Efficacy and Safety of Gemtuzumab Ozogamicin in Patients With CD33-Positive Acute Myeloid Leukemia in First Relapse

PURPOSE: Three open-label, multicenter trials were conducted to evaluate the efficacy and safety of single-agent Mylotarg (gemtuzumab ozogamicin; CMA-676; Wyeth Laboratories, Philadelphia, PA), an antibody-targeted chemotherapy agent, in patients with CD33-positive acute myeloid leukemia (AML) in untreated first relapse.PATIENTS AND METHODS: The study population comprised 142 patients with AML in first relapse with no history of an antecedent hematologic disorder and a median age of 61 years. All patients received Mylotarg as a 2-hour intravenous infusion, at a dose of 9 mg/m2, at 2-week intervals for two doses. Patients were evaluated for remission, survival, and treatment-emergent adverse events.RESULTS: Thirty percent of patients treated with Mylotarg obtained remission as characterized by 5% or less blasts in the marrow, recovery of neutrophils to at least 1,500/μL, and RBC and platelet transfusion independence. Although patients treated with Mylotarg had relatively high incidences of myelosuppression, grade 3 or 4 hyperbilirubinemia (23%), and elevated hepatic transaminase levels (17%), the incidences of grade 3 or 4 mucositis (4%) and infections (28%) were relatively low. There was a low incidence of severe nausea and vomiting (11%) and no treatment-related cardiotoxicity, cerebellar toxicity, or alopecia. Many patients received Mylotarg on an outpatient basis (38% and 41% of patients for the first and second doses, respectively). Among the 142 patients, the median total duration of hospitalization was 24 days; 16% of patients required 7 days of hospitalization or less.CONCLUSION: Administration of the antibody-targeted chemotherapy agent Mylotarg to patients with CD33-positive AML in first relapse induces complete remissions with what appears to be a favorable safety profile.

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Pharmacokinetics of Gemtuzumab Ozogamicin, an Antibody-Targeted Chemotherapy Agent for the Treatment of Patients with Acute Myeloid Leukemia in First Relapse

The Journal of Clinical Pharmacology ◽

10.1177/00912700122012751 ◽

2001 ◽

Vol 41 (11) ◽

pp. 1206-1214 ◽

Cited By ~ 97

Author(s):

James A. Dowell ◽

Joan Korth-Bradley ◽

Hanjiu Liu ◽

S. Peter King ◽

Mark S. Berger

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Gemtuzumab Ozogamicin ◽

Targeted Chemotherapy ◽

Chemotherapy Agent ◽

First Relapse ◽

Acute Myeloid

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Antibody-targeted chemotherapy of older patients with acute myeloid leukemia in first relapse using Mylotarg (gemtuzumab ozogamicin)

Leukemia ◽

10.1038/sj.leu.2402677 ◽

2002 ◽

Vol 16 (9) ◽

pp. 1627-1636 ◽

Cited By ~ 164

Author(s):

RA Larson ◽

◽

M Boogaerts ◽

E Estey ◽

C Karanes ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Older Patients ◽

Myeloid Leukemia ◽

Gemtuzumab Ozogamicin ◽

Targeted Chemotherapy ◽

First Relapse ◽

Acute Myeloid

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Sequential Combination of Gemtuzumab Ozogamicin and Standard Chemotherapy in Older Patients With Newly Diagnosed Acute Myeloid Leukemia: Results of a Randomized Phase III Trial by the EORTC and GIMEMA Consortium (AML-17)

Journal of Clinical Oncology ◽

10.1200/jco.2013.49.0771 ◽

2013 ◽

Vol 31 (35) ◽

pp. 4424-4430 ◽

Cited By ~ 51

Author(s):

Sergio Amadori ◽

Stefan Suciu ◽

Roberto Stasi ◽

Helmut R. Salih ◽

Dominik Selleslag ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Older Patients ◽

