Cell-of-origin effect of polatuzumab vedotin in diffuse large B-cell lymphoma: no ordinary subgroup analysis.

ABSTRACT: Subgroup analysis from the POLARIX trial of polatuzumab vedotin plus chemotherapy for untreated large B-cell lymphoma suggests greater efficacy among patients with activated B-cell subtype disease. Both preclinical and additional clinical evidence support this interaction between cell-of-origin and polatuzumab efficacy.

Evaluating early intervention in smoldering myeloma clinical trials: a systematic review.

BACKGROUND: Smoldering multiple myeloma (SMM), an asymptomatic precursor of multiple myeloma (MM), carries a variable risk of progression to MM. There is little consensus on the efficacy or optimal timing of treatment in SMM. We systematically reviewed the landscape of all clinical trials in SMM. We compared the efficacy of treatment regimens studied in SMM to results from these regimens when used in newly diagnosed multiple myeloma (NDMM), to determine whether the data suggest deeper responses in SMM versus NDMM. METHODS: All prospective interventional clinical trials for SMM, including published studies, meeting abstracts, and unpublished trials listed on ClinicalTrials.gov up to April 1, 2023, were identified. Trial-related variables were captured, including treatment strategy and efficacy results. Relevant clinical endpoints were defined as overall survival (OS) and quality of life. RESULTS: Among 45 SMM trials identified, 38 (84.4%) assessed active myeloma drugs, while 7 (15.6%) studied bone-modifying agents alone. Of 18 randomized trials in SMM, only one (5.6%) had a primary endpoint of OS; the most common primary endpoint was progression-free survival (n = 7, 38.9%). Among 32 SMM trials with available results, 9 (28.1%) met their prespecified primary endpoint, of which 5 were single-arm studies. Six treatment regimens were tested in both SMM and NDMM; 5 regimens yielded a lower rate of very good partial response rate or better (≥VGPR) in SMM compared to the corresponding NDMM trial (32% vs 63%, 43% vs 53%, 40% vs 63%, 86% vs 89%, 92% vs 95%, and 94% vs 87%, respectively). CONCLUSION: In this systematic review of all prospective interventional clinical trials in SMM, we found significant variability in trial design, including randomization status, primary endpoints, and types of intervention used. Despite the statistical limitations, comparison of treatment regimens revealed no compelling evidence that the treatment is more effective when introduced early in SMM compared to NDMM.

The paradox of platypnoea-orthodeoxia syndrome.

Platypnoea-orthodeoxia is a rare clinical syndrome characterised by dyspnoea and oxygen desaturation in the upright position which improves when supine. It requires two components: a sufficiently sized anatomical vascular defect (typically intra-cardiac or intra-pulmonary) combined with a functional component that promotes positional right-to-left shunting. We describe the rare occurrence of a patient with platypnoea-orthodeoxia syndrome (POS) because of a paradoxical shunt through a patent foramen ovale caused by a large right atrial line-associated thrombus in a male with metastatic oesophageal cancer undergoing chemotherapy. This case is a timely reminder to consider POS amongst differentials for hypoxia as it is often treatable if recognised.

Second-Line Chimeric Antigen Receptor T-Cell Therapy in Diffuse Large B-Cell Lymphoma : A Cost-Effectiveness Analysis.

