Michal Szymczyk

Treatment of Older Patients with Mantle-Cell Lymphoma

BACKGROUND The long-term prognosis for older patients with mantle-cell lymphoma is poor. Chemoimmunotherapy results in low rates of complete remission, and most patients have a relapse. We investigated whether a fludarabine-containing induction regimen improved the complete-remission rate and whether maintenance therapy with rituximab prolonged remission. METHODS We randomly assigned patients 60 years of age or older with mantle-cell lymphoma, stage II to IV, who were not eligible for high-dose therapy to six cycles of rituximab, fludarabine, and cyclophosphamide (R-FC) every 28 days or to eight cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 21 days. Patients who had a response underwent a second randomization to maintenance therapy with rituximab or interferon alfa, each given until progression. RESULTS Of the 560 patients enrolled, 532 were included in the intention-to-treat analysis for response, and 485 in the primary analysis for response. The median age was 70 years. Although complete-remission rates were similar with R-FC and R-CHOP (40% and 34%, respectively; P=0.10), progressive disease was more frequent with R-FC (14%, vs. 5% with R-CHOP). Overall survival was significantly shorter with R-FC than with R-CHOP (4-year survival rate, 47% vs. 62%; P=0.005), and more patients in the R-FC group died during the first remission (10% vs. 4%). Hematologic toxic effects occurred more frequently in the R-FC group than in the R-CHOP group, but the frequency of grade 3 or 4 infections was balanced (17% and 14%, respectively). In 274 of the 316 patients who were randomly assigned to maintenance therapy, rituximab reduced the risk of progression or death by 45% (in remission after 4 years, 58%, vs. 29% with interferon alfa; hazard ratio for progression or death, 0.55; 95% confidence interval, 0.36 to 0.87; P=0.01). Among patients who had a response to R-CHOP, maintenance therapy with rituximab significantly improved overall survival (4-year survival rate, 87%, vs. 63% with interferon alfa; P=0.005). CONCLUSIONS R-CHOP induction followed by maintenance therapy with rituximab is effective for older patients with mantle-cell lymphoma. (Funded by the European Commission and others; ClinicalTrials.gov number, NCT00209209.).

Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network.

BACKGROUND Mantle cell lymphoma is characterised by a poor long-term prognosis. The European Mantle Cell Lymphoma Network aimed to investigate whether the introduction of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation (ASCT) improves outcome. METHODS This randomised, open-label, parallel-group, phase 3 trial was done in 128 haemato-oncological hospital departments or private practices in Germany, France, Belgium, and Poland. Patients aged 65 years or younger with untreated stage II-IV mantle cell lymphoma were centrally randomised (1:1), with computer-assisted random block selection, to receive either six courses of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by myeloablative radiochemotherapy and ASCT (control group), or six courses of alternating R-CHOP or R-DHAP (rituximab plus dexamethasone, high-dose cytarabine, and cisplatin) followed by a high-dose cytarabine-containing conditioning regimen and ASCT (cytarabine group). Patients were stratified by study group and international prognostic index. The primary outcome was time to treatment failure from randomisation to stable disease after at least four induction cycles, progression, or death from any cause. Patients with stage II-IV mantle cell lymphoma were included in the primary analysis if treatment was started according to randomisation. For safety analyses, patients were assessed according to the treatment actually started. This study is registered with ClinicalTrials.gov, number NCT00209222. FINDINGS Of 497 patients (median age 55 years [IQR 49-60]) randomised from July 20, 2004, to March 18, 2010, 234 of 249 in the control group and 232 of 248 in the cytarabine group were included in the primary analysis. After a median follow-up of 6.1 years (95% CI 5.4-6.4), time to treatment failure was significantly longer in the cytarabine group (median 9.1 years [95% CI 6.3-not reached], 5 year rate 65% [95% CI 57-71]) than in the control group (3.9 years [3.2-4.4], 40% [33-46]; hazard ratio 0.56; p=0.038). During induction immunochemotherapy, patients who received high-dose cytarabine had increased grade 3 or 4 haematological toxicity (haemoglobin 71 [29%] of 241m vs 19 [8%] of 227 controls; platelets 176 [73%] of 240 vs 21 [9%] of 225), grade 3 or 4 febrile neutropenia (39 [17%] of 230 vs 19 [8%] of 224), and grade 1 or 2 renal toxicity (creatinine 102 [43%] of 236 vs 22 [10%] of 224). The number of ASCT-related deaths was similar (eight [3.4%]) in both groups. INTERPRETATION Immunochemotherapy containing high-dose cytarabine followed by ASCT should be considered standard of care in patients aged 65 years or younger with mantle cell lymphoma. FUNDING European Commission, Lymphoma Research Foundation, and Roche.

Confirmation of the Mantle-Cell Lymphoma International Prognostic Index in Randomized Trials of the European Mantle-Cell Lymphoma Network

PURPOSE Mantle-cell lymphoma (MCL) is a distinct B-cell lymphoma associated with poor outcome. In 2008, the MCL International Prognostic Index (MIPI) was developed as the first prognostic stratification tool specifically directed to patients with MCL. External validation was planned to be performed on the cohort of the two recently completed randomized trials of the European MCL Network. PATIENTS AND METHODS Data of 958 patients with MCL (median age, 65 years; range, 32 to 87 years) treated upfront in the trials MCL Younger or MCL Elderly were pooled to assess the prognostic value of MIPI with respect to overall survival (OS) and time to treatment failure (TTF). RESULTS Five-year OS rates in MIPI low, intermediate, and high-risk groups were 83%, 63%, and 34%, respectively. The hazard ratios for OS of intermediate versus low and high versus intermediate risk patients were 2.1 (95% CI, 1.5 to 2.9) and 2.6 (2.0 to 3.3), respectively. MIPI was similarly prognostic for TTF. All four clinical baseline characteristics constituting the MIPI, age, performance status, lactate dehydrogenase level, and WBC count, were confirmed as independent prognostic factors for OS and TTF. The validity of MIPI was independent of trial cohort and treatment strategy. CONCLUSION MIPI was prospectively validated in a large MCL patient cohort homogenously treated according to recognized standards. As reflected in current guidelines, MIPI represents a generally applicable prognostic tool to be used in research as well as in clinical routine, and it can help to develop risk-adapted treatment strategies to further improve clinical outcome in MCL.

Central nervous system involvement in mantle cell lymphoma: clinical features, prognostic factors and outcomes from the European Mantle Cell Lymphoma Network

BACKGROUND Central nervous system (CNS) involvement in mantle cell lymphoma (MCL) is uncommon, and the manifestations and natural history are not well described. PATIENTS AND METHODS We present the data on 57 patients with MCL who developed CNS involvement, from a database of 1396 consecutively treated patients at 14 institutions. RESULTS The crude incidence of CNS involvement was 4.1%, with 0.9% having CNS involvement at diagnosis. Blastoid histology, B-symptoms, elevated lactate dehydrogenase, Eastern Cooperative Group performance status ≥2 and a high Mantle Cell Lymphoma International Prognostic Index score were enriched in the cohort with CNS involvement, and the presence of ≥1 of these features defined a high-risk subset (an actuarial risk of CNS involvement 15% at 5 years) in a single-institution subset. The median time to CNS relapse was 15.2 months, and the median survival from time of CNS diagnosis was 3.7 months. The white blood cell count at diagnosis <10.9 × 10⁹/l, treatment of CNS involvement with high-dose anti-metabolites, consolidation with stem cell transplant and achievement of complete response were all associated with improved survival. CONCLUSIONS In MCL, CNS involvement is uncommon, although some features may predict risk. Once manifest outlook is poor; however, some patients who receive intensive therapy survive longer than 12 months.

Update on the molecular pathogenesis and clinical treatment of Mantle Cell Lymphoma (MCL): minutes of the 9th European MCL Network conference

