A Novel Sequential Treatment Utilizing CPX-351 As Salvage Chemotherapy Followed by a Reduced Intensity Conditioning Allogeneic Stem-Cell Transplantation for Patients with Refractory Leukemia

Allogeneic Hematopoeitic Stem cell Transplantation (HSCT) using standard ablative or reduced intensity conditioning regimens is often ineffective in patients with primary refractory and relapsed acute leukemia. Sequential administration of cytoreductive chemotherapy followed by a Reduced Intensity Conditioning (RIC) regimen may lead to improved results (Schmid et al Blood 2006). CPX-351 is a novel liposomal formulation that encapsulates the combination of cytarabine and daunorubicin in a fixed 5: 1 ratio. In vitro, it selectively concentrates in the marrow compared to other organs. Clinically, CPX-351 is well tolerated, with a favorable extramedullary toxicity profile, making it an appropriate cytoreductive agent prior to conditioning for HSCT.

Patients and Methods: In a 3+3 phase I trial, patients with relapsed or primary refractory acute leukemia were treated with escalating doses of CPX-351 starting at 60 mg/m2 on days - 28, -26 and -24 followed by RIC with IV busulfan 3.2 mg/kg/day on days -6 to -3 and fludarabine 30 mg /m2/day on days -6 to -3 (Bu/Flu). GVHD prophylaxis consisted of tacrolimus starting on day -3, at a starting dose of 0.03 mg/kg/24 hours as a continuous infusion and adjusted to achieve a trough level between 10 and 15 ng/ml. and methotrexate 10 mg/m² IV on days 1, 3, 6 and 11 (Methotrexate dose was reduced to 5 mg/m² after observing grade 3 mucositis in the first 3 patients). The protocol was amended to include a phase 1B in addition to the above mentioned phase 1A. In phase 1B, patients were treated with escalating doses of CPX-351 starting at 60 mg/m2 on days - 21, -19 and -17 followed by IV Bu/Flu conditioning. Thirty two patients (AML-27, ALL-2, CML in blast crisis-1, high risk MDS-2) have been enrolled to date. Nine patients are in-evaluable due to short follow up (2), sepsis resulting in aborted transplant plans (4), appendicitis (1), early death at day +12 due to sepsis prior to engraftment (1) and donor's unavailability after receiving one dose of CPX-351 (1). Twenty three patients who underwent HSCT are evaluable (AML-19, ALL-2, high risk MDS-2). We calculated the transplant co-morbidity index as well as the prognostic score identified by the CIBMTR in patients with refractory leukemia undergoing HSCT (Duval et al. JCO 2010). The twenty three evaluable patients have a median age of 58 (range 33–72), co- morbidity index 2 (range 0–6) and CIBMTR score 3 (range (2–5). All patients received HLA compatible grafts (MUD-15, MRD-8).

Nineteen patients achieved complete hematologic remission by day 30 post transplant. All nineteen patients had adequate donor's engraftment for neutrophils and platelets at a median time of 15 days (range 12–35) and 16.5 days (range 10–90) respectively. Four patients continued to have active disease by day 30. Five more patients had a disease relapse before or shortly after day 100 and one patient had a relapse 22 months post transplant for a total of 10 relapsed patients (43%). Three patients died of acute GI GVHD 2, 6 and 9 months after transplant (all were in remission). One patient died of a pre existing brain tumor progression and one patient died of liver cirrhosis due to iron overload one year after transplant for a total non relapse mortality of 21%. At a median follow up of 6 months, eight patients are alive without evidence of leukemia (35%). Acute GVHD grade II-IV occurred in 8 patients (35%) and was the cause of death in 3 patients. Chronic GVHD occurred in 3 patients (13%). Grade 2 mucosal injury as defined by Bearman toxicity criteria was the most common toxicity developing in 15 patients (65%).

The maximum tolerated (MTD) dose of CPX-351 followed by RIC HSCT was not found after a series of 4 treatment cohorts on Arm A and 2 treatment cohorts on arm B. Further dose escalation to define MTD is ongoing in both arms. Remission status is not a prerequisite for a successful outcome in selected patients who otherwise are candidates for transplantation.

Off Label Use: CPX is not FDA approved. Feldman:celator: Consultancy.