scholarly journals Molecular profiling and management of mantle cell lymphoma

Hematology ◽  
2019 ◽  
Vol 2019 (1) ◽  
pp. 30-40 ◽  
Author(s):  
Jia Ruan
Keyword(s):  
Cell Cycle ◽  
High Risk ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Molecular Profiling ◽  
Novel Agents ◽  
High Dose ◽  
Mantle Cell

Abstract Mantle cell lymphoma (MCL) is a distinct subtype of B-cell non-Hodgkin lymphoma characterized by the t(11;14)(q13;q32) translocation leading to cyclin D1 overexpression and cell cycle dysregulation. Molecular profiling with gene expression and deep sequencing analyses has identified genomic and epigenomic alterations in pathways regulating the cell cycle, DNA damage response, proliferation, and survival, which contribute to disease progression with important prognostic and therapeutic implications. Clinically, the nonnodal MCL subset is notable for leukemic presentation, indolent behavior, and association with hypermutated IGHV and lack of SOX11 expression, which differentiates it from the conventional nodal MCL. In addition to the Mantle Cell Lymphoma International Prognostic Index score and proliferative gene signatures, 17p/TP53 and 9p/CDKN2A alterations, and genomic complexity have emerged as clinically useful biomarkers of high-risk disease associated with aggressive disease behavior, resistance to chemotherapy, and poor overall survival. Although intensive chemoimmunotherapy regimens that incorporate high-dose cytarabine and stem cell transplantation have improved survival in young and fit MCL patients, the introduction of Bruton tyrosine kinase inhibitors and other novel agents has made effective outpatient-based treatment accessible to nearly all MCL patients. Optimizing combinations of novel agents in the relapsed setting and moving novel agents to the first-line setting have the potential to fundamentally change the MCL therapeutic landscape for the better, especially for patients ineligible for chemotherapy or those with high-risk mutations that are resistant to chemotherapy.

scholarly journals Bendamustine and rituximab as induction therapy in both transplant-eligible and -ineligible patients with mantle cell lymphoma

2020 ◽  
Vol 4 (15) ◽  
pp. 3486-3494
Author(s):  
Diego Villa ◽  
Laurie H. Sehn ◽  
Kerry J. Savage ◽  
Cynthia L. Toze ◽  
Kevin Song ◽  
...  
Keyword(s):  
High Risk ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
First Line ◽  
Ki 67 ◽  
Historical Cohort ◽  
Entire Cohort ◽  
Mantle Cell

Abstract Rituximab-containing chemotherapy regimens constitute standard first-line therapy for mantle cell lymphoma (MCL). Since June 2013, 190 patients ≥18 years of age with MCL in British Columbia have been treated with bendamustine and rituximab (BR). The overall response rate to BR was 88% (54% complete response). Of these, 61 of 89 patients (69%) aged ≤65 years received autologous stem cell transplantation and 141 of 190 patients (74%) from the entire cohort received maintenance rituximab. Twenty-three patients (12%) had progressive disease, associated with high risk per the Mantle Cell Lymphoma International Prognostic Index (MIPI), Ki-67 ≥50%, and blastoid/pleomorphic histology. Outcomes were compared with a historical cohort of 248 patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; January 2003 to May 2013). Treatment with BR was associated with significant improvements in progression-free survival (PFS), but not overall survival (OS), compared with R-CHOP in the whole cohort (3-year PFS, 66% BR vs 51% R-CHOP, P = .003; 3-year OS, 73% BR vs 66% R-CHOP, P = .054) and in those >65 years of age (3-year PFS, 56% BR vs 35% R-CHOP, P = .001; 3-year OS, 64% BR vs 55% R-CHOP, P = .063). Outcomes in transplanted patients were not statistically significantly different compared with R-CHOP (3-year PFS, 85% BR vs 76% R-CHOP, P = .135; 3-year OS, 90% BR vs 88% R-CHOP, P = .305), although in multivariate analyses, treatment with BR was associated with improved PFS (hazard ratio, 0.40 [95% confidence interval, 0.17-0.94]; P = .036) but not OS. BR is an effective first-line option for most patients with MCL, however, outcomes are suboptimal for those with high-risk features and further studies integrating novel agents are warranted.

