What clinicians should know about surrogate end points in hematologic malignancies.

ABSTRACT: Use of surrogates as primary end points is commonplace in hematology/oncology clinical trials. As opposed to prognostic markers, surrogates are end points that can be measured early and yet can still capture the full effect of treatment, because it would be captured by the true outcome (eg, overall survival). We discuss the level of evidence of the most commonly used end points in hematology and share recommendations on how to apply and evaluate surrogate end points in research and clinical practice. Based on the statistical literature, this clinician-friendly review intends to build a bridge between clinicians and surrogacy specialists.

Early complete response as a validated surrogate marker in extranodal marginal zone lymphoma systemic therapy.

ABSTRACT: Extranodal marginal zone lymphoma (EMZL) has a very indolent course, and the validation of surrogate markers could accelerate novel therapies. Although prognostic markers do exist, no surrogate markers have been validated in EMZL. We hypothesized that time to complete response within 24 months (TTCR24) and complete response (CR) at 24 months (CR24) could be valid surrogate markers of progression-free survival (PFS). The International Extranodal Lymphoma Study Group 19 phase 3 trial showed the advantage of double therapy (rituximab + chlorambucil) over single therapy (rituximab or chlorambucil) on PFS. We used 2 recently published single-trial approaches to assess whether TTCR24 and CR24 were good surrogate markers of 8-year PFS (8y-PFS). Among the 401 patients, 264 (66%) reached a CR in the first 24 months, of which 222 (84%) remained in CR at month 24. The cumulative incidence of CR over time was significantly higher in patients under double therapy (hazard ratio, 1.75; P < .001). The double therapy arm was associated with a higher CR24 rate, a shorter TTCR24, and a longer 8y-PFS. The estimated proportion of treatment effect on 8y-PFS explained by TTCR24 was 95% (95% confidence interval [CI], 0.27-1.87). CR24 was also a strong surrogate marker because it mediated 90% (95% CI, 0.51-2.22) of the treatment effect on PFS and its natural indirect effect was significant throughout the follow-up. We found that TTCR24 predicted 95% and that CR24 mediated 90% of the treatment effect on long-term PFS. Therefore, TTCR24 and CR24 could be used in clinical trials as informative and valid early indicators of treatment effect on PFS. This trial was registered at www.clinicaltrials.gov as #NCT00210353.

Twitter as a Medical Media Among French Young Oncologists: Results from a National Survey.

Since its launch in 2006, Twitter has become a commonly used platform for sharing medical information, especially in the field of oncology. However, its role and impact on young oncologists' education remain unclear. Moreover, COVID-19 and congress virtualization is likely to have modified Twitter use by the medical society.We conducted a national survey (27 questions) in France among medical oncology, hematology, and radiation therapy young doctors to help better understand the role played by Twitter on their medical education. One hundred eighty-three young oncologists participated in our survey. A majority does not use Twitter (72.1%), mostly to reduce their time spent on social media. Participants using Twitter (27.9%) often use it more than once a week, mostly by scrolling on their news feed. Interestingly, they rarely express their own opinion on Twitter: a majority of them (75.5%) tweet less than once a month while the rest of them mostly retweet others' tweets. They mainly follow English-speaking experts, scientific societies, and medical journals. Pharmaceutical laboratories' accounts are of less significance. Overall Twitter usage seems increasing since COVID-19 pandemic and the consequent digitalization of congresses. No statistical difference was observed between the baseline characteristics of Twitter users and non-users.This survey shows that Twitter is a relevant mean of continuous medical education used by around a third of French young oncologists, especially since COVID-19 pandemic and the virtualization of congresses. This media should be considered and evaluated for its educational advantages or potential biases.

Comparing apples and oranges: The ZUMA-7, TRANSFORM and BELINDA trials.

In December 2021, three phase III trials investigating Chimeric Antigen Receptor (CAR) T-cell for large B-cell lymphoma were published, only one of which showed no treatment effect on Event-Free Survival (EFS). All compared anti-CD19 CAR T-cell as second-line treatment with immunochemotherapy plus autologous stem cell transplant if an adequate response to chemotherapy was achieved. In this letter, we discuss the methodological reasons that partially explain the discrepant results observed between the ZUMA-7, TRANSFORM and BELINDA trials. A raw comparison shows that BELINDA simultaneously had the worst experimental arm and the best control arm among the three trials. This could be partially related to differences in the event definition and time of assessment. Stable Disease was considered an event as early as W9 in TRANSFORM, W12 in BELINDA and only W21 in ZUMA-7. Since tisa-cel had the longest manufacturing time, the time window may have been too short to assess its full potential compared with axi-cel and liso-cel. In comparison, a patient with stable disease in ZUMA-7 would not be considered an event until W21. On the other hand, a second salvage regimen was allowed before considering stable disease as an event only in the BELINDA control arm which could have delayed EFS. Many of these issues could be avoided if progression-free survival was preferred to EFS and if the time to manufacture CAR-T cells was shortened, as long delays can result in a higher tumor volume and more refractory diseases at the time of infusion.

