Abstract
Introduction. The immune-conjugate gemtuzumab ozogamicin (GO) represents the main available therapeutic possibility beyond combinations of anthracycilines and cytarabin for patients with refractory or relapsed acute myeloid leukemia (AML). Combining GO, intermediate dose Ara-c and mitoxantrone (MIDAM) has been shown as a valid option as salvage therapy based on a prospective phase II study including 62 patients (Chevallier JCO 2007). Whether this regimen is safe in patients undergoing allogeneic hematopoietic stem-cell transplantation (allo-HSCT) as post-remission therapy remained to be determined.
Method. This retrospective study included the consecutive patients with relapsed or refractory AML treated by the MIDAM regimen in our center (Clermont-Ferrand University Hospital) between 2008 and 2013. MIDAM consisted of GO 9 mg/m2 on day 4, cytarabine 1g/m2 every 12 hours on days 1 through 5, and mitoxantrone 12 mg/m2/d on days 1 through 3. GO is available according to a compassionate use program in France.
Results. A total of 86 consecutive patients with relapsed (n=62) or refractory (n=24) AML were included. Median age was 60 years (range, 17 to 75 years old). The MIDAM regimen was administered as salvage therapy after 1 (n=73) or more (n=13) therapeutic lines. Distribution according to ELN 2008 cytogenetic risk classification was as following: favorable (n=12), intermediate-1 (n=23), intermediate-2 (n=15) and high risk (n=22). Complete response (CR) rate was 63% including 23 patients (27%) CR with delayed platelets recovery (CRp). Treatment failure was observed in 23 (27%) patients. Nine (10%) deaths during induction occurred. Infusion-related reaction was observed in 24 (28%) patients and tumor lysis syndrome were seen in 4 (4.6%) patients. Eight (9.3%) patients had veno-occlusive disease (VOD).
CR rate (CR+CRp) was significantly better in patients with low WBC (71% if <10 G/L vs 44% if WBC >10 G/L, P=0.028) and in those with good performance status (70% if ECOG 0 or 1 vs 27% if ECOG >1, P=0.003). No significant influence of percentage of CD33 positive cells was found.
Among the 54 patients with CR or CRp, post-remission therapy consisted of chemo-based approaches in 13 patients (chemotherapy only, n=10; chemotherapy + auto-HSCT, n=3) because a lack of allogeneic donor and allo-HSCT in 29 patients (including 7 with consolidation chemotherapy prior to allo-HSCT). Twelve patients did not receive any consolidation therapy. Median follow up was 6 years. Among patients achieving CR or CRp, 2-year RFS was 25%. No influence of neither age, WBC count, percentage of CD33 positive cells nor ELN 2008 risk cytogenetic group was observed on RFS. Allo-HSCT as post-remission therapy confers significant better RFS compared to chemo-based approaches and absence of consolidation therapy (51%, 33% and 9%, respectively, P=0.001). Among the whole population, 2-year OS was 20%. High WBC count (>10 G/L), intermediate and high risk ELN cytogenetic, ECOG performance status more than one were significant adverse prognostic factors on OS. Allo-HSCT as post-remission therapy was associated with better 2-year OS (43%) compared to those without available donor and treated by chemo-based approaches (15%) (P=0.005). Importantly, among patients treated by allogenic stem cell transplantation, no veno-occlusive disease was found.
Conclusion. The MIDAM regimen in relapsed or refractory AML is an option therapeutic as a salvage chemotherapy with a relatively acceptable toxicity profile. Allogeneic transplantation is the consolidation of choice and can be performed after this regimen with no increased risk of VOD.
Tournilhac:GILEAD: Honoraria, Other: Travel Funding, Research Funding; Janssen: Honoraria, Other: travel funding; Abbvie: Honoraria, Other: Travel funding; AMGEN: Other: Travel funding, Research Funding; ROCHE: Honoraria, Other: Travel funding, Research Funding. Guieze:GILEAD: Other: Educational Presentation; JANSSEN: Other: Educational Presentation; ABBVIE: Other: Educational Presentation.