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Hematology. American Society of... Dec 2022Richter's syndrome (RS) is an aggressive histologic transformation of chronic lymphocytic leukemia (CLL), most commonly to diffuse large B-cell lymphoma (DLBCL).... (Review)
Review
Richter's syndrome (RS) is an aggressive histologic transformation of chronic lymphocytic leukemia (CLL), most commonly to diffuse large B-cell lymphoma (DLBCL). Outcomes are generally poor, with complete remission (CR) rates of only about 20% and less than 20% long-term survival with chemoimmunotherapy (CIT). RS is biologically heterogeneous, and in 80% of patients with CLL who develop DLBCL, the disease is clonally related to the CLL. Clonally unrelated cases are genetically and immunologically distinct from clonally related DLBCL-RS, have more favorable responses to CIT, and are best treated as de novo DLBCL. Relatively favorable outcomes with CIT are also seen in patients who have never previously received treatment for CLL and who lack TP53 mutation or deletion. For the remaining patients, treatment on a clinical trial is optimal. Fortunately, numerous agents are now in clinical development that show encouraging results. Here we review clinical data for some of the most promising approaches. DLBCL-RS tumor cells frequently express programmed cell death 1 protein (PD-1), and several studies have demonstrated activity for PD-1 inhibitors, especially in combination with ibrutinib. The BCL2 inhibitor venetoclax in combination with R-EPOCH CIT achieved CR in 50% of patients, and a study of venetoclax-R-CHOP is ongoing. The noncovalent Bruton's tyrosine kinase inhibitor pirtobrutinib has achieved responses in approximately two-thirds of heavily pretreated patients and, given its favorable toxicity profile, appears ideally suited to combining with other active agents. Finally, we review available data for bispecific antibodies, antibody-drug conjugates, and chimeric antigen receptor T-cell therapy, which, after revolutionizing the treatment of DLBCL, are now being evaluated in RS.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Antineoplastic Agents; Mutation
PubMed: 36485138
DOI: 10.1182/hematology.2022000345 -
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 -
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 -
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 -
Therapeutic Advances in Hematology 2021Previously considered a subtype of diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL) is now recognized by the World Health Organization... (Review)
Review
Previously considered a subtype of diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL) is now recognized by the World Health Organization as an independent entity. PMBCL has clinicopathologic features that are separate from systemic DLBCL and harbors some biologic characteristics which overlap with nodular sclerosing classic Hodgkin's lymphoma (cHL). Similar to cHL, copy number alterations of 9p24.1 are frequently seen in PMBCL, which leads to increased expression of key genes in the region, including programmed death-ligand 1( PD-L1), PD-L2, and JAK2. In addition, PMBCL cells express CD30 in a mostly patchy fashion. In the upfront setting, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (i.e., DA-EPOCH-R) is the only regimen that has been shown in a prospective setting to result in outstanding outcomes without consolidative radiation to the mediastinum, with a 5-year event-free survival rate of 93% and overall survival rate of 97%. Thus, in recent years, DA-EPOCH-R has been recognized as the preferred frontline regimen. Despite the encouraging results in the frontline setting, the outcomes in the relapsed/refractory setting remain poor. The current approach of salvage chemotherapy followed by autologous stem cell transplantation, as used in patients with DLBCL, does not result in high rates of cure in patients with rrPMBCL. In recent years, the characteristic molecular features identified in PMBCL have provided more treatment opportunities for this patient population. In the relapsed setting, single-agent PD-1 inhibitor pembrolizumab have demonstrated high and durable remission rates. Despite the expression of CD30, the CD30 antibody drug-conjugate brentuximab vedotin (BV) as a single agent has been deemed inactive in this disease. On the contrary, the combinations of BV and PD-1 inhibitor have shown higher response rates than PD-1 inhibitor alone. Moreover, anti-CD19 chimeric antigen receptor T-cell (CAR T-cell) therapy has been positioned as another successful strategy for patients with rrPMBCL. Axicabtagene ciloleucel and lisocabtagene maraleucel are two products used in rrPMBCL.
PubMed: 34659697
DOI: 10.1177/20406207211048959 -
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... Dec 2021To study the impact of transarterial Yttrium-90 radioembolization (TARE) in combination with second-line systemic chemotherapy for colorectal liver metastases (CLM). (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To study the impact of transarterial Yttrium-90 radioembolization (TARE) in combination with second-line systemic chemotherapy for colorectal liver metastases (CLM).
METHODS
In this international, multicenter, open-label phase III trial, patients with CLM who progressed on oxaliplatin- or irinotecan-based first-line therapy were randomly assigned 1:1 to receive second-line chemotherapy with or without TARE. The two primary end points were progression-free survival (PFS) and hepatic PFS (hPFS), assessed by blinded independent central review. Random assignment was performed using a web- or voice-based system stratified by unilobar or bilobar disease, oxaliplatin- or irinotecan-based first-line chemotherapy, and mutation status.
RESULTS
Four hundred twenty-eight patients from 95 centers in North America, Europe, and Asia were randomly assigned to chemotherapy with or without TARE; this represents the intention-to-treat population and included 215 patients in the TARE plus chemotherapy group and 213 patients in the chemotherapy alone group. The hazard ratio (HR) for PFS was 0.69 (95% CI, 0.54 to 0.88; 1-sided = .0013), with a median PFS of 8.0 (95% CI, 7.2 to 9.2) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. The HR for hPFS was 0.59 (95% CI, 0.46 to 0.77; 1-sided < .0001), with a median hPFS of 9.1 (95% CI, 7.8 to 9.7) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. Objective response rates were 34.0% (95% CI, 28.0 to 40.5) and 21.1% (95% CI, 16.2 to 27.1; 1-sided = .0019) for the TARE and chemotherapy groups, respectively. Median overall survival was 14.0 (95% CI, 11.8 to 15.5) and 14.4 months (95% CI, 12.8 to 16.4; 1-sided = .7229) with a HR of 1.07 (95% CI, 0.86 to 1.32) for TARE and chemotherapy groups, respectively. Grade 3 adverse events were reported more frequently with TARE (68.4% 49.3%). Both groups received full chemotherapy dose intensity.
