J. Catalano

BACKGROUND: Initial therapy for patients with acute promyelocytic leukemia most often involves the combination of all-trans-retinoic acid with anthracycline-based chemotherapy. The role of non-anthracycline drugs in induction and consolidation is less well-established and varies widely between different cooperative group protocols. DESIGN AND METHODS: In an attempt to minimize relapse and maximize survival for patients with newly diagnosed acute promyelocytic leukemia, the Australasian Leukaemia and Lymphoma Group utilized all-trans-retinoic acid and idarubicin as anti-leukemic therapy for both induction and consolidation. The protocol (known as APML3) was subsequently amended to incorporate maintenance with all-trans-retinoic acid, methotrexate and 6-mercaptopurine. RESULTS: Eight (8%) of 101 patients died within 30 days, and 91 (90%) achieved complete remission. With a median estimated potential follow-up of 4.6 years, 4-year overall survival was 84%, and 71% of the patients remained in remission at 4 years. The cumulative incidence of all relapses was 28.1%, with 15 of the 25 relapses initially identified as an isolated molecular relapse. Both FLT3 mutations (internal tandem duplications and codon 835/836 kinase domain mutations) and increased white cell count at diagnosis were associated with inferior overall survival, but in multivariate analyses only FLT3 mutations remained significant (hazard ratio 6.647, P=0.005). Maintenance therapy was significantly associated with improved remission duration (hazard ratio 0.281, P<0.001) and disease-free survival (hazard ratio 0.290, P<0.001). CONCLUSIONS: The combination of all-trans-retinoic acid and just two cycles of idarubicin followed by triple maintenance produced durable remissions in most patients, but patients with high-risk disease, especially those with FLT3 mutations, require additional agents or alternative treatment approaches. The significant reduction in relapse seen after the addition of maintenance to the protocol supports a role for maintenance in the context of relatively low chemotherapy exposure during consolidation. (actr.org.au identifier: ACTRN12607000410459).

6500 Background: Dysregulated JAK-STAT signaling is a key feature in MF, which is characterized by splenomegaly, debilitating symptoms, cytopenias and shortened survival. There are currently no effective drug therapies for MF. 424 is a selective JAK 1 and 2 inhibitor with clinical activity in MF. Methods: Patients (pts) with intermediate-2 or high-risk MF were randomized to start PB or 424 at a dose of 15 mg or 20 mg PO BID depending on baseline platelet count (100-200 X 109/L or >200 X 109/L, respectively). The dose was optimized for efficacy and safety during treatment. The primary endpoint was the proportion of pts with ≥ 35% reduction in spleen volume at week (wk) 24 of therapy, assessed by blinded review of spleen MRI or CT. Secondary endpoints were durability of spleen response, changes in symptom burden (symptom score [SS] measured daily with MFSAF v2.0), and survival. Exploratory endpoints included change in quality of life (QoL; EORTC-QLQ C30) and fatigue (PROMIS-FS), molecular and serum biomarkers, and transfusion dependence. Results: 309 pts were randomized; 155 to 424 and 154 to PB. Median follow-up is 32.2 weeks. The primary endpoint response rate was 41.9% vs 0.7% (424 vs PB p<0.0001). Median duration of response has not been reached. At wk 24 the proportion of pts with ≥ 50% improvement in SS was 45.9% vs 5.3% (424 vs PB p<0.0001) and change in total SS was an improvement of 46.1% vs a worsening of 41.8% (424 vs PB p<0.0001). There were 10 vs 14 deaths (424 vs PB, HR 0.67, p=0.33). Changes in both QoL and fatigue mirrored changes in SS over time and all showed improvement relative to PB regardless of changes in hemoglobin. The most common AEs of any grade seen in >20% of pts on either arm of the study were (424 vs PB) abdominal pain (10.3% vs 41.1%), thrombocytopenia (34.2% vs 9.3%), fatigue (25.2% vs 33.8%), anemia (31% vs 13.9%), diarrhea (23.2% vs 21.2%) and peripheral edema (18.7% vs 22.5%). Anemia and thrombocytopenia were manageable and rarely (0.6% 424 vs 0.7% PB, each) led to withdrawal from the study. Conclusions: In this study, 424 demonstrated marked and sustained clinical benefits in spleen size, debilitating symptoms and QoL and an acceptable safety profile relative to PB in MF.

Total body irradiation (TBI) is a highly emetogenic component of the majority of conditioning regimens in use for bone marrow transplantation. Conventional antiemetic therapy fails to control nausea and vomiting induced by single fraction TBI in as many as 50% of patients. In a double blind study of 20 patients undergoing marrow transplantation, a single 8 mg ondansetron dose was compared with placebo given immediately prior to TBI. Our routine premedication of phenobarbitone and corticosteroid was also administered to all patients. All patients had received high dose melphalan the previous evening. Only 1 of the 10 patients in the ondansetron group experienced an emetic event compared with 5 of the 10 in the comparison group (p = 0.029). No significant adverse events were observed. Ondansetron appears to have extremely useful antiemetic activity during single fraction low dose rate TBI.