Pretransplant Minimal Residual Disease (MRD) Positivity Independently Predicts Survival in a Unselected Cohort of Mantle Cell Lymphoma Undergoing Autologous Stem Cell Transplantation in Complete Remission

Background:

High-dose therapy and autologous stem cell transplantation (ASCT) is a standard therapy for mantle cell lymphoma (MCL) patients in first remission following induction chemotherapy yet outcomes following this approach are variable even for patients in complete remission (CR). The presence of minimal residual disease (MRD) has been shown to be associated with outcome in other settings, yet limited data exist on the utility of this measure prior to ASCT. We hypothesized that evaluation of MRD prior to initiation of conditioning could stratify CR patients into high or low risk of relapse and could be used to guide additional post-transplant therapies.

Methods:

Sequential patients with confirmed MCL, age ≥ 18 years who underwent ASCT between 1996 and 2011 at the Fred Hutchinson Cancer Research Center, University of Washington Medical Center, and Veterans Affairs Puget Sound Healthcare System were eligible. Presence of a clonal IgH rearrangement, t(11;14) by PCR or positive flow cytometry from blood or bone marrow prior to transplant was scored as MRD positive. MRD along with clinical factors were evaluated in an adjusted proportional hazards model for associations with progression-free (PFS) and overall survival (OS).

Results:

Seventy-five transplanted MCL patients in CR had pretransplant MRD evaluation performed. The median age was 58 years (range, 38-71), 59 (78.7%) were men, the median number of prior regimens was 1 (range 1 - 4), and the median MIPI score was 2 (range 0 - 7). Induction chemotherapy consisted of HyperCVAD in 37 (49.3%), CHOP in 36 (48%), CVP in 1(1.3%), and Cytoxan in 1 (1.3%). Rituximab was administered to 63 (84%) as part of their pretransplant regimen. Eight patients (11%) had evidence of MRD. Positive MRD tests included: t(11:14) only in 4 (50%), flow only in 2 (25%), and flow and t(11;14) PCR positive in 2 (25%). Sites of MRD included bone marrow in 5 (62.5%) and peripheral blood in 4 (50%). MRD positivity was highly associated with both OS and PFS in unadjusted and adjusted models (Figure 1). With a median follow-up of survivors of 5.1 years, the median OS for MRD negative patients was not reached, while for the MRD positive patients was 3.01 years (hazard ratio [HR] 4.04, p = 0.009). The median PFS for MRD negative patients was not reached, while for the MRD positive patients was 2.38 years (HR 3.69, p = 0.002).

Discussion:

These data indicate that MRD positivity is independently associated with poor outcome following ASCT for MCL patients despite achieving a clinical CR. New treatment strategies such as post transplant maintenance regimens or reduced intensity allogeneic transplantation could be evaluated in this setting in an attempt to improve remission durations and survival.

Figure 1. Pretransplant MRD predicts outcome of mantle cell lymphoma patients in complete remission undergoing ASCT. Kaplan-Meier plots for (a) overall survival and (b) progression-free survival.