Showing papers by "Lorenz Trümper published in 2021"

Alemtuzumab plus CHOP versus CHOP in elderly patients with peripheral T-cell lymphoma: the DSHNHL2006-1B/ACT-2 trial.

Abstract: PTCL patients exhibit poor survival with existing treatments. We investigated the efficacy of CHOP combined with alemtuzumab in 116 PTCL patients age 61–80 in an open-label, randomized phase 3 trial. Alemtuzumab was given on day 1, to a total of 360 mg in 21 patients, or 120 mg in 37. Hematotoxicity was increased with A-CHOP resulting in more grade ≥3 infections (40% versus 21%) and 4 versus 1 death due to infections, respectively. CR/CRu rate was 60% for A-CHOP and 43% for CHOP, and OR rate was 72% and 66%, respectively. Three-year-EFS, PFS and OS were 27% [15%–39%], 28% [15%–40%], and 37% ([23%–50%] for A-CHOP, and 24% [12%–35%], 29% [17%–41%], and 56% [44%–69%] for CHOP, respectively, showing no significant differences. Multivariate analyses, adjusted for strata and sex confirmed these results (hazard ratio HREFS: 0.7 ([95% CI: 0.5–1.1]; p = 0.094), HRPFS: 0.8 ([95% CI: 0.5–1.2]; p = 0.271), HROS: 1.4 ([95% CI: 0.9–2.4]; p = 0.154). The IPI score was validated, and male sex (HREFS 2.5) and bulky disease (HREFS 2.2) were significant risk factors for EFS, PFS, and OS. Alemtuzumab added to CHOP increased response rates, but did not improve survival due to treatment-related toxicity.

Mutational mechanisms shaping the coding and noncoding genome of germinal center derived B-cell lymphomas

Abstract: B cells have the unique property to somatically alter their immunoglobulin (IG) genes by V(D)J recombination, somatic hypermutation (SHM) and class-switch recombination (CSR). Aberrant targeting of these mechanisms is implicated in lymphomagenesis, but the mutational processes are poorly understood. By performing whole genome and transcriptome sequencing of 181 germinal center derived B-cell lymphomas (gcBCL) we identified distinct mutational signatures linked to SHM and CSR. We show that not only SHM, but presumably also CSR causes off-target mutations in non-IG genes. Kataegis clusters with high mutational density mainly affected early replicating regions and were enriched for SHM- and CSR-mediated off-target mutations. Moreover, they often co-occurred in loci physically interacting in the nucleus, suggesting that mutation hotspots promote increased mutation targeting of spatially co-localized loci (termed hypermutation by proxy). Only around 1% of somatic small variants were in protein coding sequences, but in about half of the driver genes, a contribution of B-cell specific mutational processes to their mutations was found. The B-cell-specific mutational processes contribute to both lymphoma initiation and intratumoral heterogeneity. Overall, we demonstrate that mutational processes involved in the development of gcBCL are more complex than previously appreciated, and that B cell-specific mutational processes contribute via diverse mechanisms to lymphomagenesis.

The "Burkitt-like" immunophenotype and genotype is rarely encountered in diffuse large B cell lymphoma and high-grade B cell lymphoma, NOS.

Abstract: Burkitt lymphoma (BL) is a B cell lymphoma composed of monomorphic medium-sized blastic cells with basophilic cytoplasm and a high proliferation index. BL has a characteristic immunophenotype of CD10 and BCL6 positive and BCL2 negative and harbours MYC gene rearrangements (MYCR) in >90% of the cases. Owing to its highly aggressive nature, intensified chemotherapy regimens are usually administered, requiring an exact diagnosis. Since the diagnosis usually warrants an integration of morphologic, immunophenotypic and genetic findings and because there is a morphologic overlap with the new WHO category of high-grade B cell lymphoma, not otherwise specified (HGBL, NOS) and some cases of diffuse large B cell lymphoma (DLBCL), we wanted to test the distinctiveness of the CD10+, BCL6+, BCL2- and MYCR positive immunopheno-genotype in a large cohort of >1000 DLBCL and HGBL. Only 9/982 DLBCL classified by an expert panel of haematopathologists (0.9%) displayed a single MYCR and were CD10+, BCL6+ and BCL2-. In a similar fashion, only one out of 32 HGBL, NOS (3%) displayed the "Burkitt-like" genetic/immunophenotypic constitution. The samples of non-BL showing the BL-typic immunopheno-genotype, interestingly, harboured higher copy number variations (CNV) by OncoScan analysis (mean 7.3 CNVs/sample; range: 2-13 vs. 2.4; range 0-6) and were also distinct from pleomorphic BL cases regarding their mutational spectrum by NGS analysis. This implies that the characteristic immunophenotype of BL, in concert with a single MYCR, is uncommon in these aggressive lymphomas, and that this constellation favours BL.

