A Phase I Study of Oral 6-Thioguanine, Followed by Continuous Infusion Cytarabine, Followed by Intramuscular PEG-Asparaginase (“TGAP”) in Children with Relapsed or Refractory Acute Leukemia or Non-Hodgkin’s Lymphoma.

Background: We found enhanced cytotoxicity against human leukemia cell lines resistant to cytarabine with the sequence specific three-drug combination, 6-thioguanine (6TG) + cytarabine + PEG-asparaginase (“TGAP”) [Fu et al, Cancer Chemother Pharmacol 48:123–133, 2001] and developed a Phase I study to evaluate TGAP’s feasibility in children with relapsed/refractory leukemia or non-Hodgkin’s lymphoma with marrow involvement.

Patients and Methods: Three days of twice daily 6TG was followed by cytarabine @ 487 mg/m² loading dose and 126 mg/m²/hr by 72-hour continuous infusion. Cytarabine was followed by pegylated asparaginase @ 2,500 units/m². Complete response (CR) required fewer than 5% marrow blasts with recovery of neutrophils and platelets. Partial response required marrow blasts between 5% and 25% with no peripheral blasts.

Results: Between April 1999-January 2006, 11 patients, age 1 to 18 years, were enrolled after local IRB approval and individual or parental informed consent. Six patients had relapsed/refractory ALL, 4 patients had relapsed ANLL (2/4 had Down syndrome) and 1 patient had relapsed Burkitt’s lymphoma/leukemia. Six patients were enrolled at dose level #1 (6TG @ 100mg/m2/dose) and 5 patients were enrolled at dose level #2 (6-TG @ 150mg/m2/dose). The last patient enrolled was later found ineligible, but was included for toxicity. Chemotherapy was well tolerated in 9 patients. All patients developed grade 3–4 neutropenic fevers or bacteremia. Other grade 3–4 toxicities included transient elevations in transaminases. Asparaginase related pancreatitis occurred in two patients, in one with symptoms. Dose limiting acute vascular leak syndrome occurred in two patients at dose level #2 during the cytarabine infusion and just after the completion of therapy. Both required mechanical ventilation but recovered fully. Complete responses (CR) occurred in 2 of 10 evaluable patients and partial response (PR) occurred in 2 for total response rate (CR + PR) of 40%. All four responders tolerated a second course of TGAP. Both CR patients subsequently underwent matched unrelated BMT with no veno-occlusive disease or other excessive toxicity. In one CR patient, ara-CTP incorporation in the patients leukemic blasts ex vivo studied at baseline, pre chemotherapy, and repeated after 6TG and a 24-hour infusion of cytarabine showed a four-fold increase in intracellular ara-CTP, confirming our previous work in cell lines.

Conclusions: TGAP is a feasible combination for patients with relapsed leukemias. A phase II study is currently under development using the maximum tolerated dose for 6TG of 100mg/m2/dose in combination with CI ara-C and IM PEG-asparaginase.