BACKGROUND: First-line treatment of diffuse large B-cell lymphoma (DLBCL) achieves durable remission in approximately 60% of patients. In relapsed or refractory disease, only about 20% achieve durable remission with salvage chemoimmunotherapy and consolidative autologous stem cell transplantation (ASCT). The ZUMA-7 (axicabtagene ciloleucel [axi-cel]) and TRANSFORM (lisocabtagene maraleucel [liso-cel]) trials demonstrated superior event-free survival (and, in ZUMA-7, overall survival) in primary-refractory or early-relapsed (high-risk) DLBCL with chimeric antigen receptor T-cell therapy (CAR-T) compared with salvage chemoimmunotherapy and consolidative ASCT; however, list prices for CAR-T exceed $400 000 per infusion. OBJECTIVE: To determine the cost-effectiveness of second-line CAR-T versus salvage chemoimmunotherapy and consolidative ASCT. DESIGN: State-transition microsimulation model. DATA SOURCES: ZUMA-7, TRANSFORM, other trials, and observational data. TARGET POPULATION: "High-risk" patients with DLBCL. TIME HORIZON: Lifetime. PERSPECTIVE: Health care sector. INTERVENTION: Axi-cel or liso-cel versus ASCT. OUTCOME MEASURES: Incremental cost-effectiveness ratio (ICER) and incremental net monetary benefit (iNMB) in 2022 U.S. dollars per quality-adjusted life-year (QALY) for a willingness-to-pay (WTP) threshold of $200 000 per QALY. RESULTS OF BASE-CASE ANALYSIS: The increase in median overall survival was 4 months for axi-cel and 1 month for liso-cel. For axi-cel, the ICER was $684 225 per QALY and the iNMB was -$107 642. For liso-cel, the ICER was $1 171 909 per QALY and the iNMB was -$102 477. RESULTS OF SENSITIVITY ANALYSIS: To be cost-effective with a WTP of $200 000, the cost of CAR-T would have to be reduced to $321 123 for axi-cel and $313 730 for liso-cel. Implementation in high-risk patients would increase U.S. health care spending by approximately $6.8 billion over a 5-year period. LIMITATION: Differences in preinfusion bridging therapies precluded cross-trial comparisons. CONCLUSION: Neither second-line axi-cel nor liso-cel was cost-effective at a WTP of $200 000 per QALY. Clinical outcomes improved incrementally, but costs of CAR-T must be lowered substantially to enable cost-effectiveness. PRIMARY FUNDING SOURCE: No research-specific funding.

Clinical Benefit and Regulatory Outcomes of Cancer Drugs Receiving Accelerated Approval.

Importance: The US Food and Drug Administration's (FDA) accelerated approval pathway allows approval of investigational drugs treating unmet medical needs based on changes to surrogate measures considered "reasonably likely" to predict clinical benefit. Postapproval clinical trials are then required to confirm whether these drugs offer clinical benefit. Objective: To determine whether cancer drugs granted accelerated approval ultimately demonstrate clinical benefit and to evaluate the basis of conversion to regular approval. Design, Setting, and Participants: In this cohort study, publicly available FDA data were used to identify cancer drugs granted accelerated approval from 2013 to 2023. Main Outcomes and Measures: Demonstrated improvement in quality of life or overall survival in accelerated approvals with more than 5 years of follow-up, as well as confirmatory trial end points and time to conversion for drug-indication pairs converted to regular approval. Results: A total of 129 cancer drug-indication pairs were granted accelerated approval from 2013 to 2023. Among 46 indications with more than 5 years of follow-up (approved 2013-2017), approximately two-thirds (29, 63%) were converted to regular approval, 10 (22%) were withdrawn, and 7 (15%) remained ongoing after a median of 6.3 years. Fewer than half (20/46, 43%) demonstrated a clinical benefit in confirmatory trials. Time to withdrawal decreased from 9.9 years to 3.6 years, and time to regular approval increased from 1.6 years to 3.6 years. Among 48 drug-indication pairs converted to regular approval, 19 (40%) were converted based on overall survival, 21 (44%) on progression-free survival, 5 (10%) on response rate plus duration of response, 2 (4%) on response rate, and 1 (2%) despite a negative confirmatory trial. Comparing accelerated and regular approval indications, 18 of 48 (38%) were unchanged, while 30 of 48 (63%) had different indications (eg, earlier line of therapy). Conclusions and Relevance: Most cancer drugs granted accelerated approval did not demonstrate benefit in overall survival or quality of life within 5 years of accelerated approval. Patients should be clearly informed about the cancer drugs that use the accelerated approval pathway and do not end up showing benefits in patient-centered clinical outcomes.

The promise and harms of screening for plasma cell dyscrasias.

In this perspective, we highlight both the promise and harms of screening for plasma cell dyscrasias, as well as the implications of the use of mass spectrometry for diagnosing monoclonal gammopathy of undetermined significance in routine practice.

Hypocalcaemia following denosumab in prostate cancer: A clinical review.

