Safety and Toxicity Profiles of CAR T Cell Therapy in Non-Hodgkin Lymphoma: A Systematic Review and Meta-Analysis.

BACKGROUND: The application of CD19-directed chimeric antigen receptor T (CAR T) cell therapy has improved outcomes for thousands of patients with non-Hodgkin B cell lymphoma (NHL). The toxicities associated with various CAR T cell products, however, can be severe and difficult to anticipate. METHODS: In this systematic review and meta-analysis, we set out to determine whether there are measurable differences in common toxicities, including cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), cytopenias, and infections, between CAR T products that are commercially available for the treatment of NHL. RESULTS: After a stringent study selection process, we used a cohort of 1364 patients enrolled in 15 prospective clinical trials investigating the use of axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), and tisagenlecleucel (tisa-cel). We found that the rates of CRS and ICANS were significantly higher with axi-cel as compared to both liso-cel and tisa-cel. Conversely, we demonstrated that rates of all-grade and severe neutropenia were significantly greater with liso-cel. Febrile neutropenia and all-grade infection rates did not differ significantly between products though rates of severe infection were increased with axi-cel. CONCLUSIONS: Overall, this study serves as the first to delineate toxicity profiles associated with various available CAR T products. By better understanding associated toxicities, it may become possible to tailor therapies towards individual patients and anticipate the development of toxicities at earlier stages.

Efficacy and Toxicity of CD19 Chimeric Antigen Receptor T Cell Therapy for Lymphoma in Solid Organ Transplant Recipients: A Systematic Review and Meta-Analysis.

The safety and efficacy of chimeric antigen receptor (CAR) T cell therapy in solid organ transplant recipients is poorly understood, given the paucity of available data in this patient population. There is a theoretical risk of compromising transplanted organ function with CAR T cell therapy; conversely, organ transplantation-related immunosuppression can alter the function of CAR T cells. Given the prevalence of post-transplantation lymphoproliferative disease, which often can be difficult to treat with conventional chemoimmunotherapy, understanding the risks and benefits of delivering lymphoma-directed CAR T cell therapy in solid organ transplant recipients is of utmost importance. We sought to determine the efficacy of CAR T cell therapy in solid organ transplant recipients as well as the associated adverse effects, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and compromised solid organ transplant function. We conducted a systematic review and meta-analysis of adult recipients of solid organ transplant who received CAR T cell therapy for non-Hodgkin lymphoma. Primary outcomes included efficacy, defined as overall response (OR), complete response (CR), progression-free survival, and overall survival, as well as rates of CRS and ICANS. Secondary outcomes included rates of transplanted organ loss, compromised organ function, and alterations to immunosuppressant regimens. After a systematic literature review and 2-reviewer screening process, we identified 10 studies suitable for descriptive analysis and 4 studies suitable for meta-analysis. Among all patients, 69% (24 of 35) achieved a response to CAR T cell therapy, and 52% (18 of 35) achieved a CR. CRS of any grade occurred in 83% (29 of 35), and CRS grade ≥3 occurred in 9% (3 of 35). Sixty percent of the patients (21 of 35) developed ICANS, and 34% (12 of 35) developed ICANS grade ≥3. The incidence of any grade 5 toxicity among all patients was 11% (4 of 35). Fourteen percent of the patients (5 of 35) experienced loss of the transplanted organ. Immunosuppressant therapy was held in 22 patients but eventually restarted in 68% of them (15 of 22). Among the studies included in the meta-analysis, the pooled OR rate was 70% (95% confidence interval [CI], 29.2% to 100%; I2 = 71%) and the pooled CR rate was 46% (95% CI, 25.4% to 67.8%; I2 = 29%). The rates of any grade CRS and grade ≥3 CRS were 88% (95% CI, 69% to 99%; I2 = 0%) and 5% (95% CI, 0% to 21%; I2 = 0%), respectively. The rates of any grade ICANS and ICANS grade ≥3 were 54% (95% CI, 9% to 96%; I2 = 68%) and 40% (95% CI, 3% to 85%; I2 = 63%), respectively. The efficacy of CAR T cell therapy in solid organ transplant recipients is comparable to that in the general population as reported in prior investigational studies, with an acceptable toxicity profile in terms of CRS, ICANS, and transplanted organ compromise. Further studies are needed to determine long-term effects on organ function, sustained response rates, and best practices peri-CAR T infusion period in this patient population.

