Mantle Cell Lymphoma International Prognostic Index Research Articles

Cytarabine and hematopoietic cell transplantation for mantle cell lymphoma. Analysis of 20 patients

Mantle cell lymphoma (MCL) has high relapse and mortality rates. There is a survival benefit when treatment is intensified with cytarabine (AraC), hematopoietic cell transplantation (HCT) and maintenance with rituximab. To assess the outcomes of patients with MCL treated in a university hospital. Review of an oncology center database and medical records identifying patients with MCL treated between 2006 and 2017. Death dates were obtained from the death certificate database of the National Identification Service. We analyzed the response rate, overall survival (OS) and progression-free survival (PFS). As a secondary objective, the survival impact of AraC, HCT and maintenance with rituximab, was also analyzed. Information on 20 patients aged 62 ± 11 years, followed for a median of 45 months was retrieved. Eighty-five percent were diagnosed at an advanced stage. The most used first-line regime was R-CHOP in 11 patients, followed by R-HyperCVAD in five. Only 47% achieved complete response. 4-year PFS and OS were of 30 and 77% respectively. Mantle Cell Lymphoma International Prognostic Index (MIPI) significantly predicted PFS and OS. Maintenance with rituximab or HCT was associated with better PFS (48 vs 21 months, p < 0.01). The exposure to AraC or HCT, in refractory or relapsed disease, was associated with an increase in PFS from 9 to 28 months (p = 0,02) and 4-year OS from 40 to 100% (p = 0.05). OS increased even more, from 25 to 100% in those with high-risk MIPI (p = 0.04). The incorporation of AraC, HCT and maintenance with rituximab in the therapeutic backbone of MCL, especially for high-risk cases, was associated with improved survival.

Risk stratification of mantle cell lymphoma (MCL)

Despite of a better understanding of the biology of mantle cell lymphoma (MCL), it remains an incurable disease with very variable disease courses. The biological heterogeneity of MCL requires the identification of prognostic markers for risk stratification and tailored treatment of MCL. The combined MCL International Prognostic Index (MIPI-c) represents a well-established clinical risk stratification model. Based on four clinical parameters: age, performance status, lactate dehydrogenase and leucocyte count combined with the percentage of Ki-67 positive MCL cells the model distinguishes four MCL subgroups with very different outcomes. Further prognostic markers, in particular molecular lesions might help to further improve clinical scoring. We discuss the value of clinical and molecular markers to predict outcome of MCL and how these markers could influence treatment decisions.

Retrospective Analysis of 149 Unselected Patients with Mantle Cell Lymphoma Confirms Prognostic Relevance of Mantle Cell Lymphoma International Prognostic Index: Single Center Experience

