Sequential Autologous Followed by Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation (HCT) From HLA-Matched Related or Unrelated Donors Improves Outcomes of Patients (pts) with Bulky Lymphoma or Chronic Lymphocytic Leukemia (CLL)
Authors: Sorror Mohamed L. , Storer Barry , Sandmaier Brenda M , Chauncey Thomas , Maris Michael T. , Storb Rainer F. , Maloney David G. 
Published: October 2019

Abstract
Abstract 2365
Large lymph node size or chemo-refractoriness limited the success of nonmyeloablative allogeneic HCT in eradicating CLL or lymphoma. We explored an approach of combining the cyto-reductive effect of high dose chemo/radiation therapy and autologous HCT with the graft-versus-tumor effect of nonmyeloablative allogeneic HCT for pts with rapidly progressive/refractory CLL or lymphoma. Between 4/2000 and 3/2010, 45 pts with advanced indolent (16%) or aggressive (54%) non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL, 18%), or CLL (11%) ineligible for myeloablative allogeneic HCT due to age and/or comorbidities were treated with the sequential approach. Autologous HCT alone was thought to be insufficient for disease control. Pts received high-dose therapy and autologous HCT followed [at a median of 65 (range 39–128) days] by nonmyeloablative conditioning and related (n=28) or unrelated donors (n=17) allogeneic HCT. Median pt age was 49 (range 20–71) years and number of prior regimens was 4 (range 1–12). Thirty-four percent of pts had disease responsive to the last chemotherapy before autografting [30% partial (PR) and 4% complete remission (CR)] while 44% and 22% had refractory and progressive disease, respectively. Most pts had aggressive disease (72%). Conditioning for autografts consisted of BEAM (49%) or Cyclophosphamide/12 Gy TBI±VP16 (51%). After auto-grafting, 58% of pts had CR/PR (29%/29%), 36% had responses <PR, 3% had relapse, and 3% had refractory disease. Conditioning for allografts consisted of 2 Gy TBI alone (53%) or combined with FLU (47%), 90 mg/m2. Pts received G-CSF mobilized allogeneic peripheral blood mononuclear cells. All 45 pts had sustained donor engraftment. Incidences of grades II, III, and IV acute and of chronic GVHD were 46%, 16%, 0%, and 52% respectively. With median follow up of 51 (range 5–116) months, the overall response rate was 60% (46% CR). Eighteen pts died, 12 from progression/relapse, 3 from pulmonary complications, 1 from GVHD, 1 from sepsis, and 1 from multi-focal leuko-encephalopathy. Estimated 5-year rates of non-relapse mortality, relapse, overall, and progression-free survivals from the time of autografting were 15%, 44%, 55%, and 42% respectively. Pts with CLL or indolent NHL had rates of relapse and PFS of 11% and 68% compared to 47% and 37% for those with aggressive NHL and 69% and 31% for those with HL, respectively. No statistical significant differences in outcomes were detected for lymph node size (Figure), disease status at allografting, donor type, conditioning regimens for autografts or allografts, HCT-comorbidity index scores, or time between autologous and allogeneic grafting (Table). Sequential Auto-Allo HCT resulted in relatively low NRM with median survival not yet reached among pts with rapidly progressive lymphoma/CLL. This sequential transplant approach overcame the previously reported high relapse risk of bulky lymphadenopathy.
Table: Univariate outcomes in 45 patients with CLL/lymphoma receiving sequential autologous and allogeneic nonmyeloablative HCT Factor Group 5 year outcomes (%) PFS Rel NRM OS Histology CLL or Indolent NHL 68 11 Aggressive NHL 37 47 HL 31 69 HR 3.17 6.79 2.49 7.20 p-value 0.12 0.04 Lymph node size <5 cm 44 40 ≥5 cm 36 55 HR 1.19 1.45 p-value 0.70 0.47 Disease status after autografts Chemo-responsive 40 38 Chemo-refractory 46 43 Untested relapse 36 52 HR 1.07 1.31 1.38 1.75 p-value 0.83 0.68 Autografts conditioning regimen Non TBI-based 32 53 15 TBI-based 51 34 14 HR 0.59 0.54 0.77 p-value 0.20 0.20 0.75 Allografts conditioning regimen TBI 47 45 8 Flu/TBI 32 44 24 HR 1.61 1.24 3.63 p-value 0.25 0.66 0.12 HCT-CI scores at allografts 0-2 13 61 3+ 15 49 HR 1.57 1.48 p-value 0.63 0.44 Interval between autografts and allografts ≤60 days 20 53 >60 days 11 53 HR 0.47 0.84 p-value 0.36 0.72 Donor Related 44 46 11 59 Unrelated 34 43 23 43 HR 1.25 1.01 2.35 1.51 p-value 0.60 0.99 0.30 0.41 Note: p-values reflect hazard ratios over all follow-up period
Figure: 5-years progression-free survival of 44% and 36% for CLL/lymphoma pts with lymph node size of <5 vs. ≥5cm after sequential autologous and allogeneic nonmyeloablative HCT. Figure:. 5-years progression-free survival of 44% and 36% for CLL/lymphoma pts with lymph node size of <5 vs. ≥5cm after sequential autologous and allogeneic nonmyeloablative HCT.

Disclosures:
Off Label Use: All discussions about therapeutics used for HCT preparative regimens are off-label.