Novel treatment for mantle cell lymphoma - impact of BTK inhibitors and beyond.

Mantle cell lymphoma (MCL) primarily affects older adults, accounting for 3-10% of all non-Hodgkin lymphoma (NHL) in western countries. The disease course of MCL is heterogenous; driven by clinical, cytogenetics, and molecular features that shape differences in outcomes, including proliferation index, MIPI scores, and mutational profile such as TP53 aberration. The advent of novel agents has fundamentally evolved the treatment landscape for MCL with treatment strategies that can now be more effectively tailored based on both patient- and disease-specific factors. In this review, we discuss the major classes of novel agents used for the treatment of MCL, focusing on efficacy and notable toxicities of BTK inhibitors. We further examine effective novel combination regimens and, lastly, discuss future directions for the evolution of targeted approaches for the treatment of MCL.

Nine-year follow-up of lenalidomide plus rituximab as initial treatment for mantle cell lymphoma.

Although chemoimmunotherapy is the current standard of care for initial treatment of mantle cell lymphoma (MCL), newer data suggest that there may be a role for a chemotherapy-free approach. We report the 9-year follow-up results of a multicenter, phase 2 study of lenalidomide plus rituximab (LR) as the initial treatment of MCL. The LR doublet is used as induction and maintenance until progression, with optional discontinuation after 3 years. We previously reported an overall response rate of 92% in evaluable patients, with 64% achieving a complete response. At a median follow-up of 103 months, 17 of 36 evaluable patients (47%) remain in remission. The 9-year progression-free survival and overall survival were 51% and 66%, respectively. During maintenance, hematologic adverse events included asymptomatic grade 3 or 4 cytopenia (42% neutropenia, 5% thrombocytopenia, and 3% anemia) and mostly grade 1 to 2 infections managed in the outpatient setting (50% upper respiratory infections, 21% urinary tract infections, 16% sinusitis, 16% cellulitis, and 13% pneumonia, with 5% requiring hospitalization). More patients developed grade 1 and 2 neuropathy during maintenance therapy (29%) than during induction therapy (8%). Twenty-one percent of patients developed secondary malignancies, including 5% with invasive malignancies, whereas the remainder were noninvasive skin cancers treated with local skin-directed therapy. Two patients permanently discontinued therapy because of concerns of immunosuppression during the COVID-19 pandemic. With long-term follow-up, LR continues to demonstrate prolonged, durable responses with manageable safety as initial induction therapy. This trial was registered at www.clinicaltrials.gov as #NCT01472562.

Biomarkers of Progression and Risk Stratification in Asymptomatic Waldenström Macroglobulinemia.

Waldenström macroglobulinemia is an indolent IgM-secreting B-cell lymphoplasmacytic lymphoma that is preceded by an asymptomatic stage. Clinical and molecular features have been used in risk models to predict progression rates in different asymptomatic subgroups. Risk models used both disease-specific and nonspecific biomarkers for asymptomatic patients. Recently, models that incorporate continuous variables rather than distinct cutoffs have emerged to more accurately predict the risk of progression. Integrating genetic alterations to the clinical models is a promising approach that could improve risk stratification and management of asymptomatic patients.

Synthetic CRISPR/Cas9 reagents facilitate genome editing and homology directed repair.

CRISPR/Cas9 has become a powerful tool for genome editing in zebrafish that permits the rapid generation of loss of function mutations and the knock-in of specific alleles using DNA templates and homology directed repair (HDR). We examined the efficiency of synthetic, chemically modified gRNAs and demonstrate induction of indels and large genomic deletions in combination with recombinant Cas9 protein. We developed an in vivo genetic assay to measure HDR efficiency and we utilized this assay to test the effect of altering template design on HDR. Utilizing synthetic gRNAs and linear dsDNA templates, we successfully performed knock-in of fluorophores at multiple genomic loci and demonstrate transmission through the germline at high efficiency. We demonstrate that synthetic HDR templates can be used to knock-in bacterial nitroreductase (ntr) to facilitate lineage ablation of specific cell types. Collectively, our data demonstrate the utility of combining synthetic gRNAs and dsDNA templates to perform homology directed repair and genome editing in vivo.

