ABSTRACT
Mild traumatic brain injury (mTBI) represents a significant burden for individuals, economies, and healthcare systems worldwide. Recovery protocols focus on medication and physiotherapy-based interventions. Animal studies have shown that antioxidants, branched-chain amino acids and omega-3 fatty acids may improve neurophysiological outcomes after TBI. However, there appears to be a paucity of nutritional interventions in humans with chronic (≥1 month) symptomology post-mTBI. This systematic literature review aimed to consolidate evidence for nutrition and dietary-related interventions in humans with chronic mTBI. The review was registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD42021277780) and conducted following the Preferred Reporting for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Three reviewers searched five databases (PubMed/MEDLINE, Web of Science, SPORTDiscus, CINAHL Complete and Cochrane), which yielded 6164 studies. Nine studies met the inclusion criteria. The main finding was the lack of interventions conducted to date, and a quality assessment of the included studies was found to be fair to good. Due to heterogeneity, a meta-analysis was not feasible. The six nutrition areas identified (omega-3 fatty acids, melatonin, Enzogenol®, MLC901, ketogenic diet and phytocannabinoids) were safe and well-tolerated. It was found that these nutritional interventions may improve cognitive failures, sleep disturbances, anxiety, physical disability, systolic blood pressure volume and sport concussion assessment tool scores following mTBI. Potential areas of improvement identified for future studies included blinding, reporting compliance, and controlling for confounders. In conclusion, further research of higher quality is needed to investigate the role of nutrition in recovery from mTBI to reduce the burden of chronic outcomes following mTBI.
Subject(s)
Brain Concussion , Animals , Humans , Amino Acids, Branched-Chain , Antioxidants , Anxiety , Anxiety DisordersABSTRACT
BACKGROUND: Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, is effective in heavily pretreated patients with relapsed or refractory multiple myeloma. We investigated cilta-cel in earlier treatment lines in patients with lenalidomide-refractory disease. METHODS: In this phase 3, randomized, open-label trial, we assigned patients with lenalidomide-refractory multiple myeloma to receive cilta-cel or the physician's choice of effective standard care. All the patients had received one to three previous lines of treatment. The primary outcome was progression-free survival. RESULTS: A total of 419 patients underwent randomization (208 to receive cilta-cel and 211 to receive standard care). At a median follow-up of 15.9 months (range, 0.1 to 27.3), the median progression-free survival was not reached in the cilta-cel group and was 11.8 months in the standard-care group (hazard ratio, 0.26; 95% confidence interval [CI], 0.18 to 0.38; P<0.001). Progression-free survival at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group. More patients in the cilta-cel group than in the standard-care group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%), and an absence of minimal residual disease (60.6% vs. 15.6%). Death from any cause was reported in 39 patients and 46 patients, respectively (hazard ratio, 0.78; 95% CI, 0.5 to 1.2). Most patients reported grade 3 or 4 adverse events during treatment. Among the 176 patients who received cilta-cel in the as-treated population, 134 (76.1%) had cytokine release syndrome (grade 3 or 4, 1.1%; no grade 5), 8 (4.5%) had immune effector cell-associated neurotoxicity syndrome (all grade 1 or 2), 1 had movement and neurocognitive symptoms (grade 1), 16 (9.1%) had cranial nerve palsy (grade 2, 8.0%; grade 3, 1.1%), and 5 (2.8%) had CAR-T-related peripheral neuropathy (grade 1 or 2, 2.3%; grade 3, 0.6%). CONCLUSIONS: A single cilta-cel infusion resulted in a lower risk of disease progression or death than standard care in lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies. (Funded by Janssen and Legend Biotech; CARTITUDE-4 ClinicalTrials.gov number, NCT04181827.).
