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JAMA Feb 2023Malignant primary brain tumors cause more than 15 000 deaths per year in the United States. The annual incidence of primary malignant brain tumors is approximately 7... (Review)
Review
IMPORTANCE
Malignant primary brain tumors cause more than 15 000 deaths per year in the United States. The annual incidence of primary malignant brain tumors is approximately 7 per 100 000 individuals and increases with age. Five-year survival is approximately 36%.
OBSERVATIONS
Approximately 49% of malignant brain tumors are glioblastomas, and 30% are diffusely infiltrating lower-grade gliomas. Other malignant brain tumors include primary central nervous system (CNS) lymphoma (7%) and malignant forms of ependymomas (3%) and meningiomas (2%). Symptoms of malignant brain tumors include headache (50%), seizures (20%-50%), neurocognitive impairment (30%-40%), and focal neurologic deficits (10%-40%). Magnetic resonance imaging before and after a gadolinium-based contrast agent is the preferred imaging modality for evaluating brain tumors. Diagnosis requires tumor biopsy with consideration of histopathological and molecular characteristics. Treatment varies by tumor type and often includes a combination of surgery, chemotherapy, and radiation. For patients with glioblastoma, the combination of temozolomide with radiotherapy improved survival when compared with radiotherapy alone (2-year survival, 27.2% vs 10.9%; 5-year survival, 9.8% vs 1.9%; hazard ratio [HR], 0.6 [95% CI, 0.5-0.7]; P < .001). In patients with anaplastic oligodendroglial tumors with 1p/19q codeletion, probable 20-year overall survival following radiotherapy without vs with the combination of procarbazine, lomustine, and vincristine was 13.6% vs 37.1% (80 patients; HR, 0.60 [95% CI, 0.35-1.03]; P = .06) in the EORTC 26951 trial and 14.9% vs 37% in the RTOG 9402 trial (125 patients; HR, 0.61 [95% CI, 0.40-0.94]; P = .02). Treatment of primary CNS lymphoma includes high-dose methotrexate-containing regimens, followed by consolidation therapy with myeloablative chemotherapy and autologous stem cell rescue, nonmyeloablative chemotherapy regimens, or whole brain radiation.
CONCLUSIONS AND RELEVANCE
The incidence of primary malignant brain tumors is approximately 7 per 100 000 individuals, and approximately 49% of primary malignant brain tumors are glioblastomas. Most patients die from progressive disease. First-line therapy for glioblastoma is surgery followed by radiation and the alkylating chemotherapeutic agent temozolomide.
Topics: Adult; Humans; Antineoplastic Combined Chemotherapy Protocols; Brain; Brain Neoplasms; Glioblastoma; Glioma; Lymphoma; Temozolomide
PubMed: 36809318
DOI: 10.1001/jama.2023.0023 -
Blood Sep 2022Primary central nervous system lymphoma (PCNSL) is a rare extranodal lymphomatous malignancy that affects the brain, spinal cord, leptomeninges, or vitreoretinal space,... (Review)
Review
Primary central nervous system lymphoma (PCNSL) is a rare extranodal lymphomatous malignancy that affects the brain, spinal cord, leptomeninges, or vitreoretinal space, without evidence of systemic involvement. The diagnosis of PCNSL requires a high level of suspicion because clinical presentation varies depending upon involved structures. Initiation of treatment is time sensitive for optimal neurologic recovery and disease control. In general, the prognosis of PCNSL has improved significantly over the past few decades, largely as a result of the introduction and widespread use of high-dose methotrexate (MTX) chemotherapy, which is considered the backbone of first-line polychemotherapy treatment. Upon completion of MTX-based treatment, a consolidation strategy is often required to prolong duration of response. Consolidation can consist of radiation, maintenance therapy, nonmyeloablative chemotherapy, or myeloablative treatment followed by autologous stem cell transplant. Unfortunately, even with consolidation, relapse is common, and 5-year survival rates stand at only 30% to 40%. Novel insights into the pathophysiology of PCNSL have identified key mechanisms in tumor pathogenesis, including activation of the B-cell receptor pathway, immune evasion, and a suppressed tumor immune microenvironment. These insights have led to the identification of novel small molecules targeting these aberrant pathways. The Bruton tyrosine kinase inhibitor ibrutinib and immunomodulatory drugs (lenalidomide or pomalidomide) have shown promising clinical response rates for relapsed/refractory PCNSL and are increasingly used for the treatment of recurrent disease. This review provides a discussion of the clinical presentation of PCNSL, the approach to work-up and staging, and an overview of recent advancements in the understanding of the pathophysiology and current treatment strategies for immunocompetent patients.
