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Clinical Advances in Hematology &... Nov 2021The emerging molecular and prognostic characterization of diffuse large B-cell lymphoma (DLBCL) has challenged the rituximab, cyclophosphamide, doxorubicin, vincristine,... (Review)
Review
The emerging molecular and prognostic characterization of diffuse large B-cell lymphoma (DLBCL) has challenged the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment paradigm in recent years, with the identification of several DLBCL subtypes associated with significantly inferior survival after standard R-CHOP therapy. Efforts to improve upon the R-CHOP backbone have included dose intensification as well as the addition of new agents; the infusional dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-R-EPOCH) regimen has been identified as a potential replacement for R-CHOP in high-risk DLBCL. In this review, we provide a historical perspective on the R-CHOP and DA-R-EPOCH regimens and summarize the clinical trial literature regarding the efficacy of each regimen in various risk groups of DLBCL. Further, we propose clinical management scenarios in which DA-R-EPOCH may be preferred, including some for patient populations in which the use of R-CHOP vs DA-R-EPOCH is controversial.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Etoposide; Humans; Lymphoma, Large B-Cell, Diffuse; Prednisone; Rituximab; Treatment Outcome; Vincristine
PubMed: 34807015
DOI: No ID Found -
Neuromodulation : Journal of the... Apr 2022Vagus nerve stimulation (VNS) is reemerging as an exciting form of brain stimulation, due in part to the development of its noninvasive counterpart transcutaneous... (Review)
Review
OBJECTIVES
Vagus nerve stimulation (VNS) is reemerging as an exciting form of brain stimulation, due in part to the development of its noninvasive counterpart transcutaneous auricular VNS. As the field grows, it is important to understand where VNS emerged from, including its history and the studies that were conducted over the past four decades. Here, we offer a comprehensive review of the history of VNS in the treatment of major depression.
MATERIALS AND METHODS
Using PubMed, we reviewed the history of VNS and aggregated the literature into a narrative review of four key VNS epochs: 1) early invention and development of VNS, 2) path to Food and Drug Administration (FDA) approval for depression, 3) refinement of VNS treatment parameters, and 4) neuroimaging of VNS.
RESULTS
VNS was described in the literature in the early 1900s; however, gained traction in the 1980s as Zabara and colleagues developed an implantable neurocybernetic prosthesis to treat epilepsy. As epilepsy trials proceed in the 1990s, promising mood effects emerged and were studied, ultimately leading to the approval of VNS for depression in 2005. Since then, there have been advances in understanding the mechanism of action. Imaging techniques like functional magnetic resonance imaging and positron emission tomography further aid in understanding direct brain effects of VNS.
CONCLUSIONS
The mood effects of VNS were discovered from clinical trials investigating the use of VNS for reducing seizures in epileptic patients. Since then, VNS has gone on to be FDA approved for depression. The field of VNS is growing, and as noninvasive VNS quickly advances, it is important to consider a historical perspective to develop future brain stimulation therapies.
Topics: Depression; Epilepsy; Humans; Transcutaneous Electric Nerve Stimulation; Vagus Nerve; Vagus Nerve Stimulation
PubMed: 35396067
DOI: 10.1111/ner.13528 -
The New England Journal of Medicine Apr 2013Primary mediastinal B-cell lymphoma is a distinct subtype of diffuse large-B-cell lymphoma that is closely related to nodular sclerosing Hodgkin's lymphoma. Patients are...
BACKGROUND
Primary mediastinal B-cell lymphoma is a distinct subtype of diffuse large-B-cell lymphoma that is closely related to nodular sclerosing Hodgkin's lymphoma. Patients are usually young and present with large mediastinal masses. There is no standard treatment, but the inadequacy of immunochemotherapy alone has resulted in routine consolidation with mediastinal radiotherapy, which has potentially serious late effects. We aimed to develop a strategy that improves the rate of cure and obviates the need for radiotherapy.