Introduction: Mantle cell lymphoma (MCL) is an uncommon subtype of non-Hodgkin lymphoma with distinguishes clinical, biologic, and molecular characteristics. The MCL-International Prognostic Index (MIPI) incorporates age, EGOC performance status, normalized LDH level and WBC and has improved discriminatory power. The aim of this retrospective single-center study was to evaluate the clinical characteristics and response to treatment of patients with mantle cell lymphoma.Methods: This single center retrospective study included 297 adult patients diagnosed with MCL between December 2005 and May 2018. The diagnosis of MCL was rendered in accordance with the later World Health Organization (WHO) classification. Outcome was determined as response to treatment, progression free survival (PFS) and overall survival (OS) by Kaplan-Meier analysis using SPSS (IBM SPSS Statistics 21; IBM Corp., Chicago, IL) statistical tool kit. We also compared the PFS and OS according to simplified MIPI (s-MIPI) index.Results: All clinical data were available in 149 cases and these patients were further evaluated. There were 38 (26%) female and 208 (74%) male patients. The median age at diagnosis of MCL was 66 years (range, 31-93 years). The median time of follow-up was 14.5 months (range, 3-139.3 months). The median s-MIPI was 6 points (range 2-11). Most patients were in the high-risk group (62.2%). Induction chemotherapy was administered in 128/146 patients and remaining two patients had deceased after diagnosis of MCL. Altogether 115 out of 146 patients (78.8%) were treated with a combination of chemotherapy and anti-CD20 monoclonal antibody rituximab.One elderly patient received Rituximab immunotherapy only. The majority (56.5%) of the patients received CHOP with rituximab as induction chemotherapy. Thirty-one patients underwent ASCT after remission was obtained in relapse setting. Sixty-four patients (43.8%) had bone marrow involvement and 23 patients (15.7%) had extra-nodal involvement. In total 40 patients (41.2%) achieved a complete remission (CR) with an overall response rate of 63.9% after the induction therapy. During follow up, 20 relapses and 28 deaths were noted. Infection was the most common cause of death (50%). Following ASCT, OS was significantly improved; estimated median OS in transplant cohort was 115.7 months vs. 60 months compare with non-transplant group (p=0.013) (Figure-2). According to the long-rank test, estimated 5-year OS was not significantly different between intermediate-risk and high-risk s-MIPI categories (72.4%±1.2% vs. 72.6%±0.7%; p=0,202). Estimated 5-year PFS was significantly different between intermediate-risk and high-risk s-MIPI cohorts (47.1%±1.3% vs. 33%±10.3%; p=0,05). Among the transplanted patients, there is no differences between the OS of s-MIPI groups (p=0.952). No patient died or progressed in the low-risk group.Conclusion: We have confirmed the validity of the MIPI and simplifed MIPI for the prognosis of patients with MCL even in the era of rituximab. e general results of both indexes are fully comparable, facilitating the broad application of s-MIPI as a simple bedside prognostic tool. DisclosuresCivriz Bozdag:MSD: Research Funding; TAKEDA: Consultancy; NOVARTIS: Consultancy. Özcan:Janssen: Other: Travel Support, Research Funding; Abbvie: Other: Travel payment; Novartis: Research Funding; Takeda: Honoraria, Other: Travel payment, Research Funding; Bayer: Research Funding; BMS: Honoraria; Celgene: Other: Travel support, Research Funding; Roche: Honoraria, Research Funding; Archigen: Research Funding; MSD: Other: travel support, Research Funding; MSD: Research Funding; Jazz: Other: Travel support; Jazz: Other. Beksac:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Deva: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ilhan:Roche: Speakers Bureau; BMS: Speakers Bureau; Celgene: Speakers Bureau; Alexion: Speakers Bureau.

Prognostic Implications of Specific Comorbidities in Mantle Cell Lymphoma Patients, a Swedish Lymphoma Registry Study

PurposeThe prognosis for patients with mantle cell lymphoma (MCL) is rather dismal where particularly elderly patients, often with comorbidities, have difficulties tolerating the intensive treatments needed for long-term remission. Our aim was to describe the frequency and spectrum of comorbidities among patients with MCL in a population-based setting, and assess the impact of comorbidities on treatment choice, lymphoma-specific and overall survival as well as causes of death in MCL patients by age and sex.MethodsIn the nationwide Swedish Lymphoma Register, we identified 1,385 MCL patients (1,009 males and 376 females) diagnosed 2000-2015 at all ages. Comorbid diseases within 10 years prior to diagnosis were identified from the national Swedish In- and Outpatient registers and included somatic diseases defined according to the Charlson comorbidity index (CCI; 0, 1 and 2+), with the addition of psychiatric disorders. Comorbidities were both categorized and presented individually. Hazard ratios (HR) with 95% confidence intervals (CIs) comparing lymphoma-specific and all-cause mortality among patients with different levels of CCI were estimated from flexible parametric survival models, adjusted for calendar year of diagnosis, age at diagnosis, sex, educational level, and MCL international prognostic index (MIPI). Model-based predictions were used to obtain cumulative probabilities of death due to lymphoma and other causes.ResultsIn the cohort, 24% were <59 years of age, 32% between 60-69, 30% between 70-79 and 14% >80 years. In total, 606 out of 1,385 patients (44%) had a history of one or more comorbidities at the time of diagnosis, among which 388 (28%) had a CCI=2+. The most common specific comorbidities were prior malignancy (17%), (prostate cancer was most frequent), and prior coronary heart disease (14%). Moreover, 9% of the patients had diabetes, 7% had pulmonary disease, 3% renal disease, 3% connective tissue disease and 1% had dementia. In addition, 2% had a psychiatric disorder. With a mean follow-up of 3.7 years (range: 0.0-15.6), 633 (46%) patients died from lymphoma. Lymphoma was the major cause of death among males, irrespective of CCI (Figure 1A). Lymphoma was also the major cause of death among females with CCI=0 whereas among females with comorbidities (CCI≥1), approximately half of the patients died due to other causes (Figure 1B). A CCI=2+ was associated with worse overall and lymphoma-specific survival (adjusted lymphoma-specific HR=1.31; 95% CI: 1.04-1.65). Specific comorbidities associated with significantly worse lymphoma-specific survival were history of coronary heart disease, connective tissue disease, renal disease, dementia and psychiatric disorders (Figure 1C). Patients aged below 70 years at diagnosis who presented with no comorbidities were primarily treated according to the NLG-MCL2/3 protocol* (177 out of 437, 41%). However, this was not the case among patients in the same age range but with CCI=1 (24 out of 177, 34%) or CCI=2+ (13 out of 112, 12%). Primary treatment concepts for comorbid patients were CHOP, bendamustine, or chlorambucil with the addition of rituximab.*NLG-MCL2/3= R-maxi-CHOP alternating with high dose cytarabine, rituximab, and consolidation with high-dose therapy and autologous stem-cell transplantationConclusionsA large fraction of MCL patients are elderly and comorbidity was present in almost half of the patients overall. A CCI of 2+ was an independent negative prognostic factor. Lymphoma-death was the major cause of death among males, motivating the need for MCL-specific treatment irrespectively of a high burden of comorbidities, while approximately 50% of comorbid-females died due to other reasons. Patients with comorbidities were less often treated according to intensive first-line chemotherapy protocols. In the introduction and development of new treatment regimens, consideration of toxicity and tolerability specifically in patients with comorbidities is warranted, particularly in patients with coronary heart disease, connective tissue disease and renal disorders.. [Display omitted] DisclosuresEkstroem Smedby:Janssen Pharmaceuticals: Other: The Department have recieved partial funding from Janssen Pharmaceuticals. Eloranta:Janssen Pharmaceuticals: Other: S Eloranta is currently employed as a project coordinator and her salary is funded via a public-private real world evidence collaboration between Karolinska Institutet and Janssen Pharmaceuticals.