Subject(s)
Antineoplastic Agents, Immunological , B-Cell Maturation Antigen , Immunotherapy, Adoptive , Multiple Myeloma , Humans , Lenalidomide/adverse effects , Multiple Myeloma/drug therapy , Multiple Myeloma/mortality , Neurotoxicity Syndromes , Progression-Free Survival , B-Cell Maturation Antigen/immunology , Immunotherapy, Adoptive/methods , Antineoplastic Agents, Immunological/therapeutic use , Drug Resistance, NeoplasmABSTRACT
CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T cells are novel therapies showing great promise for patients with relapsed or refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (B-NHL). Single-arm studies showed significant variations in outcomes across distinct CD19 CAR T-cell products. To estimate the independent impact of the CAR T-cell product type on outcomes, we retrospectively analyzed data from 129 patients with R/R aggressive B-NHL treated with cyclophosphamide and fludarabine lymphodepletion followed by either a commercially available CD19 CAR T-cell therapy (axicabtagene ciloleucel [axicel] or tisagenlecleucel [tisacel]), or the investigational product JCAR014 on a phase 1/2 clinical trial (NCT01865617). After adjustment for age, hematopoietic cell transplantation-specific comorbidity index, lactate dehydrogenase (LDH), largest lesion diameter, and absolute lymphocyte count (ALC), CAR T-cell product type remained associated with outcomes in multivariable models. JCAR014 was independently associated with lower cytokine release syndrome (CRS) severity compared with axicel (adjusted odds ratio [aOR], 0.19; 95% confidence interval [CI]; 0.08-0.46), with a trend toward lower CRS severity with tisacel compared with axicel (aOR, 0.47; 95% CI, 0.21-1.06; P = .07). Tisacel (aOR, 0.17; 95% CI, 0.06-0.48) and JCAR014 (aOR, 0.17; 95% CI, 0.06-0.47) were both associated with lower immune effector cell-associated neurotoxicity syndrome severity compared with axicel. Lower odds of complete response (CR) were predicted with tisacel and JCAR014 compared with axicel. Although sensitivity analyses using either positron emission tomography- or computed tomography-based response criteria also suggested higher efficacy of axicel over JCAR014, the impact of tisacel vs axicel became undetermined. Higher preleukapheresis LDH, largest lesion diameter, and lower ALC were independently associated with lower odds of CR. We conclude that CD19 CAR T-cell product type independently impacts toxicity and efficacy in R/R aggressive B-NHL patients.
Subject(s)
Immunotherapy, Adoptive , Lymphoma, B-Cell , Antigens, CD19 , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Cytokine Release Syndrome , Humans , Lymphoma, B-Cell/therapy , Receptors, Chimeric Antigen , Retrospective Studies , T-LymphocytesABSTRACT
BACKGROUND: Second autologous transplants (SAT) are routinely performed in the setting of myeloma relapse, though data on outcomes are lacking. We conducted a single-center review of all multiple myeloma patients at OHSU who received SAT (excluding tandems) with responses assessed by International Myeloma Working Group (IMWG) criteria. RESULTS: Sixty-eight patients received SAT between 1999 and 2019. Risk by IMWG was available for 50 patients (10 high-risk). Median age at SAT was 61 (45-74). Median time between 1st and 2nd Autologous stem cell transplantation (ASCT) was 5.5 years (1.1 - 15.2). Median progression-free survival (PFS) after 1st ASCT (available for 53 pts) was 2.5 years (0.3 - 10). The average # of lines of therapy prior to SAT was 2.8 (1-14). SAT prep regimens (available for 67 pts) were: Fifty-one (87%) melphalan 200 mg/m2, 6 (9%) melphalan 140 mg/m2, 1 (2%) BEAM, 1 (2%) melphalan 200 mg/m2 and bortezomib. All used PBSC mobilization. Median overall survival (OS) after SAT was 4.68 years, and median PFS was 1.72 years. By treatment era (1999-2009 vs. 2010-2019), median OS was 1.97 vs. 5.52 years (P = .15). When analyzed by IMWG group (standard/low vs. high risk) median PFS and OS were not significantly different (1.87 vs. 1.61 years and 3.58 vs. 5.91 years, respectively). Treatment-Related Mortality (TRM) occurred in 1 patient (2%). CONCLUSION: Our experience with SAT for multiple myeloma (MM) shows that it has low TRM and is effective, with median OS >4.5 years, though with a shorter PFS than after 1st ASCT.
