Low Incidence of GVHD and Treatment-Related Morbidity (TRM) with Intermediate Doses of Continuous Infusion IV Busulfan and Daily Fludarabine with Individualized Doses of Alemtuzamab for Matched Related (MRD) and Unrelated (MUD) Transplant Pts with High-Risk Hematologic Malignancies.
Authors: Shea Thomas , Serody Jonathan , Gabriel Don , Comeau Terrance , Ivanova Anastasia , Moore Dominic , Irons Robert , Julia Whitley , Andrew Sharf , Dunphy Cherie , Mark Brecher 
Published: October 2019

Reduced intensity regimens have shown decreased toxicity and favorable overall survival in older pts, those with co-morbid conditions or those who undergo a second transplant for a variety of hematologic malignancies. Nevertheless, TRM, especially GVHD and opportunistic infections have remained a problem with chronic GVHD being reported in 40–50% of most series, leading to decreased long term survival. We report on results using intermediate-dose busulfan given as a continuous infusion along with fludarabine and disease and donor-specific dosing of alemtuzamab (A) for immunosuppression.

METHODS: Pts over the age of 55, those undergoing 2nd transplants, or with decreased organ function and an advanced or high-risk CR1 hematologic malignancy or dysfunctional marrow were eligible. All pts received IV busulfan 6.4 mg/kg days −6 and −5 by 48 hour infusion; fludarabine 30 mg/m2 qd x5 on days −7 to −3, and tacrolimus from day −1 plus the following GVHD prophylaxis: Group 1: MRD pts withAML, ALL, high-risk MDS, CML; MTX 5 mg/m2 days 1,3,6 Group 2: MUD/Mismatched RD pts with AML, ALL, IPSS HR MDS, CML; A 30 mg x1 d −8 and MTX x 3 Group 3: MRD pts with all other diseases; A 30 mg x 1, d −8 Group 4: MUD/MMRD pts with all other diseases; A 30 mg x 2, d −8,−7. All pts received standard supportive care and GM-CSF from day + 7 for Gp 1 and 2; from day +5 for Gp 3 and 4 to ANC recovery > 500/ul.

RESULTS: 27 pts, 18 males, 9 females were enrolled; AML 13 (7 transformed MDS); NHL 6; MDS 4; Myelofibrosis, CLL, HD, PNH, 1 each; median age 57, MRD 12, MUD 15. Two pts are < 100 days and inevaluable for chronic GVHD. Median recovery to ANC > 500 = 14 d and platelets > 20,000 = 15 d. Grade > 3 AEs included a subdural hematoma in a pt on chronic anti-coagulation for atrial fibrillation; peripheral neuropathy 1; EBV reactivation 4, and associated PTLD 2 (both following 2nd transplant). Acute GVHD grade II, 4 pts, grade III,1 pt and grade IV, 1 pt; extensive chronic GVHD occurred in 3 pts. Secondary graft failures (GF) occurred at days 60 and 75 in two pts; one with AML and one with MDS; primary GF occurred in one pt with PNH; all 3 GF pts were MUD transplants and later re-transplanted with a Cytoxan/ATG prep regimen; two of whom subsequently died of PTLD. With a median f/u of 18 months, 13 deaths have occurred; 8 relapsed disease, 2 PTLD, 2 GVH with infection,1 CNS bleed. 12/25 pts (5 AML, 7 others) remain alive and 10/25 (4 AML, 6 others) alive and relapse free. MRD and MUD outcomes were similar. Kaplan-Meier estimates of relapse free and overall survival at 18 months for the entire group were 42% (CI 22–60%) and 53% (CI 31–71%), respectively.

CONCLUSION: Continuous infusion, reduced dose busulfan has minimal early morbidity and mortality when given with fludarabine and pt specific doses of aemtuzamab and MTX. This regimen was associated with good prevention of GVHD and acceptable EFS, but a significant rate of GF and relapse in high-risk pts. Additional efforts to correlate busulfan levels and alternative immnosuppression approaches are currently under investigation.