Long-Term Follow-up of Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Mantle Cell Lymphoma

Long-Term Follow-up of Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Mantle Cell Lymphoma

Safety and Efficacy of Acalabrutinib Plus Bendamustine and Rituximab (BR) in Patients with Treatment-Naive (TN) or Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL)

Safety and Efficacy of Acalabrutinib Plus Bendamustine and Rituximab (BR) in Patients with Treatment-Naive (TN) or Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL)

Five-year follow-up of lenalidomide plus rituximab as initial treatment of mantle cell lymphoma

AbstractWe report 5-year follow-up of a multicenter phase 2 study of lenalidomide plus rituximab (LR) as initial treatment of mantle cell lymphoma (MCL). The regimen includes induction and maintenance with the LR doublet. Treatment was continuous until progression, with optional discontinuation after 3 years. The median age of the 38 participants was 65 years, with MCL international prognostic index scores balanced among low, intermediate, and high risk (34%, 34%, and 32%, respectively). Twenty-seven (75%) of the 36 evaluable patients completed ≥3 years of study treatment. At a median follow-up of 64 months (range, 21-78), the 3-year progression-free survival (PFS) and overall survival (OS) were 80% and 90%, respectively, with 5-year estimated PFS and OS of 64% and 77%, respectively. During maintenance, hematologic adverse events (AEs) included asymptomatic grade 3 or 4 cytopenias (42% neutropenia, 5% thrombocytopenia, 3% anemia) and mostly grade 1 or 2 infections managed in the outpatient setting (45% upper respiratory infection, 21% urinary tract infection, 13% sinusitis, 11% cellulitis, 8% pneumonia). Nonhematologic AEs, such as constitutional and inflammatory symptoms, occurred at reduced frequency and intensity compared with induction. A peripheral blood minimal residual disease (MRD) assay (clonoSEQ) showed MRD-negative complete remission in 8 of 10 subjects who had completed ≥3 years of treatment and with available samples for analysis. With longer follow-up, LR continues to demonstrate durable responses and manageable safety as initial induction and maintenance therapy for MCL (ClinicalTrials.gov NCT01472562).

