Mantle Cell Lymphoma International Prognostic Index Research Articles

Mantle Hücreli Lenfoma Hastalarımızın Klinik ve Laboratuvar Özellikleri: Kesitsel Bir Çalışma

Mantle cell lymphoma (MCL) comprises less than 10% of non-Hodgkin's lymphoma cases. Major independent risk factors are identified as the MCL International Prognostic Index (MIPI) and Ki-67 proliferation index of tumor. The aim of this study is retrospectively evaluate MCL patients treated and followed-up in our department. Materials and Methods: This study included 27 MCL patients medical records of whom could be reached. The data was reviewed to figure out MIPI score, bone marrow involvement, extranodal involvement, treatment protocols, treatment response, relapse status, and transplant history. Patients were followed-up for a mean duration of 64.4 (1-246) months. Subsequent to the first-line treatment, complete response was achieved in 17 (63%) and partial response was achieved in 3 (11%) patients, whereas 7 (26%) patients experienced disease progression. Median PFS following first-line treatment was 29 (3-120) months. Based on the classification by MIPI scoring, low-risk patients had significantly longer median survival than that of high-risk patients (194 months vs 126 months, p=0.04), and the patients at moderate-risk had significantly longer PFS compared to high-risk patients (41month vs 3 months, p=0.025). Median age, stage III-IV, and short duration of PFS in patients with high MIPI score were our findings in parallel with available literature. R-hyper-CVAD/MTX-AraC was mostly preferred first-line treatment at our center with a shorter median PFS compared to literature. Given the expanding use of target-driven therapies for MCL, we believe our results are noteworthy in comparing such therapies with pre-existing therapies.

P53 is associated with high-risk and pinpoints TP53 missense mutations in mantle cell lymphoma.

SummarySurvival for patients diagnosed with mantle cell lymphoma (MCL) has improved drastically in recent years. However, patients carrying mutations in tumour protein p53 (TP53) do not benefit from modern chemotherapy‐based treatments and have poor prognosis. Thus, there is a clinical need to identify missense mutations through routine analysis to enable patient stratification. Sequencing is not widely implemented in clinical practice for MCL, and immunohistochemistry (IHC) is a feasible alternative to identify high‐risk patients. The aim of the present study was to investigate the accuracy of p53 as a tool to identify patients with TP53 missense mutations and the prognostic impact of overexpression and mutations in a Swedish population‐based cohort. In total, 317 cases were investigated using IHC and 255 cases were sequenced, enabling analysis of p53 and TP53 status among 137 cases divided over the two‐cohort investigated. The accuracy of predicting missense mutations from protein expression was 82%, with sensitivity at 82% and specificity at 100% in paired samples. We further show the impact of p53 expression and TP53 mutations on survival (hazard ratio of 3·1 in univariate analysis for both), and the association to risk factors, such as high MCL International Prognostic Index, blastoid morphology and proliferation, in a population‐based setting.

Using the primary site as a prognostic tool for nodal mantle cell lymphoma: a SEER-based study.

Background: Nodal mantle cell lymphoma (NMCL) has a worse survival than extra-nodal mantle cell lymphoma. Materials & methods: A cohort study was conducted to evaluate the primary site role as a mortality predictor using data from 1983 to 2011 from the Surveillance, Epidemiology, and End Results (SEER) database. Results: Most patients had NMCL in multiple regions (71.9%). There was a significantly increased incidence of NMCL cases over years with 83.2% of them occurred between 1998 and2011. The mean survival was 52.9 months with overall survival/cancer-specific survival rate of 29.2/42.9%, respectively. Lymph nodes of intrathoracic and multiple regions had a worse overall survival while the head, face and neck, intra-abdominal, pelvic, inguinal region and leg as well as multiple regions had worse cancer-specific survival. Conclusion: NMCL primary site can serve as a prognostic factor. We encourage adding it to MCL International Prognostic Index.

Relationship of Expression of Circ_cgga162 with the Prognosis of Patients with Mantle Cell Lymphoma

To investigate the expression of Circ_cgga162 in serum of mantle cell lymphoma (MCL) patients and analyze its potential as a prognostic biomarker. The expression of Circ_cgga162 in 86 cases of mantle cell lymphoma and 50 cases of lymph node reactive hyperplasia (RH) were detected by real-time quantitative polymerase chain reaction (qRT-PCR). The relationship between the expression of Circ_cgga162 and clinicopathological features was analyzed by univariate analysis. The relationship of Circ_cgga162 expression with progression-free survival time and overall survival time was analyzed by Kaplan-Meier. The relationship between expression of Circ_cgga162 and prognosis of patients was analyzed by univariate and multivariate analysis. The expression level of Circ_cgga162 in MCL patients was significantly higher than that in control (RH) group (P＜0.01). The expression of Circ_cgga162 not correlated with age, gender, B symptoms and LDH (all P＞0.05), but correlated with the expression of MCL International Prognostic Index (IPI), Ann Arbor stage, bone marrow infiltration and Ki67 (all P＜0.05). In addition, Kaplan-Meier analysis showed that the progression-free survival time and overall survival time of the MCL patients with high expression of Circ_cgga162 were significantly shorter than those of the MCL patients with low expression (P＜0.01). Univariate analysis showed that Ann Arbor stage, Circ_cgga162 expression, MIPI, bone marrow infiltration and Ki67 were the prognostic factors for MCL patients (all P＜0.05). Multivariate Cox regression analysis showed that Ann Arbor stage, Circ_cgga162 expression and MIPI were independent factors affecting the prognosis of MCL patients (all P＜0.05). Circ_cgga162 is highly expressed in serum of patients MCL, which relates with the prognosis of MCL patients. Circ_cgga162 can be used as a potential prognostic marker and therapeutic target for MCL patients.