Finding a consensus on time-to-event endpoints definitions in marginal zone lymphoma: A Delphi method.

A recent systematic review reported that trials involving patients with marginal zone lymphoma (MZL) show marked heterogeneity both in the choice and definitions of primary and secondary endpoints, thus hampering comparability between trials. The main objective of this study was to reach consensus, through a Delphi process, on the definitions of four time-to-event endpoints in MZL trials, by surveying clinicians and methodologists involved in the conduct of clinical trials including patients with MZL. We polled a panel of leading international experts involved in MZL trials by means of self-administered sequential questionnaires in 2021. Of these 105 experts, 62 responded to the Round 1 questionnaire regarding the definitions of progression-free survival (PFS), event-free survival (EFS), time-to-failure (TTF), and time-to-next-treatment (TTNT). Afterward, we therefore focused the Round 2 and 3 questionnaires among principal investigators, coinvestigators, and trial methodologists. Consensus was reached when there was a >80% agreement on all potential events (11 choices) of each endpoint. Participants in our survey reached consensus on three of the four time-to-event endpoints definitions. Consensus was reached on the definitions of PFS and TTNT after Round 1, of TTF after Round 2, and was not reached for EFS after Round 3. The disagreement concerned the event "treatment discontinuation" in EFS definition. The main interest of our study was to elicit investigator's interest in the importance of consistently defining endpoints in MZL trials and to highlight that composite endpoints should not be encouraged. Fifteen years after the last consensus statement on time-to-event endpoints definitions issued in Lugano (2007), both the review of literature and survey of international investigators agree on the inconsistency of endpoints definitions used within the MZL community. Hopefully, revised standardized definitions of endpoints shall be provided at the upcoming International Conference on Malignant Lymphoma in 2023.

Real-life targeted next-generation sequencing for lymphoma diagnosis over 1 year from the French Lymphoma Network.

As the impact of targeted next-generation sequencing (TNGS) on daily diagnosis has not been evaluated, we performed TNGS (46 genes) on lymphomas of unclear subtype following expert haematopathological review. The potential impact on patient care and modifications of final diagnosis were divided into major and minor changes according to the European Society of Medical Oncology (ESMO) guidelines. Among 229 patients [19 primary central nervous system lymphomas (PCNSL), 48 large B-cell lymphomas (LBCLs), 89 small BCLs (SBCLs), seven Hodgkin lymphomas (HL), 66 T-cell lymphomas], the overall concordance rate of histological and TNGS diagnosis was 89·5%. TNGS confirmed the histological diagnosis in 144 cases (62·9%), changed the diagnosis in 24 cases (10·5%) and did not help to clarify diagnosis in 61 cases (26·7%). Modifications to the final diagnosis had a clinical impact on patient care in 8·3% of cases. Diagnostic modifications occurred in all types of lymphoma except in PCNSL and HL; the modification rate was 14·6% in SBCL and 12·5% in LBCL. While comparing informative and uninformative cases, no differences were found in terms of DNA amplification, quality or depth of sequencing and biopsy type. The present study highlights that TNGS may directly contribute to a more accurate diagnosis in difficult-to-diagnose lymphomas, thus improving the clinical management in routine practice.

Exploratory analysis of intensified conditioning as first line treatment for patients with high risk multiple myeloma.

Multiple myeloma has extremely heterogeneous outcomes. Among prognostic factors, t(4;14) and del(17p) are rare oncogenic events associated with very poor prognosis. In an exploratory case-control study, we compared the combination of Busulfan-Melphalan or TBI-Melphalan with high dose Melphalan as a conditioning regimen in a series of 48 patients with del(17p) or t(4;14). These regimens were preceded by a Bortezomib-containing induction. Progression-free survival (PFS) was the primary endpoint whereas overall survival (OS) and complete response (CR) rate were the secondary endpoints. Twenty consecutive cases of high-risk myeloma received a reinforced conditioning regimen of Busulfan 0.8 mg/kg x4/j IV from day-6 to day-3 pre- graft (BuMel) or total body irradiation (TBI) 12 Gy (TbiMel), having received Melphalan 140 mg/m2 at day-2 pre-graft. These cases were matched to 28 controls treated with Melphalan 200 mg/m2 at day-2 (Mel200). After intensification ± consolidation, with a median follow-up of 6.3 years, the CR rate was higher in the BuMel/TbiMel group (65% vs 50%, P = .006). No differences were observed between both groups in terms of PFS and OS (P = .96). PFS in patients with a del(17p) mutation tended to be superior in the BuMel/TbiMel group. Our exploratory study shows that reinforcing the intensification regimen with Busulfan or TBI does not seem to improve the prognosis associated to t(4;14) and del(17p) abnormalities.

Breast Implant-associated Anaplastic Large Cell Lymphoma: Review and Multiparametric Imaging Paradigms.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a new provisional category in the 2016 World Health Organization (WHO) classification of lymphoid neoplasms, and its incidence is rising owing to increasing recognition of this complication of breast implant insertion. At a median of 10 years after implant insertion, the typical presenting features are sudden-onset breast swelling secondary to peri-implant effusion and less frequently mass-forming disease. Histologic features comprise pleomorphic cells expressing CD30 and negative anaplastic lymphoma kinase (ALK) receptor, similar to systemic and cutaneous ALK-negative anaplastic large cell lymphoma (ALCL). The effusion-only subtype is generally indolent and curable with surgery, unlike the more aggressive mass-forming disease, for which systemic therapy is advocated. High clinical suspicion and pertinent use of radiologic and pathology modalities are essential for timely and accurate diagnosis of BIA-ALCL. Contemporary imaging techniques including US, mammography, breast MRI, CT, and PET/CT are routinely used in breast disease and lymphomas; however, the unique behavior of BIA-ALCL presents significant diagnostic and radiologic interpretative challenges, with numerous nuanced imaging features being pertinent, and current lymphoma staging and response guidelines are not easily applicable to BIA-ALCL. The authors evaluate available evidence in this evolving field; detail key indications, strengths, and limitations of the panoply of radiologic techniques for BIA-ALCL; and propose multiparametric imaging paradigms for management of the peri-implant effusion and mass-forming or advanced disease subtypes, with the goal of accurate optimal patient care. The authors also predict a future model of multimodal assessment using novel imaging and molecular techniques and define key research directions. ©RSNA, 2020.

Epstein-Barr Virus-Associated Post-Transplantation Lymphoproliferative Disease in Patients Who Received Anti-CD20 after Hematopoietic Stem Cell Transplantation.

Post-transplantation lymphoproliferative disease (PTLD) is a serious complication associated with Epstein-Barr virus (EBV) infection after hematopoietic stem cell transplantation (HSCT). Although anti-CD-20 therapy is now used as a preemptive strategy for EBV reactivation, PTLD still occurs in some patients. Here we analyzed outcomes and risk factors associated with PTLD transformation in 208 HSCT recipients who were diagnosed with EBV-DNAemia and received at least 1 course of rituximab. The median patient age was 42.52 years (range, 8.35 to 74.77 years), and the median duration of follow-up was 47.33 months (range, 3.18 to 126.20 months). The 2-year overall survival of the entire cohort was 62.8 (95% confidence interval [CI], 56.4 to 69.9), and the 2-year cumulative incidence function of PTLD was 6.3% (95% CI, 3.5% to 10.1%), for a median follow-up of patients diagnosed with PTLD of 37.85 months. Multivariable analysis identified 4 risk factors associated with PTLD: HSCT from an unrelated donor, recipient HLA-DRB1*11:01, fever at diagnosis of EBV infection, and donor-recipient sex-mismatched HSCT. The presence of more than 2 of these risk factors was associated with an increased risk of developing PTLD. This retrospective study identifies risk factors associated with PTLD in EBV-infected patients after HSCT and defines patient subgroups that may benefit from intensified preemptive strategies.

Transformation in Marginal Zone Lymphoma: Results from a Prospective Cohort and a Meta-Analysis of the Literature.

Marginal zone lymphoma (MZL) includes extranodal (EMZL), splenic (SMZL), and nodal (NMZL) subtypes. Histological transformation (HT) to large B-cell lymphomas is well documented but with a large variability in published cumulative incidence rates. We report results from the Molecular Epidemiology Resource (MER) cohort for the cumulative incidence of HT (with death as competing risk) and associated risk factors and outcomes. We also conduct a meta-analysis of available studies on the cumulative incidence of HT. From 2002-2015, 529 patients with MZL were enrolled in the MER (69% EMZL, 16% SMZL, 15% NMZL). Ten-year overall survival (OS) from diagnosis was 66%. HT occurred in 21 patients, with 5-year and 10-year cumulative incidence of HT of 2.7% (95% confidence interval [CI] 0.02-0.05) and 3.6% (95%CI 0.02-0.06), respectively. HT was associated with an increased risk of death (subdistribution hazard ratio (HR)=3.95; 95%CI 2.06-7.55). Predictors of HT were ≥2 extranodal sites and MALT-IPI score ≥2. OS was 79% at 5 and 55% at 10 years after HT. Age at HT≥70 years was the only predictor of OS after HT (HR=3.57; 95%CI 1.34-9.48). In meta-analysis of 12 studies (6,161 patients), the 5- and 10-year cumulative incidence of HT across all subtypes were 5% (95%CI 0.05-0.06) and 8% (95%CI 0.07-0.09), respectively. Rates were lower in EMZL (3% and 5%) than in SMZL (7% and 13%) and NMZL (9% and 13%). While HT is relatively uncommon in the first decade after MZL diagnosis, it is associated with an inferior outcome and needs new approaches to prevention and management.

Health-related quality of life profile of newly diagnosed patients with Hodgkin and non-Hodgkin lymphomas: A real-world study including 3922 patients from the French REALYSA cohort.

INTRODUCTION: Considering the notable advances made in the treatment of lymphoma, assessment of health-related quality of life (HRQoL) of lymphoma patients has become a critical aspect to consider both in clinical research and routine practice. However, there is paucity of information about lymphoma specific HRQoL profile at diagnosis. PATIENTS AND METHODS: HRQoL at diagnosis was assessed for 3922 adult patients with newly diagnosed high-grade (HG) (n = 1994), low-grade (LG) (n = 1053) non-Hodgkin (NHL) and Hodgkin (HL) (n = 875) lymphomas included in REal world dAta in LYmphoma and Survival in Adults (REALYSA, NCT03869619), a prospective non-interventional multicentric cohort in France. Disease-specific HRQoL aspects were assessed with three validated EORTC questionnaires, namely, the QLQ-NHL-HG29, the QLQ-NHL-LG20 and the QLQ-HL27, for patients with NHL-HG, NHL-LG and HL, respectively. RESULTS: We confirmed the high-level of completion of these questionnaires in REALYSA cohort, ranging from 84 % for QLQ-HG29 to 88 % for QLQ-HL27. The proportion of patients with impaired global health status was as follows: T-cell NHL, 67 %; diffuse large B-cell (DLBCL), 62 %; Burkitt, 61 %; HL, 53 %; marginal zone, 49 %; mantle cell, 48 %; follicular, 47 %. Multivariable regression analyses for DLBCL, follicular and HL showed that gender, performance status and B symptoms were independently associated with all HRQoL dimensions. However, a variable effect of age and stage were observed among these three subtypes. CONCLUSIONS: A comprehensive analysis was made describing the HRQoL profile of newly diagnosed patients with different types of lymphomas. Our data may help to enhance the interpretation of HRQoL results in future studies using the recently validated EORTC lymphoma specific questionnaires.

Marginal zone lymphoma international prognostic index: a unifying prognostic index for marginal zone lymphomas requiring systemic treatment.

Background: Marginal zone lymphomas (MZL), comprised of three unique but related subtypes, lack a unifying prognostic score applicable to all the patients in need for systemic chemotherapy and/or immunotherapy. Methods: Patients from the prospective NF10 study (NCT02904577) with newly diagnosed MZL and receiving frontline systemic therapy at diagnosis or after observation were used to train a prognostic model. The primary endpoint was progression-free survival (PFS) from start of treatment. The model was externally validated in a pooled analysis of two independent cohorts from the University of Iowa and Mayo Clinic Molecular Epidemiology Resource and the University of Miami. Findings: We identified 501 eligible patients. After multivariable modeling, lactate dehydrogenase (LDH) above upper normal limit, hemoglobin <12 g/dL, absolute lymphocyte count <1 × 109/L, platelets <100 × 109/L, and MZL subtype (nodal or disseminated) were independently associated with inferior PFS. The proposed MZL International Prognostic index (MZL-IPI) combined these 5 factors, and we defined low (LRG, 0 factors, 27%), intermediate (IRG, 1-2 factors, 57%) and high (HRG, 3+ factors, 16%) risk groups with 5-y PFS of 85%, 66%, and 37%, respectively (c-Harrell = 0.64). Compared to the LRG, the IRG (Hazard Ratio [HR] = 2.30, 95% CI 1.39-3.80) and HRG (HR = 5.41, 95% CI 3.12-9.38) had inferior PFS. Applying the MZL-IPI to the pooled US cohort (N = 353), 94 (27%), 192 (54%), and 67 (19%) patients were classified as LRG, IRG, and HRG, respectively, and the model was validated for PFS (log-rank test p = 0.0018; c-Harrell = 0.578, 95% CI 0.54-0.62). The MZL-IPI was also prognostic for OS in both the training and the external validation sets. Interpretation: MZL-IPI is a new prognostic score for use in all patients with MZL considered for systemic treatment. Funding: The MER was supported by P50 CA97274 and U01 CA195568.