Modified VR-CAP, Alternating With Rituximab and High-dose Cytarabine: An Effective Pre-transplant Induction Regimen for Mantle Cell Lymphoma

BackgroundInitial treatment of mantle cell lymphoma (MCL) incorporating autologous stem cell transplantation affords long-term remissions, but relapses still occur. Optimal pretransplant therapy will afford high complete response rates and not impair stem cell collection. Incorporation of bortezomib represents a natural evolution of pretransplant therapy, given its proven first-line efficacy and minimal impact on stem cell collection. Patients and MethodsAt the University of Washington/Seattle Cancer Care Alliance and the Cleveland Clinic Foundation, we developed modified VR-CAP/R+ara-C (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone, alternating with rituximab and high-dose cytarabine), for transplant-eligible patients with MCL. This regimen was administered as standard-of-care, pretransplant therapy to consecutive patients with MCL from April 2015 to the present. ResultsA total of 37 patients were treated with this regimen, including 18 at the University of Washington/Seattle Cancer Care Alliance and 19 at the Cleveland Clinic Foundation. Most patients had intermediate- or high-risk disease by both (mantle-cell lymphoma international prognostic index (MIPI)-B and MIPI-C category. Complete response to induction was achieved in 32 (86%) of 37 evaluable patients; 2 achieved partial response, and 3 had primary refractory disease. Stem cell collection was successful in 1 attempt in 30 of 32 patients. The median follow-up of survivors measured from start of treatment is 17.4 months. Five patients have progressed, and 4 have died (2 owing to lymphoma, 2 from toxicity). ConclusionModified VR-CAP/R+ara-C is feasible pretransplant therapy for patients with MCL and is associated with a high rate of complete response and eligibility for autologous stem cell transplantation.

TP53 Mutation and Complex Karyotype Portends a Dismal Prognosis in Patients With Mantle Cell Lymphoma

BackgroundTP53 mutation (TP53mut) and a complex karyotype (CK) were shown to be predictors of poor outcome in mantle-cell lymphoma (MCL). In this study we examined the combined effect of both of these risk factors. Patients and MethodsPatients diagnosed with MCL between January 2000 and December 2014 (n = 74) were evaluated. Forty-eight of them had available material for TP53 and cytogenetic examination. We analyzed the prognostic effect of combined TP53mut and CK in the cohort of patients treated with rituximab-containing therapy. ResultsThree-year (3-y) overall survival (OS) and 3-y progression-free survival (PFS) in CK patients were shorter compared with non-CK (P = .001 for OS; P = .02 for PFS). TP53mut was a predictor of shorter survival compared with TP53 wild type (OS and PFS; P < .001). The incidence of TP53mut was not significantly associated with CK (P = .240). CK and TP53mut were predictors of inferior PFS and OS independent of age and Mantle-Cell Lymphoma International Prognostic Index, with hazard ratios of 2.35 (P = .024), 4.50 (P < .001) for PFS and 4.31 (P < .001), 5.46 (P < .001) for OS analysis in the CK and TP53mut groups, respectively. The combination of TP53mut and CK status stratified the patients into 3 prognostic groups (P < .001) with the worst outcome in patients with CK and TP53mut. ConclusionTP53 mutation and CK occurred independently and patients harboring both had a dismal prognosis. The study suggests the importance of molecular cytogenetics and examination of the TP53mut status to be performed simultaneously before treatment.

Validation of the MCL35 gene expression proliferation assay in randomized trials of the European Mantle Cell Lymphoma Network.

Mantle cell lymphoma (MCL) is still considered incurable and the course of the disease is highly variable. Established risk factors include the Mantle Cell Lymphoma International Prognostic Index (MIPI) and the quantification of the proliferation rate of the tumour cells, e.g. by Ki-67 immunohistochemistry. In this study, we aimed to validate the prognostic value of the gene expression-based MCL35 proliferation assay in patient cohorts from randomized trials of the European Mantle Cell Lymphoma Network. Using this assay, we analysed the gene expression proliferation signature in routine diagnostic lymph node specimens from MCL Younger and MCL Elderly trial patients, and the calculated MCL35 score was used to assign MCL patients to low (61%), standard (27%) or high (12%) risk groups with significantly different outcomes. We confirm here in our prospective clinical trial cohort of MCL patients, that the MCL35 assay is strongly prognostic, providing additional information to the Ki-67 index and the MIPI. Thus, this robust assay may assist in making treatment decisions or in devising risk-adapted prospective clinical trials in the future.

Immunophenotypic Variations in Mantle Cell Lymphoma and Their Impact on Clinical Behavior and Outcome.