Trial in progress: A phase III, randomized, open-label study comparing zanubrutinib plus rituximab versus bendamustine plus rituximab in patients with previously untreated mantle cell lymphoma (MCL).

TPS8071 Background: Bruton tyrosine kinase (BTK) mediates B-cell proliferation, migration, and adhesion. BTK inhibition has emerged as a strategy for targeting B-cell malignancies, including MCL. Zanubrutinib is a next-generation BTK inhibitor that was designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases, with favorable pharmacokinetic and pharmacodynamic properties. Zanubrutinib monotherapy has been evaluated in 118 patients (pts) with relapsed/refractory MCL in 2 single-arm studies: BGB-3111-206 [NCT03206970] and BGB-3111-AU-003 [NCT02343120]. The overall response rate (ORR) by independent review committee (IRC) in both trials was 84% with median durations of response of 19.5 and 18.5 months, respectively. First-line treatment for MCL has failed to cure most pts, particularly elderly or transplant-ineligible groups, and chemotherapy-based approaches result in cumulative, long-term risks. The study described herein is designed to evaluate the safety and efficacy of zanubrutinib plus rituximab versus bendamustine plus rituximab in elderly pts and pts with comorbidities with previously untreated MCL who are ineligible for stem cell transplant. Methods: This ongoing phase 3, open-label study will enroll ≈500 pts to be randomized 1:1, stratified by MCL International Prognostic Index score (low vs intermediate/high), age ( < 70 vs ≥70 years), and geographic region (North America/Europe vs Asia-Pacific). In arm A, pts will receive up to six 28-day cycles of oral zanubrutinib 160 mg twice daily in combination with intravenous (IV) rituximab 375 mg/m2 on day 1 of each cycle. After 6 cycles, zanubrutinib will continue as a monotherapy until progressive disease, unacceptable toxicity, or withdrawal of consent. In arm B, pts will receive up to six 28-day cycles of IV bendamustine 90 mg/m2 on days 1 and 2 of each cycle and rituximab 375 mg/m2 on day 1 of each cycle, followed by observation. Eligible pts must have histologically confirmed MCL and be aged ≥70 years, or 65-69 years with defined comorbidities. Disease response will be assessed per the 2014 Lugano Classification for non-Hodgkin lymphoma. The primary endpoint is progression-free survival (PFS) determined by IRC. Key secondary end points include PFS by investigator assessment, ORR, time to and duration of response, overall survival, and safety. Recruitment is ongoing. Clinical trial information: NCT04002297 .

Clinical features and treatment outcomes of limited-stage mantle cell lymphoma: Consortium for Improving Survival of Lymphoma report.

Limited-stage (Ann Arbor stage I or II) mantle cell lymphoma (MCL) is an extremely rare disease. Thus, there is little data on the clinical features and treatment outcomes of patients with early-stage MCL. We examined consecutive stage I or II MCL 41 cases diagnosed between 2000 and 2016 in 16 institutions of the Consortium for Improving Survival of Lymphoma group. All cases were pathologically confirmed and systemic evaluation was performed for staging. The clinical features were reviewed, and the treatment outcomes were analyzed. The median age of patients was 66years (range 19-85years); there were more men (n = 31, 75.6%) than women. Most patients (n = 28, 68.3%) had stage 2 disease, and 29 (70.7%) were symptomatic. The elevation of lactate dehydrogenase (n = 2, 4.9%) was not common; thus, 39 patients (95.1%) had a low-risk score (0 or 1) for the International Prognostic Index, and 28 (68.3%) had a low-risk score (1-3) for the MCL International Prognostic Index. Most patients (n = 37, 90.1%) received chemotherapy as the first therapeutic strategy, while some received radiotherapy (n = 2), surgical resection (n = 1), or no treatment (n = 1). Of the patients who received chemotherapy, 23 (56.9%) received a rituximab-containing regimen, and R-CHOP (n = 17) and R-bendamustine (n = 5) were commonly used. The best response was noted in 97.4% (n = 38) of patients, including 32 who showed a complete response (78%). With a median follow-up duration of 40.6months, the 42months relapse-free survival was 59.1%, and the 5-year overall survival rate was 80.4%. Limited-state MCL showed indolent clinical and low-risk prognostic features. Chemotherapy could be effective for controlling localized MCL lesions, with high complete response rates.

