Triplet Regimen Active Against Relapsed/Refractory Pediatric AML

Yoav Messinger, MD

The combination of clofarabine, cyclophosphamide, and etoposide (CCE) reached an overall response rate of 41% in a small study of children and adolescents with relapsed/refractory acute myeloid leukemia (AML).

Four of 17 patients (24%) had a complete response (CR), 1 had a CR with incomplete platelet recovery, and 2 achieved a partial response. However, only 2 of the responders were still alive at the time of analysis.

“The combination of CCE induced response in 41% of heavily pretreated children with relapsed or refractory AML. The most important limiting toxicity was prolonged bone marrow aplasia seen in 5 patients, which can be ascribed to the high dose of clofarabine and cyclophosphamide” first author Yoav Messinger, MD, Children’s Hospital and Clinics of Minnesota, and coinvestigators wrote.

“Additional infectious and hepatic toxicity was significant. Because this combination does not include anthracyclines, CCE with reduced doses of clofarabine and cyclophosphamide should be evaluated in a clinical trial for relapsed or refractory AML,” added Messinger et al.

Seventeen pediatric patients at 7 medical centers from 2009 to 2013 were assigned to 40 mg/m² daily of clofarabine, 440 mg/m² daily of cyclophosphamide, and 100 mg/m² daily of etoposide for 5 consecutive days. Fourteen patients received 1 cycle and 1 patient received 2 cycles. Two patients discontinued treatment during cycle 1 for toxicity—transaminitis in 1 patient and transaminitis, acute renal failure, and coagulopathy in the second.

Patients were selected for the regimen at the choice of their treating oncologist. No specific selection criteria were used but all patients had either relapsed with AML or were refractory to prior therapy.

Eight patients were in first relapse and 9 had primary refractory disease. One patient had therapy-related AML. One patient had refractory extramedullary disease but no bone marrow involvement at the time of treatment. The median number of previous treatment regimens was 2 (range, 1-5), and 2 patients underwent allogeneic HSCT for leukemia prior to receiving the triplet regimen.

Ten patients received G-CSF as supportive care. Nine others received antifungal prophylaxis with voriconazole or fluconazole.

Four patients were alive without disease at a median follow-up of 60 months (range, 51-65)—3 after allogeneic hematopoietic stem-cell transplantation (HSCT) following the triplet and 1 after an allogeneic HSCT following a second relapse of AML, followed by secondary acute lymphoblastic leukemia, which was successfully treated. Estimated overall survival (OS) at 60 months was 24%, with a median survival of only 3.2 months (95% CI, 0-8.7).

“Most of our patients were treated after at least 2 regimens failed and more than half had primary refractory disease, suggesting that our patients had resistant disease at the time of CCE treatment,” wrote Messinger et al. “This may explain the lower CR rate and lower OS rate observed in our review.”

Four patients (24%) had marrow aplasia with no evidence of leukemia after receiving the triplet, so researchers could not determine remission status for these patients. Of this group, 2 had refractory disease before therapy. One of these 2 patients underwent HSCT in marrow aplasia and remains alive 61 months after undergoing CCE. The other 3 patients who had aplasia after treatment died of toxicity or infection.

Five patients had disease resistant to the triplet and of these, 4 died of progressive disease shortly after receiving treatment. One patient proceeded directly to allogeneic HSCT despite active disease and remained alive without evidence of disease 58 months following HSCT.

Thirteen of 17 patients in the study have died. Six died of progressive disease, 5 from treatment-related toxicity prior to HSCT, and 2 from transplant-related complications.

Toxicity data was available for 16 patients. One patient had sinusoidal obstructive syndrome and pleural effusions that developed 24 hours after the final dose of the triplet that then progressed to multi-organ system failure. That patient died 11 days later, before bone marrow evaluation could be performed.

The most common toxicities were cytopenia in (n = 16), bone marrow aplasia in (n = 5), and liver toxicity (n = 4).

Five patients developed infectious complications: Candida Tropicalis fungemia, human herpesvirus-6 (HHV-6) viremia and coagulase negative staphylococcus sepsis, aspergillus pneumonia, HHV-6 meningitis, Clostridium difficile (C. diff) colitis, enterococcus sepsis and culture negative sepsis, and viridans streptococcus.

Messinger Y, Boklan J, Goldberg J, et al. Combination of clofarabine, cyclophosphamide, and etoposide for relapsed or refractory childhood and adolescent acute myeloid leukemia. Pediatr Hematol Oncol [published online October 17, 2017]. doi: 10.1080/08880018.2017.1360970.