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 stem cell transplantation (allo SCT) using standard ablative or reduced intensity conditioning regimens is often ineffective in patients with primary refractory and relapsed acute leukemia. Recent reports, however, have suggested that 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 attractive cytoreductive agent prior to conditioning for allo SCT.

In a phase I trial, patients with relapsed or primary refractory acute leukemia who were otherwise transplant candidates 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. 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. Eleven patients (AML-8, ALL-2, CML in blast crisis-1) have been enrolled to date. Seven patients have been entered into cohort 1 and received 60 mg.m2 and 4 patients entered cohort 2 and received 80 mg/m2 of CPX-351. Four patients are inevaluable due to short follow up (1), sepsis resulting in abrted transplant plans (2) and donor's unavailability after receiving one dose of CPX-351 (1). Seven patients who underwent allo SCT are evaluable (AML-6, ALL-1). Six patients were enrolled on cohort 1 and one patient on cohort 2. All patients received HLA compatible grafts (MUD-6, MRD-1). One patient had primary induction failure and 6 had relapsed refractory disease. Six evaluable patients had one or more poor risk features (2 patients with monosomy 7, 4 patients had prior MDS and 2 patients with secondary AML).

All evaluable patients achieved adequate neutrophil engraftment at a mean time of 18 days (range 12–35). Six patients achieved adequate platelet engraftment at a mean time of 18 days (range 12–33). All patients achieved complete hematologic and cytogenetic remission upon full blood counts recovery post transplant, mean 34 days (range 30–47). One patient (ALL) on cohort 2 had a disease relapse on day 60 and died of leukemia. The 100 days overall survival and disease free survival was 85%. At a mean follow up time of 7.5 months, one patient died of disease relapse, one patient died of acute GI GVHD at 6 months (second allo SCT) and 5 patients are alive without evidence of leukemia. Acute GVHD occurred in 3 patients. One patient with a stage 2 skin GVHD had a complete resolution and 2 patients had stage 3–4 GI GVHD upon cessation of immunosupression 5 and 9 months post transplantation. Grade 3 mucositis developed in the first 3 patients prompting a protocol amendment to change methotrexate dose to 5 mg/M2. Four patients received the lower methotrexate dose had grade 2 mucositis. One patient had a moderate decrease in left ventricular ejection fraction 2 weeks after receiving CPX-351 One patient had grade 3 transaminitis that resolved spontaneously.

CPX-351 followed by RIC allo SCT is feasible, and further dose escalation to define MTD is ongoing. A phase 1 B study is planned to shorten the interval between CPX-351 and the conditioning regimen. Remission status is not a prerequisite for a successful outcome in selected patients who otherwise are candidates for transplantation.

Roboz:Genzyme Corporation: Research Funding.