Applying Data Warehousing to a Phase III Clinical Trial From the Fondazione Italiana Linfomi Ensures Superior Data Quality and Improved Assessment of Clinical Outcomes.

Data collection in clinical trials is becoming complex, with a huge number of variables that need to be recorded, verified, and analyzed to effectively measure clinical outcomes. In this study, we used data warehouse (DW) concepts to achieve this goal. A DW was developed to accommodate data from a large clinical trial, including all the characteristics collected. We present the results related to baseline variables with the following objectives: developing a data quality (DQ) control strategy and improving outcome analysis according to the clinical trial primary end points. Data were retrieved from the electronic case reporting forms (eCRFs) of the phase III, multicenter MCL0208 trial (ClinicalTrials.gov identifier: NCT02354313) of the Fondazione Italiana Linfomi for younger patients with untreated mantle cell lymphoma (MCL). The DW was created with a relational database management system. Recommended DQ dimensions were observed to monitor the activity of each site to handle DQ management during patient follow-up. The DQ management was applied to clinically relevant parameters that predicted progression-free survival to assess its impact. The DW encompassed 16 tables, which included 226 variables for 300 patients and 199,500 items of data. The tool allowed cross-comparison analysis and detected some incongruities in eCRFs, prompting queries to clinical centers. This had an impact on clinical end points, as the DQ control strategy was able to improve the prognostic stratification according to single parameters, such as tumor infiltration by flow cytometry, and even using established prognosticators, such as the MCL International Prognostic Index. The DW is a powerful tool to organize results from large phase III clinical trials and to effectively improve DQ through the application of effective engineered tools.

Clinical Trial Participation Is Associated with Improved Overall Survival in Newly Diagnosed Patients with Mantle Cell Lymphoma

Clinical Trial Participation Is Associated with Improved Overall Survival in Newly Diagnosed Patients with Mantle Cell Lymphoma

Gene Expression Profiling Using Nanostring™ Reveals Differences According to Location, Histology and MIPI Score in Mantle Cell Lymphoma

Background Mantle cell lymphoma (MCL) is an aggressive B cell neoplasm characterized the by t(11;14)(q13;q32)/CCND1-IGH resulting in overexpression of cyclin D1. Although indolent variants are recognized, MCL is generally aggressive and incurable. The MCL International Prognostic Index (MIPI), gene expression-based proliferation signatures, Ki-67 proliferation index, p53 expression, and aggressive histologic features are used for risk stratification, but the prognostic groups defined by each of these markers are clinically heterogeneous, demonstrating that each parameter alone does not fully account for the clinical behavior of these tumors. In this study, we investigated the gene expression profile of 60 cases of MCL and evaluated which genes had expression patterns that correlate with different clinical and histopathological parameters. Design A total of 60 excisional biopsy specimens of MCL were selected for gene expression profiling. Forty (66%) and 16 (26%) cases were untreated and relapse/persistent samples, respectively; in 4 this unknown was unknown. Biopsy sites included lymph nodes (n=38), spleen (n=10), tonsil (n=6) and various other extranodal tissue sites (n=6). The morphologic features were classic in 27 and aggressive (blastoid/pleomorphic) in 33 patients. MIPI was calculated in selected patients with nodal involvement and whose biopsy was an obtained prior to treatment. Each block contained tumor cells representing ≥ 80% of all cells in the biopsy specimen. RNA was extracted from formalin-fixed paraffin-embedded tissue using the Qiagen Allprep FFPE Kit after deparaffinization, according to the manufacturer's instructions. Gene expression was quantified in 200ng of RNA on the Nanostring™ platform. Normalization for RNA loading was performed using the geometric mean of 40 housekeeping genes with a cutoff value 20. Standard QC and data processing were performed using the nSolver™ Analysis Software. Adjusted p-values were used according to the Benjamini-Hochberg procedure. Results Gene expression profiling was different according to the site of involvement of MCL. Compared with nodal involvement, MCL involving spleen showed overexpression of VEGFA (p <0.01) and NOS (p <0.05). These genes are associated with angiogenesis via the PI3K signaling pathway. Similarly, tonsillar MCL showed overexpression of SFN and HSPB1 (p <0.01) compared with nodal MCL; these genes are related to the MAPK pathway. Different gene expression profiles were observed with respect to histology. Compared to classic variant, blastoid variant demonstrated overexpression of CDK4 (p <0.01) and underexpression of KAT2B and PIK3CG (p <0.01) in all cases. However, no significant differences were found in the gene expression profiles between the classic and pleomorphic variants. We also compared gene expression profiles based on the MIPI score. Compared to cases with a low MIPI score, those with a high MIPI score showed significant overexpression of several genes including SFN, COL11A2, HDAC6 and TP53 (p <0.01). Discussion MCL is a heterogeneous neoplasm, both clinically and genetically. In the present study, significant differences in gene expression profiles were observed based on site of involvement (spleen vs lymph node vs tonsil). However, we cannot exclude the possibility that the result reflects gene expression of non-lymphoma cells in the microenvironment since we did not extract RNA from lymphoma cells. We observed different gene expression profiles in the blastoid variant, but not in the pleomorphic variant compared to the classic variant, suggesting that the biology of pleomorphic variant is probably between the blastoid and the classic variants, possibly closer to the latter. Different gene expression profiles were found with respect to MIPI score, providing scientific support that the MIPI score, in addition to being a useful stratification factor in MCL patients, is reflecting differences in underlying biology of MCL. Disclosures No relevant conflicts of interest to declare.

