Based on preclinical findings demonstrating marked antileukemic synergism between the HDAC inhibitor vorinostat and the CDK inhibitor flavopiridol (

Almenara et al.,
Leukemia
16
:
1331
–43,
2002
), a Phase I trial of these agents has been initiated in patients with refractory AML/MDS. Eligible patients (pts) have acute leukemia (AL) refractory to standard therapy or de novo AL with poor risk factors (age >60 or antecedent myelodysplastic syndrome), imatinib-refractory chronic myeloid leukemia in blast crisis, or RAEB-2. Pts are excluded for prior auto- or allogeneic marrow or stem cell transplantation, significant comorbidities or organ dysfunction, and QTc interval >0.470 seconds. All pts receive oral vorinostat (V) 200 mg 3 times daily. In the initial stages of the trial, pts also received flavopiridol (F) by 1-hour bolus infusion on days 1–5 out of a 21-day cycle. Initial F dose levels were (mg/m2): 10, 20, 30, 40. Subsequently, a “hybrid” F infusion schedule (30 minute load followed by 4 hour infusion) was adopted based on recent evidence of activity of this schedule in CLL. With the hybrid schedule, F is given on a combination of days (d) 1, 3, 8 and 11. Targeted F dose levels are, in mg/m2 (Fload/Finfusion): 20/20 on d1 and 8; 30/20 on d1 and 8; 30/30 on d1 and 8; 30/50 on d1 and 8; 30/50 on d1, 3 and 8; 30/50 on d 1,3, 8 and 11. Dose limiting toxicity (DLT) is defined as NCI CTCAE grade 4 non-hematologic (heme) toxicity (except that related to cytopenias, infection or hyperbilirubinemia), grade 3 non-heme toxicity which lasts >7 days, or grade 4 ANC/platelet toxicity that persists for > 6 weeks in absence of leukemia. 28 pts have been enrolled. With the bolus schedule 14 pts were treated at 4 dose levels without identification of an MTD, after which development of the hybrid schedule was begun. Since initiation of the hybrid schedule, 8 pts have been treated at 3 dose levels. One DLT (infectious colitis with sepsis) was seen on level 4 of the bolus schedule and one DLT (gr 3 atrial fibrillation) was seen at the 3rd hybrid dose level. The MTD of the hybrid schedule has not been reached. Non-DLT toxicities include diarrhea, anorexia, nausea, weight loss, fatigue, electrolyte abnormalities, hyperbilirubinemia, dyspnea, confusion, febrile neutropenia and infectious complications (including atypical infections). Of 22 pts treated, 20 are evaluable for response. Thus far, there have been no complete remissions in this heavily pretreated population. However, 10 pts experienced some clinical benefit despite meeting criteria for “remission induction failure” – of those, 3 were treated with ≥ 5 cycles. 10 pts had a best response of progressive disease. One heavily pre-treated pt with refractory AML, who progressed after FLAG x2 followed by gemtuzumab ozogamycin, remains in treatment following 7 cycles with improved PS and QOL, a marked improvement in peripheral WBC, and a normocellular marrow with 6% blasts. To date, hyperacute tumor lysis has not been seen with the hybrid schedule, but aggressive prophylaxis and monitoring remain integral to the treatment plan. QTc evaluation and monitoring has been implemented because of V interactions with concurrent medications commonly used in this population (azole antifungals, among others). Correlative laboratory studies reveal a regular increase in acetylated tubulin but heterogeneous post-treatment effects on p21CIP1, Mcl-1, and other proteins in leukemic blasts. Collectively, these findings indicate that a regimen combining vorinostat and flavopiridol is well tolerated in patients with refractory or high-risk AML, and may have some activity in patients highly resistant to standard therapy. Pending identification of the MTD and RPTD (recommended phase II dose), Phase II evaluation of this therapeutic strategy should define its activity more definitively.

Topics:
blast cells, flavopiridol, leukemia, acute, refractory anemia with excess blasts, refractory anemias, vorinostat, weight reduction, brachial plexus neuritis, toxic effect, infusion procedures

Disclosures: No relevant conflicts of interest to declare.

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2008, The American Society of Hematology
2008
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