The Mantle Cell Lymphoma International Prognostic Index (MIPI) at Diagnosis Is Associated with Survival of Mantle Cell Lymphoma Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1143-1143 ◽  
Author(s):  
Lihua Pan ◽  
Katherine A Guthrie ◽  
Brian G. Till ◽  
Oliver W. Press ◽  
John M. Pagel ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Performance Status ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Risk Of Death ◽  
Mantle Cell ◽  
Wbc Count

Abstract Mantle Cell Lymphoma (MCL) exhibits short remission durations and a poor prognosis. To improve on these outcomes, many have advocated the use of high-dose therapy (HDT) and ASCT. The MIPI predicts overall survival (OS) from diagnosis, yet it remains unknown if the MIPI assessed at diagnosis (MIPI-Dx) or prior to transplant (MIPI-Tx) can be used to predict OS from ASCT. To address this question we retrospectively evaluated the association of the MIPI-Dx and MIPI-Tx, and other characteristics with OS following HDT and ASCT in 87 consecutive MCL patients transplanted at our center. Baseline characteristics included: median age at diagnosis=56 years (range, 35–70), median age at transplant=57 years (range, 35 – 70), stage III-IV=97%, median LDH/upper limit of normal (ULN) at diagnosis=0.91 (range, 0.46–5.65), median LDH/ULN at transplant= 0.88 (range, 0.39–3.00), median white blood cell (WBC) count at diagnosis=7.50 x 109 / liter (range, 1.40 – 54.70), mean WBC count at transplant=4.66 x 109 /liter (range, 0.07 – 17.60), median number of prior chemotherapy regimens=2 (range, 1–5). The estimated 5-year OS and PFS for the entire cohort were 56% (95% CI, 39–73%) and 45% (95% CI, 30 – 60%), respectively with a median follow up among surviving patients of 2.0 years (range 0.1 – 10.1 years). The MIPI-Dx was a better predictor of OS (p<0.001) than MIPI-Tx (p=0.09), when evaluated as a continuous variable. Similarly, when stratified as a categorical variable, the MIPI-Dx (p=0.09) was superior to the MIPI-Tx (p=0.34) in estimating survival. When compared to patients with a MIPI-Dx of 0–2, those with a score of 3, 4, and 5–8 at diagnosis had a 3.3 (95% CI 0.3–32, p=0.3), 6.1 (95% CI 0.7–54.8, p=0.11), and 11.1 (95% CI 1.3–92.9, p=0.03) fold higher risk of mortality after transplant, respectively (Figure). We next determined if any pre-transplant factors could improve our ability to predict outcome after ASCT. Multivariable modeling identified pretransplant factors of ECOG PS >0 (hazard ratio (HR) of 3.0, p=0.03), number of prior regimens >2 (HR 5.2, p=0.01), lack of complete remission (CR) (HR 3.4, p=0.04), and elevated LDH (HR 4.4, p=0.01) as associated with higher risk of death after transplant. These results indicate that the MIPI-Dx is a robust prognostic tool that can even be used to predict outcomes after a later transplant, suggesting that it may continue to reflect the biology of an individual patient’s disease over time. Further assessment of survival predictions after ASCT can be made independently by examining pre-transplant factors including performance status, number of prior regimens, attainment of CR, and LDH. Though these data require prospective validation, our results can be used to counsel patients about outcomes and account for potential differences in results from clinical trials of HDT and ASCT for MCL. Figure Figure

Validation of the Mantle Cell Lymphoma Prognostic Index (MIPI): A Valuable Tool for Risk Stratification in Mantle Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2703-2703
Author(s):  
Stephen Douglas Smith ◽  
Eric D. Hsi ◽  
Brian J. Bolwell ◽  
Amanda Maggiotto ◽  
Meagan Effinger ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Performance Status ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
High Risk Group ◽  
Ecog Performance Status ◽  
Mantle Cell