Androgen Receptor Targeting with Enzalutamide for Mantle Cell Lymphoma: Safety and Efficacy

BACKGROUND: Mantle cell lymphoma (MCL) demonstrates a male to female ratio of 4:1. While the pathobiology underlying this gender-distribution imbalance is unknown, anecdotal clinical observations, as well as in vitro evidence of relative androgen receptor (AR) overexpression in MCL cell lines and response to androgen blockade, implicate the AR signaling axis as a potential driver of lymphomagenesis in MCL (Mostaghel et al. Experimental Hematology 2017). Thus, we hypothesized that blocking the AR axis could be a potential treatment strategy for MCL. Here, we report results from our pilot study using the second-generation AR antagonist enzalutamide for treatment of MCL. METHODS: A single arm pilot study was carried out at the Fred Hutchinson Cancer Research Center/University of Washington/Seattle Cancer Care Alliance. Patients ≥ 18 years, with relapsed/refractory or untreated MCL, metabolically active disease > 1.5 cm in long axis, ECOG ≤ 2, ANC ≥ 1000/mm3 & platelet ≥ 50,000/mm3, and acceptable liver and renal function were eligible. Enzalutamide 160 mg was administered daily until disease progression, intolerance, or decision of patient or physician to stop study drug. The primary endpoint was overall response rate (ORR) including complete response (CR) and partial response (PR). The secondary endpoints were time to treatment failure (TTF), progression free survival (PFS), overall survival (OS), adverse events (AEs) as measured by NCI-CTCAE version 4.0, and disease control rate. Correlative studies included impact of AR expression and changes in sex hormone levels on clinical outcomes. RESULTS: Eight patients were enrolled between September 2015 and January 2018. Median age at enrollment was 60 (range 47-79), six were male, median number of prior treatments was 2.5 (range 0-5), three received prior Bruton's tyrosine kinase (BTK) inhibitor therapy, and four had a prior autologous stem cell transplant. Mantle cell lymphoma international prognostic index (MIPI) scores were low (1), intermediate (4) and high (3). The median Ki-67 was 28% (range < 5 to 60). Patients were treated for a median of 3.5 28-day cycles. Reasons for discontinuation included progressive disease (6) and development of rash at day 10 (1). One patient remains on study and without disease progression at 16 months. Best responses in the six response-evaluable patients included three with stable disease (ranging from 5 to 8 months) and three with progressive disease. Low response rates led to closure of the study. Median PFS and OS were 157 days (range 38 to 248) and 1168 days (range 187 to 1289), respectively (figure 1). All patients had tumor AR expression available for review and stained positive (6 variably positive, 1 uniformly positive, and 1 weakly focally positive). No clinical factor, AR staining nor baseline or changes in hormone levels were correlated with response or PFS, though the single patient with ongoing disease control >15 months is the only evaluable female on study who is receiving enzalutamide as first-line therapy. Two grade 3 (abdominal pain, agitation) and one grade 4 (leukocytosis) AEs were reported. CONCLUSIONS: Blocking the AR axis with enzalutamide in the treatment of MCL was well tolerated but did not appear to translate into a meaningful ORR despite supportive preclinical data. This study was approved and funded in part by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Astellas. Disclosures Smith: Merck Sharp & Dohme Corp: Consultancy, Research Funding; Pharmacyclics: Research Funding; Incyte Corporation: Research Funding; Genentech: Research Funding; Denovo Biopharma: Research Funding; Portola Pharmaceuticals: Research Funding; Ayala (spouse): Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Seattle Genetics: Research Funding; Ignyta (spouse): Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma BV: Research Funding. Till:Mustang Bio: Patents & Royalties, Research Funding. Graf:AstraZeneca: Research Funding; TG Therapeutics: Research Funding; BeiGene: Research Funding. Gopal:Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy. OffLabel Disclosure: Enzalutamide is FDA approved for metastatic and non-metastatic castration-resistant prostate cancer.

