaneh Bashardoust, Larry Cripe, Sujata Chakraborty, Shaochun Bai
Journal: American Journal of Hematology (2016)

To the Editor: Mutations in nucleophosmin (NPM1) gene are seen in about 50% of patients with normal karyotype (NK) acute myeloid leukemia (AML) 1, 2. Large retrospective studies have reported higher remission rates and better long-term outcome in these patients when no FLT3 mutation was present 1-6. As a result, presence of NPM1 mutation in NK AML is now considered an established favorable prognostic finding impacting treatment strategies. We noticed a pattern of frequent relapse in patients treated at our institution for NPM1 mutation positive, FLT3 mutation negative, NK AML who received standard treatment and achieved complete remission (CR); therefore conducted a retrospective study to further investigate this observation. We reviewed patients with NK AML who had molecular testing performed upon diagnosis during years 2010–2013. We did not review patients after year 2014 since long-term follow-up was not yet available. A total of 18 patients with NPM1 mutation positive, FLT3 mutation negative, CEBPA mutation negative, NK AML were identified. Six patients were unevaluable since they either did not receive consolidation therapy following CR or were lost to follow-up. Average age of evaluable patients was 55 (39–67). The median white blood cell (WBC) count at presentation was 37.8 (3.1–116). All 12 evaluable patients received induction chemotherapy with standard 7 + 3 regimen of cytarabine 100 mg/m2/day continuous infusion for 7 days and idarubicin 12 mg/m2/day once daily for 3 days. One patient had primary refractory disease and did not achieve a CR. Eleven patients (92%) attained a CR, of whom one required a second induction therapy due to residual leukemia on day 14 bone marrow examination. All 11 patients with CR, completed 2–4 cycles of consolidation chemotherapy with intermediate-dose cytarabine (IDAC) per our institution protocol. IDAC consisted of 1.5 g/m2 cytarabine every 12 hr in patients younger than 60 and every 24 hr in older individuals, for total of 6 days. One patient was enrolled, after completion of consolidation therapies, in a randomized clinical trial with an oral agent versus placebo for maintenance. All 11 patients (100%) who had achieved CR with induction chemotherapy and received consolidation therapy, experienced relapse of the disease. Median relapse-free survival (RFS) was 16.5 (5–41) months. The remission duration did not correlate with WBC count at presentation (Pearson's correlation r = 0.228, n = 11, P = 0.49). All patients received induction chemotherapy again after relapse; various regimens were used. Eight patients (73%) achieved a second CR. Of these, 6 patients underwent allogeneic stem cell transplantation. Among transplanted patients, one died as a result of complications of transplant, two relapsed 6 and 18 months following transplant, and other 3 are still in remission with median post-transplant disease-free survival (DFS) of 14 (6–18) months. The two patients who did not pursue transplant, ultimately died from disease progression. Our data reflect single institution experience with NK NPM1-positive/FLT3-ITD-negative AML that is considered a favorable risk category. Table 1 summarizes previous reports and our findings in these patients. We observed a high CR rate with both initial and post-relapse induction therapies. We also noticed post-remission RFS and 2-year overall survival (OS) rates that are comparable with other reports. However, all of our patients who achieved an initial CR and completed planned consolidation therapy experienced a relapse. Moreover, all patients who did not undergo allogeneic stem cell transplantation following relapse, succumbed to the disease. The long-term outcome of transplanted patients is still unclear. Based on large retrospective studies NPM1 mutated AML in the setting of NK and unmutated FLT3 is established as a favorable-risk AML. These studies have uniformly confirmed a higher CR rate and better DFS. Improved OS has also been reported in some, but not all the studies. Our experience demonstrates a high CR rate, long DFS, and favorable 2-year OS, as well as a high response rate to post-relapse induction therapy. Our data however challenge the generally perceived notion of favorable long-term outcome of this type of AML, particularly without transplant. Indeed among total of 12, only 3 (25%) of our patients are still disease-free, but none in first CR or without transplant. Various induction and consolidation regimens have been given in trials, therefore it appears unlikely that the regimen used at our institution may have contributed to the observed less-favorable outcome. Schlenk et al. compared the long-term outcome in patients with and without an available matched donor, where most subjects in the former group underwent allogeneic stem cell transplantation. The study did not find a long-term benefit in the group with available donor 4. Thus, these patients are typically not considered for transplant in first remission. To our knowledge, there are no data on long-term outcome of NMP1 mutation positive patients transplanted after relapse. In conclusion, our single-institution experience supports the reported superior short-term prognosis for patients with NPM1 mutated AML, but challenges the accepted notion of favorable long-term outcome in this population. Prospective clinical trials are needed to clarify long-term prognosis and optimal management of these patients. Hamid Sayar,1* Parvaneh Bashardoust,2 Larry Cripe,1 Sujata Chakraborty,3 and Shaochun Bai3 1Indiana University Simon Cancer Center Indiana, University School of Medicine, Indianapolis, Indiana; 2Oceania University of Medicine Apia, Tuamasaga, Western Samoa; 3Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana