Busulfan (Bu) in Combination with Double Nucleoside Analogues Fludarabine (Flu) and Clofarabine (Clo) Plus Vorinostat As a Novel Reduced Toxicity Conditioning Regimen for Allogeneic Hematopoietic Cell Transplantation (HCT) in Patients (pts) with Acute Leukemia
Authors: Kebriaei Partow , Wei Wei , Thall Peter F , Ledesma Celina , Valdez Benigno C. , Popat Uday R. , Olson Amanda L. , Alousi Amin M. , Oran Betul , Ahmed Sairah , Ciurea Stefan O. , Patel Krina , Shpall Elizabeth J. , Hosing Chitra , Qazilbash Muzaffar H , Shah Nina , Marin David , Rezvani Katayoun , Nieto Yago , Champlin Richard E. , Andersson Borje S 
Published: October 2019

The combination of IV Bu and Flu is an effective and well-tolerated HCT conditioning regimen for patients with advanced acute leukemia. However, relapse remains the main reason for treatment failure. We combined two nucleoside analogues Flu and Clo, and showed cytotoxic synergy when combined with Bu, first in pre-clinical models, and subsequently in a randomized clinical study (Andersson BBMT 2011). We selected the optimized regimen from Andersson et al, and combined with escalating doses of the histone deacetylase inhibitor vorinostat in attempts to augment disease control without increasing toxicity. Herein, we describe our initial experience with this novel regimen for patients with advanced acute leukemia or MDS undergoing allogeneic HCT.

Methods: Vorinostat (200mg to 1200mg) was escalated in cohorts of 3 patients, and administered 1 hour prior to the fixed regimen of Flu 10 mg/m2 followed by Clo 40 mg/m2 followed by Bu. The nucleoside analogs were infused over 1 hour once daily for 4 days, followed on each day by Bu, infused over 3 hours to a pharmacokinetically targeted daily area under the curve (AUC) of 5500 μMol-min ± 5%. Dilantin was given for seizure prophylaxis. GVHD prophylaxis was based on tacrolimus andmini-MTX, with the addition of rabbit anti-thymocyte globulin (4 mg/kg total dose) for unrelated donor transplants. The presence of minimal residual disease (MRD) was determined by multiparameter flow cytometry.

Results: 21 patients (7 AML, 14 ALL) with median age 43 years (range 19-60) received an allogeneic matched sibling (n=10) or unrelated donor (n=11) HCT in CR1 (n=13), CR2 (n=1), primary induction failure (n=5), or relapse (n=2). Twelve patients had MRD or overt disease present at time of HCT. Ten patients had high-risk karyotype defined by t(9;22) (n=3), t(4;11) (n=2), complex (n=2), or del 5 or 7 (n=3). Median time from diagnosis to HCT was 5 months (range 3-48). Median time to ANC > 0.5 x 109/L and platelets > 20 x 109/L were 11 (range 10-15) and 12 days (5-30), respectively. Excluding grade 1 toxicities, the most commonly reported toxicities were nausea with maximum grade 2 (71%), followed by grade 2 or 3 mucositis (64%). Grade 2 or 3 reversible elevation of liver function tests was noted in 54% of pts, including 1 case of reversible VOD. No renal toxicities were noted. Two patients with prior systemic treatment for acute GVHD died of infections (disseminated adenovirus and E.coli sepsis). Ten patients achieved CR and clearance of MRD by day +30 after HCT; one patient had progressive disease and on patient died before disease restaging. Eighteen patients achieved 100% donor chimerism at 30 days following HCT, 2 patients remain with mixed chimerism by 100 day assessment following HCT, and 1 patient died before assessment. The incidence of grades II-IV acute GVHD is 43% and chronic extensive GVHD among 18 evaluable patients is 24%. With a median follow-up of 10 months among surviving patients (1-22), overall and progression-free survival at 6 months is 95% and 71%, respectively. Early results suggest excellent disease control in MRD negative patients (Figure).

Conclusion: The Vorinostat-Flu-Clo-Bu combination is well-tolerated and did not add appreciable toxicity in these patients with high-risk leukemia. Longer follow-up is needed to better assess disease control.

Figure Figure.

Disclosures

Ciurea: Spectrum Pharmaceuticals: Other: Advisory Board; Cyto-Sen Therapeutics: Equity Ownership. Patel:Ziopharm Oncology: Equity Ownership, Patents & Royalties; Intrexon: Equity Ownership, Patents & Royalties.