Long-Term Outcomes with Ibrutinib Versus the Prior Regimen: A Pooled Analysis in Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL) with up to 7.5 Years of Extended Follow-up

Long-Term Outcomes with Ibrutinib Versus the Prior Regimen: A Pooled Analysis in Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL) with up to 7.5 Years of Extended Follow-up

Ibrutinib for relapsed/refractory mantle cell lymphoma: 7-year experience

Abstract Background Mantle cell lymphoma (MLC) is nowadays an aggressive and incurable Non-Hodgkin’s lymphoma, characterized by multiple relapses.The persistent activation of B-cell receptor pathway is critical for pathogenesis. Ibrutinib is a potent covalent inhibitor of Bruton’s tyrosine kinase (BTK) that inhibits B-cell antigen receptor signaling downstream of BTK and changed for better how MCL is treated in relapsed/refractory setting. However, resistance is common and response limited. Methods Retrospective analysis and follow-up of all MCL patients treated with Ibrutinib in a Onco-Hematology Department. Results Eleven patients were identified, with a median age of 68 years [58-78], the majority of them were males (83.3%). At diagnosis, 9% were in stage III of Ann Arbor while 81.8% were in stage IV. The median MIPI (MCL International Prognostic Index) was 5.5 [4-8]. These patients were exposed to a median of 3 treatments [3-5]. The majority of them performed as 1oline treatment R-FCM (18.2%) or R-CHOP (54.5%); as 2oline R-CHOP (45.5%), as 3oline Ibrutinib (63.6%), as 4oline PEPC (60%) and as 5oline Ibrutinib (100%). Ibrutinib therapy was prescribed as a 2oline in 9.1% of the patients, as a 3oline in 63.6%, as 4oline in 40% and as a 5oline in 100%. Ibrutinib achieved a complete response rate in 9.1%, a partial response in 45.5% (response rate, RR, of 54.5%), disease progression in 36.4%, stable disease in 9,1%. At the end of the study, 5 patients were alive and still doing Ibrutinib (4 of them in full dose 560 mg/day). The median progression free survival (PFS) was 3 months [1-26]. Overall survival was not reached (3 patients died with disease progression). Conclusions Although a larger sample and a longer follow-up are needed, these data showed worse results when compared to previous phase 2 trials demonstrating a 68% response rate (RR), including for high-risk patients and heavily pretreated. Most recently, a pooled analysis of the three open-label studies of ibrutinib in MCL, PCYC-1104, SPARK, and RAY revealed an ORR of 68%, 63% and 72%. Ibrutinib may be changing the natural history of MCL as many other agents still under development. Enrollment in clinical trials is crucial not only for discovery of new agents and testing combinations but also to understand the natural history of relapsed MCL. Legal entity responsible for the study Onco-Hematology Service of Instituto Portugues de Oncologia do Porto, F.G., E.P.E. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Matching-adjusted Indirect Comparisons of the Efficacy and Safety of Acalabrutinib Versus Other Targeted Therapies in Relapsed/Refractory Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin lymphoma that can be either aggressive or indolent. Although MCL usually responds well to initial treatment with chemotherapy-based regimens, the disease often relapses or becomes refractory within a few years. Acalabrutinib is a highly selective, potent, covalent Bruton tyrosine kinase inhibitor with minimal off-target activity. WIthout head-to-head clinical trial data, estimation of the comparative efficacy and safety of new therapeutic entities provides valuable information for patients, clinicians, and health care payers. The objective of this analysis was to compare the efficacy and safety of acalabrutinib versus other targeted therapies employed for the treatment of relapsed/refractory MCL by using matching-adjusted indirect comparisons. Individual data from 124 patients treated with acalabrutinib in the Phase II ACE-LY-004 trial were adjusted to match average baseline characteristics of populations from studies using alternative targeted treatment regimens for relapsed/refractory MCL (for monotherapy: ibrutinib, bortezomib, lenalidomide, and temsirolimus; for combination therapies: ibrutinib+rituximab, bendamustine+rituximab, and lenalidomide+rituximab). Patient populations were matched on age, sex, race, Eastern Cooperative Oncology Group performance status, Simplified MCL International Prognostic Index score, tumor bulk, lactate dehydrogenase concentration, extranodal disease, bone marrow involvement, and number of previous treatment regimens. Outcomes assessed included overall response rate (ORR), complete response (CR) rate, overall survival (OS), progression-free survival (PFS), and adverse events. After matching, acalabrutinib was associated with significant increases in ORR and CR rate (estimated treatment difference [95% CI]) versus ibrutinib (ORR, 9.3% [0.3-18.3]; CR, 14.9% [5.4-24.3]), bortezomib (ORR, 50.6% [40.2-61.0]; CR, 18.8% [9.1-28.5]), lenalidomide (ORR, 38.1% [27.1-49.1]; CR, 43.5% [34.8-52.3]), and temsirolimus (ORR, 40.7% [31.0-50.4]; CR, 27.1% [19.2-35.0]). PFS (hazard ratio [95% CI]) with acalabrutinib was significantly increased versus bortezomib (0.36 [0.26-0.51]), lenalidomide (0.65 [0.48-0.89]), lenalidomide+rituximab (0.57 [0.35-0.93]), and temsirolimus (0.33 [0.24-0.45]). Acalabrutinib was associated with significantly increased OS (hazard ratio) versus bortezomib (0.36 [0.22-0.61]) and temsirolimus (0.32 [0.23-0.44]). The overall safety profile of acalabrutinib was similar or better compared with the monotherapies; however, infection risk increased versus bendamustine+rituximab, and anemia increased risk versus lenalidomide+rituximab and ibrutinib+rituximab. This comparison of targeted therapies used in the treatment of relapsed/refractory MCL showed that acalabrutinib has the potential to provide increased response rates, with trends for increased PFS and OS, and an improved safety profile.

