A Hyper-IgM Syndrome Mutation in Activation-Induced Cytidine Deaminase Disrupts G-Quadruplex Binding and Genome-wide Chromatin Localization.

Precise targeting of activation-induced cytidine deaminase (AID) to immunoglobulin (Ig) loci promotes antibody class switch recombination (CSR) and somatic hypermutation (SHM), whereas AID targeting of non-Ig loci can generate oncogenic DNA lesions. Here, we examined the contribution of G-quadruplex (G4) nucleic acid structures to AID targeting in vivo. Mice bearing a mutation in Aicda (AIDG133V) that disrupts AID-G4 binding modeled the pathology of hyper-IgM syndrome patients with an orthologous mutation, lacked CSR and SHM, and had broad defects in genome-wide AIDG133V chromatin localization. Genome-wide analyses also revealed that wild-type AID localized to MHCII genes, and AID expression correlated with decreased MHCII expression in germinal center B cells and diffuse large B cell lymphoma. Our findings indicate a crucial role for G4 binding in AID targeting and suggest that AID activity may extend beyond Ig loci to regulate the expression of genes relevant to the physiology and pathology of activated B cells.

Hysterectomy, oophorectomy and risk of non-Hodgkin's lymphoma.

Hysterectomy is associated with an increased risk for adverse health outcomes. However, its connection to the risk of non-Hodgkin's lymphoma (NHL) remains unclear. The aims of our study were to investigate the associations between hysterectomy, oophorectomy and risk of NHL and its major subtypes (eg, diffuse large B-cell lymphoma [DLBCL]), and whether these associations were modified by exogenous hormone use. Postmenopausal women (n = 141,621) aged 50-79 years at enrollment (1993-1998) from the Women's Health Initiative were followed for an average of 17.2 years. Hysterectomy and oophorectomy were self-reported at baseline. Incident NHL cases were confirmed by central review of medical records and pathology reports. During the follow-up period, a total of 1719 women were diagnosed with NHL. Hysterectomy, regardless of oophorectomy status, was associated with an increased risk of NHL (hazard ratio [HR] = 1.23, 95% confidence interval [CI]: 1.05-1.44). Oophorectomy was not independently associated with NHL risk after adjusting for hysterectomy. When stratified by hormone use, the association between hysterectomy and NHL risk was confined to women who had never used hormone therapy (HR = 1.35, 95% CI: 1.06-1.71), especially for DLBCL subtype (P for interaction = .01), and to those who had undergone hysterectomy before the age of 55. Our large prospective study showed that hysterectomy was a risk factor of NHL. Findings varied by hormone use. Future studies incorporating detailed information on the types and indications of hysterectomy may deepen our understanding of the mechanisms underlying DLBCL development and its potential interactions with hormone use.

Development of EBV Related Diffuse Large B-cell Lymphoma in Deficiency of Adenosine Deaminase 2 with Uncontrolled EBV Infection.

Deficiency of Adenosine Deaminase 2 (DADA2) patients presenting with primary immunodeficiency are at risk of uncontrolled EBV infection and secondary malignancies including EBV-related lymphoproliferative disorders (LPD). This paper describes the first case of EBV related diffuse large B-cell lymphoma in a patient with DADA2 and uncontrolled EBV infection. Consideration should be given to monitoring for EBV viraemia and to preventative EBV specific therapy in DADA2 and patients with at risk primary immunodeficiencies. A type I interferon (IFN) gene signature is associated with DADA2 though its association with immune dysregulation is unclear.

Epidermodysplasia Verruciformis and Vδ2 γδ T-cell Expansion in STK4 Deficiency.