Safety and efficacy of durvalumab with R-CHOP or R2-CHOP in untreated, high-risk DLBCL: a phase 2, open-label trial

Abstract: Patients with high-risk diffuse large B-cell lymphoma (DLBCL) have poor outcomes following first-line cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R-CHOP). Evidence shows chemotherapy and immune checkpoint blockade can increase antitumor efficacy. This study investigated durvalumab, a programmed death-ligand 1 inhibitor, combined with R-CHOP or lenalidomide + R-CHOP (R2-CHOP) in newly diagnosed high-risk DLBCL. Patients received durvalumab 1125 mg every 21 days for 2–8 cycles + R-CHOP (non-activated B-cell [ABC] subtype) or R2-CHOP (ABC), then durvalumab consolidation (1500 mg every 28 days). Of 46 patients, 43 received R-CHOP and three R2-CHOP. All patients had the high-risk disease; 14 (30.4%) and eight (17.4%) had double- or triple-hit DLBCL, respectively. Following induction, 20/37 (54.1%) patients receiving durvalumab + R-CHOP achieved complete response (CR), and seven (18.9%) partial response (PR); 25 (67.6% [95% CI 50.2–82.0]) continued to consolidation and were progression-free at 12 months. Among efficacy-evaluable patients with double- or triple-hit DLBCL (n = 12), five achieved CR and five PR. Adverse events were generally consistent with R-CHOP. Correlative analyses did not identify conclusive biomarkers of response. Durvalumab + R-CHOP is feasible in DLBCL with no new safety signals, but the combination provided no greater benefit than R-CHOP.

Age-dependent increase of treatment-related mortality in older patients with aggressive B cell lymphoma: analysis of outcome, treatment feasibility, and toxicity in 1171 elderly patients with aggressive B cell lymphoma-data from phase II and III trials of the DSHNHL (German High-Grade Non-Hodgkin's Lymphoma Study Group).

Abstract: In elderly patients (pts) with aggressive B cell lymphoma (aNHL), curative treatment often cannot be administered because of comorbidities and tolerability. We analyzed the influence of age in pts > 60 years receiving the R-CHOP-14 regimen within different prospective DSHNHL trials. Of the RICOVER-60 trial and CHOP-R-ESC trials, 1171 aNHL pts were included in this retrospective analysis of age-dependent event-free survival (EFS), progression-free survival (PFS), and overall survival (OS). All patients received prophylactic G-CSF, and anti-infective prophylaxis with amphotericin B mouth wash and oral fluorchinolone was optional. In the CHOP-R-ESC trials, prophylaxis was augmented to include mandatory continuous orally administered aciclovir and a pneumocystis prophylaxis with cotrimoxazole as well as oral fluorchinolones during neutropenia. The patient population was separated into 4 age groups (61-65 years, 66-70 years, 71-75 years, and 76-80 years). The results from the RICOVER-60 trial were subsequently confirmed in the following CHOP-R-ESC trials by a multivariate analysis adjusted for IPI factors and gender. Significant differences (p < 0.001) in EFS, PFS, and OS were seen between age groups (RICOVER-60). Hematotoxicity, infections, and TRM increased with age. TRM was significantly elevated in the age group 76-80 years. Therefore, this analysis shows that an age above 75 years defines an especially vulnerable patient population when being treated with chemoimmunotherapy for aNHL. Prophylactic anti-infective drugs are essential and clinically effective in reducing morbidity when treating elderly aNHL pts.