Is TP53 mutation screening in Mantle Cell Lymphoma (MCL) ready for prime time?

Mantle cell lymphoma (MCL) is a rare incurable subtype of B-cell lymphoma characterized by t(11;14)(q13;q32)-driven over expression of cyclin D1 [1]. MCL is associated with the highest degree of genomic instability of the B cell malignancies, and TP53 mutation in particular confers a dismal prognosis in MCL with a reported incidence of 15-20 % (blastoid=29% vs Classical= 6%) [2, 3]. TP53 mutation status is the only independent molecular marker that was able to improve the prognostic value of the Mantle cell lymphoma International Prognostic Index (MIPI) [4]. MCL Patients with a TP53 mutation were significantly less likely to achieve a CR after first-line treatment and associated early relapse. The current standard of care, Chemo-immunotherapy with high-dose Cytarabine followed by autologous stem cell transplant (ASCT) (in eligible patient), although most patients prove ineligible, have failed to overcome the poor prognostic impact of TP53 disruption [4]. Ibrutinib and Venetoclax (ABT-199) are two of the most active agents in the treatment of MCL, they have acceptable toxicity profiles and mainly are used in relapse setting. Pre-clinical models predict synergy between these novel drugs in combination. Patients who received Ibrutinib after an initial relapse had significantly longer PFS and OS than patients who received Ibrutinib after successive relapses probably related to selective advantage of resistant clone expansion [5]. In MCL, the attention should be move to the upfront treatment setting using these target therapies in high risk disease (TP53 mutated) and elderly patients whom un-fit for chemo-immunotherapy approach and phase III clinical trial eagerly awaited to support this approach. Likewise, in chronic lymphocytic leukaemia (CLL) incorporating TP53 mutation screening in routine practice prior commencing therapy is paramount in the era of novel effective therapies. Younger MCL patients with this genetic alteration should be considered for specific treatment using inhibitors for BCR, BCL2, TP53-independent pathways, the Anti-CD20 monoclonal antibodies either alone or in combination followed by allogeneic stem cell transplantation in the upfront setting. Chemo-free approach also to be considered for un-fit patients early in the disease course. Fit un-mutated TP53 MCL Patients should be treated with chemo-immunotherapy with ASCT consolidation if eligible and anti CD20 monoclonal antibody maintenance therapy.

1078P - MIPI as a superior prognostic tool in mantle cell lymphoma compared to monocyte-lymphocyte, neutrophil-lymphocyte and platelet-lymphocyte ratios

BackgroundMonocyte-lymphocyte, neutrophil-lymphocyte and platelet-lymphocyte ratio are considered prognostic tools of overall survival (OS) in several hematologic and solid tumors. All these elements have been implicated as biomarkers of tumor microenvironment and immune homeostasis. Mantle cell lymphoma (MCL) is a relatively uncommon subtype of lymphoid malignancy (5%–7% of malignant lymphoma) but could be very aggressive. Mantle Cell Lymphoma International Prognostic Index (MIPI) is the only validated prognostic tool for these patients. The aim of this study assessed the prognostic significance of monocyte-lymphocyte, neutrophil-lymphocyte and platelet-lymphocyte ratio as prognostic biomarkers for MCL. MethodsAn observational retrospective study was conducted and included a total all the patients diagnosed with MCL between 2008-2018 in our hematologic center. The ratios were calculated, and statistical analysis were assessed using Kaplan-Meier method, log-rank test and Cox regression. All the analyses were performed using SPSS. ResultsA total of 52 patients were included, 75% were male, with the median age at diagnosis being 67 years-old (max 94, min 36 years old). 77% of the patients had an ECOG PS 0-1, 67% had a high risk MIPI and 73% were a stage IV disease at diagnosis. Kaplan-Meier analysis showed that MIPI score significantly predicts the OS of the patients, with the higher scores being associated with inferior OS (p=0,02). The same did not happen with the monocyte-lymphocyte ratio (p=0,5), neutrophil-lymphocyte ratio (p=0,4) and platelet-lymphocyte ratio (p=0,3). The same results were showed in cox regression, MIPI score remained the only score associated with OS (HR, 0,35; 95% CI 0,132-0,962). ConclusionsIn conclusion, this study fails to identify monocyte-lymphocyte, neutrophil-lymphocyte and platelet-lymphocyte ratios as prognostic tools and support MIPI as predictor of the survival outcome in MCL patients and its ability to identify high-risk patients. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Clinical outcomes for ibrutinib in relapsed or refractory mantle cell lymphoma in real-world experience.

