A randomized trial of three novel regimens for recurrent acute myeloid leukemia demonstrates the continuing challenge of treating this difficult disease

Litzow, Mark R.; Wang, Xin V.; Carroll, Martin; Karp, Judith E.; Ketterling, Rhett P.; Zhang, Yanming; Kaufmann, Scott H.; Lazarus, Hillard M.; Luger, Selina M.; Paietta, Elisabeth; Pratz, Keith W.; Tun, Han W.; Altman, Jessica K.; Broun, E. Randolph; Rybka, Witold B.; Rowe, Jacob M.; Tallman, Martin S.

doi:10.1002/ajh.25333

Cited by 21 publications

(16 citation statements)

References 24 publications

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“…In another phase 3 study comparing MEC alone versus MEC with valspodar, a p-glycoprotein inhibitor, using a 5-day MEC regimen, 7 the MEC-alone arm had a response rate of 25%, with a median OS of 5.4 months. The median survival observed in this study was similar to the results from recent early-phase MEC combination studies, [10][11][12]23 including those combining either sirolimus, 23 lenalidomide, 11 or decitabine 12 with MEC re-induction therapy.…”

Section: Discussionsupporting

confidence: 85%

A phase 1 study of the antibody‐drug conjugate brentuximab vedotin with re‐induction chemotherapy in patients with CD30‐expressing relapsed/refractory acute myeloid leukemia

Narayan

Blonquist

Emadi

et al. 2019

Cancer

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Background Outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) remain poor. Novel therapies specifically targeting AML are of high interest. Brentuximab vedotin (BV) is an antibody‐drug conjugate that is specific for human CD30. In this phase 1 dose escalation study, the authors evaluated the safety of BV combined with mitoxantrone, etoposide, and cytarabine (MEC) re‐induction chemotherapy for patients with CD30‐expressing R/R AML. Methods Using a standard dose escalation design, the authors evaluated 3 dose levels of BV (0.9 mg/kg, 1.2 mg/kg, and 1.8 mg/kg) administered once on day 1 followed by MEC on days 3 through 7. Results There were no dose‐limiting toxicities noted and the maximum tolerated dose was not reached. The recommended phase 2 dose of BV was determined to be 1.8 mg/kg when combined with MEC. The side effect profile was similar to that expected from MEC chemotherapy alone, with the most common grade ≥3 toxicities being febrile neutropenia, thrombocytopenia, and anemia (toxicities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Among the 22 patients enrolled on the trial, the composite response rate was 36%, with a composite response rate of 42% noted among those who received the highest dose of BV. The median overall survival was 9.5 months, with a median disease‐free survival of 6.8 months observed among responders. Approximately 55% of patients were able to proceed with either allogeneic hematopoietic stem cell transplantation or donor lymphocyte infusion. Conclusions The combination of BV with MEC was found to be safe in patients with CD30‐expressing R/R AML and warrants further study comparing this combination with the use of MEC alone in this population (ClinicalTrials.gov identifier NCT01830777). Lay summary The outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) are exceptionally poor. New and emerging treatment combinations are actively being studied in an effort to improve outcomes. The authors examined the combination of brentuximab vedotin, an antibody product that recognizes a marker called CD30, with mitoxantrone, etoposide, and cytarabine (MEC), a common chemotherapy regimen, in patients with R/R AML that expressed the CD30 marker. The authors found that the combination was safe and well tolerated. Future studies comparing this new combination with the use of MEC alone can help to inform its effectiveness for this patient population.