Subject(s)
Hematopoietic Stem Cell Transplantation , Multiple Myeloma , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Disease-Free Survival , Humans , Melphalan/therapeutic use , Multiple Myeloma/drug therapy , Neoplasm Recurrence, Local , Oregon , Retrospective Studies , Transplantation, Autologous , UniversitiesABSTRACT
Chimeric antigen receptor T-cell therapy (CAR T) is a novel intervention for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) and other hematologic malignancies. However, it is associated with prolonged hematologic toxicity (PHT) that is unpredictable and can significantly impair patients' quality of life. Reported here is a single-center experience with PHT in adult patients with R/R DLBCL who received commercial CAR T-cell therapy between March 1, 2018 and May 30, 2020. Prolonged hematologic toxicity was defined as ≥ grade 3 neutropenia or thrombocytopenia at day +30 after CAR T-cell therapy. Of the 31 patients identified, 18 patients (58%) developed PHT. Patients with PHT had a shorter 1-year overall survival (OS) than patients without PHT (36% vs. 81%, P < .05). There were no differences in the median time to ANC recovery for those with PHT compared to patients without PHT (16 days vs. 15 days). Several risk factors were identified to be associated with PHT including CRS (P = .002), receipt of tocilizumab (P = .002) or steroids (P = .033), peak ferritin >5000 ng/ml (P = .048), peak C-reactive protein (CRP) > 100 mg/L (P = .007), and ferritin greater than the upper limit of normal at day +30. Seven patients with PHT underwent a bone marrow biopsy after CAR T-cell therapy; all showed complete aplasia or were hypocellular with cellularity ranging from <5% to 10%. These findings identify PHT as a significant toxicity associated with CAR T-cell therapy and highlight the critical need for further investigations to describe PHT in larger cohorts and identify standards for management of this condition.
Subject(s)
Immunotherapy, Adoptive/adverse effects , Lymphoma, Large B-Cell, Diffuse/therapy , Neutropenia/etiology , Thrombocytopenia/etiology , Adrenal Cortex Hormones/administration & dosage , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Bone Marrow/pathology , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Female , Ferritins/blood , Humans , Infections/etiology , Kaplan-Meier Estimate , Lymphoma, Large B-Cell, Diffuse/blood , Lymphoma, Large B-Cell, Diffuse/drug therapy , Male , Middle Aged , Retrospective Studies , Vidarabine/administration & dosage , Vidarabine/analogs & derivatives , Young AdultABSTRACT
We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma (PMBCL), 5 with diffuse large B-cell lymphoma (DLBCL), and 2 with gray zone lymphoma (GZL). There were no treatment-related deaths; 32% of patients had non-hematological grade 3/4 toxicities. The overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end of treatment response assessment was permissible and used in 52% of all patients including 59% of patients with PMBCL. With a median follow-up of 30 months, the 2-year progression-free survival (PFS) and overall survival (OS) were 85% (95% CI: 66-94) and 100%, respectively. In the PMBCL cohort, 2-year PFS was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30+ B-cell lymphomas (NCT01994850).
Subject(s)
Immunoconjugates , Lymphoma, Large B-Cell, Diffuse , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Brentuximab Vedotin , Cyclophosphamide/therapeutic use , Doxorubicin/therapeutic use , Humans , Immunoconjugates/therapeutic use , Ki-1 Antigen , Lymphoma, Large B-Cell, Diffuse/drug therapy , Prednisone/therapeutic use , Rituximab/therapeutic use , Treatment Outcome , Vincristine/therapeutic useABSTRACT
Chimeric antigen receptor T cell (CAR-T) therapy is approved for treatment of relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL). Here we evaluate whether comorbidities, calculated using the Cumulative Illness Rating Scale (CIRS), predict survival for these patients. A retrospective chart review was performed at 4 academic institutions. All patients who underwent leukapheresis for commercial CAR-T therapy for R/R DLBCL were included. CIRS scores were calculated at the time of leukapheresis. High comorbidity was defined as either CIRS ≥7 or the presence of severe impairment (CIRS 3/4 in ≥1 system; CIRS-3+). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and differences in curves were detected by the log-rank test. A total of 130 patients were analyzed, 56.9% with CIRS ≥7 and 56.2% with CIRS-3+. After a median follow-up of 13 months, the median PFS was 6.7 months, and the median OS was not reached. On univariable analysis, Eastern Cooperative Oncology Group (ECOG) performance status (PS) was associated with inferior PFS (hazard ratio [HR], 1.45; 95% confidence interval [CI], 1.03-2.05; P = .03) and OS (HR, 1.76; 95% CI, 1.17-2.64; P = .007). Higher CIRS (CIRS ≥7 or CIRS-3+) was associated with inferior OS (HR, 2.12; 95%, CI, 1.06-4.22; P = .03) and a nonsignificant trend in worse PFS (HR, 1.45; 95% CI, .87-2.44; P = .16). In multivariable analyses, CIRS ≥7 or CIRS-3+ and ECOG PS maintained independent prognostic significance. Comorbidities as determined by CIRS and ECOG PS predict inferior survival in patients receiving CAR-T therapy for R/R DLBCL.