Myeloid Leukemia ◽

Gemtuzumab Ozogamicin ◽

Phase Iii ◽

Newly Diagnosed ◽

Standard Chemotherapy ◽

Sequential Combination ◽

Grade 3 ◽

Acute Myeloid

Purpose This randomized trial evaluated the efficacy and toxicity of sequential gemtuzumab ozogamicin (GO) and standard chemotherapy in older patients with newly diagnosed acute myeloid leukemia (AML). Patients and Methods Patients (n = 472) age 61 to 75 years were randomly assigned to induction chemotherapy with mitoxantrone, cytarabine, and etoposide preceded, or not, by a course of GO (6 mg/m2 on days 1 and 15). In remission, patients received two consolidation courses with or without GO (3 mg/m2 on day 0). The primary end point was overall survival (OS). Results The overall response rate was comparable between the two arms (GO, 45%; no GO, 49%), but induction and 60-day mortality rates were higher in the GO arm (17% v 12% and 22% v 18%, respectively). With median follow-up of 5.2 years, median OS was 7.1 months in the GO arm and 10 months in the no-GO arm (hazard ratio, 1.20; 95% CI, 0.99 to 1.45; P = .07). Other survival end points were similar in both arms. Grade 3 to 4 hematologic and liver toxicities were greater in the GO arm. Treatment with GO provided no benefit in any prognostic subgroup, with the possible exception of patients age < 70 years with secondary AML, but outcomes were significantly worse in the oldest age subgroup because of a higher risk of early mortality. Conclusion As used in this trial, the sequential combination of GO and standard chemotherapy provides no benefit for older patients with AML and is too toxic for those age ≥ 70 years.

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A Prospective Monocentric Study of Fractionated Gemtuzumab Ozogamicin (GO) Combined to Standard-Dose Cytarabine in Older Patients with Acute Myeloid Leukemia (AML) in First Relapse,

Blood ◽

10.1182/blood.v118.21.3603.3603 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3603-3603

Author(s):

Sylvain Pilorge ◽

Sophie Rigaudeau ◽

Clémentine Sarkozy ◽

Anne L Taksin ◽

Hassan Farhat ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Median Duration ◽

Myeloid Leukemia ◽

Standard Dose ◽

Gemtuzumab Ozogamicin ◽

Molecular Profile ◽

Molecular Response ◽

Npm1 Mutation ◽

First Relapse ◽

Acute Myeloid

Abstract Abstract 3603 Aim. Gemtuzumab Ozogamicin (GO) is a potent antibody-directed chemotherapy against CD33 antigen. We have previously conducted a phase 2 study evaluating fractionated infusion of GO 3 mg/m2 on day 1, 4 and 7 combined to standard 3+7 DNR/cytarabine in patients aged 50 to 70 years with relapsed acute myeloid leukemia (AML) (Farhat et al., AJH, accepted). We decided to determine whether the omission of daunorubicin may retain the efficacy of fractionated GO combined to standard-dose cytarabine. Methods. GO was proposed to patients (pts) with CD33 positive AML in relapse according to the French Temporary Authorization (ATU) program. All consecutive pts from our center were eligible if they were in first relapse and aged of 50 years or more. Refractory patients and patients with a first CR of less than 6 months were excluded. Induction consisted of cytarabine 200 mg/m2/d CI on day 1–7 with GO at 3 mg/m2/d on day 1, 4 and 7. Pts achieving CR/CRp received two consolidation courses with cytarabine 1 g/m2/12h on day 1–2 with GO at 3 mg/m2/d on day 1. A maintenance phase with low-dose cytarabine was allowed. Minimal residual disease (MRD) monitoring based on NPM1 mutation or WT1 expression was assessed in informative and evaluable patients. Results. From October 2007 to June 2011, 22 pts (median age, 67 years) were recruited. All pts received an intensive regimen as part of their first line therapy (3+7 schedule or more intensive). Median duration of first CR was 16 months (6 to 33). Cytogenetic analysis at relapse was successfully assessed in all pts and karyotype was classified as favorable in 3 pts (t(8;21); t(16;16); t(15;17)), intermediate in 18 pts and adverse in 1 pt. Molecular profile analysis of intermediate-risk patients revealed the presence of a FLT3 internal tandem duplication (FLT3 -ITD) in 3 pts, a NPM1 mutation in 8 pts (including 2 cases with a concomitant FLT3 -ITD), a single CEBPA mutation in 1 pt, a EVI1 hyperexpression in 2 pts, and a MLL rearrangement in 1 pt. CR+CRp was achieved in 17/22 pts (77.3%) including 2 CRp. The 5 primary resistant pts corresponded to 1 pt with complex karyotype, 1 pt with a MLL rearrangement, 1 pt with EVI1 hyper expression, 1 pt with FLT3 -ITD, and 1 pt without any identified genetic alteration. There were 2 (9%) induction deaths including one patient that experienced veino-occlusive disease (VOD) and one patient with severe sepsis. A second case of reversible grade 2 VOD was documented during induction. Four patients (18.1%) experienced G3-4 infections and only one severe mucositis was observed. Median duration of G3-4 neutropenia and thrombocytopenia was 24 days (16–30) and 30 days (20–60), respectively. Prolonged grade ≥ 3 thrombocytopenia was observed in 2 patients. With a median follow-up of 22 months, median DFS was 17.2 months and estimated at 66.3% at 18 months. To date, the duration of CR2 was superior to that of CR1 in 5 non transplanted patients. Median overall survival was 22.6 months. Four pts who received a reduced intensity allogeneic stem cell transplantation in CR2, and one of them subsequently died. We were able to compare the molecular response obtained after CR2 and after CR1 using the same MRD marker in 6 patients that achieved CR2. In 5 out of 6 paired samples, MRD levels after CR2 were found equal or inferior to MRD levels after CR1 (see fig 1). Conclusion. Fractionated doses of GO (3 mg/m2/d on day 1, 4, and 7) combined to standard-dose cytarabine in older pts with AML in first relapse is associated with a high CR rate, a prolonged survival and a low rate of toxic deaths. A gain in MRD levels was noted in paired CR1 and CR2 samples. Disclosures: Castaigne: Pfizer/Wyeth: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Phase I/II Study of CPX-351 Followed by Fludarabine, Cytarabine, and Granulocyte-Colony Stimulating Factor for Children With Relapsed Acute Myeloid Leukemia: A Report From the Children’s Oncology Group

