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Gemtuzumab ozogamicin (GO), a CD33-directed antibody-drug conjugate, is approved for the treatment of patients with newly diagnosed (ND) and relapsed/refractory CD33-positive acute myeloid leukemia (AML).1 GO has been shown to improve survival outcomes in patients with AML with non-adverse risk cytogenetics when combined with 7+3 induction chemotherapy, which the AML Hub has previously reported on here and here.2–5 However, more information is required on the benefit of GO in patients with intermediate-risk cytogenetics.1 A higher dose with a fractionated dosing schedule may also improve outcomes and a number of clinical trials are investigating fractionated versus single dose GO treatment in patients with AML or higher-risk myelodysplastic syndromes (MDS).3,4
Several presentations at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition discussed GO in patients with AML or MDS. Below, we summarize presentations by Awada,2 Freeman,3 Russell,4 and Döhner,5 on the addition of GO to chemotherapy and fractionated versus single dose schedule in patients with AML or higher-risk MDS.
This study retrospectively analyzed outcomes of 113 patients with ND intermediate-risk AML between those who received 7+3 chemotherapy plus GO (n = 33) and those who received 7+3 therapy only (n = 80) at the Roswell Park Comprehensive Cancer Center, US, between 2015 and 2022. The study endpoints included response, subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT), relapse after remission, and overall survival (OS). Conventional cytogenetic and fluorescence in situ hybridization analysis was performed and genomic profiling was carried out using next-generation sequencing. Patients received cytarabine and daunorubicin, with or without 3 mg/m2 GO on Days 1, 4, and 7. All patients received prophylactic heparin to prevent hepatic veno-occlusive disease if not thrombocytopenic. Patients in the 7+3 group had a higher frequency of NPM1 mutations (p = 0.01), while the 7+3 plus GO group had more patients with IDH1/2 mutations (p = 0.02) and DNMT3A mutations (p = 0.0001). The median follow-up was 24 months.
Figure 1. Response rates, MRD status at the time of CR/CRi, percentage of patients receiving subsequent allo-HSCT, and relapse rates after CR/CRi in the 7+3 plus GO and the 7+3 group*
Allo-HSCT; allogeneic hematopoietic stem cell transplantation; CR, complete remission; CRi, CR with incomplete hematological recovery; GO; gemtuzumab ozogamicin; MRD; measurable residual disease.
*Adapted from Awada.2
The addition of GO to 7+3 treatment resulted in higher CR/CRi and lower relapse rates. Whilst the survival benefit was not significant, longer follow-up is justified.
The NCRI AML18 trial included 844 patients aged ≥60 years with AML or high-risk myelodysplastic syndromes (MDS) without known adverse cytogenetics. Patients were randomized to receive daunorubicin and cytarabine (DA) plus either a single dose of GO (3 mg/m2 on Day 1 of Course 1) or a fractionated dose of GO; (3 mg/m2 [maximum 5 mg] on Days 1 and 4 of Course 1). Following Course 1, measurable residual disease (MRD) was assessed by flow cytometry.
Figure 2. 5-year OS rate and allo-HSCT rate in the fractionated versus single dose group*
Allo-HSCT, allogeneic hematopoietic stem cell transplantation; CR1, first complete remission; GO1; gemtuzumab ozogamicin single dose; GO2, gemtuzumab ozogamicin fractionated dose; OS, overall survival.
*Data from Freeman.3
The fractionated dosing schedule of GO was associated with deeper remissions and improved OS in older patients with non-adverse risk genetics when compared with a single dose schedule. There was genetic heterogeneity for differential improvement in leukemia clearance and survival benefit from a fractionated dosing schedule, which was most evident in patients with IDH1/2 mutations. Receiving allo-HSCT in first remission was found to be necessary to translate the improved post-induction response from a fractionated dose schedule into a long-term survival benefit. Most patients aged >70 years did not receive allo-HSCT and there was no evidence of benefit from a fractionated dosing schedule in this group.
The NCRI AML19 trial included 1,475 patients in the UK, Denmark, and New Zealand with AML or MDS with excess blasts 2 (MDS-EB2) with no known adverse-risk cytogenetics. The patients were randomized to receive either fludarabine, cytarabine, granulocyte-colony stimulating factor, and idarubicin (FLAG-Ida) or DA. Of these, 1,031 patients were randomized to receive either a fractionated dose (maximum 5 mg on Days 1 and 4) or a single dose (3 mg/m2 on Day 1) of GO (Figure 3). Patients with known adverse-risk cytogenetics could enter randomization between FLAG-Ida or liposomal cytarabine-daunorubicin. Post-remission therapy included a second course of FLAG-Ida or DA without GO followed by up to two courses of high dose cytarabine. The median age was 51.5 years. In total, 88% of patients had de novo AML, 7% had secondary AML, and 5% had MDS-EB2. Patients were defined as favorable risk (12%), intermediate risk (75%), and adverse risk (9%).