Subject(s)
Lymphoma, Large B-Cell, Diffuse , Receptors, Chimeric Antigen , Cell- and Tissue-Based Therapy , Comorbidity , Humans , Lymphoma, Large B-Cell, Diffuse/therapy , Retrospective StudiesABSTRACT
PURPOSE OF REVIEW: Despite national-level directives to reduce healthcare waste and promote high-value care (HVC), clinical educators struggle to equip trainees with the knowledge and skills needed to practice value-based care. In this review, we analyze ongoing efforts in graduate medical education (GME) to enhance trainee competence in delivery of high-value and cost-conscious care. RECENT FINDINGS: Surveys of residents and program directors have shown that while many training programs want to offer formal training in high-value care delivery, few succeed. Although several studies suggest that trainees model stewardship behaviors after clinical preceptors, there remains a shortage of faculty role models skilled in providing HVC. Preparing future hematologist-oncologists to provide cost-conscious care will require significant cultural change at the institutional and program levels and will depend heavily on the development of skilled clinical role models.
Subject(s)
Clinical Competence , Education, Medical, Graduate , Health Care Costs , Hematology/education , Quality Indicators, Health Care , Attitude of Health Personnel , Clinical Competence/economics , Clinical Competence/standards , Cost-Benefit Analysis , Curriculum , Education, Medical, Graduate/economics , Education, Medical, Graduate/standards , Health Care Costs/standards , Hematology/economics , Hematology/standards , Humans , Medical Overuse/prevention & control , Quality Indicators, Health Care/economics , Quality Indicators, Health Care/standardsABSTRACT
The correct spelling of the co-author should be listed as Sarah Nagle, MD.
ABSTRACT
PURPOSE OF REVIEW: Chimeric antigen receptor T cell (CAR-T) adoptive cell therapy is an effective treatment for patients with refractory B cell malignancies. As its use has grown, there has been an increase in the incidence of a serious, potentially fatal neurotoxicity known as immune effector cell-associated neurotoxicity syndrome (ICANS). This review discusses the clinical manifestations of this neurotoxicity syndrome, current grading systems, management strategies, and proposed biologic mechanisms leading to neurotoxicity. RECENT FINDINGS: Current research suggests that patients with a higher disease burden and higher CAR-T cell doses are positively associated with the development of ICANS, as are elevated serum levels of proinflammatory cytokines and the presence of cytokine release syndrome (CRS). While patterns observed on neuroimaging and electroencephalogram (EEG) are non-specific for the diagnosis of ICANS, each modality may provide helpful clinical information such as the detection of cerebral edema, the most serious of associated symptoms. Anti-epileptic medications and corticosteroids may ameliorate the symptoms of ICANS. The mechanism for ICANS is currently unknown; however, systemic inflammation and cytokine production triggering a cascade of endothelial activation and BBB disruption likely contribute. With limited treatment options available, further clinical research into the precise mechanism and treatment is urgently needed as the use of CAR-T and other adoptive cell therapies continues to grow.
ABSTRACT
BACKGROUND: Falls are a major public health concern in older adults, and the proportion of older adults that has been diagnosed with cancer is growing. Yet, while falls, peripheral neuropathy, and postural instability are more common in aging cancer survivors, it is unclear how these factors interact. RESEARCH QUESTION: Our objective was to examine how components of sway related to self-reported neuropathy and falls. METHODS: Postural sway during static stance was recorded with an inertial sensor (APDM Opal), placed on the lumbar spine region in 434 older female cancer survivors (mean age 63) and 49 healthy older female control subjects (mean age 63). Measures of sway were resolved into principal components that were compared between women with and women without self-reported falls in the previous 6 months and between those with and without self-reported symptoms of peripheral neuropathy. RESULTS: Cancer survivors had worse sway than healthy control subjects in components related to sway magnitude and mediolateral frequency of sway, but no difference in the component related to resultant / AP sway jerk and frequency. Cancer survivors who reported neuropathy were more likely to have higher resultant / AP sway frequencies and jerk than asymptomatic survivors, while survivors who reported a fall were more likely to have lower frequencies of mediolateral sway than non-fallers. Falls were more strongly associated with mediolateral sway in survivors with more severe neuropathy; whereas falls were more strongly associated with resultant / AP sway frequency in survivors with less severe neuropathy SIGNIFICANCE: Postural stability, falls, and neuropathy have complex interactions that can vary across components of postural sway. While the frequency of mediolateral sway was associated with falls across our entire cohort, neuropathy influenced the associations between specific characteristics of sway and falls, which may have implications for fall prevention interventions.
