Early Trials in AML and CMML Offer Promising Results

In early-phase trials conducted in patients with acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML), two investigational agents (ASP2215 and CPI-613) and one previously approved JAK2 inhibitor demonstrated good clinical activity.

ASP2215 in Relapsed or Refractory AML

In patients with relapsed or refractory AML, ASP2215, a selective, potent inhibitor of FLT3/AXl, produced high composite complete remission (CR) rates. This first-in-human phase I/II trial also showed ASP2215 to be well tolerated in doses up to 300 mg/day, according to senior author Mark J. Levis, MD, from Johns Hopkins University in Baltimore, Maryland, who presented the study findings at the American Society of Clinical Oncology meeting.1

Noting that activating mutations of FLT3, some of which confer a poor prognosis, are found in about 30 percent of AML patients, Dr. Levis said that FLT3 inhibitors exhibit clinical promise but may have potency, safety, and tolerability issues. With the current trial, investigators sought to identify a safe, tolerable dose that fully inhibits FLT3 in all patients.

At the time of Dr. Levis’ presentation, ASP2215 had been administered to 198 patients with relapsed or refractory AML (127 of whom were FLT3-mutant positive), in doses ranging from 20 mg/day to 450 mg/day.

The investigational drug was also associated with consistent, potent, and sustained inhibition of FLT3 at all doses ≥80 mg/day, Dr. Levis reported (TABLE). In general, FLT3–mutant-positive patients responded better to treatment than FLT3–wild-type patients, with an overall response rate (complete and partial remissions) of 57% vs. 11%, respectively.

Median overall survival (OS) was highest in the 80 mg/day group (201 days), followed by the 120 mg/day group (199 days), 200 mg/day group (161 days), 20 mg/day group (128 days), and 40 mg/day group (105.5 days). The reported adverse events were similar to those of other FLT3 inhibitors.

Dr. Levis noted that combination studies are ongoing in newly diagnosed AML, and that phase III trials with ASP2215 at 120 mg/day are planned.

TABLE. Response Rates According to FLT3 Mutation Status


FLT3–wild-type, n (%)


20-300 mg/day, n (%)

≥80 mg/day, n (%)

Complete remission (CR)

4 (5%)

3 (5%)


CR, incomplete platelet recovery (CRp)

4 (5%)

4 (6%)


CR, incomplete hematologic recovery (CRi)

27 (33%)

25 (38%)

3 (8%)

Partial remission (PR)

12 (15%)

10 (15%)

1 (3%)

Composite CR

35 (43%)

32 (49%)

3 (8%)

Overall response rate (CR+PR)

47 (57%)

42 (65%)

4 (11%)

A New Indication for Ruxolitinib?

The JAK2 inhibitor ruxolitinib was initially approved in 2011 for the treatment of myelofibrosis, but may offer a promising new treatment for patients with CMML, according to results from a phase I trial conducted through the Myelodysplastic Syndromes Clinical Research Consortium (MDS CRC) and presented by Eric W. Padron, MD, from H. Lee Moffitt Cancer Center in Tampa, Florida.2

CMML is an aggressive myelodysplastic/myeloproliferative neoplasm (MDS/MPN) characterized by peripheral monocytosis and bone marrow dysplasia with limited therapeutic options. JAK2 inhibitors, though, have shown promise as therapeutic candidates in preclinical studies. “Overall survival with CMML is about 34 months, so there is a real unmet treatment need for these patients,” Dr. Padron told ASH Clinical News. “This phase I trial, we hope, is a start toward addressing that.”

Nineteen patients with CMML-1 – with no regard to prior therapies – were enrolled into the trial in four cohorts, Dr. Padron explained, with doses ranging from 5 mg twice daily to 20 mg twice daily in 5-mg dose escalations.

Median age among the 19 patients was 71 years, and 67 percent had the proliferative form of CMML. Mean duration of therapy was 122 days (range, 28-409 days).

Of the 15 patients evaluable for response, three had hematologic improvement and one had a partial response per 2006 International Working Group (IWG)  criteria. Among the nine patients with splenomegaly, six experienced a >50 percent reduction in spleen size. Ruxolitinib was particularly beneficial for patients with CMML-related B symptoms (fever, night sweats, weight loss, pruritis): 14 of 15 patients had clinically meaningful or complete resolution. No dose-limiting toxicities for ruxolitinib were identified, Dr. Padron noted.

CPI-613 for High-Risk AML Patients

CPI-613, a first-in-class, non-redox, active lipoate derivative, is a promising salvage regimen in combination with high-dose Ara-C (HDAC) and mitoxantrone – particularly for older patients with AML and those with high-risk disease – according to research presented by Timothy S. Pardee, MD, PhD, from Wake Forest University in Winston-Salem, North Carolina.3

Outcomes in these patient groups are “dismal,” said Dr. Pardee, but in this phase I trial, treatment with CPI-613,  which works by inhibiting mitochondrial metabolism, led to favorable overall response rates.

Among the 48 patients (median age = 60 years; range 21-79) in this trial, 14 had refractory disease and 11 had received one or more lines of prior salvage therapy.

Compared with a historic cohort treated with HDAC, mitoxantrone, and asparaginase, the overall response rates (ORR) in this trial were favorable (48% vs. 25%), with 19 CR and 4 CRi. Surprisingly, Dr. Pardee said, the 11 patients with poor-risk cytogenetics and the 26 patients aged 60 or older also had high ORR, compared with the historic cohort (48% vs. 25%; 46% vs. 33%). As in the historic cohort, 13 percent of patients died on or before day 30 of treatment. Twenty-three percent of patients went on to receive stem cell transplantation.

“We are very excited by these preliminary results, especially for high-risk patients,” Dr. Pardee concluded, adding that a randomized phase II study is under development.


  1. Levis MJ, Perl AE, Altman JK, et al. Results of a first-in-human, phase I/II trial of ASP2215, a selective, potent inhibitor of FLT3/Axl in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). Abstract #7003. Presented at the 2015 American Society of Clinical Oncology Annual Meeting, Chicago, Illinois, May 30, 2015.
  2. Padron E, Dezern AE, Vaddi K, et al. A multi-institution phase I trial of ruxolitinib in chronic myelomonocytic leukemia (CMML). Abstract #7021. Presented at the 2015 American Society of Clinical Oncology Annual Meeting, Chicago, Illinois, May 30, 2015.
  3. Pardee TS, Stadelman K, Isom S, et al. Activity of the mitochondrial metabolism inhibitor cpi-613 in combination with high dose Ara-C (HDAC) and mitoxantrone in high risk relapsed or refractory acute myeloid leukemia (AML). Abstract #7015. Presented at the 2015 American Society of Clinical Oncology Annual Meeting, Chicago, Illinois, May 30, 2015.