Decitabine Plus Mini Fludarabine and Busulfan Yields Durable Engraftment with Low Relapse Rates in Elderly or Medically Infirm Patients with Myeloid Malignancies

Stem cell transplantation (SCT) is an effective treatment for myeloid malignancies but is often limited to younger patients without comorbidities. Reduced intensity conditioning (RIC) regimens offer this potentially curative treatment option to elderly or medically infirm patients but are often associated with increased relapse rates. Decitabine (DAC) has been effective in the primary treatment of MDS and may be useful in “debulking” prior to transplant. However, the role of DAC immediately prior to allografting (as part of the conditioning regimen) has not yet been determined. The combination of RIC fludarabine (FLU) and busulfan (BU) along with DAC is hypothesized to increase the anti-leukemic effect and produce durable engraftment while maintaining the reduced-intensity regimen toxicity profile.

This was a single-institution, phase I study of DAC in combination with FLU/BU as a RIC regimen for myeloid malignancies. Subjects were evaluated to assess stability of engraftment, toxicity, disease response, PFS and OS. Patients received decitabine 20 mg/m² IV daily × 5 from day -15 through day -11 followed by fludarabine 30 mg /m2 IV daily × 5 on days -7 to -3 and busulfan 130 mg/m2 IV daily on days -4 and -3. Thymoglobulin was given at a dose of 2 mg/kg IV daily on days -4, -3 and -2. Hematopoietic stem cells were infused on day 0. GVHD prophylaxis consisted of tacrolimus starting on day -2 and methotrexate 5 mg/m2 IV on days +1, +3, +6, and +11.

Eighteen patients were enrolled between 8/4/2009 and 5/2/2012. Median age was 67 years (range 49–79). Diagnoses included AML in CR1 (n = 4), CR2 (n = 4), or primary induction failure (n = 3); or MDS/MPD (n = 7). Eleven (61%) were male. Ten (56%) patients had unrelated donors as stem cell source; 8 (44%) had sibling donors; 17 (94%) received PBSCs; 1 received BM. Median number of CD34+ stem cells infused was 4.01 ×10⁶ cells/kg (range 2.1 ×10⁶ to 4.92 ×10⁶).

All patients engrafted. The median duration of neutropenia (ANC <1000) was 13 days. The median CD3 donor engraftment at day 56 and day 84 (+/− 7 days) was 73% (n=14) and 81% (n=11) respectively. Seven patients (of 12 evaluated) achieved >90% donor chimerism at day 84. The actuarial OS at 31 months was 43% (Kaplan Meier). Median OS has not yet been reached. Five of the nine evaluable patients (56%) not in a CR at the time of transplantation entered CR at three months post-SCT. For the entire cohort, at 3 months 10 of 14 evaluable patients (71%) were in remission. During follow up, five patients (27%) relapsed (1 pt with MDS; 3 pts with AML CR1; 1 pt with AML CR2) with a median time to relapse of 107 days. Four patients (22%) died of treatment related complications (TRM). Cause of death was GVHD (n=2), infection or other causes (n = 2), and relapse (n = 3). Four patients received DLI at a median of 173 days after SCT for either disease relapse (n = 2) or falling chimerism (n = 2). The incidence of acute GVHD grade I-II and III-IV were 44% and 22% respectively. Chronic GVHD was seen in 8 patients (44%).

Combining DAC with reduced intensity FLU/BU appears to be a well-tolerated transplant conditioning regimen in elderly or infirm populations with myeloid malignancies. Successful engraftment was attained in 100% of patients at day 28, and 94% of patients remain alive at day +100. The toxicity profile is acceptable and the relapse rate appears favorable. Future investigation should involve DAC in combination with mini-FLU/BU in the preparative regimen for patients with myeloid malignancies who are otherwise ineligible for myeloablative therapy.

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Off Label Use: Pretransplant use of decitabine. Goldberg:Eisai: Speakers Bureau. Mato:Celgene, Milennium, Genentech, Seattle Genetics: Speakers Bureau. McKiernan:Novartis: Speakers Bureau.