Unsatisfactory Outcome of Pediatric Relapsed and Refractory AML Treated with Clofarabine Combined with Topotecan, Vinorelbine and Thiotepa (TVTC)

Introduction Current curative strategy for children after one or more relapses of AML or for those with primary refractory AML (ref/rel AML) should include allo-HSCT. There is no consensus regarding a choice of reinduction chemotherapy regimen to induce remission prior HSCT in these highly drug-resistant patients. It is important to prevent further toxicities especially associated with anthracyclines widely used in the front-line therapies. Pediatric phase II study demonstrated promising efficacy of TVTC, anthracycline-free protocol resulting in remission achievement and successful transfer to HSCT in 8 of 12 patients with pediatric ref/rel AML (Shukla N. et al. Pediatr Blood Cancer 2014;61:431-435). Further data concerning clinical effectiveness of this regimen are very limited.

Patients and Methods A retrospective analysis of clinical outcomes was performed for 10 pediatric patients (aged 2.5-17 years, median 13 years) treated with TVTC protocol for ref/rel AML at Polish Pediatric Leukemia/Lymphoma Study Group institutions between February 2014 - May 2015. Eight patients had relapsed AML (first relapse n=5, second n=3), 2 had refractory disease. The protocol consisted of clofarabine 40mg/m²/day i.v. x 5 days, topotecan 1mg/m²/day i.v. continuous infusion x 5 days, vinorelbine 20mg/m²/week i.v. x 3, and thiotepa 15mg/m²/day i.v. x 1 day. Four patients received 2 cycles, and 6 patients one cycle of the regimen. Evaluation of results was based on the criteria presented in the trial report by Shukla N.et al.

Results Two patients were not evaluable for response due to complications during the first TVTC cycle; one died of a sudden septic shock of undetermined etiology, another one developed a rapid respiratory failure in the course of invasive fungal infection and died two months later in persistent pancytopenia. Neither CR nor CRp were reported for the remaining cases. Two patients were subsequently eligible for HSCT. One patient treated for second AML relapse, demonstrated after one cycle of TVTC <5% blasts in hypocellular bone marrow without hematopoietic recovery - partial response with marrow aplasia (PRa) according to criteria in TVTC phase II trial report by Shukla N. et al. After the second cycle, his bone marrow was aplastic with no evidence of leukemia, so the patient received his second alloHSCT. He is currently alive +13 months post transplant. Another female patient suffered from second relapse of a secondary AML following multi-regimen oncological treatment of 3-year duration for neuroblastoma. She showed a massive increase in marrow blast count after one TVTC cycle, but after a second cycle she achieved PRa followed by her second alloHSCT. The patient is currently alive +4 months post transplant with no evidence of leukemia.

Of the remaining 6 patients, 2 did not respond to 2 cycles of TVTC and the other 4 to one cycle. The latter 4 patients failed to continue chemotherapy due to rapid disease progression and the following toxicities: AlAT≥ grade 3 n=3, Staphylococcus haemoliticus sepsis n=1, HSV-1 infection n=1, clonic-tonic seizures n=1.

Of the presented 10 cases, only 2 patients survived with the follow-up since HSCT of 13 and 4 months, respectively. Eight patients died of disease progression and therapy-related toxicities (including 3 early deaths).

Conclusions

In general, the outcome of ref/rel AML patients treated with TVTC protocol in presented off-trial pediatric settings deviates unfavorably from other published clofarabine-based studies. However, it shows that this regimen might be beneficial as salvage therapy for some children even extremely heavily pretreated. Progression of AML after first TVTC cycle does not definitely preclude a meaningful response to the second cycle. More data is required for further and individualized evaluation of TVTC regimen efficacy in ref/rel AML.