Diagnostic, clinical and post-sars-cov-2 scenarios in cancer patients with sars-cov-2: Retrospective analysis in three german cancer centers

Abstract: Oncologists face challenges in the management of SARS-CoV-2 infections and post-SARS-CoV-2 cancer treatment. We analyzed diagnostic, clinical and post-SARS-CoV-2 scenarios in patients from three German cancer centers with RT-PCR confirmed SARS-CoV-2 infection. Sixty-three patients with SARS-CoV-2 and hematologic or solid neoplasms were included. Thirty patients were initially asymptomatic, 10 of whom developed COVID-19 symptoms subsequently. Altogether 20 (32%) patients were asymptomatic, 18 (29%) had mild, 12 (19%) severe and 13 (20%) critical courses. Lymphocytopenia increased risk of severe/critical COVID-19 three-fold (p = 0.015). Asymptomatic course was not associated with age, remission status, therapies or co-morbidities. Secondary bacterial infection accompanied more than one third of critical COVID-19 cases. Treatment was delayed post-SARS-CoV-2 in 46 patients, 9 of whom developed progressive disease (PD). Cancer therapy was modified in 8 SARS-CoV-2 survivors because of deteriorating performance or PD. At the last follow-up, 17 patients had died from COVID-19 (n = 8) or PD (n = 9) giving an estimated 73% four-month overall survival rate. SARS-CoV-2 infection has a heterogenous course in cancer patients. Lymphocytopenia carries a significant risk of severe/critical COVID-19. SARS-CoV-2 disruption of therapy is as serious as SARS-CoV-2 infection itself. Careful surveillance will allow early restart of the anti-cancer treatment.

Treatment response to idelalisib in a patient with immunodeficiency-associated Burkitt lymphoma harboring a PIK3CA H1047R mutation.

Abstract: Dear Editor, While in Burkitt lymphoma (BL) immunochemotherapy readily induces remissions, the clinical outcomes for patients with refractory or recurrent disease are still adverse [1, 2]. The phosphatidylinositol-3 kinase (PI3K) signal transduction pathway is involved in the activation, proliferation, and migration of B lymphocytes, and a cooperation of MYC and PI3K has been described in BL oncogenesis. Idelalisib is a highly selective inhibitor of the PI3K delta isoform [3] with significant clinical activity against indolent B cell lymphomas [4, 5]. We here report the successful salvage therapy with idelalisib in a patient with relapsed immunodeficiency-associated BL exhibiting a TP53 mutation and a H1047R mutation in the PIK3CA gene. The initial diagnosis of stage IIIB BL disease and concurrent HIV-1 positivity was made in a 65-year-old male patient with multifocal lymphadenopathy and B-symptoms. The patient was started on immediate anti-viral therapy.At initial presentation, the patient appeared ineligible for multiphase leukemia-based regimens due to comorbidities (ischemic heart disease, impaired renal function), so that he received one course of R-CHOP, and upon adequate tolerance and response, further seven courses of R-CHOEP-21, inducing a complete remission. Ten months from initial diagnosis, relapse manifested as an isolated cutaneous manifestation (3 × 5 cm) in the upper thigh. Two courses of platine/Ara-C-based chemotherapy (R-DHAP) induced partial remission, consolidated by involved site radiotherapy. Fifteen months after initial diagnosis the disease recurred again, at this time refractory to methotrexate/Ara-C-based chemotherapy (dexamethasone 20 mg p.o., etoposide 60 mg/m d4 + 5 i.v., cytarabine 60 mg/m d4 + 5 i.v.; ifosfamide 400 mg/m d1–5 i.v.; methotrexate 500 mg/m i.v., methotrexate 12 mg i.th. d3). Additional radiotherapy and vinblastine every other week was started in palliative intention. Responding to the patient’s wish for further treatment, off-label idelalisib was initiated (150 mg bid) inducing shrinkage of the tumor (Fig. 1a, b) and decline of plasma LDH (Fig. 1c). Idelalisib was continued without infectious complications or adverse reactions for 10 months, until the tumor recurred and the patient succumbed to progressive disease. Analysis of the initial lymphoma by high-throughput sequencing (HTS) detected a TP53 mutation (T175H, VAF 83.5%), compatible with coincident structural loss of the second TP53 allele and presumably representing the major unfavorable molecular factor in this case [6–8]. In addition, we identified two mutations in the catalytic alpha subunit of the PIK3CA gene, i.e., p.H1047R (variant allele frequency (VAF) 5.0%) and p.Q1033R (VAF 3.7%) affecting exon 21 on the same allele. This PIK3CA H1047R mutation affects the highly conserved catalytic subunit p110a and has previously been identified at high frequency in many types of solid tumors [9, 10]. In patients receiving PI3K/AKT/mTOR inhibitors, the presence of the PIK3CA H1047R mutation was associated with improved response rates compared with patients with wild-type PIK3CA or other PIK3CA mutations (38% vs. 10% vs. 13%) [11]. So far, PIK3CA H1047R mutations have not been described in BL cell * Annalen Bleckmann annalen.bleckmann@ukmuenster.de

