Publications by authors named "Martin Dreyling"

260 Publications

Inpatient treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL): A health economic perspective.

Clin Lymphoma Myeloma Leuk 2021 Dec 24. Epub 2021 Dec 24.

Department of Medicine III; Ludwig-Maximilian-University Hospital, Munich, Germany; Institute of Medical Information Processing, Biometrics and Epidemiology (IBE), Ludwig-Maximilian-University Munich, Germany. Electronic address:

Introduction: Patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) require highly individualized therapies. Limited information exists regarding inpatient treatment patterns, outcomes, resource-use, and costs from the perspective of third-party payers in Germany. The aim of this study was to collect and evaluate routine inpatient care data to fill aforementioned gaps.

Methods: Retrospective single center observational study in a German tertiary teaching hospital. Data were collected from patient records, the hospital-pharmacy database, and claims data.

Results: Eighty-four patients (47 male; mean age at initial diagnosis, 59 years) were identified and grouped by treatment line (L): 2L (n = 78), 3L (n = 32), and >3L (n = 12). Prescribed treatments in 2L were chemotherapy 56%, auto-SCT 31%, allo-SCT 1%, other 12%; 3L: 50%, 16%, 6%, 28%, respectively, and >3L: 42%, 0%, 33%, 25%, respectively. Mean number of hospital admissions and length of inpatient stay (days) were: 2L (4, 44), 3L (2, 26), and >3L (5, 63). Average cost/patient: 2L = 44,750€, 3L = 32,589€ and >3L = 88,668€. Mean treatment costs per patient for stem-cell-transplanted patients were 55,468€ for autologous SCT (n = 28) and 131,264€ for allogeneic SCT (n = 7). Documented death was 21%, 28%, and 41% for 2L, 3L, and >3L, respectively.

Conclusion: Individualized DLBCL treatment in patients ≥ 2L is costly and results in a huge variability in resource consumption. The number of documented deaths and length of hospitalization signal a high economic burden on patients and families. A multicenter comprehensive evaluation of health and economic burdens of r/r DLBCL and linkage with other data sources (eg, registries, payers' claims data) is essential.
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http://dx.doi.org/10.1016/j.clml.2021.12.018DOI Listing
December 2021

A Clinical Prognostic Model Based on Machine Learning from the Fondazione Italiana Linfomi (FIL) MCL0208 Phase III Trial.

Cancers (Basel) 2021 Dec 31;14(1). Epub 2021 Dec 31.

Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, 28100 Novara, Italy.

Background: Multicenter clinical trials are producing growing amounts of clinical data. Machine Learning (ML) might facilitate the discovery of novel tools for prognostication and disease-stratification. Taking advantage of a systematic collection of multiple variables, we developed a model derived from data collected on 300 patients with mantle cell lymphoma (MCL) from the Fondazione Italiana Linfomi-MCL0208 phase III trial (NCT02354313).

Methods: We developed a score with a clustering algorithm applied to clinical variables. The candidate score was correlated to overall survival (OS) and validated in two independent data series from the European MCL Network (NCT00209222, NCT00209209); Results: Three groups of patients were significantly discriminated: Low, Intermediate (Int), and High risk (High). Seven discriminants were identified by a feature reduction approach: albumin, Ki-67, lactate dehydrogenase, lymphocytes, platelets, bone marrow infiltration, and B-symptoms. Accordingly, patients in the Int and High groups had shorter OS rates than those in the Low and Int groups, respectively (Int→Low, HR: 3.1, 95% CI: 1.0-9.6; High→Int, HR: 2.3, 95% CI: 1.5-4.7). Based on the 7 markers, we defined the engineered MCL international prognostic index (eMIPI), which was validated and confirmed in two independent cohorts; Conclusions: We developed and validated a ML-based prognostic model for MCL. Even when currently limited to baseline predictors, our approach has high scalability potential.
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http://dx.doi.org/10.3390/cancers14010188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750124PMC
December 2021

Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial.

Nat Med 2021 Dec 17. Epub 2021 Dec 17.

Novartis Pharma AG, Basel, Switzerland.

Tisagenlecleucel is an autologous anti-CD19 chimeric antigen receptor-T cell therapy with clinically meaningful outcomes demonstrated in patients with relapsed/refractory (r/r) B-cell lymphoma. In a previous pilot study of tisagenlecleucel in r/r follicular lymphoma (FL), 71% of patients achieved a complete response (CR). Here we report the primary, prespecified interim analysis of the ELARA phase 2 multinational trial of tisagenlecleucel in adults with r/r FL after two or more treatment lines or who relapsed after autologous stem cell transplant (no. NCT03568461). The primary endpoint was CR rate (CRR). Secondary endpoints included overall response rate (ORR), duration of response, progression-free survival, overall survival, pharmacokinetics and safety. As of 29 March 2021, 97/98 enrolled patients received tisagenlecleucel (median follow-up, 16.59 months; interquartile range, 13.8-20.21). The primary endpoint was met. In the efficacy set (n = 94), CRR was 69.1% (95% confidence interval, 58.8-78.3) and ORR 86.2% (95% confidence interval, 77.5-92.4). Within 8 weeks of infusion, rates of cytokine release syndrome were 48.5% (grade ≥3, 0%), neurological events 37.1% (grade ≥3, 3%) and immune effector cell-associated neurotoxicity syndrome (ICANS) 4.1% (grade ≥3, 1%) in the safety set (n = 97), with no treatment-related deaths. Tisagenlecleucel is safe and effective in extensively pretreated r/r FL, including in high-risk patients.
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http://dx.doi.org/10.1038/s41591-021-01622-0DOI Listing
December 2021

Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma.

N Engl J Med 2021 Dec 14. Epub 2021 Dec 14.

From the David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago (M.R.B.); Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC (M. Dickinson), Fiona Stanley Hospital, Murdoch, WA (D.P.), and the Department of Haematology, St. Vincent's Hospital Sydney, and St. Vincent's Clinical School, University of New South Wales, Sydney (N.H.) - all in Australia; Hospital Universitari Vall d'Hebron and Universitat Autònoma de Barcelona (P. Barba) and the Clinical Hematology Department, Institut Català d'Oncologia-Hospitalet de Llobregat (A. Sureda), Barcelona, and the Hematology Department, Hospital 12 de Octubre, Complutense University, Instituto de Investigación Hospital 12 de Octubre, Centro Nacional de Investigaciones Oncológicas, Madrid (J.M.-L.) - all in Spain; the Department of Biomedical Sciences, Humanitas University and IRCCS Humanitas Research Hospital-Humanitas Cancer Center, Milan (A. Santoro); the Department of Hematology, Oncology, and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka (K.K.), and Tohoku University Hospital, Sendai (H. Harigae) - both in Japan; the Third Medical Department, Paracelsus Medical University, Salzburg Cancer Research Institute-Center for Clinical Cancer and Immunology Trials and Cancer Cluster Salzburg, Salzburg (R.G.), and Internal Medicine I, Bone Marrow Transplant Unit (W.R.), and the Clinical Division of Hematology and Hemostaseology, Department of Medicine I (U.J.), Vienna General Hospital-Medical University of Vienna, Vienna - both in Austria; Assistance Publique-Hôpitaux de Paris, Hemato-Oncology, Hôpital Saint-Louis, Paris (C.T.), Centre Hospitalier Régional Universitaire de Lille, Lille (F.M.), Hospices Civils de Lyon and Université Claude Bernard Lyon 1, Lyon (E.B.), and Centre de Recherche en Cancérologie et Immunologie Nantes-Angers, INSERM, and Nantes Medical University, Nantes (S.L.G.) - all in France; the Department of Hematology, Oncology, and Tumorimmunology, Charité-University Hospital Berlin, Campus Benjamin Franklin, and the Experimental and Clinical Research Center of the Max Delbrück Center for Molecular Medicine and Charité Berlin, Berlin (M.J.), Medizinische Klinik III, LMU Klinikum, Munich (M. Dreyling), and Clinic I for Internal Medicine, University Hospital Cologne, Cologne (P. Borchmann) - all in Germany; Sarah Cannon Research Institute-Tennessee Oncology, Nashville (I.F., P.M.); the Department of Medicine, Queen Mary Hospital, Hong Kong (Y.-L.K.); the Department of Hematology, Amsterdam UMC, University of Amsterdam, Amsterdam (M.J.K.), and Universitair Medisch Centrum Utrecht, Department of Medical Oncology, Utrecht (M.C.M.) - both in the Netherlands; the Department of Oncology, Oslo University Hospital, and K.G. Jebsen Center for B-Cell Malignancies - both in Oslo (H. Holte); the National University Cancer Institute Singapore, Singapore (E.H.L.C.); the Department of Medical Oncology and Hematology, University Hospital, Zurich (A.M.S.M.), and Novartis Pharma, Basel (S.N., E.D., G.A.) - both in Switzerland; the Center for Hematologic Malignancies, Knight Cancer Institute, Oregon Health and Science University, Portland (R.T.M.); the Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Cancer Center, Westwood (J.P.M.); Ohio State University, Columbus (D.B.); Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco (C.A.); the Division of Hematology-Oncology and Blood and Marrow Transplantation and Cellular Therapy Program, Mayo Clinic, Jacksonville, FL (M.K.-D.); Novartis Pharmaceuticals, East Hanover, NJ (R.A., C.C., A.M.); the Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia (S.J.S.); and the Department of Lymphoma and Myeloma, M.D. Anderson Cancer Center, Houston (J.R.W.).

Background: Patient outcomes are poor for aggressive B-cell non-Hodgkin's lymphomas not responding to or progressing within 12 months after first-line therapy. Tisagenlecleucel is an anti-CD19 chimeric antigen receptor T-cell therapy approved for diffuse large B-cell lymphoma after at least two treatment lines.

Methods: We conducted an international phase 3 trial involving patients with aggressive lymphoma that was refractory to or progressing within 12 months after first-line therapy. Patients were randomly assigned to receive tisagenlecleucel with optional bridging therapy (tisagenlecleucel group) or salvage chemotherapy and autologous hematopoietic stem-cell transplantation (HSCT) (standard-care group). The primary end point was event-free survival, defined as the time from randomization to stable or progressive disease at or after the week 12 assessment or death. Crossover to receive tisagenlecleucel was allowed if a defined event occurred at or after the week 12 assessment. Other end points included response and safety.

Results: A total of 322 patients underwent randomization. At baseline, the percentage of patients with high-grade lymphomas was higher in the tisagenlecleucel group than in the standard-care group (24.1% vs. 16.9%), as was the percentage with an International Prognostic Index score (range, 0 to 5, with higher scores indicating a worse prognosis) of 2 or higher (65.4% vs. 57.5%). A total of 95.7% of the patients in the tisagenlecleucel group received tisagenlecleucel; 32.5% of the patients in the standard-care group received autologous HSCT. The median time from leukapheresis to tisagenlecleucel infusion was 52 days. A total of 25.9% of the patients in the tisagenlecleucel group had lymphoma progression at week 6, as compared with 13.8% of those in the standard-care group. The median event-free survival in both groups was 3.0 months (hazard ratio for event or death in the tisagenlecleucel group, 1.07; 95% confidence interval, 0.82 to 1.40; P = 0.61). A response occurred in 46.3% of the patients in the tisagenlecleucel group and in 42.5% in the standard-care group. Ten patients in the tisagenlecleucel group and 13 in the standard-care group died from adverse events.

Conclusions: Tisagenlecleucel was not superior to standard salvage therapy in this trial. Additional studies are needed to assess which patients may obtain the most benefit from each approach. (Funded by Novartis; BELINDA ClinicalTrials.gov number, NCT03570892.).
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http://dx.doi.org/10.1056/NEJMoa2116596DOI Listing
December 2021

A Phase II Study to Assess the Safety and Efficacy of the Dual mTORC1/2 and PI3K Inhibitor Bimiralisib (PQR309) in Relapsed, Refractory Lymphoma.

Hemasphere 2021 Nov 27;5(11):e656. Epub 2021 Oct 27.

Department of Medicine III, Ludwig-Maximilians-University Hospital, Munich, Germany.

Bimiralisib is an orally bioavailable pan-phosphatidylinositol 3-kinase and mammalian target of rapamycin inhibitor which has shown activity against lymphoma in preclinical models. This phase I/II study evaluated the response rate to bimiralisib at 2 continuous dose levels (60 mg and 80 mg) in patients with relapsed/refractory lymphoma. Fifty patients were enrolled and started treatment. The most common histologies were diffuse large B-cell lymphoma (n = 17), follicular lymphoma (n = 9), T-cell lymphoma (n = 8), and others (mostly indolent). Patients had been treated with a median of 5 prior lines of treatment and 44% were considered refractory to their last treatment. Mean duration of treatment (and standard deviations) with 60 mg once daily (o.d.) was 1.3 ± 1.2 months, and with 80 mg o.d. 3.7 ± 3.9 months. On an intention to treat analysis, the overall response rate was 14% with 10% achieving a partial response and 4% a complete response. Thirty-six percent of patients were reported as having stable disease. No dose-limiting toxicities were observed during the phase I portion of the study. Overall, 70% of patients had a grade 3 treatment emergent adverse events (TEAE) and 34% had a grade 4 TEAE; 28% of patients discontinued treatment due to toxicity. The most frequent TEAEs grade ≥3 was hyperglycemia (24%), neutropenia (20%), thrombocytopenia (22%), and diarrhea (12%). Per protocol, hyperglycemia required treatment with oral antihyperglycemic agents in 28% and with insulin in 14%. At 60 mg or 80 mg continuous dosing, bimiralisib showed modest efficacy with significant toxicity in heavily pretreated patients with various histological subtypes of lymphoma.
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http://dx.doi.org/10.1097/HS9.0000000000000656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8660000PMC
November 2021

The mTOR Inhibitor Temsirolimus Added to Rituximab Combined With Dexamethasone, Cytarabine, and Cisplatinum (R-DHAP) for the Treatment of Patients With Relapsed or Refractory DLBCL - Results From the Phase-II STORM Trial.

Hemasphere 2021 Oct 23;5(10):e636. Epub 2021 Sep 23.

Department of Internal Medicine III (Hematology, Oncology, Pneumology), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

There is a high need for novel treatment options in relapsed and refractory diffuse large B-cell lymphoma. Single agent mammalian target of rapamycin (mTOR) inhibitor treatment has shown promising efficacy in this entity. Here, we report on the results of the mTOR-inhibitor temsirolimus combined to standard rituximab-DHAP salvage regimen in a prospective, multicenter, phase II, open-label study. The STORM regimen consisted of rituximab 375 mg/m (day 2) and DHAP (dexamethasone 40 mg day 3-6, cisplatinum 100 mg/m day 3, cytarabine 2 × 2  g/m day 4) with temsirolimus added on day 1 and 8 of a 21-day cycle, with 2 to 4 cycles planned. In part I, dose levels of 25, 50, 75, and 100 mg for temsirolimus were predefined. Based on the observed toxicity profile, a temsirolimus dose of 25 mg was defined as recommended dose for the part II extension cohort of the trial. The intention-to-treat cohort comprised 53 patients. Median age was 63 years and median number of prior regimen was 1. All but 1 patient had prior rituximab exposure. Temsirolimus dose was 50 mg on day 1 and 8 in 6 patients from the part I of the trial and 25 mg in the remaining 47 patients. In general, treatment was well tolerated with leucopenia and thrombocytopenia as most frequent severe adverse events. The overall response rate after the last cycle of temsirolimus R-DHAP was 66% with 24% complete responses. The ability to mobilize stem cells was not impaired by the treatment regimen. Twenty-eight patients received consolidation treatment with high-dose therapy (HDT) and stem cell transplantation. Median duration of response was not reached. The total 2-year progression-free survival (PFS) and overall survival (OS) were 53% and 59%. Patients who were consolidated with HDT achieved a 2-year PFS and a 2-year OS of 77.8% and 82.1%, respectively. We conclude that temsirolimus can be safely added to rituximab and DHAP with promising activity.
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http://dx.doi.org/10.1097/HS9.0000000000000636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476051PMC
October 2021

Rituximab Treatment of Hairy Cell Leukemia in a Patient with Mycobacterium kansasii Infection: A Case Report.

Oncol Res Treat 2021 21;44(11):637-640. Epub 2021 Sep 21.

Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.

Introduction: Infectious complications represent a major cause of morbidity and mortality in hairy cell leukemia (HCL) patients. Due to the immunosuppressive nature of the disease, these patients are frequently affected by opportunistic infections and rare pathogens. Furthermore, cytotoxic chemotherapy might lead to poor or even fatal outcomes in the setting of an active infection.

Case Presentation: We report the case of a 62-year-old HCL patient who presented with recurrent fever episodes, pancytopenia, and mediastinal lymphadenopathy. A treatment decision against purine analogs and for rituximab mono was made as lymph node tissue revealed disseminated Mycobacterium kansasii infection. Together with specific antimycobacterial treatment, rituximab mono led to complete hematologic remission after 6 months without aggravating the accompanying infection.

Conclusion: Here, we demonstrate successful treatment of HCL with rituximab in a patient with concomitant disseminated M. kansasii infection.
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http://dx.doi.org/10.1159/000519301DOI Listing
November 2021

American Society of Transplantation and Cellular Therapy, Center of International Blood and Marrow Transplant Research, and European Society for Blood and Marrow Transplantation Clinical Practice Recommendations for Transplantation and Cellular Therapies in Mantle Cell Lymphoma.

Transplant Cell Ther 2021 09;27(9):720-728

Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.

Autologous (auto-) and allogeneic (allo-) hematopoietic cell transplantation (HCT) are accepted treatment modalities in contemporary treatment algorithms for mantle cell lymphoma (MCL). Chimeric antigen receptor (CAR) T cell therapy recently received approval for MCL; however, its exact place and sequence in relation to HCT remain unclear. The American Society of Transplantation and Cellular Therapy, Center of International Blood and Marrow Transplant Research, and the European Society for Blood and Marrow Transplantation jointly convened an expert panel to formulate consensus recommendations for role, timing, and sequencing of auto-HCT, allo-HCT, and CAR T cell therapy for patients with newly diagnosed and relapsed/refractory (R/R) MCL. The RAND-modified Delphi method was used to generate consensus statements. Seventeen consensus statements were generated, with a few key statements as follows: in the first line setting, auto-HCT consolidation represents standard of care in eligible patients, whereas there is no clear role of allo-HCT or CAR T cell therapy outside of clinical trials. In the R/R setting, the preferential option is CAR T cell therapy, especially in patients with MCL failing or intolerant to at least one Bruton's tyrosine kinase inhibitor, while allo-HCT is recommended if CAR T cell therapy fails or is infeasible. Several recommendations were based on expert opinion, where the panel developed consensus statements for important real-world clinical scenarios to guide clinical practice. In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a formal framework for developing consensus recommendations for the timing and sequence of cellular therapies for MCL.
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http://dx.doi.org/10.1016/j.jtct.2021.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447221PMC
September 2021

Long-term survival of patients with mantle cell lymphoma after autologous haematopoietic stem-cell transplantation in first remission: a post-hoc analysis of an open-label, multicentre, randomised, phase 3 trial.

Lancet Haematol 2021 Sep;8(9):e648-e657

Department of Medicine III, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany; Institute of Medical Information Processing, Biometry and Epidemiology, Ludwig Maximilian University of Munich, Munich, Germany.

Background: Autologous haematopoietic stem-cell transplantation (HSCT) in first remission is the current standard treatment in fit patients with mantle cell lymphoma. In this long-term follow-up study, we aimed to evaluate the efficacy of autologous HSCT versus interferon alfa maintenance after chemotherapy without or with rituximab in patients with primary advanced-stage mantle cell lymphoma.

Methods: We did a post-hoc, long-term analysis of an open-label, multicentre, randomised, phase 3 trial done in 121 participating hospitals or practices across six European countries. Patients who were aged 18-65 years with previously untreated stage III-IV mantle cell lymphoma and an ECOG performance score of 0-2 were eligible for participation. Patients were randomly assigned (1:1) to receive either myeloablative radiochemotherapy (fractionated total body irradiation with 12 Gy/day 6-4 days before autologous HSCT and cyclophosphamide 60 mg/kg per day intravenously 3-2 days before autologous HSCT) followed by autologous HSCT (the autologous HSCT group) or interferon alfa maintenance (the interferon alfa maintenance group; 6 × 10 IU three times a week subcutaneously until progression) after completion of CHOP-like induction therapy (cyclophosphamide 750 mg/m intravenously on day 1, doxorubicin 50 mg/m intravenously on day 1, vincristine 1·4 mg/m [maximum 2 mg] intravenously on day 1, and prednisone 100 mg/m orally on days 1-5; repeated every 21 days for up to 6 cycles) without or with rituximab (375 mg/m intravenously on day 0 or 1 of each cycle; R-CHOP). The primary outcome was progression-free survival from end of induction until progression or death among patients who had a remission and the secondary outcome was overall survival from the end of induction until death from any cause. We did comparisons of progression-free survival and overall survival according to the intention-to-treat principle between both groups among responding patients and explored efficacy in subgroups according to induction treatment without or with rituximab. Hazard ratios (HRs) were adjusted for the mantle cell lymphoma international prognostic index (MIPI) numerical score, and in the total group also for rituximab use (adjusted HR [aHR]). This trial was started before preregistration was implemented and is therefore not registered, recruitment is closed, and this is the final evaluation.

Findings: Between Sept 30, 1996, and July 1, 2004, 269 patients were randomly assigned to receive either autologous HSCT or interferon alfa maintenance therapy. The median follow-up was 14 years (IQR 10-16), with the intention-to-treat population consisting of 174 patients (93 [53%] in the autologous HSCT group and 81 [47%] in the interferon alfa maintenance group) who responded to induction therapy. The median age was 55 years (IQR 47-60), and R-CHOP was used in 68 (39%) of 174 patients. The median progression-free survival was 3·3 years (95% CI 2·5-4·3) in the autologous HSCT group versus 1·5 years (1·2-2·0) in the interferon alfa maintenance group (log-rank p<0·0001; aHR 0·50 [95% CI 0·36-0·69]). The median overall survival was 7·5 years (95% CI 5·7-12·0) in the autologous HSCT group versus 4·8 years (4·0-6·6) in the interferon alfa maintenance group (log-rank p=0·019; aHR 0·66 [95% CI 0·46-0·95]). For patients treated without rituximab, the progression-free survival adjusted HR for autologous HSCT versus interferon alfa was 0·40 (0·26-0·61), in comparison to 0·72 (0·42-1·24) for patients treated with rituximab. For overall survival, the adjusted hazard ratio for HSCT versus interferon alfa was 0·52 (0·33-0·82) without rituximab and 1·05 (0·55-1·99) for patients who received rituximab.

Interpretation: Our results confirm the long-term efficacy of autologous HSCT to treat mantle cell lymphoma established in the pre-rituximab era. The suggested reduced efficacy after immunochemotherapy supports the need for its re-evaluation now that antibody maintenance, high-dose cytarabine, and targeted treatments have changed the standard of care for patients with mantle cell lymphoma.

Funding: Deutsche Krebshilfe, the European Community, and the Bundesministerium für Bildung und Forschung, Kompetenznetz Maligne Lymphome.
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http://dx.doi.org/10.1016/S2352-3026(21)00195-2DOI Listing
September 2021

ASTCT, CIBMTR, and EBMT clinical practice recommendations for transplant and cellular therapies in mantle cell lymphoma.

Bone Marrow Transplant 2021 Dec 20;56(12):2911-2921. Epub 2021 Aug 20.

Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.

Autologous (auto-) or allogeneic (allo-) hematopoietic cell transplantation (HCT) are accepted treatment modalities for mantle cell lymphoma (MCL). Recently, chimeric antigen receptor (CAR) T-cell therapy received approval for MCL; however, its exact place and sequence in relation to HCT is unclear. The ASTCT, CIBMTR, and the EBMT, jointly convened an expert panel to formulate consensus recommendations for role, timing, and sequencing of auto-, allo-HCT, and CAR T-cell therapy for patients with newly diagnosed and relapsed/refractory (R/R) MCL. The RAND-modified Delphi method was used to generate consensus statements. Seventeen consensus statements were generated; in the first-line setting auto-HCT consolidation represents standard-of-care in eligible patients, whereas there is no clear role of allo-HCT or CAR T-cell therapy, outside of a clinical trial. In the R/R setting, the preferential option is CAR T-cell therapy especially in MCL failing or intolerant to at least one Bruton's tyrosine kinase inhibitor, while allo-HCT is recommended if CAR T-cell therapy has failed or is not feasible. In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a formal framework for developing consensus recommendations for the timing and sequence of cellular therapies for MCL.
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http://dx.doi.org/10.1038/s41409-021-01288-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8639670PMC
December 2021

Feasibility of Combining the Phosphatidylinositol 3-Kinase Inhibitor Copanlisib With Rituximab-Based Immunochemotherapy in Patients With Relapsed Indolent B-cell Lymphoma.

Clin Lymphoma Myeloma Leuk 2021 11 2;21(11):e886-e894. Epub 2021 Jul 2.

IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Istituto di Ematologia "Seràgnoli", Università di Bologna, Bologna, Italy.

Background: When treating indolent B-cell lymphoma, combining continuously administered oral phosphatidylinositol 3-kinase (PI3K) inhibitors with immunochemotherapy has been associated with toxicity. CHRONOS-4 (Phase III; NCT02626455) investigates the intravenous, intermittently administered pan-class I PI3K inhibitor copanlisib in combination with rituximab plus bendamustine (R-B) or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with relapsed indolent B-cell lymphoma. We report safety run-in results.

Patients And Methods: Patients aged ≥18 years with relapsed CD20-positive indolent B-cell lymphoma received copanlisib (45 mg, increasing to 60 mg if no dose-limiting toxicities) weekly on an intermittent schedule with R-B or R-CHOP. Primary objective was to identify a recommended Phase III dose (RP3D). We also assessed objective response, safety, and tolerability.

Results: Ten patients received copanlisib plus R-B and 11 received copanlisib plus R-CHOP. No dose-limiting toxicities were reported; RP3D was 60 mg. All patients had ≥1 treatment-emergent adverse event (TEAE), most commonly (all grade/grade 3/4) for copanlisib plus R-B: decreased neutrophil count (80%/50%), nausea (70%/0%), decreased platelet count (60%/10%), hyperglycemia (60%/50%); for copanlisib plus R-CHOP: hyperglycemia (82%/64%), hypertension (73%/64%), decreased neutrophil count (64%/64%). Two and 8 patients had serious TEAEs with copanlisib plus R-B and R-CHOP, respectively. Among evaluable patients, objective response rates were 90% (5 complete, 4 partial) and 100% (3 complete, 7 partial) with copanlisib plus R-B and R-CHOP, respectively.

Conclusion: Copanlisib is the first PI3K inhibitor to demonstrate safe, tolerable, and effective combinability with immunochemotherapy in patients with relapsed indolent B-cell lymphoma at full dose (60 mg). Further evaluation is ongoing.
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http://dx.doi.org/10.1016/j.clml.2021.06.021DOI Listing
November 2021

COVID-19 in Patients Receiving CD20-depleting Immunochemotherapy for B-cell Lymphoma.

Hemasphere 2021 Jul 28;5(7):e603. Epub 2021 Jun 28.

Technical University of Munich, School of Medicine, University Hospital Rechts der Isar, Department of Internal Medicine II, Munich, Germany.