The clinical penetrance of infectious diseases varies considerably among patients with inborn errors of immunity (IEI), even for identical genetic defects. This variability is influenced by pathogen exposure, healthcare access and host-environment interactions. We describe here a patient in his thirties who presented with epidermodysplasia verruciformis (EV) due to infection with a weakly virulent beta-papillomavirus (HPV38) and CD4+ T-cell lymphopenia. The patient was born to consanguineous parents living in the United States. Exome sequencing identified a previously unknown biallelic STK4 stop-gain mutation (p.Trp425X). The patient had no relevant history of infectious disease during childhood other than mild wart-like lesion on the skin, but he developed diffuse large B-cell lymphoma (DLBCL) and EBV viremia with a low viral load in his thirties. Despite his low CD4+ T-cell count, the patient had normal counts of CD3+ cells, predominantly double-negative T cells (67.4%), which turned out to be Vδ2+ γδ T cells. γδ T-cell expansion has frequently been observed in the 33 reported cases with STK4 deficiency. The Vδ2 γδ T cells of this STK4-deficient patient are mostly CD45RA-CD27+CCR7+ central memory γδT cells, and their ability to proliferate in response to T-cell activation was impaired, as was that of CD4+ T cells. In conclusion, γδ T-cell expansion may act as a compensatory mechanism to combat viral infection, providing immune protection in immunocompromised individuals.

Polatuzumab vedotin plus bendamustine and rituximab or obinutuzumab in relapsed/refractory follicular lymphoma: a phase Ib/II study.

Follicular lymphoma (FL) is the most common type of indolent non-Hodgkin lymphoma. Despite treatment advances that have improved outcomes for patients with relapsed or refractory (R/R) FL, many patients still die from progressive disease or treatment-related toxicities. In the phase Ib/II GO29365 study (clinicaltrials.gov 02257567), the safety and efficacy of polatuzumab vedotin plus bendamustine and rituximab (Pola-BR) versus bendamustine and rituximab (BR) alone, and polatuzumab vedotin plus bendamustine and obinutuzumab (Pola-BG) as a single-arm cohort were evaluated in patients with R/R FL. Following the phase Ib safety run-in, patients were randomized 1:1 to receive Pola-BR or BR alone in the phase II stage; a separate non-randomized Pola-BG cohort was examined in the phase Ib/II expansion stage. Primary endpoints included safety and tolerability (phase Ib) and positron emission tomography complete response (PET-CR) rate by independent review committee (phase II). Overall, 112 patients were enrolled (phase Ib safety run-in: Pola-BR, N=6; phase II randomized cohort: Pola-BR, N=39; BR, N=41; phase Ib/II expansion cohort: Pola-BG, N=26). PET-CR rates were 66.7% (phase Ib safety run-in, Pola-BR); 69.2% (phase II randomized, Pola-BR); 63.4% (phase II randomized, BR); and 65.4% (phase Ib/II expansion Pola-BG). There was a higher occurrence of cytopenias with Pola-BR and Pola-BG than with BR; serious adverse events were more frequent with Pola-BR (61.4%) and Pola-BG (46.2%) than with BR (29.3%). Overall, this analysis does not demonstrate a benefit of adding Pola to BR or BG regimens for patients with R/R FL.

Three cases of late-onset post CAR-T therapy isolated CNS relapse in R/R large B-cell lymphoma.

CD19-chimeric antigen receptor T-cell (CAR T-cell) therapy has improved the outcomes of relapsed/refractory large B cell lymphoma significantly. However, about 50% of patients relapsed post-CAR-T therapy. Late relapse composed of 1/3 to 1/2 of CAR-T cell therapy failure, with no previous reports of isolated relapse in immune-privileged sites. Here, we report the first case series of late-onset post CAR-T cell therapy isolated central nervous system (CNS) relapses, in systemic relapsed/refractory large B cell lymphoma patients. With these cases, we suggest that additional CNS prophylaxis should be administrated for primary refractory patients on CAR-T cell therapy with previous neurological involvements, multiple extra-nodular lesions, and high CNS-IPI score pre-CAR, as well as early disappearance of circulating CAR-T cells post infusion.

Rituximab with standard LMB chemotherapy in pediatric high-risk mature B-cell non-Hodgkin lymphoma: A report from the JPLSG B-NHL14 trial.