Topics: Antineoplastic Combined Chemotherapy Protocols; Central Nervous System; Central Nervous System Neoplasms; Humans; Lymphoma, Non-Hodgkin; Methotrexate; Neoplasm Recurrence, Local; Tumor Microenvironment
PubMed: 34699590
DOI: 10.1182/blood.2020008377 -
American Journal of Hematology Nov 2022Hodgkin lymphoma (HL) is an uncommon B-cell lymphoid malignancy affecting 8540 new patients annually and representing approximately 10% of all lymphomas in the United...
DISEASE OVERVIEW
Hodgkin lymphoma (HL) is an uncommon B-cell lymphoid malignancy affecting 8540 new patients annually and representing approximately 10% of all lymphomas in the United States.
DIAGNOSIS
HL is composed of two distinct disease entities: classical HL and nodular lymphocyte-predominant HL. Nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte-rich HL are subgroups of classical HL.
RISK STRATIFICATION
An accurate assessment of the stage of disease in patients with HL is critical for the selection of the appropriate therapy. Prognostic models that identify patients at low or high risk for recurrence, as well as the response to therapy as determined by positron emission tomography scan, are used to optimize therapy.
RISK-ADAPTED THERAPY
Initial therapy for HL patients is based on the histology of the disease, the anatomical stage, and the presence of poor prognostic features. Patients with early-stage disease are typically treated with combined modality strategies utilizing abbreviated courses of combination chemotherapy followed by involved-field radiation therapy, while those with advanced-stage disease receive a longer course of chemotherapy, often without radiation therapy. However, newer agents, including brentuximab vedotin and anti-programmed death-1 (PD-1) antibodies, are now being incorporated into frontline therapy.
MANAGEMENT OF RELAPSED/REFRACTORY DISEASE
High-dose chemotherapy (HDCT) followed by an autologous stem cell transplant (ASCT) is the standard of care for most patients who relapse following initial therapy. For patients who fail HDCT with ASCT, brentuximab vedotin, PD-1 blockade, non-myeloablative allogeneic transplant, or participation in a clinical trial should be considered.
Topics: Antineoplastic Combined Chemotherapy Protocols; Brentuximab Vedotin; Disease Management; Hodgkin Disease; Humans; Immunoconjugates; Neoplasm Recurrence, Local; Programmed Cell Death 1 Receptor
PubMed: 36215668
DOI: 10.1002/ajh.26717 -
ESMO Open Aug 2021Primary diffuse large B-cell (DLBCL) lymphoma of the central nervous system (CNS) (PCNSL) is a new lymphoma entity, recognized by the 2017 WHO classification of... (Review)
Review
Primary diffuse large B-cell (DLBCL) lymphoma of the central nervous system (CNS) (PCNSL) is a new lymphoma entity, recognized by the 2017 WHO classification of hematopoietic and lymphoid tumors. Unlike systemic DLBCL, the use of anthracycline-based chemotherapy combinations is associated with disappointing outcomes, due to low CNS bioavailability of related drugs. Therefore, international researchers investigated alternative strategies, mostly including drugs able to cross the blood-brain-barrier at low or high doses, with a progressive improvement in survival. Some effective chemotherapy combinations of high-dose methotrexate (HD-MTX) with alkylating agents and rituximab with or without cytarabine have been tested in international randomized trials and represent the induction treatment in everyday practice, with some variations among different geographical areas. In patients aged 70 years or younger, MATRix (HD-MTX/cytarabine/thiotepa/rituximab) chemotherapy followed by consolidative high-dose chemotherapy plus autologous stem cell transplantation or whole-brain irradiation has been associated with a significant improvement in overall survival. Other treatment options, such as non-myeloablative high-dose chemotherapy, oral drug maintenance, and some