The clinical and immunological impact of B-cell depletion in the context of coronavirus disease 2019 (COVID-19) is unclear. We conducted a prospectively planned analysis of COVID-19 in patients who received B-cell depleting anti-CD20 antibodies and chemotherapy for B-cell lymphomas. The control cohort consisted of age- and sex-matched patients without lymphoma who were hospitalized because of COVID-19. We performed detailed clinical analyses, in-depth cellular and molecular immune profiling, and comprehensive virological studies in 12 patients with available biospecimens. B-cell depleted lymphoma patients had more severe and protracted clinical course (median hospitalization 88 versus 17 d). All patients actively receiving immunochemotherapy (n = 5) required ICU support including long-term mechanical ventilation. Neutrophil recovery following granulocyte colony stimulating factor stimulation coincided with hyperinflammation and clinical deterioration in 4 of the 5 patients. Immune cell profiling and gene expression analysis of peripheral blood mononuclear cells revealed early activation of monocytes/macrophages, neutrophils, and the complement system in B-cell depleted lymphoma patients, with subsequent exacerbation of the inflammatory response and dysfunctional interferon signaling at the time of clinical deterioration of COVID-19. Longitudinal immune cell profiling and functional in vitro assays showed SARS-CoV-2-specific CD8 and CD4 T-effector cell responses. Finally, we observed long-term detection of SARS-CoV-2 in respiratory specimens (median 84 versus 12 d) and an inability to mount lasting SARS-CoV-2 antibody responses in B-cell depleted lymphoma patients. In summary, we identified clinically relevant particularities of COVID-19 in lymphoma patients receiving B-cell depleting immunochemotherapies.
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http://dx.doi.org/10.1097/HS9.0000000000000603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240782PMC
July 2021

Long-term outcomes from the Phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma.

Haematologica 2021 09 1;106(9):2417-2426. Epub 2021 Sep 1.

Hématologie, Hospices Civils de Lyon and Université de Lyon, Lyon, France.

Tafasitamab (MOR208), an Fc-modified, humanized, anti-CD19 monoclonal antibody, combined with the immunomodulatory drug lenalidomide was clinically active with a good tolerability profile in the open-label, single-arm, phase II L-MIND study of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem-cell transplantation. To assess long-term outcomes, we report an updated analysis with ≥35 months' follow-up. Patients were aged >18 years, had received one to three prior systemic therapies (including ≥1 CD20-targeting regimen) and Eastern Cooperative Oncology Group performance status 0-2. Patients received 28-day cycles of tafasitamab (12 mg/kg intravenously), once weekly during cycles 1-3, then every 2 weeks during cycles 4-12. Lenalidomide (25 mg orally) was administered on days 1-21 of cycles 1-12. After cycle 12, progression-free patients received tafasitamab every 2 weeks until disease progression. The primary endpoint was best objective response rate. After ≥35 months' follow-up (data cut-off: October 30, 2020), the objective response rate was 57.5% (n=46/80), including a complete response in 40.0% of patients (n=32/80) and a partial response in 17.5% of patients (n=14/80). The median duration of response was 43.9 months (95% confidence interval [95% CI]: 26.1-not reached), the median overall survival was 33.5 months (95% CI: 18.3-not reached) and the median progression-free survival was 11.6 months (95% CI: 6.3-45.7). There were no unexpected toxicities. Subgroup analyses revealed consistent long-term efficacy results across most subgroups of patients. This extended follow-up of L-MIND confirms the long duration of response, meaningful overall survival, and well-defined safety profile of tafasitamab plus lenalidomide followed by tafasitamab monotherapy in patients with relapsed/refractory diffuse large B-cell lymphoma ineligible for autologous stem cell transplantation. ClinicalTrials.gov identifier: NCT02399085.
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http://dx.doi.org/10.3324/haematol.2020.275958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409029PMC
September 2021

Rituximab Maintenance Versus Observation After Immunochemotherapy (R-CHOP, R-MCP, and R-FCM) in Untreated Follicular Lymphoma Patients: A Randomized Trial of the Ostdeutsche Studiengruppe Hämatologie und Onkologie and the German Low-Grade Lymphoma Study Group.

Hemasphere 2021 Jul 23;5(7):e600. Epub 2021 Jun 23.

Helios Klinikum Erfurt, Germany.

The German study groups, the German Low-Grade Lymphoma Study Group (GLSG) and Ostdeutsche Studiengruppe Hämatologie und Onkologie (OSHO), initiated in 2007 a double randomized trial to investigate efficacy and safety of rituximab maintenance versus observation in remission after randomly assigned induction treatment in the first-line follicular lymphoma. Previously untreated patients with stage II-IV follicular lymphoma in need of therapy were randomized to receive 6 cycles of R-CHOP, R-MCP, or R-FCM. Responding patients were subsequently randomized to 2 years rituximab maintenance or observation, stratified by type of immunochemotherapy, quality of remission, and Follicular Lymphoma International Prognostic Index (FLIPI). Recruitment was stopped in 2011 after the PRIMA results had been published. Median age of the 206 recruited patients was 66 years (range, 24-86), and (FLIPI) was low in 13%, intermediate in 28%, and high in 60%. High and comparable overall response rates were observed after R-CHOP (88%), R-MCP (89%), and R-FCM (91%). Rituximab maintenance substantially prolonged progression-free survival (PFS) in comparison to observation in remission (hazard ratio 0.39, = 0.0064). In the rituximab maintenance group, the 3-year PFS was 89% compared with 69% in the observation group. No differences in overall survival were observed for maintenance vs. observation (hazard ratio 1.04, 95% confidence interval 0.32-3.43, = 0.95). In this randomized trial, 2 years of rituximab maintenance was associated with significantly prolonged PFS in comparison to observation after response to first-line immunochemotherapy in follicular lymphoma. Our data represent an independent confirmation of the PRIMA trial results. (Clinical Trial EudraCT Number: 2005-005473-29, 2006-09-26).
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http://dx.doi.org/10.1097/HS9.0000000000000600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221804PMC
July 2021

CAR-HEMATOTOX: a model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma.

Blood 2021 12;138(24):2499-2513

Department of Medicine III, University Hospital, Ludwig Maximilian University (LMU) Munich, Munich, Germany.