CONCLUSION
The addition of TARE to systemic therapy for second-line CLM led to longer PFS and hPFS. Further subset analyses are needed to better define the ideal patient population that would benefit from TARE.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Case-Control Studies; Chemoradiotherapy; Colorectal Neoplasms; Embolization, Therapeutic; Female; Follow-Up Studies; Humans; Irinotecan; Liver Neoplasms; Male; Middle Aged; Oxaliplatin; Prognosis; Survival Rate; Yttrium Radioisotopes
PubMed: 34541864
DOI: 10.1200/JCO.21.01839 -
Haematologica Sep 2020CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is characterized by poor prognosis and a high frequency of central nervous system relapse after standard...
DA-EPOCH-R combined with high-dose methotrexate in patients with newly diagnosed stage II-IV CD5-positive diffuse large B-cell lymphoma: a single-arm, open-label, phase II study.
CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is characterized by poor prognosis and a high frequency of central nervous system relapse after standard immunochemotherapy. We conducted a phase II study to investigate the efficacy and safety of dose-adjusted (DA)- EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) combined with high-dose methotrexate (HD-MTX) in newly diagnosed patients with CD5+ DLBCL. Previously untreated patients with stage II to IV CD5+ DLBCL according to the 2008 World Health Organization classification were eligible. Four cycles of DA-EPOCH-R followed by two cycles of HD-MTX and four additional cycles of DAEPOCH- R (DA-EPOCH-R/HD-MTX) were planned as the protocol treatment. The primary end point was 2-year progression-free survival (PFS). Between September 25, 2012, and November 11, 2015, we enrolled 47 evaluable patients. Forty-five (96%) patients completed the protocol treatment. There were no deviations or violations in the DA-EPOCH-R dose levels. The complete response rate was 91%, and the overall response rate was 94%. At a median follow up of 3.1 years (range, 2.0-4.9 years), the 2- year PFS was 79% [95% confidence interval (CI): 64-88]. The 2-year overall survival was 89% (95%CI: 76-95). Toxicity included grade 4 neutropenia in 46 (98%) patients, grade 4 thrombocytopenia 12 (26%) patients, and febrile neutropenia in 31 (66%) patients. No treatment-related death was noted during the study. DA-EPOCH-R/HD-MTX might be a first-line therapy option for stage II-IV CD5+ DLBCL and warrants further investigation. (Trial registered at: UMIN-CTR: UMIN000008507.).
Topics: Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Etoposide; Humans; Lymphoma, Large B-Cell, Diffuse; Methotrexate; Neoplasm Recurrence, Local; Prednisone; Rituximab; Vincristine
PubMed: 33054055
DOI: 10.3324/haematol.2019.231076 -
Epilepsy Research Jul 2021To develop an improved interictal electroencephalogram (EEG) grading scale for children with infantile spasms founded on elements with adequate inter-rater reliability...
OBJECTIVE
To develop an improved interictal electroencephalogram (EEG) grading scale for children with infantile spasms founded on elements with adequate inter-rater reliability (IRR) to justify its further study for clinical and research purposes.
METHODS
Three blinded reviewers assessed five-minute sleep epochs in 93 EEGs from 62 children (31 consecutive controls, 31 consecutive infantile spasms [pretreatment and posttreatment studies]) using a longitudinal bipolar montage. We determined the IRR of background amplitude, epileptiform discharges, >3 spike foci (including <50 % or >50 %), grouped multifocal spikes, paroxysmal voltage attenuations, and symmetry of sleep spindles. Data were used to finalize the 2021 BASED (Burden of AmplitudeS and Epileptiform Discharges) score.
RESULTS
All elements included in the 2021 BASED score had moderate to near perfect IRR. Among controls, >200 μv background waves occurred commonly in the bilateral posterior temporal (T3-T5, T4-T6) and midline (Fz-Cz, Cz-Pz) regions. Excluding midline and occipital channels (which have normal high amplitude background waves), we designated abnormal high amplitude background waves as >200 μv for most channels, but >300 μv for T3-T5 and T4-T6. The IRR was moderate to near perfect for <50 % >3 spike foci, >50 % >3 spike foci, paroxysmal voltage attenuations, grouped multifocal spikes (GMFS), and symmetric sleep spindles. Paroxysmal voltage attenuations, GMFS, and >50 % >3 spike foci all significantly distinguished pretreatment from posttreatment studies whereas symmetric sleep spindles did not (as planned, the latter was not included in the 2021 BASED score). When the 2021 BASED score was applied to the 22 children with infantile spasms achieving clinical remission with treatment, 19 met criteria for electroclinical remission and three did not.
SIGNIFICANCE
The 2021 BASED score includes elements with high levels of IRR and correlates well with the presence or absence of infantile spasms.
Topics: Child; Electroencephalography; Humans; Infant; Reproducibility of Results; Sleep; Spasm; Spasms, Infantile
PubMed: 33839516
DOI: 10.1016/j.eplepsyres.2021.106631