METHODS
We conducted a single-group, phase 2, prospective study of infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (DA-EPOCH-R) and filgrastim without radiotherapy in 51 patients with untreated primary mediastinal B-cell lymphoma. We used results from a retrospective study of DA-EPOCH-R from another center to independently verify the outcomes.
RESULTS
The patients had a median age of 30 years (range, 19 to 52) and a median tumor diameter of 11 cm; 59% were women. During a median of 5 years of follow-up, the event-free survival rate was 93%, and the overall survival rate was 97%. Among the 16 patients who were involved in the retrospective analysis at another center, over a median of 3 years of follow-up, the event-free survival rate was 100%, and no patients received radiotherapy. No late morbidity or cardiac toxic effects were found in any patients. After follow-up ranging from 10 months to 14 years, all but 2 of the 51 patients (4%) who received DA-EPOCH-R alone were in complete remission. The 2 remaining patients received radiotherapy and were disease-free at follow-up.
CONCLUSIONS
Therapy with DA-EPOCH-R obviated the need for radiotherapy in patients with primary mediastinal B-cell lymphoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00001337.).
Topics: Adult; Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Disease-Free Survival; Dose-Response Relationship, Drug; Doxorubicin; Etoposide; Female; Filgrastim; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Kaplan-Meier Estimate; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Prednisone; Recombinant Proteins; Retrospective Studies; Rituximab; Stroke Volume; Vincristine; Young Adult
PubMed: 23574119
DOI: 10.1056/NEJMoa1214561 -
Journal of Clinical Oncology : Official... Jul 2019Alliance/CALGB 50303 (NCT00118209), an intergroup, phase III study, compared dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and... (Randomized Controlled Trial)
Randomized Controlled Trial
Dose-Adjusted EPOCH-R Compared With R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303.
PURPOSE
Alliance/CALGB 50303 (NCT00118209), an intergroup, phase III study, compared dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as frontline therapy for diffuse large B-cell lymphoma.
PATIENTS AND METHODS
Patients received six cycles of DA-EPOCH-R or R-CHOP. The primary objective was progression-free survival (PFS); secondary clinical objectives included response rate, overall survival (OS), and safety.
RESULTS
Between 2005 and 2013, 524 patients were registered; 491 eligible patients were included in the final analysis. Most patients (74%) had stage III or IV disease; International Prognostic Index (IPI) risk groups included 26% IPI 0 to 1, 37% IPI 2, 25% IPI 3, and 12% IPI 4 to 5. At a median follow-up of 5 years, PFS was not statistically different between the arms (hazard ratio, 0.93; 95% CI, 0.68 to 1.27; = .65), with a 2-year PFS rate of 78.9% (95% CI, 73.8% to 84.2%) for DA-EPOCH-R and 75.5% (95% CI, 70.2% to 81.1%) for R-CHOP. OS was not different (hazard ratio, 1.09; 95% CI, 0.75 to 1.59; = .64), with a 2-year OS rate of 86.5% (95% CI, 82.3% to 91%) for DA-EPOCH-R and 85.7% (95% CI, 81.4% to 90.2%) for R-CHOP. Grade 3 and 4 adverse events were more common ( < .001) in the DA-EPOCH-R arm than the R-CHOP arm, including infection (16.9% 10.7%, respectively), febrile neutropenia (35.0% 17.7%, respectively), mucositis (8.4% 2.1%, respectively), and neuropathy (18.6% 3.3%, respectively). Five treatment-related deaths (2.1%) occurred in each arm.
CONCLUSION
In the 50303 study population, the more intensive, infusional DA-EPOCH-R was more toxic and did not improve PFS or OS compared with R-CHOP. The more favorable results with R-CHOP compared with historical controls suggest a potential patient selection bias and may preclude generalizability of results to specific risk subgroups.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Etoposide; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Prednisone; Progression-Free Survival; Vincristine; Young Adult
PubMed: 30939090
DOI: 10.1200/JCO.18.01994 -
The Lancet. Haematology Dec 2018MYC gene rearrangement is present in approximately 10% of aggressive B-cell lymphomas, with half also harbouring a BCL2 gene rearrangement. Multiple retrospective...
Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) in untreated aggressive diffuse large B-cell lymphoma with MYC rearrangement: a prospective, multicentre, single-arm phase 2 study.
BACKGROUND
MYC gene rearrangement is present in approximately 10% of aggressive B-cell lymphomas, with half also harbouring a BCL2 gene rearrangement. Multiple retrospective studies of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone) have shown a worse outcome in patients with MYC rearrangement (alone or with rearrangement of BCL2 or BCL6, or both) than in patients without MYC rearrangement, and suggest improved outcomes after more intensive treatment. We aimed to determine the outcome of dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab; DA-EPOCH-R), an intensive infusional treatment regimen, in untreated aggressive B-cell lymphoma with MYC rearrangement.
METHODS
We present the final analysis of a prospective, multicentre, single-arm, phase 2 study of DA-EPOCH-R in patients with untreated aggressive B-cell lymphoma with MYC rearrangement. DA-EPOCH-R was scheduled to be administered with CNS prophylaxis for six cycles. Primary endpoints included event-free and overall survival. This study is registered with ClinicalTrials.gov (NCT01092182).
FINDINGS
53 patients were enrolled, with median age of 61 years (range 29-80; IQR 50-70); 43 (81%) patients had stage III-IV disease and 26 (49%) had high-intermediate or high international prognostic index (IPI) scores. 19 patients had confirmed MYC rearrangement alone (single-hit) and 24 also had rearrangement of BCL2, BCL6, or both (double-hit), with similar characteristics between these two groups. After a median follow-up of 55·6 months (IQR 50·5-61·1), 48-month event-free survival was 71·0% (95% CI 56·5-81·4) and 48-month overall survival was 76·7% (95% CI 62·6-86·1) for all patients. Toxicity included grade 4 neutropenia in 160 (53%) of 301 cycles, grade 4 thrombocytopenia in 40 (13%) cycles, and any grade of fever with neutropenia in 56 (19%) cycles. There were three treatment-related deaths (all infections).
INTERPRETATION
In this study, DA-EPOCH-R produced durable remission in patients with MYC-rearranged aggressive B-cell lymphomas and should be considered for the treatment of these diseases.
FUNDING
Cancer Trials Support Unit and Center for Cancer Research of the National Cancer Institute and Genentech.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Dose-Response Relationship, Drug; Doxorubicin; Etoposide; Female; Gene Rearrangement; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Prednisone; Proto-Oncogene Proteins c-myc; Rituximab; Treatment Outcome; Vincristine
PubMed: 30501868
DOI: 10.1016/S2352-3026(18)30177-7 -
Blood Apr 2002We hypothesized that incremental improvements in the cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) chemotherapy regimen through optimization of drug... (Clinical Trial)
Clinical Trial
We hypothesized that incremental improvements in the cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) chemotherapy regimen through optimization of drug selection, schedule, and pharmacokinetics would improve outcome in patients with large B-cell lymphomas. A prospective multi-institutional study of administration of etoposide, vincristine, and doxorubicin for 96 hours with bolus doses of cyclophosphamide and oral prednisone (EPOCH therapy) was done in 50 patients with previously untreated large B-cell lymphomas. The doses of etoposide, doxorubicin, and cyclophosphamide were adjusted 20% each cycle to achieve a nadir absolute neutrophil count below 0.5 x 10(9)/L. The median age of the patients was 46 years (range, 20-88 years); 24% were older than 60 years; and 44% were at high-intermediate or high risk according to International Prognostic Index (IPI) criteria. There was a complete response in 92% of patients, and at the median follow-up time of 62 months, the progression-free survival (PFS) and overall survival (OS) rates were 70% and 73%, respectively. Neither IPI risk factors nor the index itself was associated with response, PFS, or OS. Doses were escalated in 58% of cycles, and toxicity levels were tolerable. Significant inverse correlations were observed between dose intensity and age for all adjusted agents, and drug clearance of doxorubicin and free etoposide was also inversely correlated with age (r = -0.54 and P(2) =.08 and r = -0.45 and P(2) =.034, respectively). Free-etoposide clearance increased significantly during successive cycles (P(2) =.015). Lymphomas with proliferation of at least 80% had somewhat lower progression and those expressing bcl-2 had significantly higher progression (P(2) =.04). Expression of bcl-2 may discriminate the recently described activated B-like from germinal-center B-like large-cell lymphomas and provide important pathobiologic and prognostic information. Dose-adjusted EPOCH may produce more cell kill than CHOP-based regimens. Dynamic dose adjustment may overcome inadequate drug concentrations, particularly in younger patients, and compensate for increased drug clearance over time.
Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Drug Monitoring; Etoposide; Female; Humans; Longitudinal Studies; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Neutropenia; Platelet Count; Prednisone; Prognosis; Risk Factors; Survival Rate; Treatment Outcome; Vincristine
PubMed: 11929754
DOI: 10.1182/blood.v99.8.2685 -
Blood Feb 2022Richter syndrome (RS) of chronic lymphocytic leukemia (CLL) is typically chemoresistant, with a poor prognosis. We hypothesized that the oral Bcl-2 inhibitor venetoclax...
Richter syndrome (RS) of chronic lymphocytic leukemia (CLL) is typically chemoresistant, with a poor prognosis. We hypothesized that the oral Bcl-2 inhibitor venetoclax could sensitize RS to chemoimmunotherapy and improve outcomes. We conducted a single-arm, investigator-sponsored, phase 2 trial of venetoclax plus dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (VR-EPOCH) to determine the rate of complete response (CR). Patients received R-EPOCH for 1 cycle, then after count recovery, accelerated daily venetoclax ramp-up to 400 mg, then VR-EPOCH for up to 5 more 21-day cycles. Responders received venetoclax maintenance or cellular therapy off-study. Twenty-six patients were treated, and 13 of 26 (50%) achieved CR, with 11 achieving undetectable bone marrow minimal residual disease for CLL. Three additional patients achieved partial response (overall response rate, 62%). Median progression-free survival was 10.1 months, and median overall survival was 19.6 months. Hematologic toxicity included grade ≥3 neutropenia (65%) and thrombocytopenia (50%), with febrile neutropenia in 38%. No patients experienced tumor lysis syndrome with daily venetoclax ramp-up. VR-EPOCH is active in RS, with deeper, more durable responses than historical regimens. Toxicities from intensive chemoimmunotherapy and venetoclax were observed. Our data suggest that studies comparing venetoclax with chemoimmunotherapy to chemoimmunotherapy alone are warranted. This trial was registered at www.clinicaltrials.gov as #NCT03054896.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cyclophosphamide; Doxorubicin; Etoposide; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Neutropenia; Prednisone; Progression-Free Survival; Sulfonamides; Vincristine
PubMed: 34788401
DOI: 10.1182/blood.2021011386 -
Journal of Clinical Oncology : Official... Aug 2020Burkitt lymphoma is an aggressive B-cell lymphoma curable with dose-intensive chemotherapy derived from pediatric leukemia regimens. Treatment is acutely toxic with late...
PURPOSE
Burkitt lymphoma is an aggressive B-cell lymphoma curable with dose-intensive chemotherapy derived from pediatric leukemia regimens. Treatment is acutely toxic with late sequelae. We hypothesized that dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (DA-EPOCH-R) may obviate the need for highly dose-intensive chemotherapy in adults with Burkitt lymphoma.
METHODS
We conducted a multicenter risk-adapted study of DA-EPOCH-R in untreated adult Burkitt lymphoma. Low-risk patients received three cycles without CNS prophylaxis, and high-risk patients received six cycles with intrathecal CNS prophylaxis or extended intrathecal treatment if leptomeninges were involved. The primary endpoint was event-free survival (EFS), and secondary endpoints were toxicity and predictors of EFS and overall survival (OS).