Abstract Abstract 2703 Poster Board II-679 Introduction: Mantle cell lymphoma (MCL) is an incurable disease with a highly variable course. Improvements in therapy have been impeded by the lack of a universal prognostic model, making risk stratification and comparisons across clinical trials difficult. The International Prognostic Index (IPI) and Follicular Lymphoma International Prognostic Index (FLIPI) have been applied but show limitations in MCL, especially in distinguishing low and intermediate-risk patients (pts). The MIPI (Mantle Cell International Prognostic Index) was developed to overcome these limitations, and is based on WBC, age, and LDH (analyzed as continuous variables) and ECOG performance status.1 However, the MIPI has yet to be independently validated, and failed to predict outcome of MCL pts treated with Hyper-CVAD.2 To examine the prognostic capacity of the MIPI, we reviewed outcomes of pts diagnosed with MCL from 1998–2008 at the Cleveland Clinic Taussig Cancer Institute (CCTCI). Methods: Cases of MCL diagnosed at CCTCI were identified from our pathology database, yielding 85 unique pts. These subjects were retrospectively analyzed with approval of our Institutional Review Board. A total of 48 pts with advanced stage disease who underwent immediate treatment (within 90 days of diagnosis), and for whom adequate data for assignment of both MIPI and IPI existed, were the subject of review. Survival was identified from medical records and confirmed using a public social security database. Outcomes were compared using log-rank analysis of Kaplan-Meier survival analyses, and MIPI was calculated in accordance with the initial publication.1 Results: Pt characteristics at diagnosis were: median age 62 (range 39–85), 73% male, 75% ECOG performance status of 0-1, 96% stage IV disease, 52% elevated LDH, and 40% had extranodal involvement other than bone marrow (23% with GI involvement). Six pts had the blastoid variant of MCL. IPI scores at diagnosis were as follows: low (17%)/ low-intermediate (31%)/ high-int (25%)/ high (27%). MIPI scores at diagnosis were: low (33%) / int (25%)/ high(42%). Initial treatment included an anthracycline in 71% and rituximab in 60%. HyperCVAD was given 33%, and 23% underwent upfront (CR1/PR1) autologous transplantation. Median follow-up of survivors is 5.7 years. Median OS and RFS for all pts is 3.9 and 2.5 years, respectively. The IPI distinguished low and high-risk groups, but low-int and high-int groups were closely approximated (Figure 1). On the other hand, the MIPI distinguished 3 separate groups (Figure 2), including a high risk group with a 5-year survival of 11%. The MIPI maintained its prognostic capacity even in HyperCVAD-treated pts (log rank p=.01 for low/int/high MIPI among 16 pts, figure not shown.) The use of regimens including rituximab was not associated with improved OS (log rank p=0.21, comparing rituximab at any time vs none, figure not shown). Conclusions: Based on long-term follow-up of 48 pts diagnosed with MCL at CCTCI from 1998–2008, we verified the accuracy and ease of application of the MIPI for determining prognosis in MCL. On further analysis, rituximab did not impact OS of MCL pts. Clinical trials in MCL should employ the MIPI as a risk-stratification tool, and novel approaches are urgently needed for pts in the high-risk group. Disclosures: No relevant conflicts of interest to declare.

Transplantation for mantle cell lymphoma: is it the right thing to do?

Hematology ◽  
2013 ◽  
Vol 2013 (1) ◽  
pp. 568-574 ◽  
Author(s):  
Michael E. Williams
Keyword(s):  
Mantle Cell Lymphoma ◽  
Randomized Clinical Trials ◽  
Cell Lymphoma ◽  
Treatment Plan ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Initial Therapy ◽  
High Dose ◽  
Cell Death Pathway ◽  
Mantle Cell

Abstract Mantle cell lymphoma (MCL) is a unique subtype of non-Hodgkin lymphoma that is both biologically and clinically heterogeneous. A variety of biomarkers, the achievement of minimal residual disease negativity after initial therapy, and the MCL International Prognostic Index (MIPI) are associated with patient outcome, although none has as yet been used for routine treatment stratification. Given the lack of widely accepted and standardized treatment approaches, clinical trial enrollment should always be considered for the initial therapy of MCL. Outside of the trial setting, younger and transplantation-eligible patients with newly diagnosed MCL who require treatment should first be considered for a rituximab + a high-dose cytarabine–containing regimen, followed by autologous stem cell transplantation consolidation in first remission. Symptomatic elderly and nontransplantation-eligible individuals typically receive rituximab + bendamustine, or R-CHOP (rituximab + cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone/prednisolone) followed by maintenance rituximab, the latter a treatment plan that has demonstrated extended response duration and survival. Promising early results for consolidation approaches with proteasome inhibitors and immunomodulatory drugs are now being tested in randomized clinical trials. The availability of highly active BCR signaling pathway inhibitors and cell death pathway modulation via BH3 mimetics, among other novel agents, promise to rapidly expand treatment options, change existing treatment paradigms, and further improve outcomes for MCL patients.