BACKGROUND: The benefit of adding rituximab to standard lymphomes malins B (LMB) chemotherapy for children with high-risk mature B-cell non-Hodgkin lymphoma (B-NHL) has previously been demonstrated in an international randomized phase III trial, to which the Japanese Pediatric Leukemia/Lymphoma Study Group could not participate. METHODS: To evaluate the efficacy and safety of rituximab in combination with LMB chemotherapy in Japanese patients, we conducted a single-arm multicenter trial. RESULTS: In this study, 45 patients were enrolled between April 2016 and September 2018. A total of 33 (73.3%), 5 (11.1%), and 6 (13.3%) patients had Burkitt lymphoma/leukemia, diffuse large B-cell lymphoma, and aggressive mature B-NHL, not otherwise specified, respectively. Ten (22.2%) and 21 (46.7%) patients had central nervous system disease and leukemic disease, respectively. The median follow-up period was 47.5 months. Three-year event-free survival and overall survival were 97.7% (95% confidence interval, 84.9-99.7) and 100%, respectively. The only event was relapse, which occurred in a patient with diffuse large B-cell lymphoma. Seven patients (15.6%) developed Grade 4 or higher non-hematologic adverse events. Febrile neutropenia was the most frequent Grade 3 or higher adverse event after the pre-phase treatment, with a frequency of 54.5%. CONCLUSION: The efficacy and safety of rituximab in combination with LMB chemotherapy in children with high-risk mature B-NHL was observed in Japan.

Treatment of Monomorphic Posttransplant Lymphoproliferative Disorder in Pediatric Solid Organ Transplant: A Multicenter Review.

Posttransplant lymphoproliferative disorder (PTLD) is the most common posttransplant malignancy in children. We reviewed data from 3 Canadian pediatric centers to determine patient characteristics, treatment approaches, and outcomes for children with monomorphic PTLD. There were 55 eligible children diagnosed between January 2001 to December 2021. Forty-eight patients (87.2%) had B-cell PTLD: Burkitt lymphoma (n = 25; 45.4%) and diffuse large B-cell lymphoma (n = 23; 41.2%), the remainder had natural killer (NK)/T-cell lymphoma (n = 5; 9.1%), Hodgkin lymphoma (n = 1;1.8%), or other (n = 1;1.8%). Thirty-nine (82.1%) patients with B-cell PTLD were treated with rituximab and chemotherapy with or without a reduction in immunosuppression (reduced immune suppression). The chemotherapy used was primarily one of 2 regimens: Mature Lymphoma B-96 protocol in 22 patients (56.4%) and low-dose cyclophosphamide with prednisone in 14 patients (35%). Most patients with T/NK-cell lymphoma were treated with reduced immune suppression + chemotherapy (n = 4; 80%). For all patients with monomorphic PTLD, the projected 3-year event-free survival/3-year overall survival was 62% and 77%, respectively. Of the patients, 100% with T/NK-cell PTLD 100% progressed or relapsed and, subsequently, died of disease. For patients with B-cell PTLD, there was no significant difference in outcome between the two main chemotherapy regimens employed.

Allogeneic transplant following CAR T-cell therapy for large B-cell lymphoma.

Allogeneic hematopoietic cell transplantation (alloHCT) can potentially salvage large B-cell lymphoma (LBCL) patients experiencing treatment failure after chimeric antigen receptor T-cell therapy (CAR T). Nonetheless, data on the efficacy and toxicities of alloHCT after receipt of CAR T are limited. We report a multicenter retrospective study assessing the safety, toxicities, and outcomes of alloHCT in LBCL patients following CAR T failure. Eighty-eight patients with relapsed, refractory LBCL received an alloHCT following anti-CD19 CAR T failure. The median number of lines of therapy between CAR T infusion and alloHCT was one (range, 0-7). Low intensity conditioning was used in 77% (n=68) and peripheral blood was the most common graft source (86%, n=76). The most common donor types were matched unrelated donor (39%), followed by haploidentical (30%) and matched related donor (26%). Median follow-up of survivors was 15 months (range, 1-72). One-year overall survival, progression-free survival, and graft-versus-host disease-free relapse-free survival were 59%, 45%, and 39% respectively. One-year non-relapse mortality and progression/relapse were 22% and 33% respectively. On multivariate analysis, <2 lines of intervening therapy between CAR T and alloHCT and complete response at time of alloHCT were associated with better outcomes. In conclusion, alloHCT after CAR T failure can provide durable remissions in a subset of patients.