targeted drugs like ibrutinib or lenalidomide, are being tested in high-level international trials. These steps toward further effective treatments are motivated by an incessant search for less neurotoxic options. Thanks to international cooperation, we can affirm that PCNSL is a potentially curable tumor, especially in young patients. However, several questions remain unanswered: the optimal treatment for elderly patients as well as the management of intraocular and meningeal disease require further scientific efforts. Beside treatments, advances on molecular and radiological diagnostic tools will increase our knowledge of this disease, allowing the possibility to anticipate diagnosis and to better categorize patients' responses. This article analyzes the available literature in this setting and provides evidence-based recommendations for the management of PCNSL patients.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Large B-Cell, Diffuse; Transplantation, Autologous
PubMed: 34271311
DOI: 10.1016/j.esmoop.2021.100213 -
Current Hematologic Malignancy Reports Jun 2017Chemotherapy remains the first-line therapy for aggressive lymphomas. However, 20-30% of patients with non-Hodgkin lymphoma (NHL) and 15% with Hodgkin lymphoma (HL)... (Review)
Review
PURPOSE OF REVIEW
Chemotherapy remains the first-line therapy for aggressive lymphomas. However, 20-30% of patients with non-Hodgkin lymphoma (NHL) and 15% with Hodgkin lymphoma (HL) recur after initial therapy. We want to explore the role of high-dose chemotherapy (HDT) and autologous stem cell transplant (ASCT) for these patients.
RECENT FINDINGS
There is some utility of upfront consolidation for-high risk/high-grade B-cell lymphoma, mantle cell lymphoma, and T-cell lymphoma, but there is no role of similar intervention for HL. New conditioning regimens are being investigated which have demonstrated an improved safety profile without compromising the myeloablative efficiency for relapsed or refractory HL. Salvage chemotherapy followed by HDT and rescue autologous stem cell transplant remains the standard of care for relapsed/refractory lymphoma. The role of novel agents to improve disease-related parameters remains to be elucidated in frontline induction, disease salvage, and high-dose consolidation or in the maintenance setting.
Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Consolidation Chemotherapy; Drug Resistance, Neoplasm; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Molecular Targeted Therapy; Recurrence; Retreatment; Salvage Therapy; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome
PubMed: 28478586
DOI: 10.1007/s11899-017-0382-1 -
Mayo Clinic Proceedings May 2017Monoclonal gammopathies comprise a spectrum of clonal plasma cell disorders that include monoclonal gammopathy of undetermined significance, multiple myeloma, and... (Review)
Review
Monoclonal gammopathies comprise a spectrum of clonal plasma cell disorders that include monoclonal gammopathy of undetermined significance, multiple myeloma, and Waldenström macroglobulinemia. In this review, we outline the epidemiology, etiology, classification, diagnosis, and treatment of monoclonal gammopathy-associated peripheral neuropathy. Monoclonal gammopathy of undetermined significance is relatively common in the general population, with a prevalence of 3% to 4% among individuals older than age 50 years. Therefore, the presence of M protein in a patient with neuropathy does not automatically indicate a causal relationship. Monoclonal gammopathy-associated peripheral neuropathy is often a difficult diagnosis with limited treatment options. Studies addressing the optimal approach to diagnosis and management of this entity are limited. In addition to a review of the literature, we present a diagnostic approach to patients with monoclonal gammopathy-associated peripheral neuropathy and discuss available data and options for treatment.