The Mantle Cell Lymphoma International Prognostic Index (MIPI) is superior to the International Prognostic Index (IPI) in predicting survival following intensive first-line immunochemotherapy and autologous stem cell transplantation (ASCT)

Blood ◽  
2010 ◽  
Vol 115 (8) ◽  
pp. 1530-1533 ◽  
Author(s):  
Christian H. Geisler ◽  
Arne Kolstad ◽  
Anna Laurell ◽  
Riikka Räty ◽  
Mats Jerkeman ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Mantle Cell Lymphoma ◽  
Autologous Stem Cell Transplantation ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
First Line ◽  
Mantle Cell

Abstract Mantle cell lymphoma (MCL) has a heterogeneous clinical course. The recently proposed Mantle Cell Lymphoma International Prognostic Index (MIPI) predicted the survival of MCL better than the International Prognostic Index in MCL patients treated with conventional chemotherapy, but its validity in MCL treated with more intensive immunochemotherapy has been questioned. Applied here to 158 patients of the Nordic MCL2 trial of first-line intensive immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation, the MIPI and the simplified MIPI (s-MIPI) predicted survival significantly better (P < .001) than the International Prognostic Index (P > .004). Both the MIPI and the s-MIPI mainly identified 2 risk groups, low and intermediate versus high risk, with the more easily applied s-MIPI being just as powerful as the MIPI. The MIPIB (biological), incorporating Ki-67 expression, identified almost half of the patients as high risk. We suggest that also a simplified MIPIB is feasible. This trial was registered at www.isrctn.org as #ISRCTN 87866680.

The Pre-Transplant Mantle Cell Lymphoma International Prognostic Index Predicts Overall and Progression-Free Survival Following High-Dose Therapy and Autologus Stem Cell Transplant for Mantle Cell Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2026-2026
Author(s):  
Leslie A Thompson ◽  
Katherine A Guthrie ◽  
Lihua Elizabeth Budde ◽  
Brian G. Till ◽  
Oliver W. Press ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Progression Free Survival ◽  
High Dose ◽  
Performance Score ◽  
Free Survival ◽  
Mantle Cell ◽  
Independent Association

