Entwicklung eines neuen prognostischen Index für Patienten mit fortgeschrittenem Mantelzell-Lymphom

Background: Mantle cell lymphoma (MCL) shows a particularly bad prognosis with a median survival of less than 5 years. There is no generally established prognostic classification system for patients with MCL as the International Prognostic Index (IPI) and the Follicular Lymphoma International Prognostic Index (FLIPI) have been developed based on data of patients with diffuse large B-cell and follicular lymphoma, respectively. The data of 455 patients with advanced stage MCL treated within three randomized trials of German Low-Grade Lymphoma Study Group (GLSG) and European MCL Network were used to clarify the prognostic relevance of IPI, FLIPI and potential prognostic factors and, if needed, to develop a new prognostic index. Methods: The outcome parameter was overall survival, the time from trial registration to death from any cause. Potential prognostic factors were the clinical parameters documented after primary diagnosis before start of treatment. The prognostic relevance of IPI and FLIPI was evaluated with Kaplan-Meier estimates and the log rank test. Candidate prognostic factors were analyzed using univariate Cox regression. In multiple Cox regression, independent prognostic factors were identified with backward elimination and the prognostic score was determined. Prognostic groups were defined with optimal cutpoints for the prognostic score maximizing the log rank statistic. Internal validation was performed using the bootstrap method. Results: According to the IPI more than two thirds of patients were classified into the low intermediate or high intermediate risk groups whose survival curves were not clearly separated. According to the FLIPI, 6% of patients were classified into the low risk group, survival curves of low risk and intermediate risk patients were not separated, and the high risk group of almost two thirds of patients showed a relatively good survival. Of the candidate prognostic factors, age, ECOG performance status, B-symptoms, spleen involvement, tumor size, serum LDH activity, leukocyte, lymphocyte, granulocyte and monocyte count, hemoglobin, and beta2-microglobulin showed univariate prognostic relevance. In contrast, sex, Ann Arbor stage III vs. IV, bone marrow involvement, number of extranodal sites, number of involved nodal areas, platelet count, and albumin showed no prognostic relevance. Multiple Cox regression identified age, performance status, LDH and leukocyte count as independent prognostic factors. Using these four parameters, a new prognostic index, the mantle cell lymphoma international prognostic index (MIPI) defined three prognostic groups with significantly different overall survival. Bootstrap validation confirmed the separation of the prognostic groups and indicated superiority over IPI and FLIPI. Conclusions: In this work a new prognostic index for patients with advanced stage MCL was defined based on four easily available clinical prognostic factors. The modest prognostic relevance of IPI and FLIPI underlines the inappropriateness of transferring results from one lymphoma entity to another. The results of this work may be applied in clinical research for stratified randomization, risk-adjusted analyses, and as a reference to establish new biologic or molecular prognostic factors. Furthermore, the new prognostic index may facilitate risk-adapted treatment strategies to improve the prognosis of this severe disease

Entwicklung eines neuen prognostischen Index für Patienten mit fortgeschrittenem Mantelzell-Lymphom

Background: Mantle cell lymphoma (MCL) shows a particularly bad prognosis with a median survival of less than 5 years. There is no generally established prognostic classification system for patients with MCL as the International Prognostic Index (IPI) and the Follicular Lymphoma International Prognostic Index (FLIPI) have been developed based on data of patients with diffuse large B-cell and follicular lymphoma, respectively. The data of 455 patients with advanced stage MCL treated within three randomized trials of German Low-Grade Lymphoma Study Group (GLSG) and European MCL Network were used to clarify the prognostic relevance of IPI, FLIPI and potential prognostic factors and, if needed, to develop a new prognostic index. Methods: The outcome parameter was overall survival, the time from trial registration to death from any cause. Potential prognostic factors were the clinical parameters documented after primary diagnosis before start of treatment. The prognostic relevance of IPI and FLIPI was evaluated with Kaplan-Meier estimates and the log rank test. Candidate prognostic factors were analyzed using univariate Cox regression. In multiple Cox regression, independent prognostic factors were identified with backward elimination and the prognostic score was determined. Prognostic groups were defined with optimal cutpoints for the prognostic score maximizing the log rank statistic. Internal validation was performed using the bootstrap method. Results: According to the IPI more than two thirds of patients were classified into the low intermediate or high intermediate risk groups whose survival curves were not clearly separated. According to the FLIPI, 6% of patients were classified into the low risk group, survival curves of low risk and intermediate risk patients were not separated, and the high risk group of almost two thirds of patients showed a relatively good survival. Of the candidate prognostic factors, age, ECOG performance status, B-symptoms, spleen involvement, tumor size, serum LDH activity, leukocyte, lymphocyte, granulocyte and monocyte count, hemoglobin, and beta2-microglobulin showed univariate prognostic relevance. In contrast, sex, Ann Arbor stage III vs. IV, bone marrow involvement, number of extranodal sites, number of involved nodal areas, platelet count, and albumin showed no prognostic relevance. Multiple Cox regression identified age, performance status, LDH and leukocyte count as independent prognostic factors. Using these four parameters, a new prognostic index, the mantle cell lymphoma international prognostic index (MIPI) defined three prognostic groups with significantly different overall survival. Bootstrap validation confirmed the separation of the prognostic groups and indicated superiority over IPI and FLIPI. Conclusions: In this work a new prognostic index for patients with advanced stage MCL was defined based on four easily available clinical prognostic factors. The modest prognostic relevance of IPI and FLIPI underlines the inappropriateness of transferring results from one lymphoma entity to another. The results of this work may be applied in clinical research for stratified randomization, risk-adjusted analyses, and as a reference to establish new biologic or molecular prognostic factors. Furthermore, the new prognostic index may facilitate risk-adapted treatment strategies to improve the prognosis of this severe disease

Immunochemotherapy and Maintenance With Obinutuzumab or Rituximab in Patients With Previously Untreated Marginal Zone Lymphoma in the Randomized GALLIUM Trial

The aim of this study was to explore the efficacy and safety of obinutuzumab (G)- versus rituximab (R)-chemotherapy in a subgroup of patients with previously untreated marginal zone lymphoma (MZL) in the phase III GALLIUM trial (NCT01332968). Patients had stage III/IV (or stage II with bulky disease), splenic, nodal, or extranodal MZL requiring treatment. Patients were randomized 1:1 to receive G- or R-chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone; cyclophosphamide, vincristine, and prednisone; or bendamustine, allocated at patient level). Patients with complete/partial response at the end of induction (EOI) received G/R maintenance. Investigator-assessed progression-free survival (PFS), other time-to-event endpoints, response, and safety were assessed. Overall, 195 patients with MZL were included in this analysis: G-chemotherapy (n = 99), R-chemotherapy (n = 96). Median observation time: 59.3 months. No meaningful difference was observed between arms for PFS (4-y PFS rates: G-chemotherapy, 72.6%; R-chemotherapy, 64.1%), other time-to-event endpoints, or EOI response rates (by computed tomography [CT; G-chemotherapy, 81.8%; R-chemotherapy, 81.3%] and positron emission tomography CT [G-chemotherapy, 79.2%; R-chemotherapy, 87.5%]). All patients experienced ≥1 adverse event (AE). G-chemotherapy was associated with a higher incidence of grade 3–5 (86.1% versus 77.4%), grade 5 (14.9% versus 9.7%), and serious (66.3% versus 51.6%) AEs versus R-chemotherapy. Both arms had a higher incidence of grade 3–5 and serious AEs than patients with follicular lymphoma (GALLIUM), with G-chemotherapy being less tolerable than R-chemotherapy. Based on the observed tolerability of G-chemotherapy versus R-chemotherapy, and the comparable efficacy of G-chemotherapy and R-chemotherapy in this analysis, G-chemotherapy cannot be recommended as first-line treatment for MZL

Long-term follow-up of cytogenetically normal CEBPA-mutated AML

Background: The aim of this study was to analyze the long-term survival of AML patients with CEBPA mutations. Patients and methods: We investigated 88 AML patients with a median age of 61 years and (1) cytogenetically normal AML (CN-AML), (2) monoallelic (moCEBPA) or biallelic (biCEBPA) CEBPA mutation, and (3) intensive induction treatment. 60/88 patients have been described previously with a shorter follow-up. Results: Median follow-up time was 9.8 years (95% CI: 9.4-10.1 years) compared to 3.2 and 5.2 years in our former analyses. Patients with biCEBPA mutations survived significantly longer compared to those with moCEBPA (median overall survival (OS) 9.6 years vs. 1.7 years, p = 0.008). Patients <= 60 years and biCEBPA mutations showed a favorable prognosis with a 10-year OS rate of 81%. Both, bi- and moCEBPA-mutated groups had a low early death (d60) rate of 7% and 9%, respectively. Complete remission (CR) rates for biCEBPA and moCEBPA mutated patients were 82% vs. 70% (p = 0.17). biCEBPA mutated patients showed a longer relapse free survival (RFS) (median RFS 9.4 years vs. 1.5 years, p = 0.021) and a lower cumulative incidence of relapse (CIR) compared to moCEBPA-mutated patients. These differences in OS and RFS were confirmed after adjustment for known clinical and molecular prognostic factors. Conclusions: In this long-term observation we confirmed the favorable prognostic outcome of patients with biCEBPA mutations compared to moCEBPA-mutated CN-AML. The high probability of OS (81%) in younger patients is helpful to guide intensity of postremission therapy