Prognostic impact of peripheral eosinophil counts in patients with diffuse large B-cell lymphoma receiving chimeric antigen receptor T-cell therapy.

BACKGROUND AIMS: Chimeric antigen receptor (CAR) T-cell therapy is a breakthrough treatment for patients with relapsed or refractory diffuse large B-cell lymphoma. However, many patients do not achieve remission or relapse after remission. Previous studies have demonstrated that eosinophils have synergistic anti-tumor effects with CD8+T cells and pre-CAR T-eosinophil counts are associated with the efficacy of CAR T cells. METHODS: We retrospectively analyzed the eosinophil counts of patients with diffuse large B-cell lymphoma and found it changed remarkably pre- and post-CAR T-cell therapy. RESULTS: Patients who achieved complete remission after CAR T-cell infusion had greater post-CAR T-eosinophil counts than those who did not. Kaplan-Meier curves showed that patients with greater eosinophil counts during the second month after CAR T-cell infusion had superior progression-free survival and overall survival compared with those with lower eosinophil counts. CONCLUSIONS: For patients who responded to CAR T-cell therapy, eosinophil counts also can be used to predict 6-month duration of response. In conclusion, the post-CAR T-eosinophil count is associated with the prognosis of patients treated with CAR T-cell therapy and can be used to clinically identify patients who can achieve longer remission after CAR T-cell infusion.

Novel agents in relapsed/refractory diffuse large B-cell lymphoma.

Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), ineligible for or relapsing after autologous stem-cell transplant or chimeric antigen-receptor T-cell therapies have poor outcomes. Several novel agents, polatuzumab vedotin, tafasitamab, loncastuximab tesirine, and selinexor, have been approved and offer new opportunities for this difficult to treat population. Studies are evaluating combination of these agents with chemotherapy and other emerging therapies. Additionally, advances in our understanding of DLBCL biology, genetics, and immune microenvironment have allowed for the identification of new therapeutic targets like Ikaros and Aiolos, IRAK4, MALT1, and CD47 with several agents in ongoing clinical trials. In this chapter we review updated data supporting the use of the approved agents and discuss other emerging novel therapies for patients with R/R DLBCL.

Long-term efficacy in patients with relapsed/refractory diffuse large B-cell lymphoma achieving a complete response with pixantrone.

INTRODUCTION: The prognosis of diffuse large B-cell lymphoma (DLBCL) patients with refractory or multiply relapsed (R/R) disease is disappointing. Pixantrone is currently approved as third or fourth line regimen, with encouraging results, even if long-term follow-up data are limited. METHODS: In this post-hoc analysis of our observational study, we retrospectively investigated disease outcome and clinical characteristics of 16 R/R DLBCL patients who achieved a complete response with pixantrone. RESULTS: Pixantrone was administered as third or fourth line in 12/16 (75%) and 4/16 (25%) cases. After a median follow-up of 24 months, 14/16 patients (87.5%) were alive (causes of death were progressive disease and secondary acute myeloid leukemia, one case each). Median progression-free survival was 23.8 months, median duration of response was 17.8 months and median overall survival (OS) was not reached (2-years OS was 84%). A significant proportion of patients achieved a long-lasting response >12 months (7/16 cases). Response to prior therapy did not influence long-term remission after pixantrone. CONCLUSION: In this real-life experience, pixantrone demonstrated long-term efficacy in a cohort of R/R DLBCL cases who had previously received at least two prior regimens; many of whom had characteristics associated with poor prognosis.

Chimeric antigen receptor T-cell therapy is superior to standard of care as second-line therapy for large B-cell lymphoma: A systematic review and meta-analysis.