Abstract Abstract 2026 Background: High-dose therapy (HDT) and autologous stem cell transplantation (ASCT) is frequently employed to improve outcomes in patients with mantle cell lymphoma (MCL), yet results after transplant vary widely. We and others have shown that the Mantle Cell International Prognostic Index (MIPI) measured at diagnosis can predict overall survival (OS) after HDT and ASCT (Geisler, Blood 2010; Budde JCO 2011). Unfortunately, this approach is often limited at the time of transplant by the lack of available MIPI data from the time of diagnosis. Furthermore, the MIPI at diagnosis does not take into account other disease-related data that may be present at transplant. We hypothesized that the MIPI measured immediately before initiation of HDT could be attainable and predictive of outcomes after ASCT and explored the contribution of this measure along with other clinical factors to OS and progression-free survival (PFS). Methods: Records of consecutive MCL patients undergoing HDT and ASCT at our centers were reviewed under an IRB approved minimal risk protocol. Patients undergoing planned tandem autologus-allogenic transplants were excluded. MIPI elements, simplified MIPI score, and other clinical data were collected from the period immediately prior to initiation of conditioning and evaluated for their independent association with OS and PFS. Results: Between November 1995 and May 2011 190 MCL pts meeting the above criteria underwent HDT and ASCT at our centers, of these 186 (98%) had all available pretransplant MIPI data and were included in the analysis. Pretransplant MIPI scores of 0–1, 2, 3, 4, and 5–7 were seen in 27 (15%), 61 (33%), 60 (32%), 21 (11%), and 17 (9%) patients, respectively. Other baseline pretransplant characteristics included: median age 57 years (range 35–71years), elevated LDH = 48 (26%), median WBC = 4.51/μL (range 0.7 –42.43/μL), performance score 0 = 103 (55%), median prior regimens = 2 (range 1–9), blastoid variant = 16 (8%), leukemic variant = 6 (3%), chemosensitive disease = 157 (86%), and administration of rituximab (R) within 3 months prior to transplant = 139 (75%). The 8-year estimates of OS and PFS for the entire cohort were 43% (95% CI 27 – 57%) and 31% (95% CI 16 – 48%), respectively with 3 years median follow up for survivors. The pretransplant MIPI was highly associated with OS when modeled as a continuous (p=0.008) or categorical variable (p=0.002). Survival at 2 years was 88% (95% CI 78 – 93%) for MIPI 0–2, 73% (61 – 82%) for MIPI 3 or 4, and 65% (34 – 84%) for MIPI 5 or greater (Figure). Of the MIPI elements, age (hazard ratio [HR] for death 1.5 for every 10 yrs, p=0.03) and performance score (HR 1.6 for score >1, p=0.08) had the greatest independent impact on OS. In addition, chemosensitive disease (HR 0.3, p<0.001), number of prior regimens (p<0.001), and R within 3 months prior to transplant (HR 0.6, p=0.05) were all independently associated with OS after adjusting for the pretransplant MIPI. The pretranplant MIPI score was also predictive of PFS, but less so than with OS (global and categorical p=0.02) with age providing the greatest independent association (HR for death or progression 1.3 for every 10 years, p=0.08). Again, non-MIPI factors including number of prior regimens (p<0.001), blastoid variant (HR=2.1, p=.05), chemosensitive disease (HR 0.3, p<0.001), and R within 3 months prior to transplant (HR=0.4, p=0.001) independently added to predictive ability of the MIPI for PFS. Conclusions: Our data suggest that the simplified MIPI score measured immediately prior to HDT and ASCT is a readily available and robust predictive tool for OS and PFS in MCL pts undergoing transplant. This score along with other clinical factors can be utilized to counsel patients and to compare results between various treatment options. The independent association of pretransplant R with improved outcomes supports its use in this setting. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Clinical characteristics and outcomes of primary versus secondary gastrointestinal mantle cell lymphoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alessia Castellino ◽  
Aung M. Tun ◽  
Yucai Wang ◽  
Thomas M. Habermann ◽  
Rebecca L. King ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Performance Status ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Local Therapy ◽  
Progression Free Survival ◽  
Cell Transplant ◽  
Multiple Lesions ◽  
Mantle Cell

AbstractPrimary gastrointestinal (GI) mantle cell lymphoma (MCL) is rare and the optimal management is unknown. We reviewed 800 newly diagnosed MCL cases and found 22 primary (2.8%) and 79 (9.9%) secondary GI MCL cases. Age, sex, and performance status were similar between primary and secondary cases. Secondary cases had more elevations in lactate dehydrogenase (28% vs 0%, P = 0.03) and a trend for a higher MCL international prognostic index (P = 0.07). Observation or local therapy was more common for primary GI MCL (29% vs 8%, P < 0.01), and autologous stem-cell transplant was more common for secondary GI MCL (35% vs 14%, P < 0.05). The median follow-up was 85 months. Primary and secondary GI MCL had similar 5-year progression-free survival (PFS) (30% vs 28%, P = 0.59) and overall survival (OS) (65% vs 66%, P = 0.83). The extent of GI involvement in primary GI MCL affected treatment selection but not outcome, with a 5-year PFS of 43% vs 14% vs 31% (P = 0.48) and OS of 57% vs 71% vs 69% (P = 0.54) in cases with single lesion vs multiple lesions in 1 organ vs multiple lesions in ≥2 organs. Less aggressive frontline treatment for primary GI MCL is reasonable. It is unknown whether more aggressive treatment can result in improved outcomes.

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