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

FactorGroup5 year outcomes (%)
PFSRelNRMOS
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  
 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 
FactorGroup5 year outcomes (%)
PFSRelNRMOS
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  
 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.

Author notes

*

Asterisk with author names denotes non-ASH members.