OBJECTIVES: Denosumab is often used in men with advanced prostate cancer to prevent skeletal-related events, but can be associated with severe hypocalcaemia. Our objective was to review the pathophysiology, identify risk factors and provide recommendations for prevention and management of denosumab-associated hypocalcaemia. DESIGN: We reviewed the literature regarding denosumab-associated severe hypocalcaemia, defined as necessitating hospitalization for intravenous calcium treatment, in the context of prostate cancer. PATIENTS: Men with prostate cancer with severe denosumab-associated hypocalcemia. RESULTS: We identified 20 men with prostate cancer with severe denosumab-associated hypocalcemia, including the present case. Median age (range) was 70 years (45-86). All had skeletal metastases and presented with symptomatic hypocalcemia 16 days (4-35) after the initial (n = 18) or second (n = 2) denosumab treatment, with a serum total calcium of 1.36 mmol/L (1.13-1.91). The key risk factor was presence of active osteoblastic metastases, evidenced by elevated serum alkaline phosphatase, 838 U/L (58-2620) and supportive imaging. Other risk factors reported in some men included vitamin D deficiency (<50 nmol/L), 25-OH vitamin D 44 nmol/L (22-81), renal impairment, serum creatinine 103 µmol/L (62-1131) and hypomagnesaemia, 0.82 mmol/L (0.29-1.20). Men received intravenous calcium infusions for 16 days (1-90), and median total intravenous elemental calcium requirements were 3.17 g (0.47-26.65). CONCLUSIONS: Denosumab treatment in men with metastatic prostate cancer can be associated with life-threatening hypocalcaemia requiring prolonged hospitalization for intravenous calcium treatment. Modifiable risk factors should be corrected before denosumab administration. In men with active osteoblastic metastases, consideration should be given to delay denosumab treatment until underlying disease activity is controlled, and/or be administered with close monitoring and proactive treatment with calcium and calcitriol.

The Double-Edged Sword of Extremely High Prices for Gene Therapies in Sickle Cell Disease.

This Viewpoint discusses the high cost of new gene therapies for sickle cell disease, the challenges these costs pose for health care access, and new policy approaches to ensure fair reimbursement for payers and manufacturers without further increasing health care costs or barriers to access for underserved populations.

US Food and Drug Administration's Directive to Deal With Delayed Confirmatory Trials: Lessons From Pralatrexate and Belinostat for T-Cell Lymphoma.

The FDA's directive to deal with delayed confirmatory trials: lessons from pralatrexate and belinostat for T-cell lymphoma.

Second primary malignancies after CAR T-cell therapy: A systematic review and meta-analysis of 5,517 lymphoma and myeloma patients.

PURPOSE: CAR T-cell therapy is a potent immunotherapy for hematologic malignancies, but patients can develop long-term adverse events including second primary malignancies (SPMs) that impact morbidity and mortality. To delineate the frequency and subtypes of SPMs following CAR-T in lymphoma and myeloma, we performed a systematic review and meta-analysis. DESIGN: A literature search was conducted in the MEDLINE, Embase, and CENTRAL (Cochrane) databases. Following extraction of SPM cases and assignment of malignant origin, we analyzed SPM point estimates using random effect models. RESULTS: We identified 326 SPMs across 5,517 patients from 18 clinical trials (CT) and 7 real-world studies (RWS). With a median follow-up of 21.7 months, the overall SPM point estimate was 5.8% (95%CI 4.7-7.2). SPM estimates were associated with treatment setting (CT>RWS), duration of follow-up, and number of prior treatment lines, which were each confirmed as independent study-level risk factors of SPM in a meta-regression model. A subgroup meta-analysis of the four trials that randomized CAR-T versus standard-of-care revealed a similar risk of SPM with either treatment strategy (p=0.92). In a distribution analysis of SPM subtypes, hematologic malignancies were the most common (37%), followed by solid tumors (27%) and non-melanoma skin cancers (16%). T-cell malignancies represented a small minority of events (1.5%). We noted disease- and product-specific variations in SPM distribution. CONCLUSIONS: These data raise awareness of SPM as a clinically relevant long-term adverse event in patients receiving CAR T-cell therapy. However, our findings do not indicate that SPM frequency is higher with CAR-T versus previous standard-of-care strategies.

Multiple myeloma clinical trials exclude patients with the highest-risk disease: a systematic review of trial exclusion criteria.

