Outcome and impact of post-remission strategy after MIDAM regimen in patients with relapsing or refractory acute myeloid leukemia
Authors: Salem Bahashwan, Cécile Moluçon‐Chabrot, Eric Hermet, Aurélie Ravinet, Aurore Douge, Lauren Veronese, Andrei Tchirkov, Richard Lemal, Marc G. Berger, Richard Veyrat‐Masson, Olivier Tournilhac, Jacques‐Olivier Bay, Romain Guièze
Journal: American Journal of Hematology (2018)

Patients with relapsed or refractory acute myeloid leukemia (R/R AML) have very poor outcomes, and the management of such situations remains an acute challenge.1 Combining gemtuzumab ozogamicin (GO), intermediate-dose Ara-c, and mitoxantrone (MIDAM) has been suggested as a valid salvage therapy option based on a prospective phase II study.2 However, more extensive data on such an approach are needed to determine and improve the optimal use of this regimen. All consecutive patients with R/R AML treated with the MIDAM regimen in our center (Clermont-Ferrand University Hospital) between 2008 and 2013 were included in our study. Karyotyping was performed for all patients, and the mutational statuses of NPM1, FLT3, and CEBPA were assessed in cases of normal karyotype AML, as previously reported.3 Risk assessment was evaluated according to the European Leukemia Net (ELN) guidelines 2010. CD33 expression was assessed by flow cytometry. The MIDAM regimen consisted of GO 9 mg/m2 on day 4, cytarabine 1 g/m2 every 12 hr on days 1 through 5, and mitoxantrone 12 mg/m2/day on days 1 through 3. Patients with CR or CRp after MIDAM underwent postremission therapy. Allo-HSCT was performed in patients with available related or unrelated donors (HLA-matched or HLA-mismatched) and an appropriate fit (hematopoietic cell transplantation-specific comorbidity index [HCT-CI] <3, age <70 years). In cases where no donor was available, chemotherapy alone or autologous transplantation was proposed. MIDAM-related safety was registered within 45 days after the start of induction. CR was defined as the normalization of blood and bone marrow with ≤5% of blasts, neutrophil count above 1 × 109/L, and platelet count above 100 × 109/L. CRp was defined the same as for CR, but the criteria also included platelet transfusion independence and platelet count remaining below 100 × 109/L. Overall response (OR) was defined as CR plus CRp. Survival times were calculated from the first day of induction therapy until death or last follow-up for overall survival (OS) and until treatment failure, relapse, death, or last follow-up for relapse free-survival (RFS). A total of 86 consecutive patients with relapsed (n = 62) or refractory (n = 24) AML were included. Median age was 60 years (range, 17-75). The MIDAM regimen was administered as salvage therapy after 1 (n = 73) or more (n = 13) therapeutic lines. Distribution according to ELN 2010 cytogenetic/molecular risk classification was as following: favorable (n = 12), intermediate-1 (n = 23), intermediate-2 (n = 15), high risk (n = 22), and not available for 13 patients. Infusion-related reactions attributed to GO were observed in 24 (28%) patients, and tumor lysis syndrome was seen in 4 (4.6%) patients. Grade 3-4 hyperbilirubinemia was observed in 11 patients (12.8%), and grade 3 to 4 febrile neutropenia was observed in all the patients. Forty-six (53.5%) patients had persistent thrombocytopenia at day 45. Eight (9.3%) patients had veno-occlusive disease (VOD); all cases of reported VOD were associated with MIDAM induction rather than allo-HSCT. A total of nine (10%) deaths during the induction phase (within 30 days after the start of the MIDAM regimen) occurred. Four cases of death were related to sepsis, 2 cases to VOD, 2 cases to acute respiratory distress, and 1 to pneumonia. Deaths during the induction phase were significantly more frequent among those with poor performance status (33% if ECOG >1% vs 6% if ECOG was 0 or 1, P = .007). No significant influence of age (<60 years old vs ≥60 years old) was found. The OR rate (ORR) was 63% (CR, 36%; CRp, 27%). ORR was significantly better in patients who had relapsed vs refractory AML (69.4% vs 45.8%, respectively; P = .039), in patients with low WBC (71% if <10 G/L vs 44% if WBC >10 G/L, P = .028) and in those with good performance status (70% if ECOG was 0 or 1 vs 27% if ECOG >1, P = .003). No significant influence of age (<60 years old vs ≥60 years old), percentage of CD33-positive cells, ELN