Immunophenotypic variations in mantle cell lymphoma (MCL) from the classic CD5+/CD10-/CD23-/FMC-7+ immunophenotype have been reported in the literature, but correlation with clinical behavior and outcome has not been fully studied. To investigate clinicopathologic and prognostic differences between immunophenotypically aberrant MCL and immunophenotypically typical MCL. We evaluated differences in clinical presentation, laboratory parameters, prognostic indices, response to initial treatment, and progression-free and overall survival between patients with aberrant MCL and patients with immunophenotypically typical MCL. There were 158 patients with newly diagnosed cyclin D1 or t(11;14)(q13;q32)+ MCL identified in the original search, of which, 29 patients (18%) showed immunophenotypic aberrancies, with CD23 coexpression being the most common. When compared with 33 randomly selected patients with immunophenotypically typical MCL, statistically significant differences were seen in white blood cell counts ( P = .02), in the presence of absolute lymphocytosis ( P = .03), in the MCL International Prognostic Index score ( P = .02), and in response to initial treatment ( P = .04). The "immunophenotypic status" of the MCL was the only independent factor associated with response to treatment ( P = .05), but not with the MCL International Prognostic Index score, absolute lymphocytosis, or white blood cell count. No significant differences were seen for progression-free or overall survival. Immunophenotypic variations in MCL are associated with differences in clinical presentation and response to therapy when compared with immunophenotypically typical MCL. However, with current intensive frontline immunochemotherapy, immunophenotypic aberrations do not appear to affect progression-free or overall survival.

Genomic landscape and prognostic analysis of mantle cell lymphoma.

To gain insight into the molecular pathogenesis of patients with mantle cell lymphoma (MCL), next-generation whole-exome sequencing of 16 MCL patients was performed. We identified recurrent mutations in genes that are well known to be functionally relevant in MCL, including ATM (37.5%), TP53 (31.3%), WHSC1 (31.3%), CCND1 (18.8%), NOTCH2 (6.3%), and CDKN2A (6.3%). We also identified somatic mutations in genes for which a functional role in MCL has not been previously suspected. These genes included CCDC15, APC, CDH1, S1PR1, ATRX, BRCA2, CASP8, and NOTCH3. Further, we investigated the prognostic factors associated with MCL from clinical, pathological, and genetic mutations. Mutations of TP53 (P = 0.021) was a significant prognostic factor with shorter overall survival (OS). Although there was no statistical difference, the median survival time of patients with WHSC1 mutations was shorter than those without mutations (P = 0.070). Mutations in ATM and CCND1 had no prognostic value (P = 0.552, 0.566). When adjusted for MCL International Prognostic Index (MIPI) or combined MCL-International Prognostic Index (MIPI-c), TP53 and WHSC1 mutations were the most important prognostic factors in MCL (P < 0.05). Our data provide an unbiased view of the landscape of mutations in MCL and commend that all patients benefit from mutations of TP53 and WHSC1 at diagnosis, in addition to MIPI and MIPI-c score.

Complex karyotype in patients with mantle cell lymphoma predicts inferior survival and poor response to intensive induction therapy.

Risk stratification of newly diagnosed patients with mantle cell lymphoma (MCL) primarily is based on the MCL International Prognostic Index (MIPI) and Ki-67 proliferative index. Single-center studies have reported inferior outcomes in patients with a complex karyotype (CK), but this remains an area of controversy. The authors retrospectively reviewed 483 patients from 5 academic centers in the United States and described the effect of a CK on survival outcomes in individuals with MCL. A CK was found to be associated with inferior overall survival (OS) (4.5 vs 11.6 years; P<.01) and progression-free survival (PFS) (1.9 vs 4.4 years; P<.01). In patients who underwent high-intensity induction followed by autologous stem cell transplantation (ASCT) in first remission, a CK was associated with poor OS (5.1 vs 11.6 years; P = .04) and PFS (3.6 vs 7.8 years; P<.01). Among patients with a CK, high-intensity induction had no effect on OS (4.5 vs 3.8 years; P = .77) nor PFS (2.3 vs 1.5 years; P = .46). Similarly, ASCT in first remission did not improve PFS (3.5 vs 1.2 years; P = .12) nor OS (5.1 vs 4.0 years; P = .27). On multivariable analyses with Ki-67 and MIPI, only CK was found to be predictive of OS (hazard ratio [HR], 1.98; 95% confidence interval [95% CI], 1.12-3.49 [P = .02]), whereas both CK (HR, 1.91; 95% CI, 1.17-3.12 [P = .01]) and Ki-67 >30% (HR, 1.86; 95% CI, 1.06-3.28 [P = .03]) were associated with inferior PFS. Multivariable analysis did not identify any specific cytogenetic abnormalities associated with inferior survival. CK appears to be independently associated with inferior outcomes in patients with MCL regardless of the intensity of induction therapy and receipt of ASCT. Cytogenetics should be incorporated into the workup of a new diagnosis of MCL and novel therapeutic approaches should be investigated for patients with CK. Cancer 2018;124:2306-15. © 2018 American Cancer Society.