Cost-effectiveness of Operative Versus Non-operative Management of Acute Achilles Tendon Ruptures.

BACKGROUND: The management of acute Achilles tendon ruptures is controversial, and most injuries are treated with surgery in the USA. The cost utility of operative versus non-operative treatment of acute Achilles tendon injury is unclear. QUESTIONS/PURPOSES: The purpose of this study was to compare the cost-effectiveness of operative versus functional non-operative treatment of acute Achilles tendon ruptures. METHODS: A Markov cost-utility analysis was conducted from the societal perspective using a 2-year time horizon. Hospital costs were derived from New York State billing data, and physician and rehabilitation costs were derived from the Medicare physician fee schedule. Indirect costs of missed work were calculated using estimates from the US Bureau of Labor Statistics. Rates of re-rupture, major and minor complications, and the associated costs were obtained from the literature. Effectiveness was expressed in quality-adjusted life years (QALYs). For the base-case analysis, operative and non-operative patients were assumed to have the same utilities (quality of life) following surgery. Deterministic and probabilistic sensitivity analyses were conducted to evaluate the robustness of model assumptions. RESULTS: In the base-case model, non-operative management of acute Achilles tendon ruptures dominated operative management, resulting in both lower costs and greater QALY gains. The differences in costs and effectiveness were relatively small. The benefit of non-operative treatment was 1.69 QALYs, and the benefit of operative treatment was 1.67 QALYs. Similarly, the total cost of operative and non-operative management was $13,936 versus $13,413, respectively. In sensitivity analyses, surgical costs and days of missed work were important drivers of cost-effectiveness. If hospitalization costs dropped below $2621 (compared with $3145) or the hourly wage rose above $29 (compared with $24), then operative treatment became a cost-effective strategy at the willingness-to-pay threshold of $50,000/QALY. The model results were also highly sensitive to the relative utilities for operative versus non-operative treatment. If non-operative utilities decreased relative to operative utilities by just 2%, then operative management became the dominant treatment strategy. CONCLUSION: For acute Achilles tendon ruptures, non-operative treatment provided greater benefits and lower costs than operative management in the base case; however, surgical costs and the economic impact associated with return to work are important determinants of the preferred cost-effective strategy.

Fluoroscopically guided caudal epidural steroid injections for axial low back pain associated with central disc protrusions: a prospective outcome study.

PURPOSE: To determine if axial low back pain (LBP) associated with central disc protrusions can be improved by caudal epidural steroid injections (ESIs). METHODS: Adults with chronic (> 3 months) moderate-to-severe axial LBP with L4-5 and/or L5-S1 central disc protrusions were enrolled in this prospective study. Participants underwent caudal ESIs under standard-of-care practice. The numerical rating scale (NRS) pain score, modified North American Spine Society satisfaction, and Roland Morris Disability Questionnaire (RMDQ) were collected at one week, one month, three months, six months, and one year post-injection. Pre-injection magnetic resonance images were assessed by a musculoskeletal radiologist. RESULTS: Sixty-eight participants (42 males, 26 females) were analyzed. There were statistically significant improvements in all outcome measures at all follow-up time points, with the exception of NRS best pain at six months. Clinically significant improvements in outcomes were observed at various time points: at three months and one year for current pain; at one week, one month, three months, six months, and one year for worst pain; and at one month and one year for RMDQ. The proportion of satisfied participants ranged from 57 to 69% throughout the study. No adverse events were observed. CONCLUSIONS: This study demonstrated significant improvements in pain and function following caudal ESIs in a cohort of axial LBP with associated central disc protrusions. Further studies, including the use of randomized controlled trials, are needed to determine the ideal subset of candidates for this treatment and to explore additional applications that caudal ESIs may have for chronic LBP.

Co-diagnoses of spondylolysis and femoroacetabular impingement: a case series of adolescent athletes.