Patients with certain subsets of multiple myeloma continue to have poor outcomes and are in need of novel treatment approaches. Strict eligibility criteria for randomized controlled trials (RCTs) limit access to clinical trials and limit the external validity of trial results for these patients. We systematically reviewed RCTs in newly diagnosed myeloma from 2006 to 2023 to ascertain the prevalence of 12 key exclusion criteria and trends over time. 80 RCTs were included. Exclusion criteria included: age in 43 (51%) trials; projected life expectancy in 20 (24%); performance status in 74 (87%); non-secretory and/or oligosecretory disease in 47 (55%), hepatic function in 64 (79%), renal function in 63 (74%), hematological thresholds in 50 (59%), prior malignancy in 68 (80%), and neuropathy in 50 (59%). For 53 trials which had detailed exclusion criteria available, plasma cell leukemia was excluded in 21 (40%), extramedullary disease in 5 (9%) and CNS disease in 13 (25%). The percentage of studies invoking each of these exclusion criteria did not significantly improve over time on univariate regression analysis, and exclusion criteria relating to neuropathy have worsened. The restrictive eligibility criteria of most myeloma RCTs perpetuate a cycle where limited data exists to treat challenging myeloma subtypes.

Utility of FDG-PET in predicting the histology of relapsed or refractory lymphoma.

ABSTRACT: 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) is a valuable prognostic tool in modern lymphoma care. In this study, we explored the use of quantitative FDG-PET parameters in predicting the histology of suspected relapsed or refractory (R/R) lymphoma. We retrospectively analyzed 290 FDG-PET scans performed for suspected R/R lymphoma. FDG-PET parameters measured were maximum and mean standardized uptake value (SUVMax and SUVMean), total metabolic tumor volume, and total lesion glycolysis (TLG). Receiver operating characteristic curve analysis was used to obtain the optimal thresholds that best discriminate (1) benign vs R/R lymphoma, (2) indolent vs aggressive non-Hodgkin lymphoma (NHL), and (3) aggressive transformation of indolent NHL. We found that although all 4 FDG-PET parameters discriminated R/R lymphoma from benign histology, TLG was the best performing parameter (optimal cut-off ≥245, sensitivity 63%, specificity 86%, positive predictive value [PPV] 97%, negative predictive value [NPV] 30%, area under the curve [AUC] 0.798, and P < .001). SUVMax discriminated aggressive from indolent NHL with modest accuracy (optimal threshold ≥15, sensitivity 46%, specificity 79%, PPV 82%, NPV 38%, AUC 0.638, and P < .001). In patients with a prior diagnosis of indolent NHL, SUVMax was a modest predictor of transformation (optimal cut-off ≥12, sensitivity 71%, specificity 61%, PPV 50%, NPV 78%, AUC 0.676, and P .006). Additionally, SUVMax ≥25 and an increase in SUVMax (ΔSUVMax) from baseline ≥150% were highly specific (96% and 94%, respectively). These FDG-PET thresholds can aid in identification of suspected R/R lymphoma cases with higher likelihood of R/R disease and aggressive transformation of indolent NHL, guiding the necessity and urgency of biopsy.

Use of subjective minimizing language at hematology and oncology conferences: A systematic review.

BACKGROUND: Subjective minimizing language in oncology conferences may undermine patient-centered care and hinder comprehensive treatment strategies. Subjective terms like "safe," "tolerable," and "well-tolerated" can vary in interpretation among individuals, making it difficult to compare results across trials and potentially downplaying significant risks and limitations associated with treatments. METHODS: This study evaluates subjective minimizing language in major oncology conferences and its use in adverse event reporting. We conducted a search of three electronic databases, ASCO, ASH, and ESMO, for published abstracts from January 1, 2019, to December 31, 2021. This study included prospective cohort studies or clinical trials in humans that used safety terms like "safe," "well-tolerated," "tolerable," "no new safety signal," or "no new safety concern" in the abstract text. RESULTS: Out of 34,975 reviewed records, 5299 (15.2%) abstracts used subjective minimizing language terms. The analysis included 2797 (52.8%) abstracts meeting the inclusion criteria. The majority of studies were Phase 1 trials (45.5%), followed by Phase 2 (29.6%) and Phase 3 trials (7.4%). Solid tumors accounted for the most common disease category (56.5%), followed by malignant hematology following (37.1%). Subjective minimizing terms like "safe" (69.2%), "well-tolerated" (53.2%), "tolerable" (25.6%), and "no new safety signal/concerns" (10%) were used frequently. Of the abstracts using subjective minimizing language (n = 2797), 81.9% reported data on any grade adverse events (AEs). Grade I/II AEs were reported in 62.6% of abstracts, Grade III/IV AEs in 78%, and Grade V AEs (death related to AEs) in 8.8%. Discontinuation due to AEs occurred in 11.4% (SD 9.5%) of studies using subjective minimizing language terms. CONCLUSIONS: Frequent use of subjective minimizing language in major oncology conferences' abstracts may obscure interpretation of study results and the safety of novel treatments. Researchers and clinicians should provide precise and standardized information to avoid overstatement of benefits and understand the true impact of interventions on patients' safety and well-being.