Hematotoxicity represents a frequent chimeric antigen receptor (CAR) T-cell-related adverse event and remains poorly understood. In this multicenter analysis, we studied patterns of hematopoietic reconstitution and evaluated potential predictive markers in 258 patients receiving axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) for relapsed/refractory large B-cell lymphoma. We observed profound (absolute neutrophil count [ANC] <100 cells per µL) neutropenia in 72% of patients and prolonged (21 days or longer) neutropenia in 64% of patients. The median duration of severe neutropenia (ANC < 500 cells per µL) was 9 days. We aimed to identify predictive biomarkers of hematotoxicity using the duration of severe neutropenia until day +60 as the primary end point. In the training cohort (n = 58), we observed a significant correlation with baseline thrombocytopenia (r = -0.43; P = .001) and hyperferritinemia (r = 0.54; P < .0001) on univariate and multivariate analysis. Incidence and severity of cytokine-release syndrome, immune effector cell-associated neurotoxicity syndrome, and peak cytokine levels were not associated with the primary end point. We created the CAR-HEMATOTOX model, which included markers associated with hematopoietic reserve (eg, platelet count, hemoglobin, and ANC) and baseline inflammation (eg, C-reactive protein and ferritin). This model was validated in independent cohorts, one from Europe (n = 91) and one from the United States (n = 109) and discriminated patients with severe neutropenia ≥14 days to <14 days (pooled validation: area under the curve, 0.89; sensitivity, 89%; specificity, 68%). A high CAR-HEMATOTOX score resulted in a longer duration of neutropenia (12 vs 5.5 days; P < .001) and a higher incidence of severe thrombocytopenia (87% vs 34%; P < .001) and anemia (96% vs 40%; P < .001). The score implicates bone marrow reserve and inflammation prior to CAR T-cell therapy as key features associated with delayed cytopenia and will be useful for risk-adapted management of hematotoxicity.
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http://dx.doi.org/10.1182/blood.2020010543DOI Listing
December 2021

Efficacy and safety assessment of prolonged maintenance with subcutaneous rituximab in patients with relapsed or refractory indolent non-Hodgkin lymphoma: results of the Phase III MabCute study.

Haematologica 2021 Jun 17. Epub 2021 Jun 17.

Klinikum der Universität München, Munich, Germany.

Rituximab plus chemotherapy induction followed by rituximab maintenance for up to 2 years confers long-term progression-free survival (PFS) benefit in patients with indolent non-Hodgkin lymphoma. It is not known whether further prolonged maintenance with rituximab provides additional benefit. The phase III MabCute study enrolled 692 patients with relapsed or refractory indolent non-Hodgkin lymphoma. Patients who responded to induction with rituximab plus chemotherapy and were still responding after up to 2 years' initial maintenance with subcutaneous rituximab were randomized to extended maintenance with subcutaneous rituximab (n=138) or observation only (n=138). The primary endpoint of investigator-assessed PFS in the randomized population was un-addressed by the end of study because of an insufficient number of events (129 events were needed for 80% power at 5% significance if approximately 330 patients were randomized). In total, there were 46 PFS events, 19 and 27 in the rituximab and observation arms, respectively (P=0.410 by stratified log rank test; hazard ratio 0.76 [95% confidence interval: 0.37-1.53]). Median PFS was not reached in either randomized arm. There were no new safety signals; however, adverse events were seen slightly more frequently with rituximab than with observation during extended maintenance. Maintenance for up to 2 years with rituximab after response to initial induction therefore remains the standard of care in patients with relapsed or refractory indolent non-Hodgkin lymphoma.
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http://dx.doi.org/10.3324/haematol.2020.274803DOI Listing
June 2021

Mantle cell lymphoma-Advances in molecular biology, prognostication and treatment approaches.

Hematol Oncol 2021 Jun;39 Suppl 1:31-38

Department of Medicine III, LMU Hospital, Munich, Germany.

Mantle cell lymphoma (MCL) is clinically characterized by its heterogenous behavior with courses ranging from indolent cases that do not require therapy for years to highly aggressive MCL with very limited prognosis. A better understanding of the complex biology of MCL has already led to the approval of several innovative agents, expanding the landscape of MCL therapies and improving therapeutic options especially for refractory or relapsed disease. Nevertheless, to further optimize MCL treatment, early identification of individual risk profile and risk-adapted, patient-tailored choice of therapeutic strategy needs to be prospectively incorporated in clinical patient management. This review highlights recent advances in deciphering the molecular background of MCL, the definition of prognostically relevant factors and the identification of potential druggable targets and summarizes current treatment recommendations for primary and relapsed/refractory MCL including novel targeted therapies.
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http://dx.doi.org/10.1002/hon.2860DOI Listing
June 2021

CAR T-Cells for CNS Lymphoma: Driving into New Terrain?

Cancers (Basel) 2021 May 20;13(10). Epub 2021 May 20.

Department of Neurosurgery, Division of Neuro-Oncology, Ludwig Maximilians University School of Medicine, Marchioninistrasse, 1581377 Munich, Germany.

Primary CNS lymphomas (PCNSL) represent a group of extranodal non-Hodgkin lymphomas and secondary CNS lymphomas refer to secondary involvement of the neuroaxis by systemic disease. CNS lymphomas are associated with limited prognosis even after aggressive multimodal therapy. Chimeric antigen receptor (CAR) T-cells have proven as a promising therapeutic avenue in hematological B-cell malignancies including diffuse large B-cell lymphoma, B-cell acute lymphoblastic leukemia, and mantle-cell lymphoma. CARs endow an autologous T-cell population with MHC-unrestricted effectivity against tumor target antigens such as the pan B-cell marker CD19. In PCNSL, compelling and long-lasting anti-tumor effects of such therapy have been shown in murine immunocompromised models. In clinical studies on CAR T-cells for CNS lymphoma, only limited data are available and often include both patients with PCNSL but also patients with secondary CNS lymphoma. Several clinical trials on CAR T-cell therapy for primary and secondary CNS lymphoma are currently ongoing. Extrapolated from the available preliminary data, an overall acceptable safety profile with considerable anti-tumor effects might be expected. Whether these beneficial anti-tumor effects are as long-lasting as in animal models is currently in doubt; and the immunosuppressive tumor microenvironment of the brain may be among the most pivotal factors limiting efficacy of CAR T-cell therapy in CNS lymphoma. Based on an increasing understanding of CAR T-cell interactions with the tumor cells as well as the cerebral tissue, modifications of CAR design or the combination of CAR T-cell therapy with other therapeutic approaches may aid to release the full therapeutic efficiency of CAR T-cells. CAR T-cells may therefore emerge as a novel treatment strategy in primary and secondary CNS lymphoma.
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http://dx.doi.org/10.3390/cancers13102503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161128PMC
May 2021

CXCL13 and CXCL9 CSF Levels in Central Nervous System Lymphoma-Diagnostic, Therapeutic, and Prognostic Relevance.

Front Neurol 2021 26;12:654543. Epub 2021 Mar 26.

Department of Neurology, University Hospital, Ludwig Maximilian University, Munich, Germany.

Diagnostic delay and neurologic deterioration are still a problem for the treatment of rapidly progressing CNS lymphoma (CNSL); there is an unmet need for a diagnostic test with a high diagnostic yield and limited risk, minimizing the time to the initiation of effective treatment. In this prospective monocentric study, we analyzed the utility of CXCL13 and CXCL9 as diagnostic, therapeutic and prognostic biomarkers for CNSL. Cerebrospinal fluid (CSF) from 155 consecutive patients admitted with brain lesions of various origins was collected. Levels of CXCL13 and CXCL9 were analyzed by ELISA. Additionally, CSF was analyzed during CNSL disease course (relapse, remission, progress) in 17 patients. CXCL13 and CXCL9 CSF levels were significantly increased in patients with CNSL compared to control patients with lesions of other origin. Using logistic regression and a minimal--value approach, a cut-off value of 80 pg/ml for CXCL13 shows high sensitivity (90.7%) and specificity (90.1%) for the diagnosis of active CNSL. CXCL9 at a cut-off value of 84 pg/ml is less sensitive (61.5%) and specific (87.1%). Both cytokines correlate with the clinical course and response to therapy. Our results confirm the excellent diagnostic potential of CXCL13 and introduce CXCL9 as a novel albeit less powerful marker for PCNSL.
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http://dx.doi.org/10.3389/fneur.2021.654543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032970PMC
March 2021

Mantle cell lymphoma - advances in molecular biology, prognostication and treatment approaches.

