The only curative option for adult patients with refractory or relapsed ALL is allogeneic haematopoietic stem cell transplant (allo-HSCT), which can offer a 28-34% long term survival in transplanted patients. However the actual feasibility of allo-HSCT is only 20-30% in unselected patients because of the low rate (30-50%) of complete remission (CR) achieved with salvage regimens (Tavernier, 2007- Thomas, 1999), the high rate of early relapse (Martino, 1999) and the difficulties in finding a suitable donor before progression (Davies, 1996). Hence, relapsed ALL can be actually cured in less than 10% of unselected adult patients. Using a second line treatment capable of obtaining a higher proportion of CR of longer duration may improve the dismal overall prognosis of patients. We report on the efficacy and toxicity profile of the combination of 6-metilprednisolone, mitoxantrone, etoposide and high-dose cytarabine (MECp), a salvage regimen containing cytostatic drugs to which patients had not been exposed during first line therapy, except for cytarabine at lower doses.
Between October 2000 and May 2009, 18 refractory/relapsed ALL patients were treated at our Institution with MECp regimen, consisting of a single course of etoposide 80mg/mq/die iv, cytarabine 1000mg/mq/die iv for 6 hours and mitoxantrone 6mg/mq/die iv 9 hours after cytarabine infusion for 6 days associated to metilprednisolone 50 mg/mq/die for 21 days, subsequently tapered to zero over one week. Three patients received an experimental sequential pulsed chemotherapy program in a multiinstitutional setting. At diagnosis, all patients had been treated according to the NILG-ALL 00/09 program (Bassan, Blood 2009). Four had been refractory to induction therapy and 14 had relapsed after a median of 12 months (range 3-43), 11 while on consolidation/maintenance, one after allo-HSCT, two after 3 and 12 months from the end of maintenance. There were 10 males and 8 females with a median age of 28 (range 17-64). ALL lineage was B in 9 cases (4 pro-B, 4 common, 1 pre B), T in 8 (5 pro-T, 3 cortical-TIII) and biphenotypic in 1. Molecular studies showed MLL/AF4 rearrangement in 3 and bcr/abl rearrangement in 3 cases, all before tyrosine-kinase inhibitors were available. Karyotypic abnormalities were present in 10 of 16 evaluable cases. Patients were treated in single/double bed rooms with reverse isolation. In 3 cases treatment duration was reduced to 4 days.
CR was obtained in 13 of 18 patient (72,2%), independently of immunophenotype and time to relapse. CR rate was 100% in all ten patients with karyotypic abnormalities. Three patients (16%) died in aplasia during treatment, 2 of septic shock and 1 of unexplained shock. Two patients (T-ALL) were resistant. Recovery of neutrophils (>0,5×109/L) and platelets (>20×109/L) required a median of 22 days (range 17-37) and 28 days (range 21-45) from the start of therapy, respectively. Infections were documented in 9 of 18 (50%), being fatal in 2 (11%). Non-haematologic toxicity, mainly mucositis, was negligible. The median duration of CR was 5 months (range 2-5) which allowed 9 of 13 CR patients (69%) to undergo allo-HSCT (7 MUD, 1 HLA-identical sibling and 1 cord blood) after a median of 4 months (range 2-7) from CR. Reason for not being transplanted was failure of donor search in 4 patients who relapsed a median of 4 months. Causes of death included progressive disease in 7 patients, in 3 cases after HSCT, and transplant-related toxicity in 3 patients. The median survival of patients achieving CR was 13 months (range 7-33) and overall survival of the entire cohort was 8 months (range 1-33m).
With MECp, a combination of drugs not used during previous first-line therapy, a higher CR rate (72%) than commonly reported could be obtained, with acceptable toxicity. CR duration was long enough to allow 44,4% of patients to receive a non-family donor allo-HSCT, which is presently the best, yet still unsatisfactory, treatment option for adult patients with refractory/relapsed ALL.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.