LACE - an Effective Conditioning Regimen for Lymphoma Patients Undergoing Autologous Transplant- Analysis of Outcomes and Prognostic Factors

Background: High dose chemotherapy followed by autologous stem cell transplantation (ASCT) is the treatment of choice for patients with relapsed and refractory lymphomas. BEAM (BCNU, etoposide, cytarabine, melphalan) and CBV (cyclophosphamide, BCNU , VP-16) are most widely used conditioning regimens prior to ASCT in lymphomas. LACE has been found to be an effective regimen though outcome data is sparse.As BCNU was difficult to procure in India, we began using this regimen since November 2007. This study is a retrospective analysis to evaluate outcomes and possible prognostic factors in this cohort of patients.

Methods: All patients between November 2007- January 2014 who received LACE regimen for primary progressive, chemotherapy sensitive relapse or relapsed-refractory Hodgkin’s (HL) and non- Hodgkin’s lymphoma (NHL) were included.Patients received salvage chemotherapy with either GDP, ICE, MINE or DHAP with or without rituximab (NHL patients). PET-CT was performed in all patients after 2-3 cycles of salvage chemotherapy. Response assessment was performed according to Cheson’s criteria. Patients underwent peripheral blood stem cell collection after 3^rd or 4^th cycle of salvage chemotherapy.Conditioning regimen used was LACE (lomustine-200 mg/m² d-7, etoposide 1000mg/m² d-7, ara-c 2000 mg/m² d-6, d-5 and cyclophosphamide 1800 mg/m² d-4 to d-2). PET-CT was done on day 100, 1 year post transplant and then yearly for next 4 years. Incidence and grade of treatment related toxicity was recorded according to CTCAE V-3. Prognostic factors evaluated for overall survival (OS) and progression-free survival (PFS) included time between diagnosis – transplant; time between CR1 - first relapse; baseline, presalvage and pretransplant serum albumin,LDH and B2 microglobulin; PET positivity pretransplant, at day 100 and day 360; remission status at time of transplant; IPI (NHL) and IPS (HL) at baseline and at relapse; stage at diagnosis and at relapse. Probabilities of OS and PFS were estimated using the Kaplan–Meier method. Univariate comparisons of survival times for potential prognostic factors were made using the log-rank test. Multivariate analysis of significant factors was performed by Cox –regression analysis.

Results: Seventy patients had HL while 30 NHL (Male-73, Female-27) with median age at transplant of 23 years. In NHL cohort, 19 were DLBCL, 6 were T-cell lymphomas, 4 mantle cell lymphoma and 1 Burkitt’s lymphoma.The median time from complete remission (CR) to first relapse and time from diagnosis to transplant were 1.4 and 1.9 years respectively. The median number of lines of chemotherapy pre transplant was 2. GDP (53 patients) was the most commonly used salvage chemotherapy. At the time of transplant, 68% were in CR, 29% in partial remission (PR) and 3% had refractory state. The incidence of grade 3-4 oral mucositis was 8% with a median duration of 3.5 days. The incidence of grade 3-4 diarrhea was 4% with median duration of 3 days. Median days to myeloid and platelet engraftment were 10 and 13 respectively. The median follow-up was 2.9 years. The probability of OS and PFS at 5 years was 67% and 57% for the whole group, 73% and 62% in HL group and 51% and 46% in NHL group. Seven patients died due to transplant related causes which included 6 due to sepsis and 1 due to herpes simplex encephalitis. In univariate analysis for OS, PET negativity pre transplant (P= 0.03), at day 100 (P= 0.019) and at day 360 (P= 0.01) were associated with better OS. Similarly, HL patients with IPS 0-2 (P=0.002) at time of relapse had better OS. Univariate analysis for PFS showed that PET negativity pre transplant (P=0.002), at day 100 (P= 0.0001) and at day 360 (P=0.00) was associated with better PFS. HL patients with IPS 0-2 (P=0.000) and NHL patients with IPI 0-2 at time of relapse (P=0.007) had better PFS. Patients in CR at the time of transplant had better PFS than those in not in CR (P=0.008). Overall HL patients had better OS (P=0.037) and PFS (P=0.097) compared to NHL group. Multivariate analysis for OS (P= 0.021) and PFS (P=0.001) revealed PET negativity at day 100 as the only significant prognostic factor.

Conclusions: This is the largest reported cohort of lymphoma patients transplanted with LACE regimen. LACE is effective and well tolerated conditioning regimen in lymphoma transplant. PET negativity at various time points pre and post transplant prognosticates for better survival.