Minimal Residual Disease (MRD) Kinetics after Autologous Stem Cell Transplantation for Chronic Lymphocytic Leukemia (CLL) Correlate to IgH VH Mutational Status and Predict Post Transplant Outcome: Real Time ASO-IgH PCR Results of the GCLLSG CLL3 Protocol.

Abstract

The purpose of the present study was (1) to assess the quantitative impact of myeloablative therapy with autologous stem cell transplantation (SCT) on MRD levels in patients with CLL; (2) to assess the predictive value of post transplant MRD kinetics for clinical outcome; and (3) to study the influence of the IgH VH mutational status on MRD kinetics. Blood and bone marrow (BM) samples were obtained from patients from a prospective multicenter trial of the German CLL Study Group (GCLLSG CLL3 protocol) after informed consent. MRD monitoring was performed by real-time quantitative IgH PCR using allele-specific primers (ASO RQ-PCR).Results: As of July 2004, 476 blood samples from 46 patients who had an informative primer and repeated follow-up material available were analyzed by ASO RQ-PCR with a minimum sensitivity of 1E-4. In 145 cases, BM samples obtained on the same occasion were analyzed in parallel. Blood and BM showed highly significant correlating MRD values (p=.0001; slope 0.9, r<.0001), with a tendency to higher MRD levels and higher sensitivity in BM. Myeloablative treatment with SCT resulted in a strong reduction of the CLL load (median MRD level 6.6E-3 pretransplant vs. 1.0E-4 at 90–180 days post transplant; p<.0001) with no significant difference between patients with mutated and unmutated VH, respectively. Whereas MRD levels had no prognostic impact during the first 6 months after SCT, stable or decreasing MRD kinetics below 1E-4 between 6 and 12 months after SCT were strongly predictive for a favourable outcome (4-year progression-free survival (PFS) 100%). In contrast, PFS of those patients who had increasing MRD levels at this time was significantly poorer (4-year PFS 37%; p 0.02; n = 25). Patients with increasing MRD levels early post transplant almost exclusively belonged to the subgroup with unmutated VH.Conclusions: Myeloablative SCT can lead to substantial additional reduction of the tumor load in patients with CLL in remission. The cause of the dismal post transplant outcome of patients with unmutated VH is faster regrowth of the leukemic clone rather than less effective reduction of MRD levels immediately after SCT.