Ibrutinib is highly effective in patients with relapsed or refractory mantle cell lymphoma (MCL) in major clinical trials. Although there has been a dramatic improvement in survival outcomes in the salvage setting, nonresponders to ibrutinib have a bleak prognosis. Therefore, this retrospective study was conducted to identify the most appropriate therapeutic strategy and prognosis‐related factors to predict the response of patients with relapsed or refractory MCL to ibrutinib monotherapy. Thirty‐three consecutive refractory or relapsed MCL patients treated with ibrutinib were analyzed in this study. The median overall survival (OS) and progression‐free survival (PFS) after initiation of ibrutinib were 35.1 months and 27.4 months, respectively. Risk factor analysis showed that high risk according to the Mantle Cell Lymphoma International Prognostic Index (MIPI) and nonresponse to ibrutinib at the first three cycles were significantly associated with inferior OS. Poor PFS was associated with high‐risk biologic MIPI, prior bendamustine exposure, and nonresponse to ibrutinib during the first three cycles. After ibrutinib failure, primary nonresponders had poorer OS and PFS than inconsistent responders. The overall response rate for the first salvage therapy was only 33%, with a median TTP of 3.2 months. There was no effective therapeutic strategy except for allogeneic hematopoietic stem cell transplantation (allo‐HSCT). Although ibrutinib responders exhibited favorable survival outcomes, nonresponders had a dismal prognosis. To overcome these limitations, it may be necessary to modify therapeutic strategies, such as selecting inconsistent responders for earlier allo‐HSCT.

Prognostic Significance of MIPI and MIPI-B Scoring Systems for Mantle Cell Lymphoma in the Turkish Population

Our objective in this study is assessment of Mantle Cell Lymphoma International Prognostic Index (MIPI) and biological MIPI (MIPI-B) scores as prognostic markers based on real-life data of patients diagnosed with mantle cell lymphoma (MCL) in Turkey.

Can the prognosis of mantle cell lymphoma be predicted by simple CBC counts?

Mantle cell lymphoma (MCL) exhibits a heterogenous clinical course. The MCL International Prognostic Index (MIPI) is the most commonly used risk classification system in MCL. However, it does not contain a parameter associated with the tumor microenvironment. The aim of this study was to develop a more powerful prognostic index by evaluating the absolute monocyte count (AMC), neutrophil/lymphocyte ratio (NLR), and platelet/lymphocyte ratio (PLR) at diagnosis in conjunction with the clinical and laboratory parameters.The data of 96 MCL patients with newly diagnosed from January 2014 to December 2018 were retrospectively evaluated in this study. The AMC, NLR, and PLR cut-off values were determined using the receiver operating characteristic (ROC) analysis.The clinical behavior and results of the disease exhibited significant variation in high and low value groups at the time of diagnosis. In univariate analysis, the AMC ≥ 580, NLR ≥ 2.43, and PLR ≥ 120.85 were determined as negative prognostic factors for 5-year progression free survival (PFS) (AMC: PFS, P < .001; NLR: PFS, P < .001; PLR: PFS, P < .001) and for 5-year overall survival (OS) (P < .001, P < .001, P < .001, respectively). Beta-2 microglobulin (B2-MG), and MIPI for PFS, and for OS were found to be independent risk factors in the multivariate analysis (for PFS: P = .006, P = .002, respectively; and for OS: P = .007, P = .001, respectively). The 5-year OS was 20% in the group with B2-MG ≥ 3.5. The patients in high-risk MIPI group had poorer 5-year OS (median OS: 40 months, P < .001).The results stated that the use of B2-MG in conjunction with MIPI was a more sensitive method in determining the prognosis in MCL (median OS: 12 months in high-risk MIPI group with a B2-MG ≥3.5, P < .001). Additionally, it was found that parameters reflecting the tumor microenvironment such as AMC, NLR, and PLR increased the risk of progression in MCL. In view of these findings, in addition B2-MG to the MIPI to create a more sensitive prognostic scoring system may provide an insight into personalization of treatment with early recognition of patients with poor prognosis.