Treatment with high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is considered standard of care (SOC) second-line treatment for relapsed or refractory large B-cell lymphoma (LBCL). However, outcomes remain suboptimal. A systematic review and meta-analysis of randomised controlled trials comparing efficacy and safety of SOC versus chimeric antigen receptor T-cell (CAR-T) therapy as second-line for patients with LBCL refractory or relapsing within 12 months. Outcomes included overall survival (OS), event-free survival (EFS), overall response rate (ORR) and safety. Three trials published in 2021 (involving 865 participants) fulfilled the eligibility criteria. EFS as well as OS were significantly improved with CAR-T therapy as compared to SOC, hazard ratio (HR) 0.57 (95% confidence interval [CI] 0.49-0.68) and HR 0.77 (95% CI 0.60-0.98) respectively. CAR-T therapy was associated with significantly better ORR, relative risk (RR) 1.55 (95% CI 1.12-2.13, p = 0.001). The risk of Grade III/IV adverse event was comparable between the two arms, RR 1.03 (95% CI 0.93-1.14). In summary, CAR-T therapy has superior outcomes as compared to SOC in patients with LBCL refractory or relapsing within 12 months, without excess of toxicity. Longer follow-up is needed to confirm these results and determine the optimal sequencing of CAR-T therapy in the management of LBCL.

United we stand: Double targeting of CD79B and CD20 in diffuse large B-cell lymphoma.

Polatuzumab vedotin is antibody-drug conjugate (ADC) targeting CD79B approved for the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma when given in combination with bendamustine and rituximab. The report by Kawasaki et al. provide hints on what might be happening in lymphoma cells exposed to polatuzumab vedotin and to rituximab and on potential mechanism of resistance to the ADC. Commentary on: Kawasaki et al. The molecular rationale for the combination of polatuzumab vedotin plus rituximab in diffuse large B-cell lymphoma. Br J Haematol 2022;199:245-255.

Body size and risk of non-Hodgkin lymphoma by subtype: A pooled analysis from six prospective cohorts in the United States.

In 2022, more than 100 000 non-Hodgkin lymphoma (NHL) diagnoses are expected, yet few risk factors are confirmed. In this study, data from six US-based cohorts (568 717 individuals) were used to examine body size and risk of NHL. Over more than 20 years of follow-up, 11 263 NHLs were identified. Hazard ratios (HRs) and 95% confidence intervals (CI) estimated associations with NHLs for adult body mass index (BMI), height, weight change, waist circumference and predicted fat mass. Adult height was broadly associated with NHL, but most strongly with B-cell NHLs among non-White participants (e.g. HRBLACK  = 2.06, 95% CI: 1.62-2.62). However, the strongest association among the anthropometric traits examined was for young adult BMI and risk of diffuse large B-cell lymphoma (DLBCL), particularly those who maintained a higher BMI into later adulthood. Individuals with BMI over 30 kg/m2 throughout adulthood had more than double the DLBCL risk (HR = 2.67, 95% CI: 1.71-4.17) compared to BMI 18.5-22.9 kg/m2 . Other anthropometric traits were not associated with NHL after controlling for BMI. These results suggest that sustained high BMI is a major driver of DLBCL risk. If confirmed, we estimate that up to 23.5% of all DLBCLs (and 11.1% of all NHLs) may be prevented with avoidance of young adult obesity.

Liposomal doxorubicin supercharge-containing front-line treatment in patients with advanced-stage diffuse large B-cell lymphoma or classical Hodgkin lymphoma: Preliminary results of a single-centre phase II study.

