Predicting Response to Alvocidib in Patients With Relapsed/Refractory AML

The CDK9 inhibitor alvocidib induced a high rate of responses in patients with relapsed or refractory acute myeloid leukemia (AML) who had MCL1-dependent disease, according to results from the first stage of the phase II Zella 201 trial. These findings suggest that MCL1 dependence is a valuable biomarker in this patient population, said lead author Joshua Zeidner, MD, from the University of North Carolina Lineberger Comprehensive Cancer Center, during his presentation at the 2018 ASH Annual Meeting.

“By inhibiting CDK9, alvocidib downregulates and inhibits MCL1 expression,” Dr. Zeidner explained. “MCL1 is a dominant pro-survival mechanism that is upregulated in [patients with AML].”

Based on previous research that found that patients with AML and MCL1 dependence ≥40 percent had an increased sensitivity to alvocidib, the authors hypothesized that alvocidib, followed by cytarabine and mitoxantrone, would be “preferentially active” in this patient population.

The Zella 201 trial included adult patients (age range = 18-65 years) with AML that was refractory to induction therapy or that was in first relapse with a complete remission (CR) for less than two years. Patients who had undergone prior allogeneic hematopoietic cell transplantation were included if the procedure happened longer than two months before enrollment and if there was no active graft-versus-host disease.

A total of 170 patients were enrolled and screened for MCL1 dependence ≥40 percent; 48 participants (28%) were determined to have MCL1-dependent disease and were treated with the following regimen:

  • alvocidib 30 mg/m2 administered as a 30-minute intravenous (IV) bolus, followed by 60 mg/m2 over 4 hours on days 1-3
  • cytarabine 667 mg/m2 per day by continuous IV infusion on days 6-8
  • mitoxantrone 40 mg/m2 IV on day 9 starting 12 hours after completing cytarabine

Patients who responded to treatment were permitted to receive up to three additional cycles of the same regimen (with or without mitoxantrone).

Dr. Zeidner shared results from the first 23 evaluable patients. Per study protocol, stage 1 of the trial was determined to be positive if at least 13 CRs were observed in this group; if this benchmark was met, stage 2 of the trial could proceed.

The overall response rate (ORR) was 61 percent, and 13 patients (57%) achieved the primary endpoint (CR or CR with incomplete recovery [CRi]). One additional patient experienced a partial remission.

CRs and CRis also were observed in patients with high-risk disease characteristics, defined as follows:

  • refractory disease: 7 of 12 patients (58%)
  • early relapse: 4 of 7 patients (57%)
  • late relapse: 2 of 4 patients (50%)
  • unfavorable cytogenetics: 2 of 5 patients (40%)

Four of the first 23 enrolled patients died early before response assessment (3 due to sepsis, 1 due to mitral valve rupture), Dr. Zeidner reported.

The median duration of response was 8.5 months (range = 2.1-15.9 months) and the median overall survival was 11.2 months (range = 3.0-16.8 months).

The most common grade 3 non-hematologic adverse events (AEs) included diarrhea (24%) and tumor lysis syndrome (TLS; 20%). TLS occurred rapidly, within eight to 12 hours after alvocidib administration.

TLS events observed in this population were “only a biochemical phenomenon [and] not associated with clinical decline,” Dr. Zeidner said, adding that “we can manage the TLS, we just have to vigorously monitor these patients.”

“The clinical activity rate compares favorably to historical controls,” Dr. Zeidner concluded, though the lack of a comparator arm is a limitation of this study. Based on the positive results observed in stage 1, investigators are moving forward to stage 2, which will compare the alvocidib regimen with a standard cytotoxic chemotherapy regimen in patients with relapsed/refractory AML.

The authors report relationships with Tolero Pharmaceuticals, which sponsored this trial.


Zeidner JF, Lin TL, Vigil CE, et al. Zella 201: a biomarker-guided phase II study of alvocidib followed by cytarabine and mitoxantrone in MCL-1 dependent relapsed/refractory acute myeloid leukemia (AML). Abstract #30. Presented at the 2018 ASH Annual Meeting, December 1, 2018; San Diego, CA.