Journal of Clinical Oncology ◽

10.1200/jco.19.03306 ◽

2020 ◽

Vol 38 (19) ◽

pp. 2170-2177

Author(s):

Todd M. Cooper ◽

Michael J. Absalon ◽

Todd A. Alonzo ◽

Robert B. Gerbing ◽

Kasey J. Leger ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Dose Finding ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

First Relapse ◽

Grade 3 ◽

Stimulating Factor ◽

Relapsed Acute Myeloid Leukemia ◽

Acute Myeloid

PURPOSE Effective regimens are needed for children with relapsed acute myeloid leukemia (AML). AAML1421 is a phase I/II study of CPX-351, a liposomal preparation of daunorubicin and cytarabine. AAML1421 sought to determine the recommended phase II dose (RP2D) of CPX-351 and the response rate after up to 2 cycles of therapy. PATIENTS AND METHODS Children > 1 and ≤ 21 years of age with relapsed/refractory AML were eligible for dose finding; those in first relapse were eligible for the efficacy phase. Dose-limiting toxicity (DLT) assessment occurred during cycle 1. Two cycles of therapy were offered (cycle 1: CPX-351; cycle 2: FLAG [fludarabine 30 mg/m2/dose on days 1-5; cytarabine 2,000 mg/m2/dose on days 1-5; and granulocyte-colony stimulating factor 5 µg/kg/dose, days 1-5 and day 15 through absolute neutrophil count > 500/µL]). Response was assessed after each cycle. RESULTS Thirty-eight patients enrolled: 6 in the dose-finding phase and 32 in the efficacy phase. During dose finding, 1/6 patients experienced a DLT (grade 3 decrease in ejection fraction). The RP2D was 135 units/m2 on days 1, 3, and 5. Toxicities of grade ≥ 3 during cycle 1 included fever/neutropenia (45%), infection (47%), and rash (40%). There was no toxic mortality. Best responses included 20 complete response (CR; 54%), 5 CR with partial recovery of platelet count (CRp; 14%), and 5 CR with incomplete blood count recovery (14%). Twenty-one of 25 with CR/CRp had no detectable residual disease (RD; 84%) by flow cytometry. Hematopoietic stem cell transplantation (HSCT) was used as consolidation in 29/30 responders (96.7%); 20/25 (80%) had no RD before HSCT. CONCLUSION The RP2D of CPX-351 is 135 units/m2/dose on days 1, 3, and 5. Toxicity was manageable, and protocol therapy was effective. Response rates are superior to prior published North American cooperative group clinical trials for children with AML in first relapse.

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