Topics: Administration, Intravenous; Biomarkers; Demyelinating Autoimmune Diseases, CNS; Diagnosis, Differential; Glycoproteins; Humans; Immunoglobulins; Immunologic Factors; Monoclonal Gammopathy of Undetermined Significance; Myeloablative Agonists; Peripheral Nervous System Diseases; Plasmapheresis; Prognosis; Rituximab; Vidarabine
PubMed: 28473042
DOI: 10.1016/j.mayocp.2017.02.003 -
Current Treatment Options in Oncology Nov 2022Primary CNS lymphoma (PCNSL) constitutes a rare extranodal variant of non-Hodgkin lymphoma (NHL) with an annual incidence of 0.45/100,000. Given the paucity of large... (Review)
Review
Primary CNS lymphoma (PCNSL) constitutes a rare extranodal variant of non-Hodgkin lymphoma (NHL) with an annual incidence of 0.45/100,000. Given the paucity of large prospective clinical trials, there is no consensus treatment for refractory or relapsed (r/r) PCNSL, and available strategies are largely based on retrospective analyses. Patient age, performance status, previously administered treatment, duration of response, and molecular characteristics guide selection of salvage therapy. Patients with a good performance status (KPS >70), particularly ≤65 years, and adequate organ function should be considered for salvage polychemotherapy. Based on its high overall response rate even in the relapsed setting, we choose high-dose (≥ 3.5g/m) methotrexate (HD-MTX) based regimens, e.g., R-MPV (rituximab, HD-MTX, procarbazine, and vincristine), for remission re-induction as long as patients were sensitive to first line HD-MTX-based regimens, especially when duration of previous response was ≥ 1 year. Following successful remission induction, we choose myeloablative chemotherapy (e.g., thiotepa, busulfan, cyclophosphamide) and subsequent autologous stem cell transplant in curative intent whenever feasible. Alternatively, conventional chemotherapy regimens (for example, monthly HD-MTX) or low-dose whole-brain radiation therapy (WBRT) are selected for consolidation in non-transplant candidates in complete remission. In cases of HD-MTX refractory disease or contraindications, we use pemetrexed; temozolomide/rituximab; high-dose cytarabine; or whole brain radiation for remission induction. Clinical trial participation is considered as well. Emerging therapies for upfront or salvage therapy under ongoing investigation include bruton tyrosine kinase inhibition (e.g., ibrutinib), immunomodulatory drugs (e.g., lenalidomide), immune checkpoint inhibitors (ICI, e.g., nivolumab), and chimeric antigen receptor T (CAR-T) cell therapy.
Topics: Humans; Thiotepa; Busulfan; Rituximab; Central Nervous System Neoplasms; Agammaglobulinaemia Tyrosine Kinase; Receptors, Chimeric Antigen; Methotrexate; Vincristine; Brain Neoplasms; Retrospective Studies; Lenalidomide; Pemetrexed; Nivolumab; Temozolomide; Immune Checkpoint Inhibitors; Procarbazine; Prospective Studies; Antineoplastic Combined Chemotherapy Protocols; Cranial Irradiation; Lymphoma, Non-Hodgkin; Cytarabine; Cyclophosphamide
PubMed: 36205806
DOI: 10.1007/s11864-022-01016-5 -
Blood Jul 2014An essential component of allogeneic and autologous hematopoietic cell transplantation (HCT) is the conditioning regimen administered before the hematopoietic cell... (Review)
Review
An essential component of allogeneic and autologous hematopoietic cell transplantation (HCT) is the conditioning regimen administered before the hematopoietic cell infusion. Early regimens relied on dose intensity, assuming that high-dose chemoradiotherapy would eliminate malignant disease and reinfusion of the graft would then restore hematopoiesis. However, as the contribution of graft-versus-tumor effects to the success of allogeneic HCT was recognized over time, in an effort to exploit these, many investigators lowered the dose of radiation and chemotherapeutic agents in the preparative regimen. This resulted in a major paradigm shift, and consequently, the pool of eligible patients underwent a remarkable expansion. In this article, we provide a review of the definition of high-dose, reduced-intensity, and nonmyeloablative conditioning regimens, the most commonly used agents and combinations, and the evolution of some early regimens. We also provide a brief review of the toxicities associated with these regimens.
Topics: Allografts; Antilymphocyte Serum; Antineoplastic Combined Chemotherapy Protocols; Autografts; Clinical Trials as Topic; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Myeloablative Agonists; Radioimmunotherapy; Transplantation Conditioning; Whole-Body Irradiation
PubMed: 24914142
DOI: 10.1182/blood-2014-02-514778 -
Blood May 2023Patients treated with cytotoxic therapies, including autologous stem cell transplantation, are at risk for developing therapy-related myeloid neoplasms (tMN)....