Locating the source of lumbopelvic-hip pain requires the consideration of multiple clinical pathways. Although low back pain has an incidence of 50% in the adolescent population, the pathophysiology in this population typically differs from that of other age groups. Dynamic mechanical impairments of the hip, such as femoroacetabular impingement, may contribute to the pathogenesis of adolescent low back pain. Eight adolescent male athletes who presented to a single provider with a primary complaint of low back pain with hip pain or motion loss on exam and were ultimately diagnosed with lumbar spondylolysis and dynamic mechanical hip issues between 2009 and 2011 were included. The age at spondylolysis diagnosis ranged from 15 to 19 years (mean ± standard deviation: 16.3 ± 1.3 years). Seven patients had cam-type impingement, whereas one presented with pincer-type impingement. All patients demonstrated either decreased internal rotation at 90 degrees of hip flexion and neutral abduction or pain on the Flexion Adduction Internal Rotation test on at least one of hip. All eight patients were treated initially with 6 weeks of physical therapy consisting of attempted restoration of hip motion and the graduated progression of hip and spine stabilization exercises. Five patients (62.5%) returned to sport at an average of 11.2 weeks (range: 6-16 weeks). For three patients (37.5%), hip pain and motion loss persisted, thus requiring surgery. All subjects had symptoms for at least 6 weeks, with 6 months as the longest duration. This report is the first documented series of adolescent athletes with co-diagnoses of spondylolysis and femoroacetabular impingement. Study Information: This retrospective case series was approved by the Institutional Review Board at Hospital for Special Surgery.

The electrodiagnostic natural history of parsonage-turner syndrome.

INTRODUCTION: Recovery from Parsonage-Turner syndrome (PTS) is generally favorable, although recovery times have been shown to vary, in part because there are no universally accepted outcome measures. In this study, we describe the electrodiagnostic natural history of this condition based on objective electrodiagnostic testing, and propose that complete electrodiagnostic recovery can be seen as early as 1 year. METHODS: Twenty-six subjects with 29 affected nerves confirmed as PTS were followed every 3 months for electrodiagnostic testing, or until full reinnervation was confirmed. RESULTS: Twenty-three cases (79.3%) demonstrated electrodiagnostic evidence of initial recovery at a mean of 5.8 months. Nine cases (31%) showed complete electrodiagnostic recovery at a mean of 1 year. When excluding cases with <1 year of follow-up, 52.9% achieved complete electrodiagnostic recovery. CONCLUSIONS: In contrast to previous reports, full electrodiagnostic recovery of PTS was demonstrated at a mean of 1 year in > 50% of patients with longer term follow-up. Muscle Nerve 56: 737-743, 2017.

Relationship of Radiographic and Clinical Parameters With Hallux Valgus and Second Ray Pathology.

BACKGROUND: Hallux valgus is frequently associated with additional forefoot pathologies, including hammertoes and midfoot osteoarthritis (OA). However, the pathogenesis of these concurrent pathologies remains to be elucidated. We sought to determine whether there is a relationship between demographic and radiographic parameters and the incidence of secondary pathologies in the setting of a bunion, with an emphasis on second tarsometatarsal (TMT) OA and hammertoes. METHODS: A total of 153 patients (172 feet) who underwent reconstruction for hallux valgus were divided into 3 groups: (1) bunion only (61 patients), (2) bunion with hammertoe without second TMT joint OA (78 patients), and (3) bunion with second TMT joint OA (14 patients). Preoperative age, sex, and body mass index (BMI) as well as hallux valgus angle (HVA), intermetatarsal angle (IMA), metatarsus adductus angle (MAA), ratio of second to first metatarsal length, and Meary's angle were recorded. One-way analysis of variance (normality demonstrated) and Kruskal-Wallis (normality not demonstrated) tests were used to assess differences in continuous variables. Post hoc tests were conducted with the Bonferroni technique. Associations between discrete variables and the study groups were analyzed using χ2 tests. Following the univariate analysis, multinomial logistic regression models were built to determine potential risk factors for hammertoe or TMT OA group placement. RESULTS: Patients in the hammertoe and TMT OA groups were significantly older than patients in the bunion only group ( P < .001 for both pairwise comparisons) and had significantly higher BMIs ( P = .024 and P < .001, respectively). Patients in the TMT OA group had a significantly higher mean HVA than patients in the bunion-only group ( P = .004) and a significantly higher mean MAA relative to both other study groups ( P ≤ .001 for both comparisons). IMA, Meary's angle, and the ratio of second to first metatarsal length did not differ significantly between groups. In the multivariate analysis, hammertoe group assignment was predicted only by age and HVA, while midfoot OA group assignment was predicted by age, HVA, BMI, and MAA. CONCLUSION: Our data show that older age and increased HVA were predictors of both second ray pathologies studied. Higher BMI and MAA were predictive only of TMT joint OA. These data may help identify patients with hallux valgus who are at greater risk for developing secondary pathologies. LEVEL OF EVIDENCE: Level III, retrospective comparative series.