RESULTS
Between 2010 and 2017, 113 patients were enrolled across 22 centers, and 98 (87%) were high risk. The median age was 49 (range, 18-86) years, and 62% were ≥ 40 years. Bone marrow and/or CSF was involved in 29 (26%) of patients, and 28 (25%) were HIV positive. At a median follow-up of 58.7 months, EFS and OS were 84.5% and 87.0%, respectively, and EFS was 100% and 82.1% in low- and high-risk patients. Therapy was equally effective across age groups, HIV status, and International Prognostic Index risk groups. Involvement of the CSF identified the group at greatest risk for early toxicity-related death or treatment failure. Five treatment-related deaths (4%) occurred during therapy. Febrile neutropenia occurred in 16% of cycles, and tumor lysis syndrome was rare.
CONCLUSION
Risk-adapted DA-EPOCH-R therapy is effective in adult Burkitt lymphoma regardless of age or HIV status and was well tolerated. Improved therapeutic strategies for adults with CSF involvement are needed (funded by the National Cancer Institute; ClinicalTrials.gov identifier: NCT01092182).
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Burkitt Lymphoma; Cyclophosphamide; Doxorubicin; Etoposide; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prednisone; Prognosis; Risk Factors; Rituximab; Survival Rate; Vincristine; Young Adult
PubMed: 32453640
DOI: 10.1200/JCO.20.00303 -
Physical Therapy Nov 2017Evidence-based guidelines are needed to inform rehabilitation practice, including the effect of number of exercise training sessions on recovery of walking ability after... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Evidence-based guidelines are needed to inform rehabilitation practice, including the effect of number of exercise training sessions on recovery of walking ability after stroke.
OBJECTIVE
The objective of this study was to determine the response to increasing number of training sessions of 2 interventions-locomotor training and strength and balance exercises-on poststroke walking recovery.
DESIGN
This is a secondary analysis of the Locomotor Experience Applied Post-Stroke (LEAPS) randomized controlled trial.
SETTING
Six rehabilitation sites in California and Florida and participants' homes were used.
PARTICIPANTS
Participants were adults who dwelled in the community (N=347), had had a stroke, were able to walk at least 3 m (10 ft) with assistance, and had completed the required number of intervention sessions.
INTERVENTION
Participants received 36 sessions (3 times per week for 12 weeks), 90 minutes in duration, of locomotor training (gait training on a treadmill with body-weight support and overground training) or strength and balance training.
MEASUREMENTS
Talking speed, as measured by the 10-Meter Walk Test, and 6-minute walking distance were assessed before training and following 12, 24, and 36 intervention sessions.
RESULTS
Participants at 2 and 6 months after stroke gained in gait speed and walking endurance after up to 36 sessions of treatment, but the rate of gain diminished steadily and, on average, was very low during the 25- to 36-session epoch, regardless of treatment type or severity of impairment.
LIMITATIONS
Results may not generalize to people who are unable to initiate a step at 2 months after stroke or people with severe cardiac disease.
CONCLUSIONS
In general, people who dwelled in the community showed improvements in gait speed and walking distance with up to 36 sessions of locomotor training or strength and balance exercises at both 2 and 6 months after stroke. However, gains beyond 24 sessions tended to be very modest. The tracking of individual response trajectories is imperative in planning treatment.
Topics: Aged; Female; Humans; Male; Middle Aged; Postural Balance; Recovery of Function; Resistance Training; Single-Blind Method; Stroke; Stroke Rehabilitation; Treatment Outcome; Walking; Walking Speed
PubMed: 29077960
DOI: 10.1093/ptj/pzx079 -
British Journal of Haematology Feb 2019
Clinical Trial
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Etoposide; Female; Humans; Male; Middle Aged; Plasmablastic Lymphoma; Prednisone; Retrospective Studies; Survival Rate; Vincristine
PubMed: 29527667
DOI: 10.1111/bjh.15156