Expression of TP53 is associated with the outcome of MCL independent of MIPI and Ki-67 in trials of the European MCL Network

AbstractCurrently, prediction of time to treatment failure (TTF) and overall survival (OS) in mantle cell lymphoma (MCL) is based on the clinical factors included in the Mantle Cell Lymphoma International Prognostic Index (MIPI), and proliferation is assessed by Ki67. However, TP53 and SOX11 immunohistochemistry might improve risk stratification. We performed SOX11 and TP53 immunohistochemistry on the so far largest published cohort of lymphoma specimens (n = 365). All patients were treated in prospective trials of the European MCL Network. In multivariate analyses, including MIPI and Ki67, SOX11 expression was not associated with TTF, but patients with low SOX11 expression had shorter OS. On the contrary, high TP53 expression was a strong predictor of TTF and inferior OS compared with low TP53 expression in univariate and multivariate analyses adjusting for MIPI score and Ki-67 index (hazard ratio [HR], 2.0; P = .0054 for TTF, and HR, 2.1; P = .068 for OS). In particular, patients with high TP53 expression (>50% positive lymphoma cells) had a shorter TTF and poor OS independent of both MIPI score and Ki-67 index. Thus, TP53 immunohistochemistry is a suitable test for routine diagnostic practice to assess MCL prognosis.

Epidemiological Analysis of Lymphoma Subtypes in a Reference Center in João Pessoa

A gradual increase in diagnosed cases of lymphoma has led to greater dissemination of relevant information and has simultaneously revealed a need to improve understanding of the pathology. The prevalence of lymphomas involves many factors that vary regionally, with regional differences in prognosis indeed playing a role in therapeutic decisions. This observational study aimed to retrospectively evaluate the prevalence of lymphoma subtypes diagnosed between 2011 and 2015 at the Napoleao Laureano Hospital, the largest hematology facility in Paraiba, northeastern Brazil and a state reference for hematological oncology. Immunohistochemistry findings and associated prognostic variables were analyzed, including calculation of prognostic indexes such as the international prognostic index (IPI), age adjusted IPI, National Comprehensive Cancer Network IPI (NCCN-IPI), mantle cell lymphoma IPI (MIPI) and follicular lymphoma IPI (FLIPI). The most noteworthy findings include the large number of young people diagnosed with aggressive disease, with poor prognostic indexes but low mortality rates, confirming the technical strength of the institution as reflected in the improved prognosis associated with the disease. The prevalence of Hodgkin lymphoma was found to be high, contradicting a considerable part of the international literature but in agreement with some studies conducted with pediatric populations in Brazil. In addition, the most prevalent subtypes of non-Hodgkin lymphoma, already well discussed in the international literature, were also represented in the present sample. All cases of lymphoma registered at this center were catalogued, with their prognoses and anatomopathological and immunohistochemical diagnoses being analyzed, consequently providing a better database for this geographical region of Brazil.

CD10-positive mantle cell lymphoma: clinicopathologic and prognostic study of 30 cases.

Mantle cell lymphoma is usually negative for CD10 which is useful in distinguishing MCL from other CD10 + B cell lymphomas. Here we assessed the clinicopathologic features of 30 cases of CD10+ MCL, the largest series to date in the English literature, and compared them with a group of 212 typical MCL cases (CD5+, CD10-negative, CD23-negative, cyclin D1+). The 30 patients with CD10+ MCL included 17 men and 13 women with a median age of 68 years. Compared with CD10-negative MCL, patients with CD10+ MCL showed a lower male predominance (p = 0.01), more often had a diffuse growth pattern (p = 0.04) and blastoid/pleomorphic morphology (p < 0.0001), and more often showed BCL6 expression (p = 0.009). In all MCL patients, CD10 expression was not associated with overall survival (OS) (p = 0.16). However, in more aggressive subsets of MCL patients including those with high Ki67 (> 60%), blastoid/pleomorphic morphology, or high MCL International Prognostic Index (MIPI), CD10 expression was associated with a worse OS (p = 0.003, 0.04, and 0.001, respectively). High Ki67 (> 60%), blastoid/pleomorphic morphology, and high MIPI were also been identified as poor prognostic factors patients with in CD10+ MCL (p = 0.001, 0.0003, and 0.01, respectively). In summary, CD10+ MCL more often has a diffuse growth pattern, blastoid/pleomorphic morphology, and BCL6 expression. In MCL patients with a high Ki-67 (> 60%), blastoid/pleomorphic morphology, or high MIPI, CD10 expression contributes to an even worse prognosis. MCL should be included in the differential diagnosis of CD10 + B cell lymphomas.