Subject(s)
Accidental Falls/prevention & control , Aging/physiology , Cancer Survivors , Peripheral Nervous System Diseases/physiopathology , Postural Balance/physiology , Self Report , Aged , Female , Humans , Middle Aged , Neoplasms/complications , Peripheral Nervous System Diseases/etiologyABSTRACT
Molecular imaging with 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is an established modality for response assessment in patients with lymphoma undergoing treatment. However, patients treated with novel immunotherapies may have false-positive PET/CT findings due to tumor site and systemic inflammation. In particular, treatment with autologous chimeric antigen receptor modified T-cells redirected at CD19 (CTL019 CAR-T cells) is often complicated by "cytokine release syndrome" (CRS) due to a severe systemic inflammatory reaction. Infiltration of tumors by activated CTL019 cells may impact radiographic and functional imaging findings. The role of PET/CT in patients treated with CTL019 has not previously been described. We performed a pilot, single-arm, prospective study to explore the utility of early PET/CT in patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) undergoing treatment with CTL019 CAR-T cells. Patients had PET/CT prior to CTL019 infusion and then early PET/CT at 1 month after treatment. The primary outcome was the amount/change in metabolically active tumor volume (MTV) and FDG uptake. We enrolled seven patients (DLBCL, three; FL, four). Six of 7 had baseline PET/CT with active disease. On post-treatment PET/CT, three patients had no residual MTV, two patients had a decrease in MTV and two patients had an increase in MTV. The three patients with no residual MTV all remain in remission >2 years post-treatment. The patients with less than complete response all subsequently relapsed. Development of CRS did not confound PET/CT findings. In patients with DLBCL and FL receiving CTL019 CAR-T cells, early PET/CT may predict response to this novel immunotherapy.
ABSTRACT
Posttransplant lymphoproliferative disorders (PTLD) represent an immunosuppression-related lymphoid or plasmacytic proliferation that occur in the setting of solid organ transplant or allogeneic hematopoietic stem cell transplantation (HSCT). PTLD is a devastating consequence of HSCT and solid organ transplantation with a high morbidity and mortality. Most commonly, PTLD is related to Epstein-Barr virus (EBV) infection, but an increasing number of non-EBV-related cases are occurring. Initial therapy involves withdrawal of immunosuppression with or without antibody or cytotoxic chemotherapy. Novel therapeutic approaches including EBV-specific cytotoxic T lymphocytes are currently being studied.
Subject(s)
Hematopoietic Stem Cell Transplantation/adverse effects , Lymphoproliferative Disorders/etiology , Transplantation Conditioning/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Humans , Lymphoproliferative Disorders/immunology , Lymphoproliferative Disorders/pathology , Transplantation Conditioning/methodsABSTRACT
Patients with relapsed/refractory Hodgkin lymphoma (RR-HL) who progress or relapse following autologous stem cell transplantation (ASCT) have historically had a poor prognosis. Several novel agents, particularly brentuximab vedotin, have shown efficacy in this setting. However, there remains a paucity of data characterizing outcomes outside of clinical trials and how these novel agents have impacted prognosis in general population of patients with RR-HL. Here, we conducted a retrospective analysis to evaluate outcomes in 87 patients with RR-HL with relapse post-ASCT. Treatment with novel agents (including brentuximab vedotin) was associated with significant improvement in median overall survival (OS) compared to patients who did not receive novel agents (85.6 vs 17.1 months; P < .001). Additional factors associated with improved OS in univariate analysis include treatment with radiation therapy post-ASCT (34.1 vs 17.0 months; P = .015), chemosensitivity (i.e., relapsed compared to primary refractory disease; 51.8 vs 25.6 months; p = 0.013), initial response to ASCT (i.e., CR/PR compared to SD/PD; 46.1 vs 20.4 months; P = .011), and transplantation in 2010 and later compared to prior to 2010 (not reached vs 24.5 months; P = .025). The current study demonstrates markedly improved OS in RR-HL patients treated with novel therapeutics and lends "real world" credence to the role of these agents in improving outcomes in the current era.
