Abstract
Myeloablative busulfan and cyclophosphamide (BuCy2) is one of the most used preparative regimens for allogeneic hematopoietic cell transplantation for myeloid malignancies from HLA-identical (MRD) and 8 of 8 HLA-A, B, C and DRB1 allele matched unrelated (MUD) donors. However, mixed T-cell chimerism may be relatively common during the early post-engraftment phase using this regimen. The significance of early incomplete donor T-cell chimerism following BuCy2 allotransplants with respect to post-transplant outcomes is unclear. Methods: We analyzed 179 consecutive patients who underwent allotransplants for myeloid malignancies using myeloablative BuCY2 conditioning at our center. Cyclophosphamide was administered at 60mg/m2/d x 2 and busulfan was administered over four days with pharmacokinetically targeted exposure (usually 4.9 mgxhr/L) based on test dosing. Tacrolimus/methotrexate was used for GVHD prophylaxis. Uniform institutional supportive care protocols were employed for all patients. Lineage specific chimerism on T-cell (CD3) and myeloid (CD33) peripheral blood (PB) cells separated using immunomagnetic beads was performed monthly through d 100 following transplant. Patients with < 50% donor CD3 chimerism on d30 were scheduled to receive low dose DLI if available (starting at 5-10 x 10e5 CD3 cells /kg) while maintaining therapeutic tacrolimus levels. No intervention was performed if d30 donor CD3 chimerism was > 50%. Outcomes were analyzed using data extracted from our institutional database where information had been prospectively entered. GVHD diagnosis and grading were determined by a single dedicated practitioner. Results: Patient characteristics were: median age 50 (18-66), male 51%; diagnosis AML (65%), CML (23%) MDS/MPS (12%); MRD (52%) MUD (48%); graft source- PBSC 81%, BM18%, both 1%; DRI - low 12%, intermediate 57%, high 25%, very high 6%; donor CMV pos 51%, neg 49%; year of transplant- 2004-2012 (35%), 2013-2016 (32%) 2017-2021(33%). Median follow-up for surviving patients was 84 months (6-213). Kaplan-Meier (K-M) estimates for survival and relapse-free survival at 5 years for all patients were 66% (95%CI 58-73%) and 59% (51-66%). Median (range) donor chimerism on d 30 for CD3 cells was 80% (6-100%) and for CD33 cells was 100% (84-100%). Median CD3 chimerism on d 60, d 100 and d 180 were 86%(7-100%), 91% (8-100%) and 95% (12-100%) respectively. Twenty-four patients (13%) had CD3 <50% on d30 of which 9 received DLI. On multiple regression modeling (Table1) the following factors were associated with higher d 30 CD3 chimerism - diagnosis (AML vs other) (difference 0.104, p=0.001), DRI (high/v.high vs low/intermediate)(diff 0.070, p=0.03) and graft CD3 dose (>15.5x 10e7/kg vs < 15.5) (diff 0.105, p<0.001) For patients who had > 80% vs <80% donor CD3 chimerism on d 30, 5-year K-M estimates of survival and RFS were 56% vs 76% (p=0.003) and 54% vs 64% (p=0.16). Five-year cumulative incidences of NRM and relapse were 20% vs 8% (p=0.010) and 26% vs 28% (p=0.85). Cumulative incidences of grade 2-4 and grade 3-4 acute GVHD at 6 months were 49% vs 27% (p=0.002) and 20% vs 4% (p=0.001) respectively. Cumulative incidences of moderate to severe and severe chronic GVHD at 3 years were 81% vs 64% (p=0.017) and 53% vs 34% (p=0.008). On a Cox proportional-hazards model adjusting for significant patient, disease and transplant covariates, d 30 CD3 chimerism > 80% was associated with a significantly higher risk of NRM (HR 3.42, p=0.007), aGVHD gd 2-4(HR1.79, p=0.013), aGVHD gd 3-4 (HR 2.66, p=0.008) and severe cGVHD (HR 1.84, p=0.011). However, d 30 CD3 chimerism was not significantly associated with relapse, survival and relapse-free survival (Fig 1). Conclusions: These data suggest that while pharmacokinetically-targeted BuCy2 as administered is almost always myeloablative (CD33 chimerism 100%), early mixed T-cell chimerism is relatively common (CD3 chimerism < 80% in 50% of patients). d30 CD3 chimerism ≥80% is not associated with lower relapse rates or better survival outcomes, but is associated with higher rates of acute and chronic GVHD. No intervention to improve CD3 chimerism appears necessary for patients with d 30 CD3 chimerism between 50 and 80%. Patients with ≥ 80% CD3 chimerism at d 30 may benefit from more aggressive measures to prevent acute and chronic GVHD
Disclosures
Solh:ADC Therapeutics: Research Funding; Partner Therapeutics: Research Funding.
OffLabel Disclosure:
Busulfan and Cyclophosphamide for transplant preparative regimen
