Tuesday, December 5, 2023
| Overall N = 844 |
GO1 n = 422 |
GO2 n = 422 |
|
|---|---|---|---|
| Age, y, median (range) | 68 (50–81) | 67.5 (51–79) | 68 (50–81) |
| Age ≥65 y | 606 (72%) | 301 (71%) | 305 (72%) |
| Age ≥70 y | 283 (34%) | 141 (33%) | 142 (34%) |
| Male | 511 (61%) | 256 (61%) | 255 (60%) |
| WBC ×109/L median (range) | 5.8 (0.3–416.6) | 6.25 (0.3–416.6) | 5.65 (0.4–365) |
| <10 | 493 (58%) | 247 (59%) | 246 (58%) |
| ≥50 | 101 (12%) | 50 (12%) | 51 (12%) |
| Diagnosis | |||
| Clinical de novo AML | 673 (80%) | 338 (80%) | 335 (79%) |
| Clinical secondary AML | 89 (11%) | 44 (10%) | 45 (11%) |
| High-risk MDS | 82 (10%) | 40 (10%) | 42 (10%) |
| Performance ID (ECOG) | |||
| 0 | 404 (48%) | 202 (48%) | 202 (48%) |
| 1 | 386 (46%) | 193 (46%) | 193 (46%) |
| 2 | 54 (6%) | 27 (6%) | 27 (6%) |
| Genetic risk | |||
| Cytogenetic (Grimwade 2010) | |||
| Favorable | 30 (4%) | 22 (6%) | 8 (2%) |
| Intermediate | 558 (81%) | 277 (79%) | 281 (82%) |
| Adverse | 103 (15%) | 50 (14%) | 53 (16%) |
| Failed | 56 | 25 | 31 |
| Not reported | 97 | 48 | 49 |
| TP53+ | 69 (9%) | 32 (9%) | 37 (10%) |
| ELN 2017 | |||
| Favorable | 236 (33%) | 121 (33%) | 115 (32%) |
| Intermediate | 166 (23%) | 85 (23%) | 81 (23%) |
| Adverse | 323 (45%) | 160 (44%) | 163 (45%) |
| Unknown | 119 | 56 | 63 |
| ALFA 1200* | |||
| Go-go (favorable) | 274 (40%) | 140 (40%) | 134 (39%) |
| Slow-go (intermediate) | 360 (52%) | 180 (52%) | 180 (53%) |
| No-go (unfavorable) | 57 (8%) | 29 (8%) | 28 (8%) |
| Unknown | 153 | 73 | 80 |
Table 1. Patient demographics and clinical characteristics
ECOG, Eastern Cooperative Oncology Group; ALFA, Acute Leukemia French Association; MDS, myelodysplastic syndrome; WBC, white blood cell count.
*Details of ALFA 1200 genetic score classification10 are provided in "Methods."
| GO1 n = 422 (%) |
GO2 n = 422 (%) |
P value | OR (95% CI) | |
|---|---|---|---|---|
| Response | ||||
| CR + CRi | 346 (82) | 342 (81) | .723 | 1.06 (0.75–1.52) |
| CR | 306 (73) | 305 (72) | .939 | 1.01 (0.75–1.37) |
| CRi | 40 (10) | 37 (9) | .720 | 1.1 (0.68–1.75) |
| CR after course 1 | 239 (57) | 264 (63) | .079 | 0.78 (0.59–1.03) |
| CR + CRi after course 1 | 268 (64) | 284 (67) | .247 | 0.85 (0.64–1.12) |
| Response including MRD status after course 1 | N = 373 (%)* | N = 372 (%)* | ||
| CR + CRi | 219 (59) | 234 (63) | .241 | 0.84 (0.63–1.12) |
| CR + CRi MRD <0.1%† | 171 (46) | 194 (52) | .085 | 0.78 (0.58–1.03) |
| CR MRD <0.1%† | 154 (41) | 184 (50) | .025 | 0.72 (0.54–0.96) |
| CR + CRi MRD negative | 144 (39) | 158 (43) | .282 | 0.85 (0.64–1.14) |
| CR MRD negative | 130 (35) | 152 (41) | .091 | 0.78 (0.57–1.04) |
| Early death | ||||
| Day 30 | 32 (8) | 34 (8) | .797 | 0.94 (0.56–1.54) |
| Day 60 | 44 (10) | 52 (12) | .386 | 0.83 (0.54–1.27) |
| ASCT 144 (34) | 128 (30) | .239 | 1.19 (0.89–1.59) | |
| Allograft in CR1 | 122 (29) | 107 (25) | .215 | 1.22 (0.89–1.64) |
| Time to allograft in CR1. median (range) days‡ | 108 (0–462) | 111 (16–342) | .349 | — |
Table 2. Response, early deaths, and rates of ASCT
χ2 or exact test used to generate the P values. MRD measured by flow cytometry.
OR, odds ratio.
*All patients not attaining CR/CRi (including day 30 deaths) + patients in CR/CRi with MRD data.
†MRD <0.1%, MRD negative or detectable but <0.1%.
