Somatic Hypermutation in Mantle Cell Lymphoma

Somatic hypermutation (SH) of the immunoglobulin heavy chain gene is a well-described prognostic factor in chronic lymphocytic leukemia (CLL), with patients (pts) exhibiting < 98% homology having an improved prognosis compared to their unmutated counterparts. Prior series have identified loci V_H 1–69, 3–23, and 4–34, as the most frequently utilized loci in CLL (Donisi et al, Diagn Mol Pathol, 15: 206–215, 2006). The impact of SH remains unclear in mantle cell lymphoma (MCL). While one retrospective series found an incidence of 60% of SH with an improved overall survival (OS) in pts with SH (Lai et al, Modern Pathology, 19: 1498–1505, 2006), a prospective study reported an incidence of 28% and no association with OS (Camacho et al, Blood, 101: 4042–4046, 2003). The immunoglobulin heavy chain gene loci most commonly utilized in the two series also differed, V_H 1–69, 4–59, and 3–74 in the retrospective review, and V_H 3–21, 3–23, 4–34, and 4–59 in the prospective study. Given the variable rates of SH and unclear association with prognosis, we evaluated SH in a series of pts with MCL with available tissue treated at the Ohio State University.

Non-bone marrow tissue samples for all pts with MCL were evaluated for the presence of SH. The sequences of the IgV_H results were compared to the most homologous germline V sequences in IMGT/Gene-DB. Sequences that differed by more than 2% from their corresponding germline sequences were considered hypermutated whereas sequences that differed by less than 2% were considered unmutated. Summary statistics are presented and survival estimates were calculated by the Kaplan-Meier method.

In 11 pts, the median age was 63 years (range 43–80), 82% were male, all pts had stage IV disease, and the median MIPI score was 5.7 (range 5.3–8.1). Five of 10 pts with available data had splenomegaly, 6 pts had BM involvement, and 6 pts had extranodal disease (GI tract n=2, upper airway n=2, lung n=1, and kidney n=1). Median lactate dehydrogenase (LDH) and median white blood cell (WBC) count at diagnosis were 156 U/L (range 102–274) and 6.6 × 10⁹/L (range 5.3–235.0), respectively. 9 patients received 1 therapy while one patient received 2 and one received 3 therapies. Five pts underwent autologous transplant in first remission, and 1 pt underwent allogeneic transplant at first relapse. Median time from initial diagnosis to first treatment was 1.7 months (range 0.5–10.2 months). With a median follow up of 2.1 years (range 0.6–3.7) median progression-free survival (PFS) from diagnosis was 3.2 years (95% CI 1.1–5.0) and median OS was 7.8 years (95% CI 1.5–7.8). There have been 4 deaths due to disease progression (n=3) and pneumonia (n=1). The most frequently utilized IgV_H gene loci were V_H1-8 (n=3), with V_H 4-34 (n=2). Although V_H 4-34 is implicated in CLL, both patients had immunophenotyping consistent with MCL, a t(11;14) translocation, and no lymphocytosis. 2 pts demonstrated SH, representing 18% of the sample (95% CI 2–52%). One of these 2 pts with SH was a 63 year old male, with nodal and bone marrow involvement and a MIPI score of 5.5. He was treated with RMCHOP for two cycles followed by autologous transplant according to Damon et al (J Clin Oncol, 27: 6101–6108, 2009), and died 3 years after transplant due to pneumonia without evidence of relapse. The second pt was a 66 year old female treated with 6 cycles of RCHOP who relapsed 4.8 years later. Salvage regimens included R-Bortezomib, R-Bendamustine, FCR, and R-GemOx, and she died due to disease progression 7.8 years after diagnosis. These two pts utilized loci V_H 3-9 and V_H 4-59 respectively.

In our series, the estimated incidence of SH is lower than what has previously been reported, and the utilized IgV_H loci are different. While V_H 3-9 and V_H 4-59 were observed in the 2 pts with SH, in prior series, both were associated with a decreased rate of SH. The duration of PFS and OS appears longer for these two hypermutated pts in our review; however, further evaluation is needed due to the small numbers of pts with evaluable tissue and the limited follow-up. In addition, the most commonly utilized Ig locus V_H1-8 in this study does not appear to be utilized as frequently in other series, which may reflect regional differences in antigen exposure or other environmental factors. Multicenter prospective evaluations should be undertaken to determine the incidence of SH as well as associations of SH and selective IgV_H loci with pt prognosis in MCL.

No relevant conflicts of interest to declare.