Subject(s)
Hematopoietic Stem Cell Transplantation , Hodgkin Disease/mortality , Hodgkin Disease/therapy , Immunoconjugates/administration & dosage , Adolescent , Adult , Aged , Autografts , Brentuximab Vedotin , Disease-Free Survival , Female , Humans , Male , Middle Aged , Recurrence , Retrospective Studies , Survival RateABSTRACT
AIM: To describe the long-term outcomes of patients with lymphoma in the CNS treated with rituximab, temozolomide and high-dose methotrexate without consolidation therapy. PATIENTS & METHODS: A retrospective cohort study of 46 consecutive patients with primary CNS lymphoma (PCNSL, 27 patients) or secondary CNS involvement of diffuse large B-cell lymphoma (DLBCL, 19 patients) who were treated with rituximab on day 1 in combination with high-dose methotrexate (days 1 and 15) and temozolomide (days 1-5) in 28-day cycles without further consolidation. RESULTS: Median follow-up was 21.2 months. Patients received a median of five cycles (range 1-15). Median overall survival (OS) was 26 months and median progression-free survival was 8.6 months. At 3 years, 37% of patients were alive and without evidence of disease. The patients with PCNSL had a significantly higher response rates (ORR 81 vs 47%; p = 0.015) and longer median OS (55.3 vs 4.8 months; p < 0.01) than those with secondary CNS DLBCL. Toxicities were mild and manageable. CONCLUSION: The rituximab, temozolomide and methotrexate regimen is an effective therapy for patients with PCNSL without the toxicities typically associated with consolidation therapy.
ABSTRACT
Relapsed and refractory hematologic malignancies have a very poor prognosis. Chimeric antigen receptor T cells are emerging as a powerful therapy in this setting. Early clinical trials of genetically modified T cells for the treatment of non-Hodgkin lymphoma, chronic lymphocytic leukemia, and acute lymphoblastic leukemia have shown high complete response rates in patients with few therapeutic options. Exploration is ongoing for other hematologic malignancies including multiple myeloma, acute myeloid leukemia, and Hodgkin lymphoma (HL). At the same time, the design and production of chimeric antigen receptor T cells are being advanced so that this therapy can be more widely utilized. Cytokine release syndrome and neurotoxicity are common, but they are treatable and fully reversible. This review will review available data as well as future developments and challenges in the field.
Subject(s)
Hematologic Neoplasms/immunology , Hematologic Neoplasms/therapy , Immunotherapy, Adoptive , Receptors, Antigen, T-Cell/genetics , Recombinant Fusion Proteins/genetics , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Animals , Antigens, Neoplasm/immunology , Cell- and Tissue-Based Therapy , Genetic Therapy , Hematologic Neoplasms/genetics , Humans , Immunotherapy, Adoptive/adverse effects , Immunotherapy, Adoptive/methods , Treatment OutcomeABSTRACT
Primary mediastinal B-cell lymphoma (PMBL) is a subtype of diffuse large B-cell lymphoma (DLBCL) that arises in the mediastinum from B-cells of thymic origin. Optimal management of patients with PMBL remains controversial. The present study evaluates outcomes of 27 PMBL patients treated with R-CHOP with or without radiation therapy (RT). It investigates the role of both interim and posttreatment fluorodeoxyglucose-positron emission tomography (FDG-PET) as prognostic markers of outcome. Additionally, it assesses postprogression therapies in the six patients who had progressive disease. At a median follow-up of 41.5 months (range: 6.1-147.2 months), OS was 95.5% (95% CI = 71.9-99.4) and progression-free survival (PFS) was 70.4% (95% CI = 49.4-83.9) for the entire cohort. The negative predictive values of interim and posttreatment FDG-PET scans were both 100%. Patients who failed initial therapy and were treated with salvage regimens and autologous stem cell transplantation (ASCT) all achieved and maintained CR. PMBL patients can achieve excellent outcomes with minimal toxicities when treated with R-CHOP with or without RT. Negative interim and negative posttreatment FDG-PET results identified PMBL patients who achieve long-term remission. However, the significance of both positive interim and positive posttreatment FDG-PET results needs to be better defined. Those who failed initial therapy were successfully treated with salvage regimens and ASCT.