We evaluated the impact of liposomal doxorubicin (NPLD) supercharge-containing therapy on interim fluorodeoxyglucose positron emission tomography (interim-FDG-PET) responses in high-risk diffuse large B-cell lymphoma (DLBCL) or classical Hodgkin lymphoma (c-HL). In this phase II study (2016-2021), 81 adult patients with advanced-stage DLBCL (n = 53) and c-HL (n = 28) received front-line treatment with R-COMP-dose-intensified (DI) and MBVD-DI. R-COMP-DI consisted of 70 mg/m2 of NPLD plus standard rituximab, cyclophosphamide, vincristine and prednisone for three cycles (followed by three cycles with NPLD de-escalated at 50 mg/m2 ); MBVD-DI consisted of 35 mg/m2 of NPLD plus standard bleomycin, vinblastine and dacarbazine for two cycles (followed by four cycles with NPLD de-escalated at 25 mg/m2 ). Patients underwent R-COMP-DI and MBVD-DI with a median dose intensity of 91% and 94% respectively. At interim-FDG-PET, 72/81 patients (one failed to undergo interim-FDG-PET due to early death) had a Deauville score of ≤3. At end of treatment, 90% of patients reached complete responses. In all, 20 patients had Grade ≥3 adverse events, and four of them required hospitalisation. At a median 21-months of follow-up, the progression-free survival of the entire population was 77.3% (95% confidence interval 68%-88%). Our data suggest that the NPLD supercharge-driven strategy in high-risk DLBCL/c-HL may be a promising option to test in phase III trials, for improving negative interim-FDG-PET cases incidence.

LUBAC accelerates B-cell lymphomagenesis by conferring resistance to genotoxic stress on B cells.

The linear ubiquitin chain assembly complex (LUBAC) is a key regulator of NF-κB signaling. Activating single-nucleotide polymorphisms of HOIP, the catalytic subunit of LUBAC, are enriched in patients with activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL), and expression of HOIP, which parallels LUBAC activity, is elevated in ABC-DLBCL samples. Thus, to clarify the precise roles of LUBAC in lymphomagenesis, we generated a mouse model with augmented expression of HOIP in B cells. Interestingly, augmented HOIP expression facilitated DLBCL-like B-cell lymphomagenesis driven by MYD88-activating mutation. The developed lymphoma cells partly shared somatic gene mutations with human DLBCLs, with increased frequency of a typical AID mutation pattern. In vitro analysis revealed that HOIP overexpression protected B cells from DNA damage-induced cell death through NF-κB activation, and analysis of the human DLBCL database showed that expression of HOIP positively correlated with gene signatures representing regulation of apoptosis signaling, as well as NF-κB signaling. These results indicate that HOIP facilitates lymphomagenesis by preventing cell death and augmenting NF-κB signaling, leading to accumulation of AID-mediated mutations. Furthermore, a natural compound that specifically inhibits LUBAC was shown to suppress the tumor growth in a mouse transplantation model. Collectively, our data indicate that LUBAC is crucially involved in B-cell lymphomagenesis through protection against DNA damage-induced cell death and is a suitable therapeutic target for B-cell lymphomas.

Optimizing MATRix as remission induction in PCNSL: de-escalated induction treatment in newly diagnosed primary CNS lymphoma.

BACKGROUND: Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (PCNSL) is a rare disorder with an increasing incidence over the past decades. High-level evidence has been reported for the MATRix regimen (high-dose methotrexate (HD-MTX), high-dose AraC (HD-AraC), thiotepa and rituximab) followed by high-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) supporting this approach to be considered a standard therapy in newly diagnosed PCNSL patients ≤ 70 years. However, early treatment-related toxicities (predominantly infectious complications), occurring in up to 28% per MATRix cycle, diminish its therapeutic success. Furthermore, sensitivity to first-line treatment is an independent prognostic factor for improved overall survival (OS) in PCNSL. Thus, patients achieving early partial remission (PR) after 2 cycles of MATRix might be over-treated with 4 cycles, in the context of consolidation HCT-ASCT. METHODS: This is an open-label, multicentre, randomized phase III trial with two parallel arms. 326 immunocompetent patients with newly diagnosed PCNSL will be recruited from 37 German, 1 Austrian and 12 UK sites. Additional IELSG (International Extranodal Lymphoma Study Group) sites are planned. The objective is to demonstrate superiority of a de-escalated and optimised remission induction treatment strategy, followed by HCT-ASCT. Randomization (1:1) will be performed after completion of all screening procedures. Patients in Arm A (control treatment) will receive 4 cycles of MATRix. Patients in Arm B (experimental treatment) will receive a pre-phase (R/HD-MTX), followed by 2 cycles of MATRix. Patients in both arms achieving PR or better will proceed to HCT-ASCT (BCNU, thiotepa). The primary endpoint of the study is event-free-survival (EFS), defined as time from randomization to premature end of treatment due to any reason, lymphoma progression or death whichever occurs first. Secondary endpoints include OS, progression free survival (PFS), toxicity, neurocognitive impairment and quality of life. Minimal follow-up is 24 months. DISCUSSION: Current treatment options for PCNSL in patients ≤ 70 years have improved remarkably over recent years. However, the potential efficacy benefits are offset by an increased incidence of short-term toxicities which can impact on treatment delivery and hence on survival outcomes. In patients ≤ 70 years with newly diagnosed PCNSL addressing the need to reduce treatment-related toxicity by de-escalating and optimising the induction phase of treatment, is a potentially attractive treatment strategy. TRIAL REGISTRATION: German clinical trials registry DRKS00022768 registered June 10th, 2021.