Mantle cell lymphoma (MCL) is a distinct subtype of malignant lymphoma which is characterized by the chromosomal translocation t(11;14)(q13;q32), resulting in constitutional overexpression of cyclin D1 and cell cycle dysregulation in virtually all cases. Clinically, MCL shows an aggressive clinical course with a continuous relapse pattern and a median survival of only 3–5 years. However, recently a subset of 15% long-term survivors has been identified with a rather indolent clinical course, even after conventional treatment strategies only. Advanced stage disease is usually apparent already at first clinical manifestation; thus, conventional chemotherapy is only palliative, and the median duration of remissions is only 1–2 years. Emerging strategies including proteasome inhibitors, immune modulatory drugs (IMiDs), mTOR inhibitors, and others are based on the dysregulated control of cell cycle machinery and impaired apoptotic pathways. Monotherapy of these compounds achieves efficacy comparable to conventional chemotherapy in relapsed MCL, and combination strategies are currently being investigated in numerous trials; however, their introduction into clinical practice and current treatment algorithms remain a challenge. In 2000 the European MCL Network (http://www.european-mcl.net) was founded, consisting of 15 national lymphoma study groups supplemented by experts in histopathology and molecular genetics. During the past decade, the European consortium has successfully initiated the largest phase III trials in MCL worldwide, with a current annual recruitment of almost 200 patients per year in first-line studies. In detail, in prospective randomized studies, the addition of a B-lymphocyte specific antibody doubled the median progression-free survival from 14 to 28 months, and a dose-intensified consolidation with high-dose radiochemotherapy and subsequent autologous stem cell transplant resulted in superior response duration (3.7 vs. 1.6 years) and even improved overall survival in a recent analysis. Future strategies will apply individualized approaches according to the molecular risk profile of the patient. At the recent annual conference in Jerusalem, recent results of molecular pathogenesis, analyses of current clinical trials, and new study concepts were discussed.

Total body irradiation after high-dose cytarabine in mantle cell lymphoma: a comparison of Nordic MCL2, HOVON-45, and European MCL Younger trials

In patients with mantle cell lymphoma (MCL) up to 65 years, recommended first-line treatment consists of immuno-chemotherapy including high-dose cytarabine (HA), followed by autologous stem cell transplantation (ASCT) in complete (CR) or partial remission (PR).1 However, it remains unclear whether total body irradiation (TBI) should be part of conditioning before ASCT.1 A large registry study by the European Society for Blood and Marrow Transplantation (EBMT) including 418 MCL patients reported a significantly reduced relapse incidence after TBI in comparison to a non-TBI conditioning (mostly carmustine, etoposide, cytarabine, and melphalan, BEAM), but only for patients transplanted in first PR.2 In contrast, a single-center evaluation of 73 MCL patients who underwent ASCT did not find a significant PFS difference according to the use of TBI vs BEAM.3 A recently published consensus project by EBMT/European MCL Network involving twelve expert clinicians showed that, while consensus was achieved on ASCT as standard first-line consolidation therapy, no consensus was reached on the role of TBI.4 Three recently completed prospective studies including untreated MCL patients up to 65 years investigated the efficacy of HA-containing immuno-chemotherapy followed by ASCT: Nordic MCL2,5, 6 HOVON-45(ref. 7) and European MCL Younger.8, 9 We combined the individual patient data from these studies to compare the long-term clinical outcome of MCL patients transplanted without TBI (Nordic MCL2 and HOVON-45) vs with TBI (MCL Younger, experimental HA-containing arm).

SOX11 expression as a MRD molecular marker for MCL in comparison with t(11;14) and IGH rearrangement

The main cause of death in mantle cell lymphoma (MCL) patients is relapse due to undetermined minimal residual disease (MRD) and therefore monitoring MRD is crucial for making the best treatment decisions. The gold standard method for MRD analysis is the quantitative polymerase chain reaction. The most commonly used molecular markers for measuring MRD in MCL are: t(11;14)(q13;p32) translocation or CCND1 expression and IGH rearrangement. Such markers can, however, be found in other B cell non-Hodgkin lymphomas. Recent studies demonstrate that SOX11 expression is highly specific for MCL and could be used as a marker for measuring MRD. Moreover, evidence shows that SOX11 level could be predictive for overall survival (OS) and progression-free survival (PFS). We have measured MRD level in follow-up samples from 27 patients diagnosed with MCL using the molecular markers: t(11;14), IGH rearrangement and SOX11 expression. We compared all markers by their sensitivity, utility and quantitative range. We also examined the predictive value of SOX11 expression for OS and PFS. SOX11 expression was found to have better specificity, quantitative range and utility than the t(11;14). The predictive value of SOX11 expression was confirmed. At diagnosis, patients with high SOX11 expression had shorter PFS than patients with low SOX11 expression (p = 0.04*); differences between OS being statistically insignificant. To our best knowledge this is a first study comparing SOX11 with t(11;14) and IGH rearrangement as markers of MRD level. Moreover, in this study we confirmed that SOX11 is useful in cases when other molecular markers cannot be used.