cytogenetic/molecular risk or disease status (de novo vs secondary AML) was found. The median follow-up was 6 years. Among the 54 patients with CR or CRp, postremission therapy consisted of chemo-based approaches in 13 patients (chemotherapy only, n = 10; chemotherapy + auto-HSCT, n = 3) and allo-HSCT in 29 patients (including 7 with consolidation chemotherapy prior to allo-HSCT). The allo-HSCT conditioning was MAC in 8 patients and RIC in 21 patients. The stem cell sources included related donors (n = 7), unrelated donors (HLA-matched in 17 patients and HLA-mismatched in 3 patients) or umbilical cord (n = 2). Twelve patients did not receive any consolidation therapy. The 2-year RFS was 28%. No influence of age (P = .480), WBC count (P = .078), percentage of CD33-positive cells (<30% vs >30%, P = .215) or ELN risk classification group was observed for 2-year RFS. Allo-HSCT as postremission therapy conferred significantly better 2-year RFS compared with chemo-based approaches and on consolidation therapy (51%, 33%, and 9%, respectively, P = .001) (Figure 1). Among the whole population, the 2-year OS was 20%. High WBC count greater than 10 G/L (P = .025), intermediate- and high-risk ELN cytogenetic findings (P = .036), and ECOG performance status greater than one (P = .009) were significant adverse prognostic factors of OS, and no influence was found for age, disease status (P = .108), and percentage CD33-positive cells (P = .457) on OS. Allo-HSCT as postremission therapy was associated with improved 2-year OS (43%) compared with patients without an available donor and those treated with chemotherapy-based approaches (15%) (P = .005) (Figure 1). Importantly, none of the patients treated with allo-HSCT had VOD. Of note, no patient with VOD after MIDAM induction therapy received allo-HSCT. Cause of death was related to AML in 62% of cases. For the remaining cases, 18% were related to sepsis, 7% to hemorrhagic complications and 13% to other causes, including graft versus host disease (GVHD) in 2 patients, VOD in 2 patients (related to MIDAM induction rather than allo-HSCT), pneumonia in 2 patients, cardiac arrythmia in 1 patient, and pulmonary embolism in 1 patient. The MIDAM regimen is a valid option for achieving CR in patients with R/R AML.2 This study aimed to investigate the efficacy and tolerance of this approach in an extended cohort and to analyze the impact of postremission therapy. We analyzed data from 86 patients with relapsed or refractory AML, which represents the largest series of patients treated with this protocol thus far. The CR rate was 63%, which was in line with the results of a previous phase 2 trial.2 Disease status before induction of the MIDAM regimen plays an important role in the response to salvage therapy. Indeed, the CR rate was found to be improved in patients with relapsed compared with refractory disease, likely due to the increased incidence of genetic alterations and multidrug resistance phenotype associated with refractory AML. Conversely, no impact of molecular cytogenetic abnormalities was found on response rate, in contrast to results observed in newly diagnosed AML.4 One major concern is the risk of VOD related to the use of GO, particularly for patients who undergo subsequent allo-HSCT. The use of MIDAM before allo-HSCT is thought to increase this risk.5 In our cohort, allo-HSCT in patients who achieved CR after the MIDAM regimen was well tolerated and showed an acceptable toxicity profile, and no VOD was found after an extended follow-up. GO in fractionated doses has been shown to be highly effective in association with chemotherapy and could be an interesting option in our MIDAM regimen because this approach allows the delivery of high cumulative doses without excessive toxicity.6 In a univariate analysis related to age, this study revealed no significant difference in CR between the different age groups, and the results suggest that the MIDAM regimen could be an acceptable choice as salvage treatment in the elderly. Induction-related death was linked to performance status, with no significant influence of age. In conclusion, the MIDAM regimen in R/R AML is a viable therapeutic option as salvage chemotherapy and is associated with an acceptable toxicity profile. Allogeneic transplantation is the consolidation of choice and can be performed safely after MIDAM with no increased risk of VOD. Nothing to report.