Br J Haematol 2021 10 30;195(2):162-173. Epub 2021 Mar 30.

Department of Medicine III, LMU Hospital, Munich, Germany.

Mantle cell lymphoma (MCL) is clinically characterised by its heterogenous behaviour with courses ranging from indolent cases that do not require therapy for years to highly aggressive MCL with a very limited prognosis. A better understanding of the complex biology of MCL has already led to the approval of several innovative agents, expanding the landscape of MCL therapies and improving therapeutic options especially for refractory/relapsed (R/R) disease. Nevertheless, to further optimise MCL treatment, early identification of individual risk profile and risk-adapted, patient-tailored choice of therapeutic strategy needs to be prospectively incorporated into clinical patient management. The present review highlights recent advances in deciphering the molecular background of MCL, the definition of prognostically relevant factors and the identification of potential druggable targets and summarises current treatment recommendations for primary and R/R MCL including novel targeted therapies.
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http://dx.doi.org/10.1111/bjh.17419DOI Listing
October 2021

Rituximab plus high-dose chemotherapy (MegaCHOEP) or conventional chemotherapy (CHOEP-14) in young, high-risk patients with aggressive B-cell lymphoma: 10-year follow-up of a randomised, open-label, phase 3 trial.

Lancet Haematol 2021 Apr 2;8(4):e267-e277. Epub 2021 Mar 2.

Department of Medicine A, Haematology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany. Electronic address:

Background: R-MegaCHOEP was the first phase 3 study comparing high-dose chemotherapy plus rituximab followed by autologous haematopoietic stem-cell transplantation (HSCT) with conventional chemotherapy plus rituximab in first-line therapy for patients aged 60 years or younger with high-risk aggressive B-cell lymphoma. Little is known about the long-term outcomes of these patients. We aimed to evaluate the long-term efficacy and safety of conventional chemotherapy versus high-dose chemotherapy after 10 years of follow-up in the R-MegaCHOEP trial.

Methods: In this open-label, randomised, phase 3 trial done across 61 centres in Germany, patients aged 18-60 years with newly diagnosed, high-risk (age-adjusted International Prognostic Index [IPI] 2 or 3) aggressive B-cell lymphoma were randomly assigned (1:1, using Pocock minimisation) to eight cycles of conventional chemotherapy (cyclosphosphamide, doxorubicin, vincristine, etoposide, and prednisolone) plus rituximab (R-CHOEP-14) or four cycles of high-dose chemotherapy plus rituximab followed by autologous HSCT (R-MegaCHOEP). The trial was unmasked. Patients were stratified by age-adjusted IPI factors, presence of bulky disease (tumour mass ≥7·5 cm diameter), and treatment centre. The primary endpoint was event-free survival, analysed here 10 years after randomisation. 10-year overall survival, progression-free survival, conditional survival, relapse patterns, secondary malignancies, and molecular characteristics were also analysed. All analyses were done on the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT00129090.

Findings: Between March 3, 2003, and April 7, 2009, 275 patients were randomly assigned to R-CHOEP-14 (n=136) or R-MegaCHOEP (n=139). 130 patients in the R-CHOEP-14 group and 132 patients in the R-MegaCHOEP group were included in the intention-to-treat population. After a median follow-up of 9·3 years (IQR 5·1-11·1), 10-year event-free survival was 51% (95% CI 42-61) in the R-MegaCHOEP group and 57% (47-67) in the R-CHOEP-14 group (adjusted hazard ratio [HR] 1·3 [95% CI 0·9-1·8], p=0·23). 10-year progression-free survival was 59% (50-68) in the R-MegaCHOEP group and 60% (51-70) in the R-CHOEP-14 group (adjusted HR 1·1 [0·7-1·7], p=0·64). 10-year overall survival was 66% (57-76) in the R-MegaCHOEP group and 72% (63-81) in the R-CHOEP-14 group (adjusted HR 1·3 [0·8-2·1], p=0·26). Relapse occurred in 30 (16% [95% CI 11-22]) of 190 patients who had complete remission or unconfirmed complete remission; 17 (17%) of 100 patients in the R-CHOEP-14 group and 13 (14%) of 90 patients in the R-MegaCHOEP group. Seven (23%) of 30 patients had low-grade histology at relapse and had better outcomes compared with patients who relapsed with aggressive histologies. Lymphoma affected the CNS in 18 (28%) of 64 patients with treatment failure. 22 secondary malignancies were reported in the intention-to-treat population; in 12 (9%) of 127 patients in the R-CHOEP-14 group and ten (8%) of 126 patients in the R-MegaCHOEP group.

Interpretation: Event-free survival and overall survival were similar between groups after 10 years of follow-up; outcomes were not improved in the R-MegaCHOEP group by high-dose chemotherapy and autologous HSCT. Patients who relapsed with aggressive histology showed a high incidence of CNS involvement and poor prognosis. For these patients, novel therapies are greatly warranted.

Funding: Deutsche Krebshilfe (German Cancer Aid).
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http://dx.doi.org/10.1016/S2352-3026(21)00022-3DOI Listing
April 2021

Efficacy and safety of copanlisib in patients with relapsed or refractory marginal zone lymphoma.

Blood Adv 2021 02;5(3):823-828

LMU Hospital, Department of Medicine III, Munich, Germany.

Marginal zone lymphoma (MZL) is challenging to treat, with many patients relapsing following initial treatment. We report the long-term efficacy and safety of copanlisib, a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, in the subset of 23 patients with relapsed/refractory MZL treated in the phase 2 CHRONOS-1 study (#NCT01660451, Part B; www.clinicaltrials.gov). Patients had a median of 3 prior lines of therapy, including rituximab and alkylating agents, and received IV copanlisib 60 mg on days 1, 8, and 15 of 28-day cycles for a median of 23 weeks. The objective response rate was 78.3% (18/23; 3 complete responses and 15 partial responses). The median duration of response was 17.4 months (median follow-up, 9.4 months), and median time to response was 2.1 months. Median progression-free survival was 24.1 months (median follow-up, 10.3 months), and median overall survival was not reached (median follow-up, 28.4 months). The most common all-grade treatment-emergent adverse events (TEAEs) included fatigue (52.2%, 12/23), diarrhea, and transient, infusion-related hyperglycemia (each 47.8%, 11/23). Nineteen patients (82.6%) had grade 3/4 TEAEs, most commonly transient, infusion-related hyperglycemia and hypertension (each 39.1%, 9/23). TEAEs led to dose reduction or dose interruptions /delays in 9 patients (39.1%) and 18 patients (78.3%), respectively. Patients with activated PI3K/B-cell antigen receptor signaling had improved response rates. Overall, copanlisib demonstrated strong efficacy, with a short time to objective response, improved objective response rate with longer treatment duration, durable responses, and manageable safety, in line with previous reports. These data provide rationale for long-term treatment with copanlisib in patients with relapsed/refractory MZL.
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http://dx.doi.org/10.1182/bloodadvances.2020002910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876879PMC
February 2021

LRPAP1 autoantibodies in mantle cell lymphoma are associated with superior outcome.

