Fractionated gemtuzumab ozogamicin and standard dose cytarabine produced prolonged second remissions in patients over the age of 55 years with acute myeloid leukemia in late first relapse

Abstract

Fractionated gemtuzumab ozogamicin and standard dose cytarabine produced prolonged second remissions in patients over the age of 55 years with acute myeloid leukemia in late first relapse Gemtuzumab ozogamicin (fGO), a humanized anti-CD33 monoclonal antibody linked to calicheamicin in combination with intensive chemotherapy gives high response rates in adult acute myeloid leukemia (AML) patients in relapse. However, reduced intensity chemotherapy in combination with fractionated GO has not been tested in aged relapsing patients. Patients from our institution with CD331 AML aged 55 years or more in first late relapse ( 6 months) were proposed participation in a GO compassionate use program. Induction therapy consisted in fractionated GO (fGO; 3 mg/m 2 , days 1, 4, 7) with standard-dose cytarabine (200 mg/m 2 /day, 7 days). Patients were consolidated with two courses of GO and intermediate dose cytarabine. Twenty-four patients (median age 68 years) received fGO with cytarabine. Median follow-up was 42 months. The response rate was 75%, including complete remission (CR) in 16 patients and CR with incomplete platelet recovery (CRp) in two patients. Two-year overall survival (OS) was 51% (95% CI: 28-69) and 2 years relapse-free survival (RFS) was 51% (95%CI: 25-72). Duration of second CR (CR2) was longer than first CR (CR1) in 9 out of 18 patients. Minimal residual disease (MRD) was negative in evaluable patients in CR2, particularly in NPM1 mutated cases. Toxicity was in line with that of the same fractionated single agent GO schedule. Fractionated GO with low intensity chemotherapy produced high response rates and prolonged CR2 in aged AML patients in first late relapse.

Salvage therapy with ARA-C and gemtuzumab ozogamicin in AML patients relapsing after stem cell transplantation

“…We found that a combination of standard dose GO and IDAC at 1 g/m 2 in CD33 positive AML patients relapsing after SCT was a highly effective cytoreductive regimen, with CR/CRp of 60 %. Therapy was relatively safe with 27 % grade 3-4 hepatic toxicity, comparable to the rates reported in non-transplant patients [3,13]. Response rates in our cohort compare favorably with a previous report of GO monotherapy as post-SCT salvage were only 2/8 (25 %) of patients responded to GO [14].…”

“…Results of single agent GO phase I and II studies in relapsed AML patients demonstrated CR+ CRp (CR with incomplete platelet recovery) of approximately 30 % and toxicity rates comparable to standard salvage chemotherapy regimens, with mainly hematologic and hepatic toxicities [3]. Studies in relapsed AML using different combinations of GO and chemotherapy, most commonly with ARA-C have resulted in variable results [4][5][6][7][8][9][10][11][12][13], while concerns of an increased hepatotoxicity risk in the pre-and postAllo-SCT setting have limited the use of GO in such cases. Nevertheless, case reports and small case series of GO monotherapy in AML patients relapsing after an Allo-SCT have reported on long-term remission in some patients and limited toxicity [14][15][16][17][18][19].…”

Flai (fludarabine, cytarabine, idarubicin) plus low‐dose Gemtuzumab Ozogamicin as induction therapy in CD33‐positive AML: Final results and long term outcome of a phase II multicenter clinical trial

“…In the last two decades, few new compounds have been approved for the treatment of AML (Gemtuzumab‐Ozogamicin, decitabine, azacitidine, midostaurin), whose therapeutic approach still relies on the administration of conventional chemotherapy (“3 + 7” regimens as induction, followed by cytarabine‐based consolidation courses) followed or not by allogeneic SCT based on the cytogenetic and molecular risk stratification . In the scenario of innovative compounds, GO was the first antibody targeted therapy to be developed and approved, showing promising results both in the setting of elderly relapsed or refractory AML patients, and in the context of induction schedule for the treatment of the young AML population, in association with standard chemotherapy regimens …”

“…In our opinion, taking into account all the available data, the best AML candidate to receive GO plus induction chemotherapy should have the following characteristics: age less than 60 years, no hepatic diseases, de novo AML, first induction phase, favorable or intermediate cytogenetic risk, no PGP overexpression (no MDR phenotype), and expression of CD33 on blast cells over 20%. The preferred schedule of GO, in addition to induction chemotherapy, should include lower doses (eg, 3 mg/sqm) and repeated administrations (2–3 doses) avoiding toxicity without affecting efficacy as proposed by the ALFA group . Chemotherapy in association with GO should include cytarabine plus daunorubicin based regimens (eg, DA, DAE) or FLAI scheme (our preference) that is well tolerated and includes MDR reversing drugs, such as fludarabine and a more potent and less PGP‐sensitive anthracycline (idarubicin).…”

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

“…30,31,37,38 Thus, in contrast to previous data showing an enormously increased incidence of SOS (64%) by pre-treatment with GO (6 mg/m 2 or 9 mg/m 2 ) in a 3.5-month period prior to transplant, 39 we were able to show that salvage therapy including GO in a dosage of 3 mg/m 2 is safe and can be followed by allogeneic HCT without increasing the rate of SOS. Whether an increment of the GO dosage by using fractionated administration, 40,41 comparable to successful attempts in first-line therapy, 35 is safe in terms of SOS and even more effective compared to our GO-A-HAM regimens remains elusive.…”