Mantle cell lymphomas with concomitant MYC and CCND1 breakpoints are recurrently TdT positive and frequently show high-grade pathological and genetic features

Chromosomal breakpoints involving the MYC gene locus, frequently referred to as MYC rearrangements (MYC - R+), are a diagnostic hallmark of Burkitt lymphoma and recurrent in many other subtypes of B-cell lymphomas including follicular lymphoma, diffuse large B-cell lymphoma and other high-grade B-cell lymphomas and are associated with an aggressive clinical course. In remarkable contrast, in MCL, only few MYC - R+ cases have yet been described. In the current study, we have retrospectively analysed 16 samples (MYC - R+, n = 15, MYC - R-, n = 1) from 13 patients and describe their morphological, immunophenotypic and (molecular) genetic features and clonal evolution patterns. Thirteen out of fifteen MYC - R+ samples showed a non-classical cytology including pleomorphic (centroblastic, immunoblastic), anaplastic or blastoid. MYC translocation partners were IG-loci in 4/11 and non-IG loci in 7/11 analysed cases. The involved IG-loci included IGH in 3 cases and IGL in one case. PAX5 was the non-IG partner in 2/7 patients. The MYC - R+ MCL reported herein frequently displayed characteristics associated with an aggressive clinical course including high genomic-complexity (6/7 samples), frequent deletions involving the CDKN2A locus (7/10 samples), high Ki-67 proliferation index (12/13 samples) and frequent P53 expression (13/13 samples). Of note, in 4/14 samples, SOX11 was not or only focally expressed and 3/13 samples showed focal or diffuse TdT-positivity presenting a diagnostic challenge as these features could point to a differential diagnosis of diffuse large B-cell lymphoma and/or lymphoblastic lymphoma/leukaemia

The addition of rituximab to chemotherapy improves overall survival in mantle cell lymphoma—a pooled trials analysis

Mantle cell lymphoma (MCL) is a distinct subtype of B-cell lymphoma and commonly used induction immunochemotherapies include the anti-CD20 antibody rituximab. However, efficacy data for rituximab regarding overall survival (OS) in first line MCL therapy remain conflicting. We report long-term outcomes of a pooled trials analysis comparing Cyclophosphamide, Doxorubicine, Vincristine, Prednisone (CHOP) to R-CHOP in MCL to confirm efficacy on failure free survival (FFS) and OS in relevant subgroups. Untreated, adult MCL patients of two prospective trials assigned to CHOP or R-CHOP were included. Primary endpoints were FFS and OS, secondary endpoints included duration of response (DOR), secondary malignancies and OS after relapse. Between 1996 and 2003, 385 MCL patients were assigned to CHOP (201) or R-CHOP (184). After a median follow-up of 13.4 years, the addition of Rituximab significantly improved FFS (1.36 vs. 2.07 years, HR 0.62 (0.50–0.77)), OS (4.84 vs. 5.81 years, HR 0.78 (0.61–0.99)) and DOR (1.48 vs. 2.08 years, HR 0.67 (0.53–0.86)). Furthermore, Rituximab improved survival across different MCL risk groups. In a post-hoc analysis of OS after relapse comparing patients receiving chemotherapy with / without rituximab, rituximab maintained efficacy with a median OS of 3.10 vs. 2.11 years (HR 0.70, 0.54–0.91). The rate of secondary malignancies was 0.5 and 3.9% for hematological and 7 and 8% for non-hematological malignancies for CHOP and R-CHOP patients, respectively. We present mature results of a pooled MCL cohort, demonstrating prolonged FFS, OS and DOR for the combined immuno-chemotherapy, confirming the standard of care in first line treatment

Treatment of RET-Positive Advanced Medullary Thyroid Cancer with Multi-Tyrosine Kinase Inhibitors — A Retrospective Multi-Center Registry Analysis

