Novel Assay Identifies Molecular Subtypes in MCL

Jason Harris

The 16-gene Leukemic-MCL16 (L-MCL16) Assay reliably distinguished between classic and indolent mantle cell lymphoma subtypes in patients with leukemic presentation, according to results published in <em>Blood</em>. Combined with genomic complexity, the assay was prognostic for overall survival.

The 16-gene Leukemic-MCL16 (L-MCL16) Assay reliably distinguished between classic and indolent mantle cell lymphoma (MCL) subtypes in patients with leukemic presentation, according to results published inBlood. Combined with genomic complexity, the assay was prognostic for overall survival (OS).1

At 3 years, the OS rate in patients with leukemic non-nodal MCL (nnMCL) was 92%, compared with 69% in patients with classic MCL (cMCL;P= .006). Investigators found that genomic complexity was associated with poorer OS and shorter time to treatment (TTT) in the nnMCL group. In the whole series and the cMCL group,TP53/CDKN2Amutations and genomic complexity were predictors for poorer OS.

Investigators noted that nodal presentation and LDH level at diagnosis were not associated with shorter OS (P>.1).

“The novel molecular assay developed for leukemic MCL reliably identifies the two cMCL and nnMCL subtypes and confirms the different clinical and biological characteristics of these patients,” corresponding author Elias Campo, MD, PhD, research director and professor of anatomic pathology at the Hospital Clinic of the University of Barcelona, and colleagues wrote.

“The combination of this assay with the analysis of the genomic complexity identifies subsets of patients with different outcome and, therefore, it may provide useful biological information for management decisions in these patients.”

MCL is an aggressive disease, but previous studies have identified a population of patients with indolent disease classified by the World Health Organization as nnMCL. This subtype is characterized by lack of expression ofSOX11andIGHVhypermutation. cMCL evolves from a molecular profile that includes expression ofSOX11and unmutatedIGHV.SOX11has very low expression in nnMCL and high expression in conventional disease.

Indolent patients are often asymptomatic, but may present with low-level lymphocytosis without lymphadenopathy or splenomegaly. Previous studies have shown that these patients can be managed with watchful waiting without increasing the risk for poor outcomes.

In contrast, the median OS for patients with classic MCL is approximately 5 years, even with early administration of immunochemotherapy.2

In this study by lead author Guillem Clot, of the University of Barcelona Institute of Biomedical Research August Pi i Sunyer, and colleagues, investigators performed global gene expression profiling on RNA extracted from peripheral blood samples collected from 70 patients with MCL. The final L-MCL16 assay included 16 genes upregulated in cMCL along withCD200,BTLA, andSLAMF1, novel genes that are highly expressed in nnMCL.

The assay identified 39 (56%) patients with cMCL, 26 (37%) with nnMCL, and 5 (7%) who were undetermined. Ninety-two percent of cMCL samples were collected within a year of diagnosis, compared with 58% of nnMCL samples.

Investigators analyzed sequential samples from 9 treatment-naïve patients with nnMCL collected at diagnosis and again at 9 to 86 months of follow-up. The second sample was collected at the time of clinical progression and before any treatment in 7 patients.

Four patients had developed splenomegaly but remained asymptomatic when the second sample was collected, and 3 patients required chemotherapy. Two patients remained asymptomatic and untreated, 1 at 1 year and the other at 4 years.

Investigators analyzed 2 samples from patients with cMCL collected at diagnosis and again at relapse at 4 and 38 months after treatment.

Clot et al found that the L-MCL16 Assay accurately predicted the initial and sequential samples for all 11 patients. There was no difference in mean score between the initial and sequential samples (95% CI, -13.5 to 122.9;P= .104).

“These findings emphasize the stability of the nnMCL and cMCL signatures, suggesting that they may represent a constitutive feature of the tumor cells,” investigators wrote.

At diagnosis, no patient with nnMCL disease had an ECOG score ≥2, compared with 24% of the cMCL group (P= .07), and cMCL patients were more likely to have nodal presentation (62% vs 17%;P= .001). No patient in the nnMCL cohort had elevated LDH, compared with 37% of the cMCL cohort (P= .008).

Eight-eight percent of patients in the nnMCL group did not receive treatment at diagnosis, while 74% of the cMCL cohort received chemotherapy-based treatment. Three years post-diagnosis, 88% (95% CI, 70-96) of patients with cMCL had received treatment, compared with 31% (95% CI, 9-48) of the nnMCL cohort.

Patients with nnMCL were more likely to express mutatedIGHV(83% vs 13%;P<.001) and less likely to have 9p/CDKN2Aand11q/ATMdeletions. nnMCL patients had a median of 1 chromosomal alterations per case, compared with 10 per case in the cMCL cohort (P<.001). nnMCL and cMCL patients were equally likely to have 17p/TP53alterations (38% vs 36%, respectively).

While 82% of patients in the cMCL cohort were treated at diagnosis or shortly thereafter, 70% of nnMCL patients remained treatment-free after a year of sampling. In the nnMCL cohort, greater number of chromosomal alterations was a predictor for shorter TTT, but the presence of 17p/TP53alterations was not (P= .03).

In the cMCL group, 17p/TP53and/or 9p/CDKN2Aalterations, and the increased number of chromosomal alterations were associated with poor OS. Increased number chromosomal alterations was a predictor for shorter OS (P= .005) in the nnMCL group, but the presence of 17p/TP53alterations was not.

References:

  1. Clot G, Jares P, Gin&eacute; E, et al. A new molecular assay and genomic complexity predict outcome in conventional and leukemic non-nodal mantle cell lymphoma [published online May 16, 2018].Blood. doi: 10.1182/blood-2018-03-838136.
  2. His ED, Martin P. Indolent mantle cell lymphoma.Leuk Lymphoma. 2014;55(4):761-767. doi: 10.3109/10428194.2013.815353.

Investigators found no correlation between the L-MCL16 score and number of chromosomal alterations orTP53/CDKN2Aalterations in either subtype (P>.05).