AL-02. Treatment options for the patients over 18 years old with refractory/relapsing acute myeloid leukemia

Summary

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients (pts) with refractory/relapsed acute myeloid leukemia (r/rAML) offers a chance for long-term remission. The use of high-dose cytarabine in combination with purine analogues increases response rates in pts with a primary refractory AML (refAML) from 45% to 65%. The search for targeted drugs to treat r/rAML is a major trend in hematological malignancies. Gemtuzumab ozogamicin* (GO) is a recombinant, humanized anti-CD33 monoclonal antibody covalently attached to the cytotoxic antitumor antibiotic calicheamicin. Our aim was to evaluate efficacy and toxicity of FLAG and GO-FLAG therapy in adult pts with r/rAML and to determine predictors of response to GO-FLAG therapy.

Patients and methods

87 pts were included in the analysis. “FLAG” received 39 pts, with a median age of 34 (18-59). RefAML – 20 pts, relapsed AML (RelAML) – 19 pts. Genetic risk was stratified as favorable – 3/39, 7%; intermediate – 17/39, 44%; unfavorable – 19/39, 49%. “GO-FLAG”: 48 pts at a median age of 34 (18-61). RefAML – 16/48, 33%; RelAML – 32/48, 67%. Distribution by genetics risk: favorable – 5/48, 10%; intermediate – 20/48, 42%; unfavorable – 23/48, 48%.

Results

Overall response (OR) after “FLAG” was achieved in 23/39 (59%), i.e., complete remission (CR), in 46% (n=18); CR with incomplete recovery (PRi/r), in 13% of cases (n=5). Allo-HSCT was performed in 23 pts (59%): haploidentical, 6; matched, 17 (related, 1; unrelated, 16). The median time from OR to allo-HSCT was 55 days. Median follow-up was 42 (0.4-52.6) months. Overall survival (OS) was 28.2% (CI95% 16.5-43.8). The pts with OR (n=23) had two-year OS (2OS) 43.5% (CI95% 25.6-43.2) and two-year disease-free survival (2DFS) was 34.8% (CI95%18.8-55.1). Complications: grade 4 neutropenia; grade 4 thrombocytopenia, 100%; sepsis – 28% (n=11); invasive fungal diseases, 13% (n=5); bacterial pneumonia, 8% (n=3); hemorrhagic complications, 8% (n=3). Early mortality was observed in 10% of the cases (n=4), due to intracranial hemorrhage (n=3); AML progression (n=1). After “GO-FLAG”, OR was achieved in 36/48 (75%), with CR rate of 50%, CRi/r, in 25% of the cases. Pts with extramedullary diseases achieved OR in 87% (13/15), with CR of 60%. The lowest OR rate was in unfavorable genetic cases (p=0.02). Increased OR was observed in the pts with blast levels of <50% (p=0.042) and in relapsed AML (p=0.07). Allo-HSCT after “GO-FLAG” was performed in 25 pts (52%): haploidentical (n=11), matched (n=14; related HSCT, 5 and unrelated, 9). Median time to allo-HSCT was 40 days. Median follow-up was 14.4 (0.4-35) months. OS – 31.3% (CI95% 20-45). Among pts with OR (n=36), 2OS was 38.9% (CI95% 25-55), 2DFS, 27.8% (CI95% 17-44). Complications: grade 4 neutropenia and grade 4 thrombocytopenia were documented in all cases; sepsis, 40% (n=19), invasive fungal diseases, 6% (n=3); bacterial pneumonia, 8% (n=4); severe hemorrhagic complications were seen in 1 case, with no SOS observed. Early mortality comprised 4/48 (8%; CI95% 3-20), due to infections (n=3), AML progression (n=1).

Conclusions

“FLAG” and “GO-FLAG” showed high efficacy and acceptable toxicity. In the “GO-FLAG” group, a higher rate of OR was observed (75% vs 59%, p=0.16). Significantly increased OR rate was achieved after “GO-FLAG” in the pts with extramedullary disease (87%, p=0.04). The following predictors of clinical response could be considered: blast levels of < 50% (p=0.042), relAML (p=0.07), favorable genetic background (p=0.02).

*GO was provided as part of the early access program.

Keywords

Acute myeloid leukemia, target therapy, gemtuzumab ozogamicin.