PF488 AUTOLOGOUS STEM CELL TRANSPLANTATION FOR MANTLE CELL LYMPHOMA ‐ OUTCOMES FROM A SINGLE ACADEMIC CENTRE

Background:The introduction of intensive cytarabine‐containing treatment regimens followed by autologous stem cell transplantation (ASCT) has led to substantial improvements in survival for patients with mantle cell lymphoma (MCL). The Nordic MCL2 trial, in which three cycles of Rituximab(R)‐Cytarabine and three cycles of R‐Maxi CHOP were followed by ASCT, reported a median overall survival (OS) of 12.7 years and a median progression‐free survival (PFS) of 8.5 years. This approach has been adopted in many centres, including in our own, for the first‐line treatment of MCL in suitable patients.Aims:The aim of this study was to retrospectively assess OS and PFS for patients undergoing ASCT for MCL over an 11‐year period in a single academic centre and to compare these real world outcomes to those reported from the Nordic MCL2 study. We also evaluated the prognostic significance of the Mantle Cell Lymphoma International Prognostic Index (MIPI) score at diagnosis.Methods:A retrospective analysis of all patients undergoing ASCT for MCL between January 2006 and October 2017 was performed. Data collected included baseline characteristics, treatment history, MIPI score at diagnosis, radiological response assessment prior to ASCT, treatment‐related morbidity and mortality, date of relapse, date of death and date of most recent follow‐up.Results:Ninety‐two patients underwent ASCT for MCL between January 2006 and October 2017. Of these, 73 were male and the median age at the time of ASCT was 58 years. All patients had a performance score of 0 or 1. A MIPI score could be calculated for 66 patients – 28 low‐risk, 24 intermediate‐risk and 14 high‐risk. Sixty‐one patients (77%) received treatment according to the Nordic MCL2 protocol. Other treatment regimens included R‐CHOP, R‐Cytarabine and R‐ESHAP and 15 patients (16%) required more than one line of treatment before proceeding to ASCT. Of 61 patients who had PET‐CT imaging before ASCT 58 (95%) had a complete metabolic response. Of 27 patients who had CT imaging before ASCT 22 (81%) had a complete response.With a median follow‐up of 5.7 years 35 patients (38%) relapsed and 32 patients (35%) died. The transplant‐related mortality rate was 4.3%. Overall, the median OS was 8.5 years and the median PFS was 5.1 years. Median OS for the low‐risk MIPI group was not reached and was superior to that for the intermediate (5.8 years, P = 0.012) and high‐risk groups (5.5 years, P = 0.0004). Median PFS for the low‐risk MIPI group (8.3 years) was superior to that for the high‐risk group (2.6 years, P = 0.001) but not significantly different to that for the intermediate group (4.5 years, P = 0.11). Outcomes for patients aged less than 60 years at the time of ASCT were superior those for older patients (median OS 9.2 versus 5.8 years, P = 0.035, median PFS 5.7 versus 4.5 years, P = 0.038). No significant difference in OS or PFS was found for any other variable.Summary/Conclusion:These real‐world data demonstrate prolonged patient survival following ASCT in MCL, although outcomes in this group appear inferior to those reported in the Nordic MCL2 trial. This may in part be due to the varied treatment regimens used in this group – 9% received R‐CHOP alone and 16% received more than 1 line of treatment prior to ASCT. In our cohort, baseline MIPI score and age (under 60 versus 60 or older) strongly predicted outcome both in terms of OS and PFS. This suggests that Nordic MCL2‐type therapy followed by ASCT may be most effective in younger patients and those with low‐risk MIPI scores, but alternative approaches should be considered for older patients and those with high‐risk scores.image

Low absolute NK cell counts in peripheral blood are associated with inferior survival in patients with mantle cell lymphoma.

Although risk stratification of mantle cell lymphoma (MCL) is most frequently performed using the simplified MCL International Prognostic Index (sMIPI), the identification of host-related factors and tumor microenvironment, including absolute monocyte counts (AMC) and peripheral blood T lymphocyte subsets, especially absolute natural killer cell counts (ANKC) has been suggested to be critical in the prediction of prognosis and the guidance of treatment. This study was aimed at investigating whether peripheral blood ANKC and AMC at diagnosis had an impact on MCL prognosis. A total of 92 newly diagnosed MCL patients was enrolled in this retrospective study. Flow cytometric analysis was conducted on fresh peripheral blood samples with a FACSCalibur flow cytometer (BD Biosciences, San Jose, CA, USA). The median follow-up was 42 months (range, 2-144 months) and the median overall survival (OS) of all cases was 45 months. High AMC (> 0.6 × 109/L) was the parameter associated with inferior progression free survival (PFS) (P= 0.044) and poor OS (P= 0.028) while low ANKC (⩽ 0.1 × 109/L) was associated with unfavorable OS (P= 0.023) by univariable analysis. Multivariable analysis revealed that only low ANKC (⩽ 0.1 × 109/L) was statistically significant in worse OS (P= 0.009) independent of sMIPI. Low ANKC (⩽ 0.1 × 109/L) proved to be a significant predictor of inferior OS in patients with MCL.