Blood 2021 06;137(23):3251-3258

Department of Medicine III, LMU Hospital, Munich, Germany.

Low-density lipoprotein (LDL) receptor-related protein-associated protein 1 (LRPAP1) had been identified by B-cell receptor (BCR) expression cloning and subsequent protein array screening as a frequent and proliferation-inducing autoantigen of mantle cell lymphoma (MCL). Of interest, high-titered and light chain-restricted LRPAP1 autoantibodies were detected in 8 of 28 patients with MCL. In the present study, LRPAP1 autoantibodies in sera of patients treated within the Younger and Elderly trials of the European MCL Network were analyzed regarding frequency, association with disease characteristics, and prognostic impact. LRPAP1 autoantibodies were detected in 41 (13%) of 312 evaluable patients with MCL. These LRPAP1 autoantibodies belonged predominantly to the immunoglobulin G (IgG) class and were clonally light chain restricted (27 with κ light chains, 14 patients with λ light chains). Titers ranged between 1:400 and 1:3200. The presence of LRPAP1 autoantibodies was not significantly associated with any baseline clinical characteristic, however, it was associated with a superior 5-year probability for failure-free survival (FFS) of 70% (95% confidence interval [CI], 57% to 87%) vs 51% (95% CI, 44% to 58%), P = .0052; and for overall survival (OS) of 93% (95% CI, 85% to 100%) vs 68% (95% CI, 62% to 74%), P = .0142. LRPAP1-seropositive patients had a Mantle Cell Lymphoma International Prognostic Index-adjusted hazard ratio for FFS of 0.48 (95% CI 0.27-0.83, P = .0083) and for OS of 0.47 (95% CI 0.24-0.94, P = .032). LRPAP1 autoantibodies were frequently detected in a large cohort of MCL patients treated within prospective multicenter clinical trials. Our results suggest better outcomes for LRPAP1-autoantibody seropositive patients.
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http://dx.doi.org/10.1182/blood.2020008835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351899PMC
June 2021

A randomized phase 3 trial of autologous vs allogeneic transplantation as part of first-line therapy in poor-risk peripheral T-NHL.

Blood 2021 05;137(19):2646-2656

Service d'Hematologie Clinique, Centre Hospitalier Universitaire, Hôpital Robert Debre, Reims, France.

First-line therapy for younger patients with peripheral T-cell non-Hodgkin lymphoma (T-NHL) consists of 6 courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with or without etoposide (CHOEP), consolidated by high-dose therapy and autologous stem cell transplantation (auto-SCT). We hypothesized that allogeneic stem cell transplantation (allo-SCT) could improve outcomes. 104 patients with peripheral T-cell non-Hodgkin lymphoma, except ALK+ anaplastic large cell lymphoma, 18 to 60 years, all stages, and all age adjusted International Prognostic Index scores, except 0 and stage I, were randomized to 4 cycles of CHOEP and 1 cycle of dexamethasone, cytosine-arabinoside, and platinum (DHAP) followed by high-dose therapy and auto-SCT or myeloablative conditioning and allo-SCT. The primary end point was event-free survival (EFS) at 3 years. After a median follow-up of 42 months, the 3-year EFS after allo-SCT was 43%, as compared with 38% after auto-SCT. Overall survival at 3 years was 57% vs 70% after allo- or auto-SCT, without significant differences between treatment arms. None of the 21 responding patients proceeding to allo-SCT relapsed, as opposed to 13 of 36 patients (36%) proceeding to auto-SCT. Eight of 26 patients (31%) and none of 41 patients died of transplant-related toxicity after allo- and auto-SCT, respectively. The strong graft-versus-lymphoma effect after allo-SCT was counterbalanced by transplant-related mortality. This trial is registered at www.clinicaltrials.gov as #NCT00984412.
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http://dx.doi.org/10.1182/blood.2020008825DOI Listing
May 2021

Severe Candida glabrata pancolitis and fatal Aspergillus fumigatus pulmonary infection in the setting of bone marrow aplasia after CD19-directed CAR T-cell therapy - a case report.

BMC Infect Dis 2021 Jan 28;21(1):121. Epub 2021 Jan 28.

Department of Hematology and Oncology, University Hospital, LMU Munich, Munich, Germany.

Background: Prolonged myelosuppression following CD19-directed CAR T-cell transfusion represents an important, yet underreported, adverse event. The resulting neutropenia and multifactorial immunosuppression can facilitate severe infectious complications.

Case Presentation: We describe the clinical course of a 59-year-old patient with relapsed/refractory DLBCL who received Axicabtagene-Ciloleucel (Axi-cel). The patient developed ASTCT grade I CRS and grade IV ICANS, necessitating admission to the neurological ICU and prolonged application of high-dose corticosteroids and other immunosuppressive agents. Importantly, neutropenia was profound (ANC < 100/μl), G-CSF-refractory, and prolonged, lasting more than 50 days. The patient developed severe septic shock 3 weeks after CAR transfusion while receiving anti-fungal prophylaxis with micafungin. His clinical status stabilized with broad anti-infective treatment and intensive supportive measures. An autologous stem cell backup was employed on day 46 to support hematopoietic recovery. Although the counts of the patient eventually started to recover, he developed an invasive pulmonary aspergillosis, which ultimately lead to respiratory failure and death. Postmortem examination revealed signs of Candida glabrata pancolitis.

Conclusions: This case highlights the increased risk for fatal infectious complications in patients who present with profound and prolonged cytopenia after CAR T-cell therapy. We describe a rare case of C. glabrata pancolitis associated with multifactorial immunosuppression. Although our patient succumbed to a fatal fungal infection, autologous stem cell boost was able to spur hematopoiesis and may represent an important therapeutic strategy for DLBCL patients with CAR T-cell associated bone marrow aplasia who have underwent prior stem cell harvest.
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http://dx.doi.org/10.1186/s12879-020-05755-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841988PMC
January 2021

The M factor: maintenance in mantle cell lymphoma.

Authors:
Martin Dreyling

Lancet Haematol 2021 01 22;8(1):e3-e4. Epub 2020 Dec 22.

LMU Hospital, Munich 80539, Germany. Electronic address:

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http://dx.doi.org/10.1016/S2352-3026(20)30396-3DOI Listing
January 2021
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