Figure 3. NCRI AML19 trial schema*
APL, acute promyelocytic leukemai; Ara-C, cytarabine; DA, daunorubicin and cytarabine; FLAG-Ida, fludarabine, cytarabine, granulocyte-colony stimulating factor, and idarubicin; GO1; gemtuzumab ozogamicin single dose; GO2, gemtuzumab ozogamicin fractionated dose.
*Adapted from Russell.4
APL, acute promyelocytic leukemai; Ara-C, cytarabine; DA, daunorubicin and cytarabine; FLAG-Ida, fludarabine, cytarabine, granulocyte-colony stimulating factor, and idarubicin; GO1; gemtuzumab ozogamicin single dose; GO2, gemtuzumab ozogamicin fractionated dose.
*Adapted from Russell.4
Table 1. Response post Cycle 2*
Response, % |
DA-GO |
FLAG-Ida-GO |
GO1 |
GO2 |
---|---|---|---|---|
CR |
86.8 |
87.2 |
— |
— |
ORR |
90.7 |
92.5 |
92.3 |
91.2 |
30-day mortality |
2.9 |
3.1 |
2.1 |
3.3 |
60-day mortality |
4.6 |
4.3 |
3.3 |
5.65 |
CR, complete remission; DA, daunorubicin and cytarabine; FLAG-Ida, fludarabine, cytarabine, granulocyte-colony stimulating factor, and idarubicin; GO, gemtuzumab ozogamicin; GO1, GO single dose; GO2, GO fractionated dose; ORR, overall response rate. |
Overall, treatment with FLAG-Ida plus GO improved EFS but not OS when compared with DA plus GO. There was no survival benefit from a fractionated GO dosing schedule compared with single dose. In patients with FLT3 or NPM1 mutations, FLAG-Ida plus GO treatment was associated with improved EFS and OS over DA plus GO.
During the 4th National Cancer Research Institute (NCRI) AML Academy Meeting, the AML Hub was pleased to speak to Nigel Russell, Guy’s and St Thomas’ NHS Foundation Trust, London, UK. They discuss the latest updates from the NCRI AML18 and AML19 clinical trials.
What are the updates from the NCRI AML18 and AML19 clinical trials?
The AMLSG 09-09 trial included 588 patients aged ≥18 years with ND NMP1 mutated AML. It evaluated intensive induction and consolidation therapy plus all-trans retinoic acid (standard arm) with or without single dose GO; 3 mg/m2 administered in two induction cycles and the first consolidation cycle.
Response rates and allo-HSCT rates were similar between the standard arm and the GO arm (Table 2). Furthermore, EFS and OS were similar between treatment arms.
Table 2. Response and allo-HSCT rates post induction therapy*
Response, % |
Intensive induction and consolidation therapy + all‑trans retinoic acid |
Intensive induction and consolidation therapy + all‑trans retinoic acid + GO |
---|---|---|
CR/CRi |
90.2 |
86.0 |
CR |
58.1 |
46.6 |
CR/CRh |
72.3 |
66.8 |
Refractory disease |
2.4 |
2.4 |
30-day mortality |
4.0 |
7.0 |
60-day mortality |
6.0 |
9.0 |
Allo-HSCT in CR/CRi |
6.4 |
5.5 |
Any allo-HSCT during disease course |
37.2 |
28.8 |
Allo-HSCT, allogeneic hematopoietic stem cell transplantation; CR, complete remission; CRh, CR with partial hematologic recovery; CRi, CR with incomplete hematologic recovery; GO, gemtuzumab ozogamicin |
Post hoc analysis by age group:
The addition of GO to intensive chemotherapy led to lower rates of CIR without an effect on OS, with the beneficial effect on CIR and EFS driven by patients aged 18–60 years. Mutational subgroup analysis showed that patients with NPM1 mutations who were FLT3-ITD wild-type and patients with NPM1/DNMT3A co-mutations significantly benefitted from the addition of GO.
In the retrospective analysis of 7+3 plus GO versus 7+3 in patients with ND intermediate-risk AML, the addition of GO resulted in higher remission rates, lower rates of relapse, and a higher percentage of patients receiving allo-HSCT when compared with 7+3 therapy alone in patients with intermediate risk ND AML.2 Conversely, in the AMLSG 09–09 trial, the addition of GO to intensive chemotherapy did not improve survival outcomes in patients with ND NPM1 mutated AML; although, in patients aged 18–60 years, there were lower relapse rates noted with GO.5
In the NCRI AML18 trial, a fractionated dose schedule of GO was associated with improved survival outcomes compared with single dose in older patients with AML or high-risk MDS with non-adverse risk genetics. However, in the NCRI AML19 fractionated dose GO did not confer a survival benefit over a single dose in patients with ND AML or MDS-EB2.3,4
Age and molecular profile had a significant impact on outcomes across the above studies. Given the variation in study populations, treatments received, and findings, further investigation is warranted to assess the benefit of the addition of GO to chemotherapy and whether a fractionated or single dosing schedule is optimal.
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