965PPROLONGED RELAPSE PATTERN IN PRIMARY TESTICULAR LYMPHOMA AFTER SUCCESSFUL INDUCTION THERAPY

ABSTRACT Aim: Testicular lymphoma is characterised by aggressive clinical course and in cases of treatment failure frequently involviesCNS and contralateral testis. Late relapses have been reported in occasional series. Here we looked at clinical features and outcome of patients treated at a single instiution over a period of 25 years. Methods: We retrospectively reviewed medical records of consecutive patients diagnosed with primary testicular lymphoma treated at our institution between 1988 and 2013. Results: Sixty four patients with a diagnosis of diffuse large B-cell lymphoma and primary testicular involvement were identified. Median age was 67. All patients had initial surgery including bilateral orchiectomy in 5 patients. Majority of patients (n = 48, 75%) were in clinical stage IE ad IIE at presentation. Risk category according to the modified NCCN-IPI was low or low-intermediate in 48 (75%) patients. Chemotherapy was given to 57 (89%) inluding rituximab in 29 (45%) of patients. CNS prophylaxis with intrathecal methotrexate was applied in 35 (55%) patients. Radiotherapy to contralateral testis was applied to 3 patients. Out of 48 (70%) patients in complete remission after initial treatment, 19 (38%) subsequently relapsed at median (range) of 36 (3.5 -144) months with many relapses occuring far beyond of 3 years. 62% of relapsed patients died of disease. In patients who relapse late, extranodal sites were frequently involved. Eight patients had CNS relapse including 6 patients not given CNS prophylaxis. Four patients relapsed in contralateral testis. Conclusions: Despite low- or low-intremediate risk status of majority of patients median time to relapse of 3years is disappointing and many relapses occurred late. Non-use of radiotherapy seems unlikely reason as only 4 patients relapsed in contralateral testis. Less than half of the patients received rituximab which might contribute to the worse outcome. Disclosure: All authors have declared no conflicts of interest.

Wczesna niehematologiczna toksyczność po chemioterapii w wysokich dawkach i autologicznym przeszczepieniu komórek krwiotwórczych u chorych na nowotwory limfoidalne powyżej 60. roku życia

STRESZCZENIE Chemioterapia w wysokich dawkach (HDT) z autologicznym przeszczepieniem szpiku (AutoHCT) jest leczeniem z wyboru w przypadkach nowotworow hematologicznych, w ktorych standardowa terapia nie pozwala na uzyskanie dobrych wynikow leczenia. Pacjenci powyzej 60. roku zycia ze wspolistniejącymi chorobami są wylączani z HDT ze wzgledu na toksycznośc wielonarządową i śmiertelnośc okoloprzeszczepową. Celem badania byla analiza czestości i stopnia nasilenia powiklan narządowych we wczesnym okresie, do 30 dni po autotransplantacji, u chorych na chloniaki w wieku 60 lat i wiecej. W latach 2005–2011 zakwalifikowano do leczenia mieloablacyjnego 44 chorych. Mediana wieku wynosila 62 lata (zakres: 60–67). Chemioterapie BEAM (karmustyna, etopozyd, cytarabina, melfalan) podano 16 chorym, melfalan 200 otrzymalo 22 chorych, 6 chorym podano inne kondycjonowanie (cytarabina, melfalan lub cyklofosfamid). W 32% przypadkow stwierdzono choroby wspolistniejące, w tym w 71% choroby sercowo-naczyniowe. Wczesną wielonarządową toksycznośc stwierdzono w 84% przypadkow. Najczestszym powiklaniem byly zaburzenia zolądkowo-jelitowe (77% chorych). Biegunka III-IV stopnia wystąpila u 24 chorych (55%), przedluzone powyzej 7 dni wymioty u 17 chorych (40%). Zmiany śluzowkowe jamy ustnej III-IV stopnia obserwowano u 15 chorych (34%). Gorączka neutropeniczna (59%), z sepsą wystąpila u 1 chorego (2%). Powiklania kardiologiczne stwierdzono u 4 chorych (9%). Mediana czasu hospitalizacji wynosila 21 dni (16–44). Jeden chory zmarl z powodu toksyczności związanej z autotransplantacją (2%). We wczesnym okresie potransplantacyjnym, u chorych powyzej 60. roku HDT towarzyszy znaczna toksycznośc narządowa. Do najczestszych niehematologicznych objawow ubocznych leczenia mieloablacyjnego nalezą powiklania z przewodu pokarmowego, gorączka neutropeniczna, powiklania kardiologiczne. Przy niskiej śmiertelności okoloprzeszczepowej (2%) HDT jest procedurą bezpieczną dla osob starszych.