Allogeneic Hematopoietic Stem Cell Transplantation for CLL: Eradication of Specific FISH Abnormalities with Relation to Gvhd and Transplant Outcomes.
Authors: Toze Cynthia , Dalal Chinmay B. , Gillan Tanya L. , Nevill Thomas J. , Barnett Michael J. , Nantel Stephen H. , Hogge Donna E. , Forrest Donna L. , Sutherland Heather , Song Kevin , Broady Raewyn , Power Maryse , Narayanan Sujaatha , Smith Clayton A. , Shepherd John 
Published: October 2019

Abstract
Abstract 3465
Multiple studies have demonstrated the curative potential of allogeneic hematopoietic stem cell transplantation (allo HSCT) for CLL, with a clear and strong role for graft vs. leukemia and a less certain role for other factors including dose intensity. It is also known that FISH abnormalities (abn) are prognostic for CLL. The ability and timing of SCT to eradicate CLL in specific FISH categories, and the relationship of this clearance to onset of gvhd has not been clarified. In order to ascertain factors related to outcomes including achievement of CR, clearance of FISH abN, NRM, relapse/progression (REL) and survival, patients (pts) proceeding to allo HSCT at the Leukemia/BMT Program of BC with CLL (n=49 consecutive, 1991–2009) were studied with the use of prospective databases. HSCT Comorbidity index (Sorror) (CoI) was calculated for all pts. FISH was performed pre and post SCT in 35 and 33 pts respectively. Chimerism was performed for all pts not receiving myeloablative (MA) regimens. Gender was F:M 16:33 for pts, 15:34 donor (dn). Median (med) age at SCT was 54 yrs (32-68) for pts; 45 (19-76) yrs for dn. Max stage was Rai advanced (III/IV) in 32 (65%). 30 of 45 pts (67%) who had received prior fludarabine (flu) were flu refractory (REF); 26 (53%) were REF to their last pre-SCT therapy (tx). Med number of prior tx was 3 (1-14). CoI was 0 in 25 (50%), 1 or 2 in 17 (35%), and 3 or more in 7 pts (15%). Conditioning was MA (Cy/TBI) in 22 (45%), and reduced-intensity (RIC) in 27 (55%), consisting of flu/cy in 16 (33%), and flu/bu +/− campath (for UD only, n=9) in 11 (22%) pts. Dn was UD in 20 (41%), and HLA-mismatched (mm) in 12 (25%). PB was used for most pts (38, 78%). GVHD prophylaxis was CSP/MTX for the majority (47, 96%). With med post SCT follow-up (FU) of 5 yrs (0.2-15) 31 of 49 pts are alive. Med FU (range) from dx is 11.6 yrs (3 - 35). 18 are deceased at a med of 292 days (39 days - 5.7 yrs) post SCT, 9 with NRM and 9 with REL. All pts who died with REL had either del 17p or 11q, as did 3 of 9 pts with NRM. CR has been achieved in 33 pts, a med of 103 days (range 28 days to 5.4 yrs) post SCT, and 69 days post earliest onset of gvhd. 30 pts with CR did not REL, 3 did; 3 pts without CR have progressed, and 13 pts have not achieved CR to date but do not have progressive CLL. DLI was administered in 8 pts, a med of 154 days post SCT (86-710), resulting in CR for 6 of these 8 pts. Pre-SCT FISH abN (n, % of pts) included: del 13q (20, 57%); +12 (7, 20%); del 11q (16, 46%) and del 17p (10, 29%). 2 of 32 pt with FISH abN cleared these pre and 17 post SCT at a med of 149 days (36 days to 3.7 yrs). All pts who failed to clear FISH abN had del 17p (n=8) or 11q (n=4) with the exception of 1 pt who had del 13q and graft failure. KM estimate of OS is 63% at 2 yr, 55% at 5 yr and beyond. Factors predictive for OS include (p value): CoI <3 (0.02), FISH rank (Dohner) (0.004), achievement of CR post SCT (0.002), chimerism >90% on all tests (0.01) and clearance of FISH abN post SCT (0.04). Importantly, age of pt and dn, UD, MA vs RIC, HLA mm, sensitivity to fludarabine and last tx did not affect OS. AGVHD gr 3–4 (but not gr 0–2 or CGVHD) had negative impact on OS (0.004). Studies are ongoing to evaluate the role of HSCT timing, intensity of conditioning and gvhd in the eradication of CLL in the FISH subgroups. Specific tailoring of transplant intensity and manipulation of graft vs leukemia effects may be required for individual patients in particular to improve outcomes for poor risk patients with del 17p, and to minimize risk for patients with better prognosis.

Disclosures:
Toze: Hoffman La Roche: Consultancy, Honoraria, Research Funding; Genzyme: Honoraria, Research Funding; Glaxo Smith Kline: Honoraria. Sutherland:Celgene: Honoraria; Orthobiotech: Honoraria.