July 2014 Edition Vol.11, Issue 7

Novel Therapies for Leukemia Attract Attention at ASCO 2014

Novel Therapies for Leukemia Attract Attention at ASCO 2014 (continued)

Pan-cyclin-dependent Kinase Inhibitor in AML

Joshua F. Zeidner, MD, The Johns Hopkins Hospital and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, presented results of a phase 2 trial of timed-sequential therapy with flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus “7+3” (cytarabine plus daunorubicin) for adults with newly diagnosed acute myeloid leukemia (AML).7 The trial was supported by the Leukemia and Lymphoma Society, NIH, and NCI.

Most patients with acute myelogenous leukemia (AML) who have a complete response (CR) to induction therapy will relapse; the long-term OS in relapsed/refractory AML is less than 10%. Flavopiridol is a pan-cyclin-dependent kinase inhibitor previously shown to result in high CR rates when followed by cytarabine and mitoxantrone in newly diagnosed, poor-risk AML.

Patients in this trial (NCT01349972) were randomly assigned 2:1 to FLAM (n=109) or 7+3 (n=56). The primary endpoint, CR, was 70% for FLAM and 46% for 7+3 alone (P=.003), and 57% for 7+3 followed by 5+2 (additional cytarabine plus daunorubicin for residual leukemia on day 14, n=14; P=0.08 compared with FLAM). There was no significant difference in OS, relapse rate, or toxicities. There was a great deal of heterogeneity among patients in transplant-related treatments. Follow-up time may be too short to evaluate survival, or FLAM may not improve OS. In an ad hoc analysis, CR rates were highest in patients younger than age 60 years and in those with secondary AML. Dr. Zeidner said they have treated over 150 patients with newly diagnosed secondary AML across 4 studies with FLAM; these patients have a CR rate of 60% to 67%, suggesting these are the patients to focus on in future trials with FLAM.

Looking Ahead

Patients with CLL, including the elderly and those with poor prognostic features, e.g., deletion 17p13.1, can look forward to more treatment options, including modalities that are orally administered and have reduced toxicities. It remains to be determined which agents and in what combinations will benefit which patient subgroups. Relapsed/refractory ALL and newly diagnosed AML in adults remain difficult to treat and continue to present unmet medical needs.

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References

  1. Byrd JC, Brown JR, O'Brien SM, et al. Randomized comparison of ibrutinib versus ofatumumab in relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma: Results from the phase III RESONATE trial. J Clin Oncol 2014;32:5s (suppl; abstr LBA7008). http://meetinglibrary.asco.org/content/129571-144.
  2. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. New Engl J Med 2014; Online First May 31, 2014;DOI: 10.1056/NEJMoa1400376. http://www.nejm.org/doi/pdf/10.1056/NEJMoa1400376.
  3. US FDA. Novel New Drugs 2013 Summary. January 2014, http://www.fda.gov/downloads/drugs/developmentapprovalprocess/druginnovation/ucm381803.pdf.
  4. US FDA. Ibrutinib (Imbruvica). February 13, 2014. http://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm385878.htm.
  5. Sharman JP, Klein LM, Boxer, M, et al. Phase 2 trial of GS-9973, a selective Syk inhibitor, in chronic lymphocytic leukemia (CLL). J Clin Oncol 2014;32:5s, (suppl; abstr 7007). http://meetinglibrary.asco.org/content/126970-144.
  6. Topp MA, Goekbuget N, Stein AS, et al. Confirmatory open-label, single-arm, multicenter phase 2 study of the BiTE antibody blinatumomab in patients (pts) with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL). J Clin Oncol 2014;32:5s, (suppl; abstr 7005^). http://meetinglibrary.asco.org/content/129500-144.
  7. Zeidner JF, Foster, MC, Blackford A, et al. Randomized multicenter phase II trial of timed-sequential therapy with flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus “7+3” for adults with newly diagnosed acute myeloid leukemia (AML). J Clin Oncol  2014;32:5s, (suppl; abstr 7002). http://meetinglibrary.asco.org/content/125532-144.

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