TCL-150: The ECHELON-2 Trial: 5-Year Results of a Randomized, Double-Blind, Phase 3 Study of Brentuximab Vedotin and CHP (A+CHP) Versus CHOP in Frontline Treatment of Patients with CD30-Positive Peripheral T-Cell Lymphoma

Abstract: Objective Brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) significantly prolonged progression-free survival (PFS) and overall survival (OS) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with systemic anaplastic large-cell lymphoma (sALCL) or other CD30-positive peripheral T-cell lymphomas (PTCL) in ECHELON-2 (Horwitz S et al., Lancet 2019). We report updated results; median follow-up was 47.6 months for PFS and 66.8 months for OS. Design This phase 3, double-blind study (NCT01777152) randomized patients aged ≥18 years with previously untreated CD30-positive PTCL (targeting 75% ± 5% with sALCL) to A+CHP or CHOP for 6 or 8 cycles. Primary endpoint of PFS was assessed per investigator in this updated analysis. Key secondary endpoints included OS and PFS in sALCL. BV or BV-containing regimens were permitted as subsequent/retreatment therapies. Results 452 patients were enrolled (226 patients in each arm); 316 (70%) patients had sALCL. Patients with advanced disease were included (stage III [27%] and stage IV [53%]; International Prognostic Index ≥2 [78%]). Data continues to favor A+CHP: HRs were 0.70 (95% CI: 0.53–0.91, P=0.0077) for PFS per investigator and 0.72 (95% CI: 0.53–0.99, P=0.0424) for OS. 5-year PFS was 51.4% (95% CI: 42.8–59.4) with A+CHP versus 43.0% (95% CI: 35.8–50.0) with CHOP; median PFS was 62.3 months (95% CI: 42.0–not evaluable) with A+CHP and 23.8 months (95% CI: 13.6–60.8) with CHOP. 5-year OS was 70.1% (95% CI: 63.3–75.9) and 61.0% (95% CI: 54.0–67.3) with A+CHP and CHOP, respectively. Median OS was not reached in either arm. PFS favored A+CHP (HR: 0.55 [95% CI: 0.39–0.79]) in sALCL. 29 (13%) and 54 (24%) patients with A+CHP and CHOP received subsequent BV, respectively. Treatment-emergent peripheral neuropathy (PN), resolved/improved in 72% (n=84/117) and 78% (n=97/124) of patients with PN on A+CHP and CHOP, respectively; 98% and 97% of ongoing PN events were grade 1/2 with A+CHP and CHOP, respectively. Conclusions At this important 5-year milestone, A+CHP still provides clinically meaningful improvement in both PFS and OS versus CHOP, with a manageable safety profile, including continued resolution/improvement of PN. Funded by NIH/NCI Support Grant P30 CA008748.

The genomic and transcriptional landscape of primary central nervous system lymphoma