Subject(s)
Fluorodeoxyglucose F18 , Lymphoma, B-Cell/diagnosis , Lymphoma, B-Cell/mortality , Mediastinal Neoplasms/diagnosis , Mediastinal Neoplasms/mortality , Positron-Emission Tomography , Adolescent , Adult , Antibodies, Monoclonal, Murine-Derived/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cyclophosphamide/therapeutic use , Doxorubicin/therapeutic use , Female , Humans , Lymphoma, B-Cell/therapy , Male , Mediastinal Neoplasms/therapy , Middle Aged , Neoplasm Staging , Outcome Assessment, Health Care , Prednisone/therapeutic use , Prognosis , Radiotherapy , Retrospective Studies , Rituximab , Survival Analysis , Tumor Burden , Vincristine/therapeutic use , Young AdultABSTRACT
Salvage chemotherapy followed by autologous stem cell transplant (ASCT) remains the current standard of care for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with chemosensitive disease. The addition of rituximab results in improved overall survival (OS) after first-line treatment, but cure rates of salvage therapy with ASCT are inferior when compared to historical controls. Historically, patients with DLBCL with disease progression following ASCT have had an extremely poor prognosis with a median OS of 3 months. However, there are little data regarding outcomes in the rituximab era. We performed a retrospective study of 56 patients with relapsed or refractory DLBCL with prior exposure to rituximab who had disease progression following ASCT. The median OS from progression following ASCT for the cohort was 9.9 months (95% CI: 5.3-13.1 months). Patients who progressed less than 1 year from ASCT had a significantly shorter OS than those who progressed at 1 year or greater from ASCT (8.2 vs. 26.7 months, P = 0.01). Patients with at least stable disease following ASCT had a longer OS than those who progressed immediately after ASCT (12.3 vs. 5.3 months, P = 0.01). Other factors associated with OS were International Prognostic Index (IPI) (P = 0.01) and LDH level (P = 0.0003) at the time of progression following ASCT. In the rituximab era, the prognosis for patients with disease progression following ASCT remains poor, but is improved when compared with historical controls. Ultimately, more work needs to be done to develop novel therapeutic strategies tailored to individual patients in this heterogeneous population.
Subject(s)
Antibodies, Monoclonal, Murine-Derived , Lymphoma, Large B-Cell, Diffuse/mortality , Lymphoma, Large B-Cell, Diffuse/therapy , Stem Cell Transplantation , Adolescent , Adult , Aged , Aged, 80 and over , Disease-Free Survival , Female , Humans , Male , Middle Aged , Recurrence , Retrospective Studies , Rituximab , Survival Rate , Time Factors , Transplantation, AutologousABSTRACT
OBJECTIVE: A prospective observational study of mycophenolate mofetil (MMF) treatment in patients with diffuse progressive cutaneous systemic sclerosis (SSc) of recent onset. METHODS: Twenty-five previously untreated consecutive patients with recent-onset (< 24 mo) diffuse progressive cutaneous SSc received MMF as the only disease-modifying therapy. Modified Rodnan skin score (mRSS) and affected body surface area (BSA) were compared from initiation of MMF to study end. Pulmonary function tests performed at the same institution before therapy and at study end were available in 15 patients. Histopathology and real-time PCR assessment of fibrosis-related gene expression were performed before and after treatment in skin biopsies from 3 patients. RESULTS: At 18.2 ± 8.73 months of MMF therapy (median 2000 mg/day) the mRSS decreased from 24.56 ± 8.62 to 14.52 ± 10.9 (p = 0.0004) and the affected BSA from 36% ± 16% to 14% ± 13.3% (p = 0.00001). Pulmonary function tests remained stable from initiation of MMF to the end of the study. Skin histopathology showed a remarkable reduction in accumulation of fibrotic tissue. Real-time PCR of skin biopsies demonstrated a marked decrease in expression of fibrosis-related genes. CONCLUSION: Patients with diffuse progressive cutaneous SSc of recent onset treated with MMF experienced marked improvement in skin involvement and stabilization of pulmonary function. Skin biopsies from 3 patients demonstrated histopathological improvement and decreased expression of fibrosis-related genes.