Alternating R-CHOP and R-cytarabine is a safe and effective regimen for transplant-ineligible patients with a newly diagnosed mantle cell lymphoma.

Implementation of cytarabine into induction therapy became standard of care for younger patients with mantle cell lymphoma (MCL). On the basis of its beneficial impact, many centers incorporated cytarabine at lower doses also into first-line treatments of elderly patients. We conducted a multicenter observational study that prospectively analyzed safety and efficacy of alternating 3+3cycles of R-CHOP and R-cytarabine for newly diagnosed transplant-ineligible MCL patients. A total of 73 patients were enrolled with median age 70years. Most patients had intermediate (39.7%) and high-risk (50.7%) disease according to MCL international prognostic index. Rituximab maintenance was initiated in 58 patients. Overall response rate reached 89% by positron emission tomography-computed tomography, including 75.3% complete remissions. Two patients (2.7%) did not complete the induction therapy because of toxicity. Three patients (4.1%) were considered nonresponders, which led to therapy change before completion of induction. Estimated progression-free survival and overall survival were 51.3% and 68.6% at 4years, respectively. Mantle cell lymphoma international prognostic index, bulky disease (≥ 5cm), and achievement of positron emission tomography-negativity independently correlated with progression-free survival. Grade 3 to 4 hematologic and nonhematologic toxicity was documented in 48% and 20.5% patients, respectively. Alternation of R-CHOP and R-cytarabine represents feasible and very effective regimen for elderly/comorbid MCL patients. This study was registered at GovTrial (clinicaltrials.gov) NCT03054883.

Outcomes in 370 patients with mantle cell lymphoma treated with ibrutinib: a pooled analysis from three open-label studies.

Ibrutinib is highly active in treating mantle cell lymphoma (MCL), an aggressive B-cell lymphoma. We pooled data from three ibrutinib studies to explore the impact of baseline patient characteristics on treatment response. Patients with relapsed/refractory MCL (n=370) treated with ibrutinib had an objective response rate (ORR) of 66% (20% complete response; 46% partial response); median duration of response (DOR), progression-free survival (PFS) and overall survival (OS) were 18·6, 12·8 and 25·0months, respectively. Univariate analyses showed patients with one versus >one prior line of therapy had longer OS. Multivariate analyses identified that one prior line of therapy affected PFS; Eastern Cooperative Oncology Group (ECOG) performance status, simplified MCL international prognostic index (sMIPI) score, bulky disease, and blastoid histology affected OS and PFS. Patients with blastoid versus non-blastoid histology had similar time to best response, but lower ORR, DOR, PFS and OS. OS and PFS were longer in patients with better sMIPI, patients with ECOG performance status 0-1, non-bulky disease and non-blastoid histology. Additionally, the proportion of patients with poor prognostic factors increased with increasing lines of therapy. Together, results suggest that patient outcomes following treatment failure with ibrutinib are related to the natural biological evolution of the disease.

Mantle cell lymphoma: 2017 update on diagnosis, risk-stratification, and clinical management.

Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma characterized by involvement of the lymph nodes, spleen, blood and bone marrow with a short remission duration to standard therapies and a median overall survival (OS) of 4-5 years. Diagnosis is based on lymph node, bone marrow, or tissue morphology of centrocytic lymphocytes, small cell type, or blastoid variant cells. A chromosomal translocation t (11:14) is the molecular hallmark of MCL, resulting in the overexpression of cyclin D1. Cyclin D1 is detected by immunohistochemistry in 98% of cases. The absence of SOX-11 or a low Ki-67 may correlate with a more indolent form of MCL. The differential diagnosis of MCL includes small lymphocytic lymphoma, marginal zone lymphoma, and follicular lymphoma. The MCL International Prognostic Index (MIPI) is the prognostic model most often used and incorporates ECOG performance status, age, leukocyte count, and lactic dehydrogenase. A modification of the MIPI also adds the Ki-67 proliferative index if available. The median OS for the low-risk group was not reached (5-year OS of 60%). The median OS for the intermediate risk group was 51 months and 29 months for the high risk group. For selected indolent, low MIPI MCL patients, initial observation may be appropriate therapy. For younger patients with intermediate or high risk MIPI MCL, aggressive therapy with a cytotoxic Regimen followed by autologous stem cell transplantation should be considered. Rituximab maintenance after autologous stem cell transplantation has also improved the progression-free and overall survival. For older symptomatic MCL patients with intermediate or high risk MIPI, combination chemotherapy with R-CHOP, R-Bendamustine, or a clinical trial should be considered. In addition, rituximab maintenance therapy may prolong the progression-free survival. At the time of relapse, agents directed at activated pathways in MCL cells such as bortezomib (NFkB inhibitor), lenalidamide (anti-angiogenesis) and Ibruitinib (Bruton's Tyrosine Kinase [BTK] inhibitor) have demonstrated excellent clinical activity in MCL patients. Autologous or allogeneic stem cell transplantation can also be considered in young patients. Clinical trials with novel agents are always a consideration for MCL patients.

R‐CHOP/R‐HDAC AND RITUXIMAB MAINTENANCE RESULTS IN HIGH COMPLETE REMISSION RATE, MINIMAL RESIDUAL DISEASE NEGATIVITY, AND EXCELLENT SURVIVAL IN ELDERLY MCL PATIENTS

Introduction: Mantle cell lymphoma (MCL) is an incurable subtype of B-cell non-Hodgkin lymphoma. Implementation of high-dose cytarabine (HDAC) into induction therapy followed by stem-cell transplantation and rituximab maintenance (RM) became standard of care for the younger patients with newly dg. MCL. Treatment of the transplant-ineligible patients is still largely based on CHOP or alkylating agents and RM. Methods: We conducted a multicenter observational study designed by the Czech lymphoma study group (CLSG-MCL-01, GovTrial #NCT03054883), which prospectively analyzed safety and efficacy of alternating 3 + 3 cycles of R-CHOP and R-HDAC (1 or 2 g / m2, 2 doses over 24 hours) for newly diagnosed transplant-ineligible MCL patients. Pathological review of all samples was performed. MRD assessment was implemented in Euro-MRD member CLIP laboratory Prague. Primary objectives included response after induction by PET-CT, and progression-free survival (PFS). Secondary objectives included safety, overall survival (OS), and prognostic significance of PET imaging and minimal residual disease (MRD) after induction. Results: 73 patients were enrolled with median age 70 years. Most patients had intermediate (39.7%) and high-risk (50.7%) disease according to MCL International Prognostic Index (MIPI). Out of the 56 analyzed biopsies 55.4% revealed high proliferation index by Ki-67 (≥ 30%). The overall response rate in the 68 evaluable patients was 95.6% by PET-CT, including 80.9% complete remissions. MRD was evaluated after induction in 54 patients using paired samples of bone marrow (BM) and peripheral blood (PB). Grade 3-4 hematologic and non-hematologic toxicity was documented in 48% and 20.5% patients, respectively. RM was initiated in 59 patients. At the median follow-up of 43.8 months, median PFS and OS were not reached and were 53.9% and 71.3% at 4 years, respectively. For pts on RM 4-year PFS and OS was 61% and 77.2%, respectively. By univariate analysis MIPI, Ki-67 (≥ 30%), bulky disease (≥5 cm), involvement of the spleen, and MRD in PB after induction correlated with PFS. Interestingly, MRD in BM after induction did not correlate with PFS or OS. Multivariate analysis revealed that MIPI, bulky disease ≥5 cm, achievement of PET-negativity, and MRD in PB after induction independently correlated with PFS. Conclusion: Alternating R-CHOP and R-HDAC represents feasible and very effective regimen for elderly/comorbid MCL patients. The observed loss of predictive value of MRD in BM after induction appears to be impacted by rituximab maintenance. Keywords: Ara-C; mantle cell lymphoma (MCL); minimal residual disease (MRD)