What Prognostic Markers Should Be Evaluated in Marginal Zone Lymphoma? A Survey Among Leading International Experts.

Supplemental Digital Content is available in the text.

Systematic review reveals urgent need to homogenize endpoints choices and definitions in marginal zone lymphomas trials.

Marginal zone lymphoma (MZL) is a heterogeneous disease and has various end-point measures. Our aim was to describe the endpoints used in trials involving patients with MZL. We searched over the last 35 years via PubMed, The Cochrane Library, clinicaltrials.govandclinicaltrialsregister.eu for published and registered clinical trials using the keyword "marginalzone lymphoma." We excluded studies focusing on pediatric populations, cutaneous MZL and on use of allogenic stem cell transplant. Endpoints were reviewed as well as their influencing factors and their definitions. Among 1192 references Q7 dentified by initial screening, 309 references were included (111 published, 198 registered), with 213 (69%) phase 2, 65 (21%) phase 1/2 and 31 (10%) phase 3 trials. The majority were open-label (n»295, 95%) non-randomized (n»256, 83%) trials, concerned all subtypes of MZLs at once (n»239, 77%), and were often merged with non-MZL patients (n»232, 75%). Among phase 1/2 and 2 trials, Overall/complete response rate (ORR/CRR) (n»196, 70.5%) and progression-free survival (PFS,n»28, 10.1%) were the most used primary endpoints; in phase 3 trials PFS was the most used primary endpoint (n»18, 58.1%; ORR/CRR n»6, 19.4%, p<0.001). Overall, the most frequent secondary endpoints were overall survival (OS, n»153, 50%), PFS (n»142, 46%) and ORR/CRR (n»116, 38%). Distribution was similar when considering trials with only patients with MZL. Endpoints definitions were inconsistent across published trials (up to 9 definitions per endpoint). Trials involving patients with MZL showed marked heterogeneity both in the choice and definitions of primary and secondary endpoints, thus hampering comparability between trials.

Radiotherapy for gastric mucosa-associated lymphoid tissue lymphoma.

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a rare disease which is often associated with Helicobacter pylori (H. pylori) infection. First-line treatment of stage IE and IIE localized gastric MALT lymphoma is based on the eradication of H. pylori. The presence of H. pylori resistance factors such as translocation t (11;18), peri-gastric lymph node involvement and the degree of tumor infiltration of the gastric wall; or lack of response to antibiotic therapy are two main indications to treat with definitive radiotherapy (RT). RT is an effective treatment in localized gastric MALT lymphoma. A moderate dose of 30 Gy allows a high cure rate while being well tolerated. After treatment, regular gastric endoscopic follow-up is necessary to detect a potential occurrence of gastric adenocarcinoma.

Chapter 7. What symbolic answers to death in the medical world?

INTRODUCTION: By threatening our lives, death becomes a medical as well as an institutional issue. To remedy the quest of sense, Man develops a culture amongst which the symbols will be the basis of rites. Recent studies have shown a high rate of burnout syndromes and suicide within the medical community. With a qualitative approach, we aimed to answer the following question: do doctor possess symbolic means of personal defence in front of the dissolvent action of death? METHODS: We built up a questionnaire from key points raised by anthropology and sociology of death. It was addressed to residents of Saint Louis Hospital (Paris, France) during winter 2016-2017. RESULTS: Twenty comprehensive answers were obtained. Young physicians were between 25 and 33 years old (55% haematologists, 35% oncologists, others general practitioners & internal medicine physicians). We show that, to remedy the quest of sense in presence of death, young physicians reckon having repetitive gestures with corpses, thus elaborating the beginning of a personal rite. We also demonstrate the role of empathy and palliative medicine in diminishing the pain of seeing agony and death. Finally, we weave a tie between the lack of collective catharsis at hospital and the high rate of suicide and depressions within the medical community. CONCLUSION: In the West, we are out of effective symbolism due to the shift of rituals on less metaphysical symbols. This shift of symbolism also affects hospital which failed to develop or protect means to transcend death in a collective scale.