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Qualitative and quantitative PCR monitoring of minimal residual disease (MRD) in relapsed poor-risk chronic lymphocytic leukemia (CLL): early assessment can predict long-term outcome after reduced intensity allogeneic transplantation. Farina L, Carniti C, Dodero A, Vendramin A, Raganato A, Patriarca F, Narni F, Spina F, Benedetti F, Olivieri A, Corradini P.
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BACKGROUND The median overall survival of CLL patients is about 10 years but : patients younger than 65 years with high risk disease (17p deletion) and poor risk relapsed patients may become eligible to a stem cell transplantation (SCT)
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post-trasplant molecular
MRD status influences the clinical outcome after auto-SCT in CLL and indolent lymphomas PCR - PCR - Mixed-PCR PCR + PCR + DFS according to the PCR status of stem cell harvests DFS according to post-trasplant molecular status Corradini P et al, JCO 2004
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Outcome according to MRD status at 3-6 months after auto-SCT in CLL
Progression risk Overall Survival Consensus PCR PCR+ PCR- PCR- PCR+ Moreno C et al, Blood 2006
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Clinical and molecular outcome according to the VDJ mutational status after auto-SCT
Molecular event-free survival Progression-free survival Mutated pts median time not reached Mutated pts Unmutated pts median time: 25 months Unmutated pts p p Experiments were done using consensus PCR Ritgen M et al, Blood 2003
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Rationale for reduced intensity (RIC) allo-SCT in CLL
Allogeneic stem cells are free of tumor contamination “Graft-versus-Leukemia effect”: donor derived immune cells are potentially capable of mediating an anti-tumor effect, either specifically or as part of an alloreactive phenomenon RIC alloSCT can be a suitable option for CLL patients who are usually old, heavely pretreated and/or affected by comorbidities
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AIMS OF THE STUDY Can we achieve molecular remission (MR) after RIC allo-SCT? What is the clinical relevance of MRD results? Are there any clinical or biological factors that can be correlated with the MRD status?
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PATIENT CHARACTERISTICS (1)
Molecular monitoring of MRD was carried out by PCR on BM samples of 29 relapsed CLL patients achieving complete remission after RIC alloSCT. Donor type n (%) Conditioning regimen and GVHD prophylaxis HLA identical sibling 21 (72) Thio/Flu/Cy MTX/CSA Unrelated 6 (21) Thio/Cy/ATG Haploidentical sibling 2 (7) Thio/Flu/Cy/TBI200 cGy/Alemtuzumab
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PATIENT CHARACTERISTICS (2)
n° patients 29 Median age (years) 60 range: 44-69 Unmutated VDJ 22/29 76% 17p deletion 6/16 38% Median n° previous therapy 3 range: 1-6 Previous autoSCT 8 29% Chemorefractory 11
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MRD MONITORING Qualitative monitoring n=29 L V D J L FR1 CDR1 FR2 CDR2 FR3 CDR3 FR4 1st PCR Probe JH VH primers 2nd PCR Patient-specific primers Quantitative monitoring n=6 ΔΔCT= (CTIgH-CTGAPDH )follow-up– (CTIgH-CTGAPDH) pre-transplant
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RESULTS (1): MR can be achieved after RIC allo-SCT
% Status at last follow-up Median follow-up (range, months) PCR-neg 9 31* 9 alive and CR 40 (14-97) PCR-mixed 7 24 1 nodal relapse 1 TRM 5 alive and CR 46 (38-77) PCR-pos 13 45 8 relapse** 2 TRM 3 alive and CR 49 (33-57) *4 patients experienced a delayed clearance of MRD within the first year after transplant **Relapse occurred after a median time of 9 months (range, 3-26)
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RESULTS (2): clinical impact of MRD status after RIC allo-SCT
PCR+ n=13 PCR-/mixed n= 16 p Relapse after alloSCT 8 (62%) 1 (6%) 0.003 After RIC allo-SCT PCR positivity correlates with a high relapse risk
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RESULTS (2): clinical impact of MRD status after RIC alloSCT
Cumulative incidence of relapse based on PCR status at 6 mos DFS based on PCR status at 6 mos p = 0.031 p = 0.012 2-yr DFS 93% MRD- --- MRD+ 2-yr DFS 46%
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RESULTS (3): no clinical or biological factors were predictive for the achievement of MR
PCR+ n=13 PCR-/mixed n= 16 p Previous treatment (≤ 2 vs > 2) 9 (69%) 8 (50%) 0.451 Chemorefractory 4 (31%) 7 (44%) 0.702 Donor type (HLA identical sib vs MUD/mismatched) 6 (46%) 3 (19%) 0.225 GVHD 12 (75%) 0.142 ….but the incidence of GVHD was 22% and 70% in relapsed and not relapsed patients, respectively (p= 0.040).
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RESULTS (4): the GVL effect may prevent clinical relapse in PCR –positive patients
Quantitative monitoring in PCR-pos. patients n=6 Decreasing or stable tumor load with extensive cGVHD n=4 Increasing tumor load without GVHD n=2 CR Relapse
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Qualitative MRD monitoring: PCR pos.
UPN 16 UPN 17 UPN 28 UPN 29 UPN 179 UPN 1u UPN 4u UPN 1a UPN 2a UPN 33 UPN 123 UPN 7u UPN 111 Rel Rel Rel Death Rel Death PCR + PCR - DLI CT or mAb Relapse acute and chronic GVHD Rel Death Rel Rel Rel 17pdel TRM 17pdel TRM Rel 17pdel UPN # identical sibling UPN #u unrelated UPN #a haploidentical Months
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Qualitative MRD monitoring: PCRneg/mixed
UPN 9 UPN 26 UPN 31 UPN 142 UPN 178 UPN 6 UPN 2u UPN 3u UPN 6u UPN 11 UPN 27 UPN 36 UPN 37 UPN 30 UPN 34 UPN 50 Qualitative MRD monitoring: PCRneg/mixed 17pdel 17pdel Rel Death 17pdel TRM Months
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CONCLUSIONS In poor risk relapsed CLL, molecular remission can be achieved after RIC allo-SCT. Persistent PCR positivity correlates with a high incidence of relapse, while a mixed-PCR pattern can be observed without clinical relapse. The postulated GVL effect may contribute to prevent clinical relapse in patients with detectable MRD, including chemorefractory and 17p deletion positive patients. Qualitative and quantitative PCR patterns can suggest the timing for early immune therapy intervention.
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Acknowledgments Carniti C. Raganato A. Dodero A. Vendramin A. Spina F.
Corradini P. Hematology dept. Istituto Nazionale Tumori University of Milano Patriarca F. University of Udine Benedetti F. University of Verona Narni F. Hematology dept. University of Modena Olivieri A. AOS San Carlo, Potenza
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