Complex Karyotype in Mantle Cell Lymphoma (MCL) Is Associated with Inferior Progression-Free Survival in Patients (pts) Receiving R-Hypercvad Followed By Autologous Stem Cell Transplant
Authors: Lee Michael Jinpyo , Switchenko Jeffrey , Thomas Janeen S , Koff Jean L. , Nastoupil Loretta , Lechowicz Mary Jo , Langston Amelia A , Flowers Christopher , Cohen Jonathon B. 
Published: October 2019

Abstract
Introduction: While cytogenetic assessments are frequently utilized in many hematologic malignancies as prognostic markers, their role in MCL is less well defined. Prior studies have identified a complex karyotype (≥3 chromosomal abnormalities) in 40 - 59.2 % of patients (pts) with MCL, and it has been associated with inferior progression-free survival (PFS) in those series (Cohen et al, 2015; Sarkozy et al, 2014). Our group recently published outcomes for MCL pts at our institution, including 35 pts who received R-HyperCVAD followed by autologous stem cell transplantation (ASCT) who had an overall survival (OS) at 5-years of 74% (Nastoupil et al, 2014). We conducted an analysis of the impact of pretreatment cytogenetics on outcomes for MCL.
Methods: We included all pts diagnosed with MCL at Winship Cancer Institute of Emory University between 2002 and 2014 who had available pretreatment conventional cytogenetic and clinical data. Baseline demographic, clinical, laboratory, and therapeutic variables of interest were assessed. Univariate Cox proportional hazards models were fit for each covariate, and hazard ratios are reported. Overall survival (OS) was defined as time to death or last follow-up from diagnosis, and PFS was defined as time to progression, death, or last follow-up from diagnosis. These curves were estimated via the Kaplan-Meier method, and the groups were compared using log-rank tests. We performed a similar analysis for the subset of pts initially treated with HyperCVAD and ASCT. Statistical significance was defined as α=0.05.
Results: Among 184 MCL pts, 52 had pretreatment cytogenetics data available. The median age at diagnosis was 64 years (range: 32-81), 36 (69%) were male, and 37 (86%) had stage IV disease. At diagnosis, 36 pts (97%) had ECOG performance status of 0 or 1, 16 (34%) had B-symptoms, 43 (86%) had bone marrow involvement, 8 (16%) had gastrointestinal tract involvement, and 29 (71%) had splenomegaly. Initial induction therapies included R-HyperCVAD (n=27), R-CHOP (n=10), R-bendamustine (n=6), and other/unknown (n=9). Thirty pts (58%) underwent ASCT in first complete or partial remission. Five pts (10%) met criteria for a complex karyotype, 11 (21%) had 1 or 2 detectable chromosomal abnormalities, and 36 (69%) pts had a normal karyotype. Cytogenetics were assessed on nodal samples (n=7) or bone marrow/peripheral blood (n=45). Among all assessed covariates, only elevated WBC count was associated with cytogenetic abnormalities (p=0.04). Overall, there was no significant association of PFS or OS with the presence of a complex karyotype or an abnormal karyotype with < 3 abnormalities when compared to a normal karyotype. Among all assessed variables, only splenomegaly was associated with worsened PFS (p=0.02). We conducted an exploratory analysis of the 24 pts who received R-HyperCVAD followed by ASCT, of which 2 had a complex karyotype. In that subset, median PFS for pts with a complex karyotype was 35.3 months, compared to 77.9 months for those with a non-complex abnormal karyotype or a normal karyotype.
Conclusion: Contrary to prior reports, a smaller percentage of pts had complex karyotype (10%) in this cohort, and pretreatment cytogenetics did not impact PFS or OS among the entire heterogeneously treated sample. However, there appears to be inferior PFS for pts with a complex karyotype in the subset who received R-HyperCVAD followed by ASCT, and a larger, multi-center series, may illuminate the impact of a complex karyotype on this subset of aggressively treated patients.

Disclosures
Nastoupil: AbbVie: Research Funding; Genentech: Honoraria; Celgene: Honoraria; TG Therapeutics: Research Funding; Janssen: Research Funding. Flowers:Infinity Pharmaceuticals: Research Funding; Spectrum: Research Funding; Acerta: Research Funding; Janssen: Research Funding; Infinity Pharmaceuticals: Research Funding; Onyx Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy; Gilead Sciences: Research Funding; Millennium/Takeda: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Gilead Sciences: Research Funding; Acerta: Research Funding; AbbVie: Research Funding; Pharmacyclics: Research Funding; Onyx Pharmaceuticals: Research Funding; Millennium/Takeda: Research Funding; OptumRx: Consultancy; AbbVie: Research Funding; Seattle Genetics: Consultancy; Genentech: Research Funding; OptumRx: Consultancy; Genentech: Research Funding; Celegene: Other: Unpaid consultant, Research Funding; Celegene: Other: Unpaid consultant, Research Funding; Spectrum: Research Funding. Cohen:Celgene, Pharmacyclics, Millennium, Seattle Genetics: Consultancy; BMS, Janssen: Research Funding.