Jamie Oliva

Phase I study of cladribine, cytarabine (Ara-C), granulocyte colony stimulating factor (G-CSF) (CLAG Regimen) and simultaneous escalating doses of imatinib mesylate (Gleevec) in relapsed/refractory AML.

Receptor activated tyrosine kinases such as c-kit, c-fms and PDGFR are known targets of inhibition by imatinib mesylate (Gleevec) and are expressed on AML blasts. Marrow stromal cells and monocytes express KIT ligand, M-CSF and PDGF and are therefore capable of activating survival pathways in these leukemic cells. Given the synergy in vitro between Ara-C and imatinib mesylate on AML cell growth inhibition, we initiated a Phase I study combining CLAG+imatinib mesylate in AML patients. Patients with relapsed, refractory AML or CML myeloid blast crisis were eligible to receive Cladribine 5mg/m(2) days 3-7, Cytarabine 2gm/m(2) days 3-7, G-CSF 300mcg days 2-7, and escalating doses of imatinib mesylate given on days 1-15. The level 1 Gleevec dose was 400mg, while level 2 was 600mg and the level 3 dose 800mg. A total of 16 patients were enrolled, 15 AML and 1 CML myeloid blast crisis. The dose escalation occurred as planned and there was no clear evidence of added toxicity due to imatinib mesylate. One patient with an extensive cardiac history died of cardiac causes on day 1 of therapy however no other deaths occurred within 30 days of starting therapy. One patient had a Grade 3 skin rash at dose level 2. The most common toxicities encountered during induction therapy were nausea, vomiting, rash and diarrhea that were transient and/or reversible. At the 800mg dose 1 patient developed a decline in cardiac ejection fraction on day 20 who later died of sepsis, so this was considered a dose limiting toxicity. Of 16 evaluable patients 11 achieved a hypocellular marrow after initial induction with 1 additional patient achieving a hypocellular marrow following a second course of the same regimen. Four patients (25%) achieved a complete morphologic response with normal cytogenetics, 2 patients (12.5%) achieved a complete morphologic response only and 1 patient had a complete response in the bone marrow but incomplete blood count recovery. The overall response rate was 43.8%. The median overall survival was 175 days (95% CI 16.24-333.76) and the median relapse free survival was 76 days. The addition of imatinib mesylate to CLAG was well tolerated with acceptable toxicities and response rates comparable to other salvage regimens. To assess the efficacy of imatinib mesylate in combination with CLAG, a larger phase II trial is now planned.

Late relapses following high-dose autologous stem cell transplantation (HD-ASCT) for Hodgkin's lymphoma (HL) in the ABVD therapeutic era.

Salvage chemotherapy followed by high-dose autologous stem cell transplantation (HD-ASCT) is the standard of care for patients who have relapsed or refractory Hodgkins lymphoma (HL). Few trials have had long-term follow-up post-HD-ASCT in the ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) era of treatment. We reviewed 95 consecutive patients who received HD-ASCT for relapsed or refractory HL following ABVD failure between 1990 and 2006 at the University of Rochester. Median follow-up for survivors was 8.2 years. All patients received HD-ASCT following upfront ABVD (or equivalent) failure. At 5 years, overall survival (OS) and event-free survival (EFS) were 54% and 37%, respectively. In total, 54 patients have died; 37 of these patients died directly of HL. Notably, there were 19 deaths >3 years post-HD-ASCT and 13 of these late deaths are directly attributable to HL. Furthermore, there were 51 documented relapses, 9 of which occurred >3 years post-HD-ASCT. In contrast to other studies, we did not observe a plateau in EFS following transplantation. Patients appear to be at continuous risk of recurrence beyond 3 years after HD-ASCT. Our results emphasize the importance of long-term follow-up for both toxicity and recurrence, and have important implications in defining success of posttransplantation maintenance strategies.

The hematopoietic cell transplantation specific comorbidity index and survival after extracorporeal photopheresis, pentostatin, and reduced dose total body irradiation conditioning prior to allogeneic stem cell transplantation

Hematopoietic-cell-transplantation-specific-comorbidity-index (HCT-CI) has been reported as a predictor of survival in allogeneic-transplant recipients; however its validity has recently been challenged. We evaluated the association of HCT-CI with survival of transplant recipients who underwent reduced-intensity-conditioning (RIC) with photopheresis, pentostatin, and total-body-irradiation. Median age of 103 patients selected was 55 years. Most patients (58.3%) had high (≥ 3) HCT-CI. Median OS was 298 days. Age, disease-type, disease-status, HCT-CI correlated with survival on bivariate analysis. On multivariate analysis, only HCT-CI was significantly associated with OS (low HCT-CI HR=0.29, CI 0.091-0.886; intermediate HCT-CI HR=0.41, CI 0.226-0.752). Our findings suggest HCT-CI as an independent predictor of survival in the setting of RIC transplants.