Venetoclax plus FLAG-IDA as frontline and salvage therapy in patients with ND and R/R AML

Despite the development of synergistic multidrug regimens, 30–40% of patients with newly diagnosed (ND) acute myeloid leukemia (AML) ultimately relapse. Furthermore, few patients with relapsed or refractory (R/R) AML experience long-term remission despite salvage therapy. The multiagent induction regimen of fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) is an effective frontline treatment in patients with AML, with favorable survival rates compared with alternate induction chemotherapy, and can also be used as salvage therapy in R/R AML.

The B-cell lymphoma-2 inhibitor venetoclax (VEN), combined with azacitidine, decitabine, or low-dose cytarabine, is approved for the treatment of AML in older unfit patients. A synergistic effect of VEN with standard chemotherapeutic agents has also been shown preclinically, suggesting further potential in AML treatment.

Here we summarize results from a phase Ib/II study, published by DiNardo, et al. in the Journal of Clinical Oncology, investigating the safety and efficacy of combining VEN with FLAG-IDA as frontline or salvage therapy in younger patients with ND AML or R/R AML (NCT03214562).¹ The AML Hub has previously reported interim results from this study.

Study design and patient characteristics¹

Eligible adult patients had:

• De novo AML, secondary AML, treated secondary AML, or therapy-related AML
• High-risk myelodysplastic syndrome (≥10% blasts)
• R/R AML (persistent leukemia without achievement of an International Working Group-defined response following at least one cycle of induction chemotherapy, or patients in first relapse or beyond); only patients with R/R AML were eligible for phase Ib

Treatment regimen consisted of:

• FLAG-IDA induction: 28-day cycles of intravenous (IV) fludarabine (30 mg/m²) and IV cytarabine (1.5–2 g/m²) on Days 2–6, IV idarubicin (8 mg/m² Days 4–6 in patients with ND AML and 6 mg/m² Days 4–5 in patients with R/R AML), and filgrastim (5 mcg/kg Days 1–7).
• Consolidation: reduced durations of fludarabine and cytarabine (Days 2–4), and filgrastim (Days 1–5).
• VEN: orally on Days 1–14 during induction and Days 1–7 in consolidation (starting at 200 mg and escalating to 400 mg).

Primary objectives were the safety and tolerability of combined FLAG-IDA and VEN, and overall activity (overall response rate [ORR]). Secondary objectives included:

• Composite complete response rates (CRc), defined as complete response (CR) + CR with incomplete hematologic recovery (CRi) + CR with partial hematologic recovery (CRh)

• ORR, defined as CR + CRh + CRi + morphologic leukemia-free state + partial response
• Overall survival (OS)
• Event-free survival
• Duration of response

To date, 68 patients have enrolled, with a median age of 46 years (range, 20–73 years). Of these, 16 were included in phase Ib, the dose escalation cohort, and a further 52 in phase II, the dose-expansion cohort. Patient characteristics for each cohort are summarized in Table 1.

Table 1. Characteristics of patients in each cohort*

AML, acute myeloid leukemia; CR, complete response; ELN, European LeukemiaNet; HSCT, hematopoietic stem cell transplant; ND, newly diagnosed; R/R, relapsed or refractory; sAML, secondary AML; t-AML, treatment related AML; ts-AML, treated secondary AML; VEN, venetoclax. *Adapted from DiNardo, et al.1 †Includes patients with isolated extramedullary AML. ‡Active signaling: K/NRAS, FLT3-ITD/TKD, KIT, CBL, and PTPN11. §Tumor suppressor: TP53, WT1, FBXW7, and PHF6.
Characteristic, n (unless otherwise stated)	Phase IIa ND AML (n = 29)	Phase Ib R/R AML (n = 16)	Phase IIb R/R AML (n = 23)
Median age (range), years	45 (20–65)	51 (20–73)	47 (22–66)
Male, n	13	10	14
Median number of prior therapies (range)	—	2 (1–6)	1 (1–3)
Prior HSCT	—	7	7
Median duration of prior CR (range), months	—	15.1 (2.3–44)	12.6 (2.7–70)
Salvage 1	—	8	19
Salvage 2	—	3	3
Salvage 3 or greater	—	5	1
Median blast at enrolment (range), %†	41 (4–85)	63 (6–94)	46 (1–89)
AML type
de novo AML	17	—	—
sAML	5	—	—
ts-AML	2	—	—
t-AML	5	—	—
R/R AML	—	16	23
ELN risk group
Favorable	5	6	6
Intermediate	13	2	3
Adverse	11	8	14
Cytogenetic group
Favorable	—	4	2
Diploid	13	2	8
Other intermediate	8	2	3
Adverse-risk or complex	4	4	9
Insufficient mitoses	1	1	—
KMT2A-rearranged	3	3	1
Molecular mutations
NPM1	3	2	3
IDH1	3	1
IDH2	7	1	1
RUNX1	5	—	5
ASXL1	2	—	3
TP53	3	2	5
Active signaling‡	11	6	9
Tumor suppressor§	5	5	8

Safety

As summarized in Table 2, the most frequent Grade 3 and 4 adverse events across all cohorts were febrile neutropenia (50%), bacteremia (35%), and pneumonia (28%). Febrile neutropenia and pneumonia occurred at similar rates in patients with R/R AML (54%) and ND AML (48%), whereas bacteremia was more common in those with R/R AML than ND AML (46% vs 21%; p = 0.04).

