Escalation Trial of Clofarabine Followed by Escalating Dose of Fractionated Cyclophosphamide in Adults with Relapsed or Refractory Acute Leukemias,

The prognosis of patients with relapsed/refractory acute leukemias (RRAL) continues to be very poor, with a complete remission (CR) rate of ≤ 30% and a one-year disease-free survival of ≤ 10%. Consequently, there is no standard of care for the treatment of RRAL at the current time. Clofarabine (CLO) is a second-generation purine nucleoside analog that has shown activity against RRAL. The administration of CLO followed by Cyclophosphamide (Cy) enhances the DNA damage induced by Cy and increases AML/ALL blast apoptosis rates. We previously published a phase I study in RRAL patients in which a timed-sequential approach using CLO followed by Cy (days 1–3/8-10 or 1–2/8-9) resulted in promising clinical responses, but was associated with unacceptable toxicity (Karp, Blood 2007). Given the lengthy marrow aplasia, which was a dose-limiting toxicity (DLT), we conducted another phase I dose-escalation trial of CLO followed by escalating doses of fractionated Cy in adults with RRAL using an infusion schedule of 4 consecutive days (CLO-Cy × 4).

One cycle of CLO-Cy was defined as 28 days. In order to assess the impact of CLO on Cy induced DNA damage, a 50% dose of CY was given alone on day zero and the remaining 50% was given after CLO on day 1. Thereafter, full dose Cy was given after CLO days 2–4. Full daily Cy doses ranged from 600–800mg/m2/day (total 2.4–3.2gms/m2). CLO was administered days 1 through 4 at 10 mg/m²/day for dose levels 1 and 2, 15 mg/m²/day for dose level 3, and 20 mg/m²/day for dose level 4.

Between 12/07 and 3/09, 26 adults (age 18 yrs) were entered on study. An additional 14 patients (pts) were enrolled between 4/09 and 3/10 in an expansion cohort determined by the phase 1 trial (dose level 1). 40 pts (28 AML [4 relapsed, 24 refractory], 12 ALL [3 relapsed, 9 refractory]) were given 45 cycles of CLO-Cy (5 pts received 2 cycles each). The average age was 48.5 years (range 22–73 years). The median number of prior regimens was 2 (range 1–5), including 6 who had prior allogeneic stem cell transplant. Of pts with AML, 21 (75%) had adverse cytogenetics, while 8 pts with ALL (67%) had adverse cytogenetics (2 with Philadelphia-positive ALL). The most common side effects were grade 3 and 4 hematologic toxicity. 6 pts (15%) died within 60 days of induction, 2 from septic complications and 4 from progressive disease. The average time to recovery of absolute neutrophilic count (ANC) of ≥ 500 was 40 days (range 31–78). 7 pts developed bacteremia and 2 developed fungemia. 10 pts developed grade 3 pneumonias, of which 7 were probably fungal. 5 pts developed pericardial/pleural inflammation or effusions (1=grade 3). 3 pts had reversible non-oligouric acute renal failure, but only one developed tumor lysis syndrome. Elevated liver function tests were noticed in 4 pts (2 grade 3). CLO-cytokine release syndrome (3 pts), hand-foot syndrome (3 pts), CLO-induced fever (1 pt), and mucositis (1 pt) were all ≤ grade 2. On day 14, 24 pts achieved complete tumor clearance, 4 pts had minimal disease, and 9 pts had residual disease. Of the 40 pts, 13 pts had an objective response (33%) with 11 CR, 2 PR. Of the 11 CR, 6 were in pts with non-adverse cytogenetics and 5 in pts with adverse cytogenetics. For AML, overall response rate (OR) was 25% (7/28) with 5 CR and 2 PR. For ALL, OR was 50% (6/12), all CR. At dose level 1 (total of 21 pts), OR was 48% (8 CR, 2 PR). Notably, the clinical responses were not dependent on the dose level. Among clinical responders, median pretreatment total white blood cell (WBC) was 3,310 (260–29,560) and median absolute lymphocyte count (ALC) was 1,737 [252–5948]. Median pretreatment IgG was 998 (226–1930), IgM was 67 (29–191), and IgA was 53 (<7–349). Median % decline in the ALC was 99%. The median % decline in IgG from D0 to D30 was 3%, for IgA was 4% and for IgM was 37%. Mean time to ALC recovery (ALC>200) was 47 days (32–85).

This 4-day regimen of CLO followed by Cy demonstrated activity and tolerability in this heavily pretreated patient population with RRALs, with an OR of 33% (13/40). While the numbers are small, CLO-Cy may have particular activity in relapsed ALL. Immune reconstitution analysis showed profound and protracted decline in ALC without significant effects on IgG and IgA but perhaps with negative impact on early immunoglobulin responses (IgM). Further immunologic correlates should accompany clinical studies using CLO.

Karp:Genzyme: Research Funding.