Salvage therapy with high-dose cytarabine and mitoxantrone in combination with all-trans retinoic acid and gemtuzumab ozogamicin in acute myeloid leukemia refractory to first induction therapy

Abstract

O utcome of patients with primary refractory acute myeloid leukemia remains unsatisfactory. We conducted a prospective phase II clinical trial with gemtuzumab ozogamicin (3 mg/m² intravenously on day 1), all-trans retinoic acid (45 mg/m² orally on days 4-6 and 15 mg/m² orally on days 7-28), high-dose cytarabine (3 g/m²/12 h intravenously on days 1-3) and mitoxantrone (12 mg/m² intravenously on days 2-3) in 93 patients aged 18-60 years refractory to one cycle of induction therapy. Primary end point of the study was response to therapy; secondary end points included evaluation of toxicities, in particular, rate of sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation. Complete remission or complete remission with incomplete blood count recovery was achieved in 47 (51%) and partial remission in 10 (11%) patients resulting in an overall response rate of 61.5%; 33 (35.5%) patients had refractory disease and 3 patients (3%) died. Allogeneic hematopoietic cell transplantation was performed in 71 (76%) patients; 6 of the 71 (8.5%) patients developed moderate or severe sinusoidal obstruction syndrome after transplantation. Four-year overall survival rate was 32% (95% confidence interval 24%-43%). Patients responding to salvage therapy and undergoing allogeneic hematopoietic cell transplantation (n=51) had a 4-year survival rate of 49% (95% confidence intervaI 37%-64%). Patients with fms-like tyrosine kinase internal tandem duplication positive acute myeloid leukemia had a poor outcome despite transplantation. In conclusion, the described regimen is an effective and tolerable salvage therapy for patients who are primary refractory to one cycle of conventional intensive induction therapy. (clinicaltrials.gov identifier: 00143975) Salvage therapy with high-dose cytarabine and mitoxantrone in combination with all-trans retinoic acid and gemtuzumab ozogamicin in acute myeloid leukemia refractory to first induction therapy

The promising role of antibody drug conjugate in cancer therapy: Combining targeting ability with cytotoxicity effectively

“… 52 , 53 The fractionated dosage of GO was observed in the phase 2 MyloFrance‐1 trial for the first Relapsed or refractory (R/R) CD33‐positive AML patients; 26% of patients achieved complete remission (CR) with a median relapse‐free survival (RFS) of 11 months and manageable toxicities, which led to FDA approval. 54 Several studies explored the efficacy of GO in combination with chemotherapy as salvage therapy, including the combination of GO and DA therapy (daunorubicin plus cytarabine) (overall response rate [ORR]: 38.8%; CR rate: 22.2%; 2‐year RFS rate: 18.5%; 2‐year overall survival [OS] rate: 26%), 55 the combination of GO and MYLODAM schema (cytarabine and mitoxantrone) (ORR: 67%; 2‐year RFS rate: 36%; 2‐year OS rate: 54%), 56 the combination of GO and high‐dose cytarabine, mitoxantrone, and all‐trans retinoic acid (ATRA) (CR/CR with incomplete hematologic recovery [CRi] rate: 51%; ORR: 61.5%; 4‐year OS rate: 32%), 57 as well as the combination of GO and decitabine (CR/CRi rate: 18%; median OS: 3.5 months). 58 Moreover, two phase 1/2 trials showed the enhanced efficacy of hypomethylating agent therapy in addition to GO through epigenetic effects in R/R AML patients (NCT00766116 trial, GO, plus azacytidine; CR/CRi rate: 24%; NCT00895934 trial, GO, azacytidine, plus vorinostat; CR/CRi rate: 41.9%; median OS: 224.5 days).…”

Pediatric acute myeloid leukemias treatment: current scientific view

“…Проведение последующей ТГСК оказалось возможным у 30 % больных, но лишь треть из них пережили 3летний рубеж без признаков забо левания [80,81]. Обсуждаются возможности комбина ции гемтузумаба озогамицина с цитарабином, мито ксантроном и ATRA [32], а также с цитарабином и Lаспарагиназой [82].…”

Gemtuzumab ozogamicin and novel antibody-drug conjugates in clinical trials for acute myeloid leukemia

“…57 (61.5%) patients achieved ORR including 47 (51%) CR. Among them, 51 patients underwent AlloSCT and had a 4-year OS rate of 49% [54]. For patients who were unable to tolerate intensive chemotherapies, HMAs appeared to be appropriate alternatives.…”