A systematic review and meta-analysis of nonrelapse mortality after CAR T cell therapy.

Although chimeric antigen receptor (CAR) T cell therapy represents a transformative immunotherapy, it is also associated with distinct toxicities that contribute to morbidity and mortality. In this systematic review and meta-analysis, we searched MEDLINE, Embase and CINAHL (Cochrane) for reports of nonrelapse mortality (NRM) after CAR T cell therapy in lymphoma and multiple myeloma up to March 2024. After extraction of causes and numbers of death, we analyzed NRM point estimates using random-effect models. We identified 7,604 patients across 18 clinical trials and 28 real-world studies. NRM point estimates varied across disease entities and were highest in patients with mantle-cell lymphoma (10.6%), followed by multiple myeloma (8.0%), large B cell lymphoma (6.1%) and indolent lymphoma (5.7%). Entity-specific meta-regression models for large B cell lymphoma and multiple myeloma revealed that axicabtagene ciloleucel and ciltacabtagene autoleucel were independently associated with increased NRM point estimates, respectively. Of 574 reported nonrelapse deaths, over half were attributed to infections (50.9%), followed by other malignancies (7.8%) and cardiovascular/respiratory events (7.3%). Conversely, the CAR T cell-specific side effects, immune effector cell-associated neurotoxicity syndrome/neurotoxicity, cytokine release syndrome and hemophagocytic lymphohistiocytosis, represented only a minority of nonrelapse deaths (cumulatively 11.5%). Our findings underline the critical importance of infectious complications after CAR T cell therapy and support the comprehensive reporting of NRM, including specific causes and long-term outcomes.

Dietary interventions in cancer: a systematic review of all randomized controlled trials.

BACKGROUND: Prior systematic reviews addressing the impact of diet on cancer outcomes have focused on specific dietary interventions. In this systematic review, we assessed all randomized controlled trials (RCTs) investigating dietary interventions for cancer patients, examining the range of interventions, endpoints, patient populations, and results. METHODS: This systematic review identified all RCTs conducted before January 2023 testing dietary interventions in patients with cancer. Assessed outcomes included quality of life, functional outcomes, clinical cancer measurements (eg, progression-free survival, response rates), overall survival, and translational endpoints (eg, inflammatory markers). RESULTS: In total, 252 RCTs were identified involving 31 067 patients. The median sample size was 71 (interquartile range 41 to 118), and 80 (32%) studies had a sample size greater than 100. Most trials (n = 184, 73%) were conducted in the adjuvant setting. Weight or body composition and translational endpoints were the most common primary endpoints (n = 64, 25%; n = 52, 21%, respectively). Direct cancer measurements and overall survival were primary endpoints in 20 (8%) and 7 (3%) studies, respectively. Eight trials with a primary endpoint of cancer measurement (40%) met their endpoint. Large trials in colon (n = 1429), breast (n = 3088), and prostate cancer (n = 478) each showed no effect of dietary interventions on endpoints measuring cancer. CONCLUSION: Most RCTs of dietary interventions in cancer are small and measure nonclinical endpoints. Although only a small number of large RCTs have been conducted to date, these trials have not shown an improvement in cancer outcomes. Currently, there is limited evidence to support dietary interventions as a therapeutic tool in cancer care.

Disseminated Invasive Mucormycosis Infection Following Autologous Stem Cell Transplantation for Diffuse Large B-Cell Lymphoma.

Invasive fungal infections (IFI) are challenging to predict, diagnose and treat, and are associated with a particularly high mortality among patients with hematological malignancies. They are relatively uncommon in patients with lymphoma, compared with those with acute leukemia or undergoing allogeneic transplantation. We present a patient, autografted for recurrent lymphoma, with fever and refractory diarrhea persisting post engraftment, eventually attributable to disseminated mucor infection. This case illustrates the challenge of timely diagnosis and initiation of treatment for IFI in lymphoma patients, who do not routinely receive antifungal prophylaxis, and the importance of aggressive investigation and symptom-directed tissue sampling for evidence of IFI in febrile immunocompromised hosts not responding to broad-spectrum antibiotics.