Obinutuzumab does not improve complete methabolic response but does not compromise mobilization or engraftment of autologous peripheral blood stem cells in diffuse large B cell lymphoma: Results from a fondazione italiana linfomi prospective phase II study (the GIOTTO study).

Salvage immunochemotherapy and transplant consolidation is the standard treatment for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). We tested a combination of Obinutuzumab and DHAP for treating R/R DLBCL. The primary end point was the rate of complete metabolic response (CMR). Secondary end points were stem cell mobilization, stem cell engraftment, overall survival, and feasibility. In this prospective, phase-2, single-arm trial (EudraCT 2014-004014-17) patients received the standard three doses of Obinutuzumab for the first cycle, and then one dose. Patients with CMR were consolidated with an autologous stem cell transplantation (ASCT). An interim analysis was provided after the first 29 patients to confirm the initial null hypothesis that at least 10/29 patients would achieve CMR. Among the 29 patients evaluated for the first stage only six patients (6/29, 21%) achieved CMR, thus, study enrollment was stopped. Nine patients exhibited extra-hematologic toxicities ≥ grade 3. Among the 19 patients that started stem cell mobilization, one failed (5%) and 18 achieved mobilization (95%). Of these 18 patients, nine were reinfused. Mobilization was observed in 16 patients (89%) after one or two apheresis rounds. The mean number of CD34 + cells mobilized was 5.8 × 106 /Kg (median: 5.5, IQR: 5-6.75). The mean number of reinfused CD34 + cells in the nine patients was 4.1 × 106 /Kg (median: 4.1, IQR: 3.5-5). Obinutuzumab combined with DHAP did not compromise stem cell mobilization or engraftment after ASCT in patients with DLBCL. However, Obinutuzumab + DHAP provided a lower CMR rate than expected.

Efficacy and safety comparison between R-CHOP and modified NHL-BFM-90 regimens in children and adolescents with diffuse large B-cell lymphoma.

Studies comparing the efficacy and safety of R-CHOP and modified non-Hodgkin lymphoma Berlin-Frankfurt-Münster-90 (NHL-BFM-90) regimens in children and adolescents with diffuse large B-cell lymphoma (DLBCL) are lacking. Thus, we retrospectively analyzed 85 DLBCL patients aged ≤18 years from 2000 to 2020; 74 patients received the modified NHL-BFM-90 regimen, and 11 received the R-CHOP regimen. The 5-year OS and event-free survival (EFS) rates between the modified NHL-BFM-90 and R-CHOP regimens were 91.0% vs. 90.9% (P = 0.466) and 89.8% vs. 68.6% (P = 0.055), respectively. In the stratified analysis, the survival outcome of pediatric patients treated with the modified NHL-BFM-90 regimen was not significantly different from that of adolescent patients. The OS and EFS rates of patients with early-stage disease were both 100%. Patients in the advanced-stage group who were treated with the modified NHL-BFM-90 regimen had superior EFS rates (P < 0.05). The frequency of severe adverse events from the two regimens was similar. There were no treatment-related deaths. We concluded that the modified NHL-BFM-90 regimen has better efficacy than R-CHOP in DLBCL patients with advanced-stage disease. However, the R-CHOP regimen might be an option for early-stage DLBCL. Further prospective studies are needed to guide clinical decisions about treatment.