All-Trans Retinoic Acid and Gemtuzumab Ozogamicin as Adjunct To Salvage Therapy in Primary Refractory Acute Myeloid Leukemia: Results of Consecutive Phase II Studies of the AMLSG.

Background: In primary refractory patients the achievement of a response to salvage therapy is of enormous prognostic impact.

Aims: To evaluate the impact of all-trans retinoic acid (ATRA) and gemtuzumab ozogamicin (GO) given as adjunct to high-dose cytarabine based intensive salvage therapy in primary refractory younger patients on clinical outcome.

Methods: Between 1993 and 2006 264 consecutive patients (median age: 48 yrs) were evaluated. All patients had primary refractory AML after one cycle of ICE (idarubicine, cytarabine, etoposide). The different salvage therapies were as follows: from 1993–1998: S-HAM for patients <55 years of age [cytarabine 3g/m² bid. days 1,2,8,9, mitoxantrone 10mg/m² days 3,4,10,11] and HAM for patients >=55 years of age [cytarabine 3g/m² bid., days 1–3, mitoxantrone 12mg/m² days 2,3]; from 1998 to 2004 A-HAM [HAM with ATRA 45mg/m² days 3–5, 15mg/m² days 6–28]; from 2004 up to date: GO-A-HAM [A-HAM with gemtuzumab ozogamicin 3g/m² day 1].

Results: The distribution of the different salvage therapies was HAM n=21, S-HAM n=22, A-HAM n=118, GO-A-HAM n=62, other n=31, or no further therapy n=10. CR-rate according to salvage therapy was GO-A-HAM 49%, A-HAM 34% S-HAM 23%, HAM 14%. Treatment related mortality did not differ between regimens. No CTC-grade 3–5 liver toxicity was seen in patients receiving GO-A-HAM. Logistic regression on the achievement of CR revealed that regimens containing ATRA (odds ratio 2.0, p=0.05) and GO (odds ratio 1.9 p=0.05) were associated with response. 151 of 264 patients have received a stem cell transplantation as consolidation therapy (n=59 MRD, n=79 MUD, n=6 haplo-identical donor, n=7 autologous). The rates of severe veno occlusive disease after transplant was identical (5%) for patients receiving a salvage therapy including GO and those who did not. Survival analysis revealed a significant difference (p= 0.00178) with a median survival of 16.2 months for GO+ATRA, 12.5 months for ATRA versus 7.2 months for the others.

Conclusions: Although retrospective in nature our study suggests that ATRA and GO as adjunct to salvage therapy improves CR rates and survival in primary refractory AML patients.