SIMPLE SUMMARY: Lately, a more personalized approach in the management of advanced thyroid cancer patients has improved the outcomes, and several novel molecularly guided therapies, including selective RET inhibitors (sRETis), have demonstrated promising efficacy in clinical trials. RET (rearranged during transfection) variants are the most prevalent oncogenic event in medullary thyroid cancer (MTC). We here found RET oncogene variants in 44/48 prospectively collected MTC tumor samples from patients treated with more unselective kinase inhibitors vandetanib and/or cabozantinib. Our study shows that RET variants were highly prevalent in patients with advanced MTC, and the treatment results in RET-positive cases were similar to those reported in unselected cohorts. ABSTRACT: Background: RET (rearranged during transfection) variants are the most prevalent oncogenic events in medullary thyroid cancer (MTC). In advanced disease, multi-tyrosine kinase inhibitors (MKIs) cabozantinib and vandetanib are the approved standard treatment irrespective of RET status. The actual outcome of patients with RET-positive MTC treated with MKIs is ill described. Methods: We here retrospectively determined the RET oncogene variant status with a targeted DNA Custom Panel in a prospectively collected cohort of 48 patients with advanced MTC treated with vandetanib and/or cabozantinib at four German referral centers. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan-Meier method. Results: In total, 44/48 (92%) patients had germline or somatic RET variants. The M918T variant was found in 29/44 (66%) cases. In total, 2/32 (6%) patients with a somatic RET variant had further somatic variants, while in 1/32 (3%) patient with a germline RET variant, additional variants were found. Only 1/48 (2%) patient had a pathogenic HRAS variant, and no variants were found in 3 cases. In first-line treatment, the median OS was 53 (95% CI (95% confidence interval), 32–NR (not reached); n = 36), and the median PFS was 21 months (12–39; n = 33) in RET-positive MTC patients. In second-line treatment, the median OS was 18 (13–79; n = 22), and the median PFS was 3.5 months (2–14; n = 22) in RET-positive cases. Conclusions: RET variants were highly prevalent in patients with advanced MTC. The treatment results in RET-positive cases were similar to those reported in unselected cohorts

The CAR-HEMATOTOX risk-stratifies patients for severe infections and disease progression after CD19 CAR-T in R/R LBCL

BACKGROUND: CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) represents a promising treatment modality for an increasing number of B-cell malignancies. However, prolonged cytopenias and infections substantially contribute to the toxicity burden of CAR-T. The recently developed CAR-HEMATOTOX (HT) score-composed of five pre-lymphodepletion variables (eg, absolute neutrophil count, platelet count, hemoglobin, C-reactive protein, ferritin)-enables risk stratification of hematological toxicity. METHODS: In this multicenter retrospective analysis, we characterized early infection events (days 0-90) and clinical outcomes in 248 patients receiving standard-of-care CD19 CAR-T for relapsed/refractory large B-cell lymphoma. This included a derivation cohort (cohort A, 179 patients) and a second independent validation cohort (cohort B, 69 patients). Cumulative incidence curves were calculated for all-grade, grade ≥3, and specific infection subtypes. Clinical outcomes were studied via Kaplan-Meier estimates. RESULTS: In a multivariate analysis adjusted for other baseline features, the HT score identified patients at high risk for severe infections (adjusted HR 6.4, 95% CI 3.1 to 13.1). HT(high) patients more frequently developed severe infections (40% vs 8%, p<0.0001)-particularly severe bacterial infections (27% vs 0.9%, p<0.0001). Additionally, multivariate analysis of post-CAR-T factors revealed that infection risk was increased by prolonged neutropenia (≥14 days) and corticosteroid use (≥9 days), and decreased with fluoroquinolone prophylaxis. Antibacterial prophylaxis significantly reduced the likelihood of severe bacterial infections in HT(high) (16% vs 46%, p<0.001), but not HT(low) patients (0% vs 2%, p=n.s.). Collectively, HT(high) patients experienced worse median progression-free (3.4 vs 12.6 months) and overall survival (9.1 months vs not-reached), and were hospitalized longer (median 20 vs 16 days). Severe infections represented the most common cause of non-relapse mortality after CAR-T and were associated with poor survival outcomes. A trend toward increased non-relapse mortality in HT(high) patients was observed (8.0% vs 3.7%, p=0.09). CONCLUSIONS: These data demonstrate the utility of the HT score to risk-stratify patients for infectious complications and poor survival outcomes prior to CD19 CAR-T. High-risk patients likely benefit from anti-infective prophylaxis and should be closely monitored for potential infections and relapse