Abstract: Primary lymphomas of the central nervous system (PCNSL) are mainly diffuse large B-cell lymphomas (DLBCLs) confined to the central nervous system (CNS). Despite extensive research, the molecular alterations leading to PCNSL have not been fully elucidated. In order to provide a comprehensive description of the genomic and transcriptional landscape of PCNSL, we here performed whole-genome and transcriptome sequencing and integrative analysis of 51 lymphomas presenting in the CNS, including 42 EBV-negative PCNSL, 6 secondary CNS lymphomas (SCNSL) and 3 EBV+ CNSL and matched controls. The results were compared to an independent validation cohort of 31 FFPE CNSL specimens (PCNSL, n = 19; SCNSL, n = 9; EBV+ CNSL, n = 3) as well as 39 FL and 36 systemic DLBCL cases outside the CNS. Somatic genomic alterations in PCNSL mainly affect the JAK-STAT, NFkB, and B-cell receptor signaling pathways, with hallmark recurrent mutations including MYD88 L265P (67%) and CD79B (63%), CDKN2A deletions (83%) and also non-coding RNA genes such as MALAT1 (70%), NEAT (60%), and MIR142 (80%). Kataegis events, which affected 15 of 50 identified driver genes and 21 of the top 50 mutated ncRNAs, played a decisive role in shaping the mutational repertoire of PCNSL. Compared to systemic DLBCL, PCNSLs exhibited significantly more focal deletions in 6p21 targeting the HLA-D locus that encodes for MHC class II molecules as a potential mechanism of immune evasion. Mutational signatures correlating with DNA replication and mitosis (SBS1, ID1 and ID2) were significantly enriched in PCNSL (SBS1: p = 0.0027, ID1/ID2: p

Stem cell transplantation for hemoglobinopathy Vila Real

Abstract: Dear Editor, Hemoglobinopathy Vila Real (HbVR) is a rare congenital disease caused by a hemoglobin beta chain P36H mutation [1, 2]. The hemoglobin variant is associated with increased oxygen affinity, resulting in reduced oxygen delivery to target tissues, painful hypoxic organ damage, and compensatory erythrocytosis. Diagnosis is based on clinical presentation of erythrocytosis with high oxygen saturation and tissue hypoxia, to be confirmed by hemoglobin sequence analysis. Hitherto, therapy of symptomatic patients consists of phlebotomy plus transfusions to alleviate symptoms. We report the case of a 47-year-male diagnosed with HbVR 10 years before in the work-up of erythrocytosis. When the patient experienced progressive pain attacks in the head, testis, and muscles, phlebotomy and transfusions of cumulative 168 erythrocyte concentrates were started, without amelioration in the recent year. As yet, antibodies against red blood cells were not detected to this point of time. Bone marrow transplantation (BMT) was offered to the patient to avoid the long-term complications of transfusion dependency and disease-related end-organ damage [3]. To avoid disease-related ischemic injury and reperfusion events during transplantation, similar to symptoms of sickle cell crisis, but with different pathomechanism, complete blood exchanges were performed before the preparative regimen was started. Following conditioning with thiotepa, fludarabine, and treosulfan, bone marrow from a HLA-matched unrelated donor containing 1.5 × 10 leukocytes/kg body weight (BW) was transfused after depletion of erythrocytes and plasma. Graft-versus-host-disease prophylaxis consisted of anti-thymocyte-globulin, cyclosporin A (CSA), and mycophenolate mofetil. During aplasia, CMV reactivation and a sepsis responded to treatment. Leukocyte engraftment occurred 21 days post-BMT with complete donor chimerism. The patient remained dependent on transfusion for erythrocytes and thrombocytes. Bone marrow investigation on day 27 revealed graft failure suspected to be due to the low cell count in the transplanted product. Fifty-one days post-BMT, we transfused 4.0 × 10 CD34+ cells/kg BW purified from the mobilized peripheral blood stem cells of the original donor. From day 8 after the stem cell boost, the patient was transfusion independent and the reticulocytes rose with continuous complete donor chimerism. Further complications post-BMT resembled typical sickle cell complications: seizures and visual impairments compatible with posterior reversible encephalopathy syndrome (PRES) by NMR imaging (Fig. 1), diabetes insipidus centralis due to the PRES or CSA, and diabetes insipidus renalis due to foscarnet turned out to be manageable. Following recovery, further followup was uneventful through 2.5 years, without immunosuppression and according to hemoglobin analysis complete correction of the hemoglobinopathy. This is the first report of allogeneic hematopoietic stem cell transplantation (HSCT) for a patient with HbVR, a condition associated with severely reduced quality of life and high prevalence of end-organ complications. The curative potential of HSCT in hemoglobinopathies is well-established [3] but is hampered by the dilemma to outweigh the benefits from definite cure versus the transplant-related risks for. Particular in adult patients with advanced disease, comorbidities precipitate complications [4]. PRES is elsewise common in pediatric hemoglobinopathy patients receiving HSCT [5–7]. * Justin Hasenkamp j.hasenkamp@med.uni-goettingen.de