Low Day 30 Total Donor Chimerism After Reduced-Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation Is Associated with Poorer Overall Survival In Myeloid but Not Lymphoid Disorders

Abstract 1325

While some studies associated an increased relapse rate and poorer progression-free survival with lower donor T-cell chimerism after reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (HSCT); early total donor cell chimerism, despite its use as a clinical trial endpoint, is not established as a predictor of survival. In part this may reflect its non-uniform impact across hematologic malignancies. Clarifying the survival impact of early donor chimerism could help identify patients who may benefit from additional interventions; and also define its value as a disease-specific endpoint.

We undertook a retrospective analysis of adult patients undergoing 8/8 HLA-matched RIC HSCT from 2002–2008 with available day 30 total donor cell chimerism (range, 20–50 days; PB or marrow). All received fludarabine/busulfan-based conditioning with sirolimus- and/or tacrolimus-based GVHD prophylaxis. Umbilical cord blood transplants; ex-/in-vivo T-cell depletion (e.g. ATG); or malignant relapse/progression at or prior to day 30 chimerism were excluded. 414 patients with a median age of 58 years (range, 41–69) and median follow-up among survivors of 34 months (range, 6–80) were analyzed. Patient characteristics: 211 myeloid (116 AML, 63 MDS, 20 CML, 12 MPD); 203 lymphoid (70 NHL, 66 CLL, 39 HD, 21 MM, 6 ALL); 343 (83%) with high-risk disease; 265 (64%) were males; 404 (98%) received peripheral blood stem cells; 234 (57%) had matched-unrelated donors; and 132 (32%) had prior transplants.

Day 30 total donor cell chimerism was <50% in 32 patients (8%); 50–89% in 99 patients (24%); and ≥90% in 283 patients (68%). Factors predictive of lower day 30 chimerism were high-risk disease (p<0.01), no prior transplant (p<0.01), male sex (p=0.02) and myeloid diagnosis (p=0.03). In univariable analyses patients with lower day 30 chimerism had worse 3-year progression-free and overall survival (PFS, OS) (p<0.0001; p=0.003). The cumulative incidence of chronic GVHD correlated with the degree of day 30 chimerism (p=0.049). Stratified by diagnosis, lower day 30 chimerism was associated with poorer 3-year PFS and OS in myeloid (p<0.0001; p<0.001) but not in lymphoid disorders (p=0.09; p=0.66) (Figure ). For both myeloid and lymphoid disorders, lower day 30 chimerism was associated with increased incidence of relapse (p<0.0001; p=0.02) but not of non-relapse mortality (p=0.24; p=0.41).

In multivariable Cox-models, day 30 chimerism <50% was associated with lower PFS and OS (HR 3.13, 95% CI 2.04–5, p<0.0001; HR 2.27, 95% CI 1.41–3.57, p<0.001). For myeloid disorders, day 30 chimerism <50% was associated with poorer PFS and OS (HR 6.25, 95% CI 3.23–11.11, p<0.0001; HR 3.33, 95% CI 1.82–6.25, p=0.0001). For lymphoid disorders, day 30 chimerism <50% was associated with poorer PFS (HR 2.13, 95% CI 1.09–4.17, p=0.03) but not OS (HR 1.44, 95% CI 0.65–3.23, p=0.36), that may reflect in-part longer survival after lymphoid compared to myeloid relapse. However, there may also be disease-specific differences. For instance, low day 30 chimerism was highly associated with poorer PFS and OS in AML/MDS (HR 4.54, 95% CI 2.13–10, p<0.0001; HR 3.33, 95% CI 1.67–10, p=0.001); had a trend of PFS impairment in CLL/NHL (HR 2.17, 95% CI 0.97–5, p=0.06); but had no impact in HD or myeloma.

In conclusion day 30 total donor chimerism <50% is an independent predictor of poor survival after T-cell replete RIC HSCT. Routine assessment of day 30 chimerism in myeloid disorders helps identify a patient subset with significantly worse RIC HSCT outcomes, who may be candidates for trials of additional therapies to improve survival. Conversely, it may be a less relevant RIC HSCT endpoint in lymphoid disorders, where its survival impact appears more limited.

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Day 30 Total Donor Chimerism and RIC HSCT Overall Survival: by Diagnosis

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Day 30 Total Donor Chimerism and RIC HSCT Overall Survival: by Diagnosis

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