Utilization of Routine Primary Care Services Among Dancers.

This study examines the current utilization of primary and preventive health care services among dancers in order to assess their self-reported primary care needs. Participants were 37 dancers from a variety of dance backgrounds who presented for a free dancer health screening in a large US metropolitan area (30 females, 7 males; mean age: 27.5 ± 7.4 years; age range: 19 to 49 years; mean years of professional dancing: 6.4 ± 5.4 years). Dancers were screened for use of primary care, mental health, and women's health resources using the Health Screen for Professional Dancers developed by the Task Force on Dancer Health. Most dancers had health insurance (62.2%), but within the last 2 years, only approximately half of them (54.1%) reported having a physical examination by a physician. Within the last year, 54.1% of dancers had had a dental check-up, and 56.7% of female dancers received gynecologic care. Thirty percent of female participants indicated irregular menstrual cycles, 16.7% had never been to a gynecologist, and 16.7% were taking birth control. Utilization of calcium and vitamin D supplementation was 27.0% and 29.7%, respectively, and 73.0% were interested in nutritional counseling. A high rate of psychological fatigue and sleep deprivation was found (35.1%), along with a concomitant high rate of self-reported need for mental health counseling (29.7%). Cigarette and recreational drug use was low (5.4% and 5.4%); however, 32.4% engaged in binge drinking within the last year (based on the CDC definition). These findings indicate that dancers infrequently access primary care services, despite high self-reported need for nutritional, mental, and menstrual health counseling and treatment. More studies are warranted to understand dancers' primary health care seeking behavior.

Lumbar Intradiskal Platelet-Rich Plasma (PRP) Injections: A Prospective, Double-Blind, Randomized Controlled Study.

OBJECTIVE: To determine whether single injections of autologous platelet-rich plasma (PRP) into symptomatic degenerative intervertebral disks will improve participant-reported pain and function. DESIGN: Prospective, double-blind, randomized controlled study. SETTING: Outpatient physiatric spine practice. PARTICIPANTS: Adults with chronic (≥6 months), moderate-to-severe lumbar diskogenic pain that was unresponsive to conservative treatment. METHODS: Participants were randomized to receive intradiskal PRP or contrast agent after provocative diskography. Data on pain, physical function, and participant satisfaction were collected at 1 week, 4 weeks, 8 weeks, 6 months, and 1 year. Participants in the control group who did not improve at 8 weeks were offered the option to receive PRP and subsequently followed. MAIN OUTCOME MEASURES: Functional Rating Index (FRI), Numeric Rating Scale (NRS) for pain, the pain and physical function domains of the 36-item Short Form Health Survey, and the modified North American Spine Society (NASS) Outcome Questionnaire were used. RESULTS: Forty-seven participants (29 in the treatment group, 18 in the control group) were analyzed by an independent observer with a 92% follow-up rate. Over 8 weeks of follow-up, there were statistically significant improvements in participants who received intradiskal PRP with regards to pain (NRS Best Pain) (P = .02), function (FRI) (P = .03), and patient satisfaction (NASS Outcome Questionnaire) (P = .01) compared with controls. No adverse events of disk space infection, neurologic injury, or progressive herniation were reported following the injection of PRP. CONCLUSION: Participants who received intradiskal PRP showed significant improvements in FRI, NRS Best Pain, and NASS patient satisfaction scores over 8 weeks compared with controls. Those who received PRP maintained significant improvements in FRI scores through at least 1 year of follow-up. Although these results are promising, further studies are needed to define the subset of participants most likely to respond to biologic intradiskal treatment and the ideal cellular characteristics of the intradiskal PRP injectate.