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Section: Discussionsupporting

confidence: 85%

A phase 1 study of the antibody‐drug conjugate brentuximab vedotin with re‐induction chemotherapy in patients with CD30‐expressing relapsed/refractory acute myeloid leukemia

Narayan

Blonquist

Emadi

et al. 2019

Cancer

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“…TST with cytarabine, mitoxantrone and etoposide as salvage chemotherapy previously showed encouraging efficacy with a CR rate of 61% (45% of refractory and 81% of relapsed AML patients) as a single-arm study [13]. Our small single institution experience showed 40% of the patients achieved CR or CRi (17% of refractory and 75% of relapsed patients), comparable to results from other salvage intensive chemotherapy studies [19,20].…”

Section: Discussionsupporting

confidence: 79%

Timed Sequential Salvage Chemotherapy for Relapsed or Refractory Acute Myeloid Leukemia

Popescu¹,

Sheela²,

Thompson³

et al. 2019

CHI

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A B S T R A C TTherapy for those with relapsed or refractory acute myeloid leukemia is suboptimal. Studies have suggested that timed sequential salvage combination cytotoxic chemotherapy may be particularly useful for that indication. We report here a series of ten such adult patients treated sequentially at a single center with EMA (cytarabine 500 mg/m 2 /day as continuous infusion on days 1-3 and days 8-10, mitoxantrone 12 mg/m 2 /day on days 1-3, and etoposide 200 mg/m 2 /day as continuous infusion on days 8-10). The overall complete remission rate was 40% (including 3 of 4 of those with relapsed disease), but use of this regimen was associated with prolonged cytopenia and a high rate of infectious adverse events. Even with the availability of modern infectious prophylaxis and therapies, the EMA regimen is likely best reserved for those with relapsed disease treated with curative intent prior to an allogeneic hematopoietic cell transplant.

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“…Alvocidib has been investigated in a timed-sequential therapy (TST) approach in combination with cytarabine and mitoxantrone (ACM) in 405 patients with both newly diagnosed (n=256) and relapsed/refractory (n=149) AML with encouraging findings (10)(11)(12)(13)(14)(15)(16)(17). To date, there have been two dosing strategies done with alvocidib: a 60-minute IV bolus versus a "hybrid" dosing of a 30-minute loading dose followed by a 4-hour infusion.…”

Section: Downloaded Frommentioning

confidence: 99%

Phase I Study of Alvocidib Followed by 7+3 (Cytarabine + Daunorubicin) in Newly Diagnosed Acute Myeloid Leukemia

Zeidner

Lee

Frattini

et al. 2021

Clinical Cancer Research

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Standard frontline therapy for younger fit patients with newly diagnosed AML includes induction chemotherapy with continuous infusion cytarabine and an anthracycline (i.e., 7+3) with or without targeted agents such as midostaurin or gemtuzumab ozogamicin. However, overall outcomes are poor with 5-year survival rates <50%. Alvocidib is a cyclin-dependent kinase-9 (CDK9) inhibitor that leads to transcriptional suppression of MCL-1, an anti-apoptotic BCL-2 family member that is up-regulated in AML. Prior studies showed that alvocidib followed by cytarabine and mitoxantrone has anti-leukemic activity in both newly diagnosed and relapsed/refractory AML. This phase 1 study revealed that alvocidib 30 mg/m 2 IV over 30minutes followed by 60 mg/m 2 IV over 4-hours on days 1-3 can be administered prior to 7+3 induction in newly diagnosed AML patients with overall CR rates of 69% in patients with nonfavorable cytogenetics. Preliminary clinical activity was seen in secondary AML patients who have poor outcomes with conventional chemotherapy. Research.

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A randomized trial of three novel regimens for recurrent acute myeloid leukemia demonstrates the continuing challenge of treating this difficult disease

Cited by 21 publications

References 24 publications

A phase 1 study of the antibody‐drug conjugate brentuximab vedotin with re‐induction chemotherapy in patients with CD30‐expressing relapsed/refractory acute myeloid leukemia

A phase 1 study of the antibody‐drug conjugate brentuximab vedotin with re‐induction chemotherapy in patients with CD30‐expressing relapsed/refractory acute myeloid leukemia

Timed Sequential Salvage Chemotherapy for Relapsed or Refractory Acute Myeloid Leukemia

Phase I Study of Alvocidib Followed by 7+3 (Cytarabine + Daunorubicin) in Newly Diagnosed Acute Myeloid Leukemia

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