‡Wilcoxon rank-sum test is used to generate the P value.
Physicians - maximum of 1.00 AMA PRA Category 1 Credit(s)™
ABIM Diplomates - maximum of 1.00 ABIM MOC points
This activity is intended for hematologists, oncologists, internists, geriatricians, geneticists, and other clinicians caring for patients aged older than 60 years with acute myeloid leukemia (AML).
The goal of this activity is for learners to be better able to describe whether fractionated dosing of gemtuzumab ozogamicin (GO) provides a survival advantage in older adults with AML, based on the randomized NCRI AML18 trial comparing a single vs a fractionated schedule of GO in the first induction course (2 doses of GO given on days 1 and 4) and using molecular profiling together with flow cytometric MRD testing to assess any differential efficacy between the GO schedules across molecular subgroups.
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CME / ABIM MOC Released: 11/16/2023
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Addition of gemtuzumab ozogamicin (GO) to induction chemotherapy improves outcomes in older patients with acute myeloid leukemia (AML), but it is uncertain whether a fractionated schedule provides additional benefit to a single dose. We randomized 852 older adults (median age, 68-years) with AML/high-risk myelodysplasia to GO on day 1 (GO1) or on days 1 and 4 (GO2) of course 1 induction. The median follow-up period was 50.2 months. Although complete remission (CR) rates after course 1 did not significantly differ between arms (GO2, 63%; GO1, 57%; odds ratio [OR], 0.78; P = .08), there were significantly more patients who achieved CR with a measurable residual disease (MRD)<0.1% (50% vs 41%; OR, 0.72; P = .027). This differential MRD reduction with GO2 varied across molecular subtypes, being greatest for IDH mutations. The 5-year overall survival (OS) was 29% for patients in the GO2 arm and 24% for those in the GO1 arm (hazard ratio [HR], 0.89; P = .14). In a sensitivity analysis excluding patients found to have adverse cytogenetics or TP53 mutations, the 5-year OS was 33% for GO2 and 26% for GO1 (HR, 0.83; P = .045). In total, 228 (27%) patients received an allogeneic transplantation in first remission. Posttransplant OS was superior in the GO2 arm (HR, 0.67; P = .033); furthermore, the survival advantage from GO2 in the sensitivity analysis was lost when data of patients were censored at transplantation. In conclusion, GO2 was associated with a greater reduction in MRD and improved survival in older adults with nonadverse risk genetics. This benefit from GO2 was dependent on allogeneic transplantation to translate the better leukemia clearance into improved survival. This trial was registered at www.isrctn.com as #ISRCTN 31682779.
Currently, available treatment with a combination of daunorubicin and cytosine arabinoside (Ara-C) has achieved a remission rate of >60% in patients aged >60 years with acute myeloid leukemia (AML) considered fit for intensive treatment. However, approximately three-quarters of these patients relapse within 3 years. In the National Cancer Research Institute (NCRI) AML16 trial for older adults (median age, 67 years), we previously reported that the addition of a single dose of gemtuzumab ozogamicin (GO) to 2 different induction therapies, daunorubicin/Ara-C (DA) and daunorubicin/clofarabine, was found to improve overall survival (OS; 20% vs 15% at 4 years; hazard ratio [HR], 0.82 [0.72–1.0]; P = .05) because of a reduction in relapse risk.[1] This was not associated with any increased hematologic or nonhematologic toxicity. In a second study, ALFA 0701, the ALFA (Acute French Leukemia Association) group reported that the addition of a fractionated schedule of 3 doses of GO to DA induction chemotherapy for patients aged from 50 to 70 years also significantly improved the event-free survival, leading to regulatory approval; they observed no increase in induction deaths, but hematologic toxicity was augmented, particularly with regard to platelet recovery.[2,3] GO was also given at consolidation in this ALFA trial. These 2 studies demonstrate that the addition of GO to standard chemotherapy improves outcomes in older patients with AML. Although direct comparison of the 2 trials is difficult because of different age ranges, there is some suggestion that the fractionated GO schedule used in the ALFA 0701 trial gave a greater survival benefit than the single dose used in AML16, albeit with increased toxicity.[4] In the NCRI AML18 trial, we randomized a single vs a fractionated schedule of GO in the first induction course to address the question of whether fractionated dosing provides a survival advantage in older adults. The fractionated schedule used 2 doses of GO administered on days 1 and 4 rather than the 3-dose schedule used in the ALFA 0701 study because of concerns over toxicity, particularly delayed platelet count recovery. Owing to the previously observed lack of benefit of GO in the adverse cytogenetic risk group,[4] patients were excluded from the randomization if they were known to have adverse cytogenetics before trial entry, but awaiting cytogenetic results was not mandated for trial entry. Here, we report the 5-year outcomes from this trial. In addition to cytogenetics, specific gene mutations have been reported to predict the benefit fromGO through a post hoc analysis of the ALFA 0701 study.[5] Molecular profiling together with flow cytometric measurable residual disease (MRD) testing were performed in AML18 to evaluate for any differential efficacy between the GO schedules across molecular subgroups.