Table 2. Most common Grade 3 and 4 adverse events across patient cohorts*

AE, adverse event; AML, acute myeloid leukemia; GI, gastrointestinal; ND, newly diagnosed; R/R, relapsed or refractory. *Adapted from DiNardo, et al.1
AE, n	All patients (N = 68)	Phase IIa ND AML (n = 29)	Phase Ib R/R AML (n = 16)	Phase IIb R/R AML (n = 23)
Febrile neutropenia	34	14	8	12
Bacteremia	24	6	8	10
Pneumonia	19	8	4	7
Sepsis	8	3	4	1
Abdominal pain	5	2	1	2
Skin and soft tissue infection	4	3	—	1
Colitis or typhlitis	3	1	2	—
GI disorders	2	—	—	2
GI hemorrhage	2	2	—	—
Hyperglycemia	2	1	1	—
Hypotension	2	—	1	1
Intracranial hemorrhage	2	—	—	2
Urinary tract infection	2	1	—	1

Across all groups, 30-day mortality rate was 0% and 60-day mortality was 4.4%. Six patients with R/R AML died during the study. Causes of death for patients in which the treatment did not yield a response were sepsis (n = 2), pneumonia (n = 1), and pulmonary hemorrhage (n = 1). Sepsis and hemophagocytic syndrome occurred in two patients.

Efficacy

• Among all patients, ORR was 82% (95% confidence interval [CI], 71–91), with a CR of 53% and CRc of 76% (95% CI, 65–86).
• Additionally, CRc was attained by 67% of patients with R/R AML, 90% with ND AML, and 83% with secondary AML, therapy-related AML, or treated secondary AML.
• There was no difference in response between patients with refractory AML (56%) and relapsed AML (70%).
• Ongoing responses were observed in 70% of patients; 12 patients were refractory to FLAG-IDA + VEN induction.
• Overall, 6-month OS was 81% (95% CI, 71–91) and 12-month OS was 70% (95% CI, 58–83).
• In total, 69% patients (n = 20) with ND AML and 46% patients (n = 18) with R/R AML progressed to hematopoietic stem cell transplantation.

Treatment responses across different cohorts are shown in Table 3.

Table 3. FLAG-IDA and VEN treatment outcomes among patient groups*

AML, acute myeloid leukemia; CI, confidence interval; CR, complete response; CRc, composite CR (CR + CRi + CRh); CRh, CR with partial hematologic recovery; CRi, CR with incomplete hematologic recovery; EFS, event-free survival; MLFS, morphologic leukemia-free state; MRD, measurable residual disease; ND, newly diagnosed; NE, not estimated; NR, not recorded; ORR, overall response rate; OS, overall survival; R/R, relapsed or refractory. *Adapted from DiNardo, et al.1 †95% credible intervals per protocol-defined primary efficacy outcome (95% credible interval estimation assumed ORR follows a prior distribution of beta [1.4, 0.6] (phase IIa) and beta [0.6, 1.4] (phase IIb). All other reported intervals represent exact 95% CIs. ‡Measured by flow cytometry.
Outcome	Phase IIa ND AML (n = 29)	Phase Ib R/R AML (n = 16)	Phase IIb R/R AML (n = 23)
ORR (95% CI), %	97 (85–99) †	75 (48–93)	70 (47–83) †
CRc (95% CI), %	90 (73–98)	75 (48–93)	61 (39–80)
CR, %	69	38	48
CRh, %	17	13	13
CRi, %	3	25	—
MRD negative CR (95% CI) ‡,     %	96 (80–99)	58 (28–85)	79 (49–95)
MLFS	2	—	2
No response	1	4	7
Median DOR (95% CI), months	NR	6 (3–NE)	NR
EFS (95% CI), %
6-month	89 (78–100)	50 (31–82)	59 (41–84)
12-month	85 (72–100)	31 (15–65)	41 (21–77)
OS (95% CI), %
6-month	100	63 (43–91)	68 (49–94)
12-month	94 (84–100)	38 (20–71)	68 (49–94)

Conclusion

The combination of venetoclax with FLAG-IDA induction and consolidation therapy was found to be tolerable in this younger group of patients with ND AML and R/R AML, with no early mortality. Adverse events were mostly infectious in nature and similar across AML types. High rates of MRD negative composite CR rates were noted, in both ND AML and R/R AML cohorts, suggesting deep remissions. Furthermore, the majority of patients were able to transition to allogenic hematopoietic stem cell transplantation.

The dose-expansion part of this study is ongoing, and the authors noted that randomized comparison with standard-of-care induction regimens would be helpful in establishing whether FLAG-IDA with VEN is an effective frontline therapy in ND AML and an optimal salvage treatment in fit patients with R/R AML.