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Quizartinib with low-intensity treatment in AML
Online Supplementary Tables S1-S4). TET2 mutation was found to have a negative impact on CRc, but only 13/73 patients had a TET2 mutation (Online Supplementary Tables S5 and S6).
At the last follow-up of all patients, two (5%) in the quizartinib/AZA cohort and one (3%) in the quizartinib/LDAC cohort continued to receive study treat- ment (Table 4). Disease relapse or loss of response was the most common reason for study discontinuation in both cohorts. Molecular data at the end of treatment were available for 41 patients (including data collected using an 81-gene panel in 9 patients). New mutations identified at the end of treatment included FLT3-D835 (11/41, 27%), IDH1 (2/9, 22%), RAS (2/11, 18%), and KIT (1/9, 11%) (Online Supplementary Figure S3). Eleven (28%) patients in the quizartinib/AZA cohort and two (6%) in the quizar- tinib/LDAC cohort proceeded to SCT. Three patients (23%) treated with quizartinib/AZA relapsed after a medi- an time of 3.2 months (range, 2.7 - 18 months) following SCT. Seven patients (54%) are alive after SCT without any evidence of disease (5 treated with quizartinib/AZA and 2 treated with quizartinib/LDAC). Of the six patients who died after SCT, three died in CR/CRi/CRp from multi-organ failure secondary to Klebsiella pneumoniae bac- teremia, late gastrointestinal graft-versus-host disease, and an unknown cause, respectively. The three other patients had relapsed disease and died, one each, from multi-organ failure secondary to enteroviral pneumonia, intracerebral hemorrhage, and renal failure.
Safety and dose reduction
The most common treatment-emergent adverse events are listed in Table 5. Among grade ≥3 adverse events, febrile neutropenia and pneumonia were frequently reported in both cohorts. Other common grade ≥3 adverse events that occurred in the cohort of patients treated with quizartinib/AZA were hypokalemia (33%), hypotension (24%), and hypophosphatemia (18%). The median time to absolute neutrophil count recovery (neutrophils >1 x 109/L) for all cycles in patients treated frontline was 32 days (range, 8 - 125 days): it was 35 days (range, 9 - 125 days in the quizartinib/AZA cohort and 27 days (range, 8 - 68 days in the quizartinib/LDAC cohort. Similarly, the median time to platelet recovery (platelets >100 x 109/L) for all cycles was 29 days (range, 7 - 125 days), 30 days (range, 7 - 125 days) in the quizartinib/AZA cohort and 29 days (range, 25 - 60 days) in the quizartinib/LDAC cohort. The median times to recovery of absolute neutrophil count and platelet count were similar in R/R patients.
QTc prolongation was observed infrequently. Only one (3%) patient had grade 3, and three (9%) patients had grade 1-2 QTc prolongation in the quizartinib/AZA cohort, and one (3%) had grade 3 prolongation in the quizartinib/LDAC cohort (Online Supplementary Figures S4 and S5). One (3%) patient who received quizartinib/AZA as frontline treatment died early (day 7 of treatment) due to multi-organ failure secondary to sepsis from an unknown organism.
A total of nine (23%) patients required a dose modifica- tion in the quizartinib/AZA cohort. Of them, three patients received quizartinib for only 7 days, 14 days, and 16 days in the first cycle due to the development of multi- organ failure, SCT, and febrile neutropenia, respectively. The quizartinib dose was decreased to 30 mg in six patients (4 due to grade 3 myelosuppression, 1 due to
Table 4. Summary of disposition of all study patients (n=73).
Reasons
Relapse/loss of response
Stem cell transplant
Lack of response/disease progression
Deatha
Continuing treatment
Patient’s choiceb
Lost to follow-up
Infection/toxicityc
Quizartinib/AZA Quizartinib/LDAC
(n=40)
11 (28)
11 (28) 8 (20) 6 (15) 2 (5) 1 (3) 1 (3) 0
N (%)
(n=33)
11 (33)
2 (6)
10 (30)
4 (12)
1 (3)
1 (3)
1 (3)
3 (9)
AZA: azacitidine; LDAC: low-dose cytarabine. aOf six patients in the AZA cohort who died, one died early, two died in complete response with incomplete hematologic recovery (CRi),two in complete response (CR) and one without response.In the LDAC cohort,fourpatientsdied:oneinCRwithoutplateletrecovery,oneinCRi,onewitha partial response and one with no response. bOne patient in the AZA cohort chose to be treated at a different institution and one in the LDAC cohort chose to discontinue treatment for financial reasons.cOne patient each discontinued treatment due to atrial fibrillation and meningitis.One additional patient developed atrial fibrillation prior to receiving quizartinib and was taken off study.
grade 2 supraventricular tachycardia, and 1 due to grade 3 QTc prolongation). Similarly, the quizartinib dose was decreased to 30 mg in three patients (9%) in the quizar- tinib/LDAC cohort: in two cases due to grade 3 myelosup- pression and in one case due to grade 3 QTc prolongation.
Discussion
With the limitations of comparisons across studies, the CRc rates and the median overall survival observed in patients treated frontline with quizartinib/AZA in this study seem to compare favorably to what has been report- ed for similar combinations using other FLT3 inhibitors. With midostaurin plus AZA, the reported CRc and medi- an overall survival were 31% and 9 months, respectively.20 Similarly, with sorafenib plus AZA, the CRc and median overall survival were 70% and 8.3 months, respectively.21 The results with quizartinib/AZA also appear comparable to the results reported with a hypomethylating agent/venetoclax24 (CR/Cri: 72% in FLT3-mutated cases; median overall survival not reached). Although patients with FLT3 mutations had good responses to hypomethylating agents/venetoclax, mutations in FLT3- ITD constitute one of the mechanisms of acquired resist- ance to venetoclax in preclinical models,25,26 and have been reported to emerge in some patients as they develop resistance to therapy with venetoclax.27 Ongoing clinical studies are trying to overcome this resistance by adding FLT3 inhibitors to venetoclax (gilteritinib - NCT03625505 and quizartinib - NCT03735875).
Quizartinib, as a single agent, was found to produce a CRc of 48% in patients with R/R AML, who achieved a median overall survival of 6.2 months.16 Similarly, AZA monotherapy in R/R AML produced CR/CRi in 16% of patients, who had a median overall survival of 6.8 months.28 The combination of quizartinib/AZA in our study pro- duced a CRc of 67% with a median overall survival of 12.8 months in patients with R/R AML. Although no compar- isons could be made between different studies, higher response rates and longer survival observed with the com- bination could perhaps be attributed to a possible synergy
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