Identical-Twin Transplants for B-Cell Chronic Lymphocytic Leukemia (B-CLL).
Authors: Pavletic Steven , Zhou Guimei , Sobocinski Kathleen , Doney Kristine , DiPersio John , Feremans Walter , Foroni Letizia , Prentice H. Grant , LeMaistre Charles , Bandini Giuseppe , Ferrant Augustin , Jacobsen Niels , Khouri Issa , Gale Robert Peter , Giralt Sergio , Montserrat Emilio , Chan John , Bredeson Christopher 
Published: October 2019

Abstract
Studies of genetically identical-twin transplants are a novel opportunity to study how transplants work because: (1) there is no allogeneic effect; (2) no leukemia cells in the graft; and (3) no graft exposure to therapy. We conducted an international study that identified 19 subjects who received syngeneic bone marrow (N=11) or blood cell (N=8) transplants after myeloablative conditioning. 11 were males; age 51 y (range, 37–68 y). 18 received total body radiation. None had Richter transformation. Interval from diagnosis to transplant was 27 mo (5–171 mo). At transplant 8 had Rai stage 3/4, 5 had >50x10e9/L lymphocytes, 10 received ≥3 prior therapies, 8 had prior fludarabine, and 5 had a prior complete remission (CR). 18 engrafted and 13 achieved posttransplant CR; median time to CR was 3 mo (1–5 mo). Probability of 100 d survival was 89% (95% CI, 72–99%).10 subjects are alive (8 disease-free) at median follow-up of 63 mo (9–116 mo). Ten subjects either never achieved CR (N=6) or relapsed posttransplant (N=4). 5-y cumulative incidence of relapse was 52% (27–77%). Estimated 5-y survival and disease-free survival were 59% (34–81%) and 43% (20–67%), respectively. Causes of death included interstitial pneumonitis (N=1) and leukemia (N=8). 5-y cumulative incidence of treatment-related mortality (TRM) is 5% (0–20%). We used a highly sensitive (10e-4 to 10e-5) PCR method to examine post transplant blood (2 pts) or bone marrow (2 pts) samples for the tumor specific IgH gene (CDR)III to assess minimal residual disease (MRD). IgH CDR III was PCR amplified in pre transplant B-CLL samples from 4 pts to obtain the sequence to design tumor-specific primer probes for MRD. No evidence of MRD was detected in two pts at 12 and 21 mo posttransplant. A very weak clonal signal was identified in one pt at 64 mo. All three of these pts were in continuous clinical CR at 12, 60, and 66 mo, respectively. In one pt, who relapsed with B-CLL 6 y after transplant, molecular studies at 10 y follow-up demonstrated a very strong molecular signal but of a different clone. Additional investigation identified familial CLL where the donor was also diagnosed with B-CLL soon after marrow donation. Molecular analysis of the donor B-CLL showed a clone identical to the recipient’s post-transplant relapse, strongly indicating B-CLL transmission at the time of transplant. This study demonstrates that identical twin transplants can be performed in advanced B-CLL with little TRM and with a high-rate of durable clinical and molecular remissions. The 5-y leukemia relapse rate of 52% is higher than that in studies of similar subjects receiving allotransplants but lower than after autotransplants. We also report B-CLL transfer from a twin donor demonstrating the need for careful evaluation of allogeneic donors prior to graft collection.