Patients treated with cytotoxic therapies, including autologous stem cell transplantation, are at risk for developing therapy-related myeloid neoplasms (tMN). Preleukemic clones (ie, clonal hematopoiesis [CH]) are detectable years before the development of these aggressive malignancies, although the genomic events leading to transformation and expansion are not well defined. Here, by leveraging distinctive chemotherapy-associated mutational signatures from whole-genome sequencing data and targeted sequencing of prechemotherapy samples, we reconstructed the evolutionary life-history of 39 therapy-related myeloid malignancies. A dichotomy was revealed, in which neoplasms with evidence of chemotherapy-induced mutagenesis from platinum and melphalan were hypermutated and enriched for complex structural variants (ie, chromothripsis), whereas neoplasms with nonmutagenic chemotherapy exposures were genomically similar to de novo acute myeloid leukemia. Using chemotherapy-associated mutational signatures as temporal barcodes linked to discrete clinical exposure in each patient's life, we estimated that several complex events and genomic drivers were acquired after chemotherapy was administered. For patients with prior multiple myeloma who were treated with high-dose melphalan and autologous stem cell transplantation, we demonstrate that tMN can develop from either a reinfused CH clone that escapes melphalan exposure and is selected after reinfusion, or from TP53-mutant CH that survives direct myeloablative conditioning and acquires melphalan-induced DNA damage. Overall, we revealed a novel mode of tMN progression that is not reliant on direct mutagenesis or even exposure to chemotherapy. Conversely, for tMN that evolve under the influence of chemotherapy-induced mutagenesis, distinct chemotherapies not only select preexisting CH but also promote the acquisition of recurrent genomic drivers.
Topics: Humans; Melphalan; Hematopoietic Stem Cell Transplantation; Transplantation, Autologous; Leukemia, Myeloid, Acute; Neoplasms, Second Primary; Antineoplastic Agents
PubMed: 36626250
DOI: 10.1182/blood.2022018244 -
Journal of Clinical Oncology : Official... Jan 2023JCO In 2004, the European Mantle Cell Lymphoma (MCL) Network initiated the randomized open-label, phase III MCL Younger trial for first-line treatment of patients with... (Randomized Controlled Trial)
Randomized Controlled Trial
High-Dose Cytarabine and Autologous Stem-Cell Transplantation in Mantle Cell Lymphoma: Long-Term Follow-Up of the Randomized Mantle Cell Lymphoma Younger Trial of the European Mantle Cell Lymphoma Network.
JCO In 2004, the European Mantle Cell Lymphoma (MCL) Network initiated the randomized open-label, phase III MCL Younger trial for first-line treatment of patients with advanced-stage MCL, age < 66 years, comparing an alternating rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone/rituximab plus dexamethasone, high-dose cytarabine, and cisplatin (R-CHOP/R-DHAP) induction followed by high-dose cytarabine-containing myeloablative radiochemotherapy conditioning and autologous peripheral blood stem-cell transplantation (R-DHAP arm) to R-CHOP with standard myeloablative radiochemotherapy and autologous stem-cell transplantation (R-CHOP arm). After a median follow-up of 10.6 years, the time to treatment failure was still significantly improved in the R-DHAP versus R-CHOP arms (medians 8.4 3.9 years, 5-/10-year rates 64%/46% 41%/25%, = .038, hazard ratio, 0.59). Median overall survival (OS) was not reached in the R-DHAP arm versus 11.3 years in R-CHOP arm (5-/10-year rates, 76%/60% 69%/55%, = .12). The unadjusted OS hazard ratios (0.80 [95% CI, 0.61 to 1.06], = .12) reached significance when adjusted for Mantle Cell Lymphoma International Prognostic Index (MIPI) and MIPI + Ki-67 (MIPI-c) (0.74; 95% CI, 0.56 to 0.98; = .038 and .60; 95% CI, 0.41 to 0.87; = .0066). The incidence of secondary hematologic malignancies tended to be higher in the R-DHAP arm (4.5% 1.4% at 10 years). With mature long-term data, we confirm the previously observed substantially prolonged time to treatment failure and, for the first time to our knowledge, show an improvement of OS. Some patients with MCL may be cured.
Topics: Adult; Humans; Aged; Lymphoma, Mantle-Cell; Rituximab; Follow-Up Studies; Cytarabine; Antineoplastic Combined Chemotherapy Protocols; Hematopoietic Stem Cell Transplantation; Cyclophosphamide; Prednisone; Doxorubicin; Vincristine
PubMed: 36469833
DOI: 10.1200/JCO.22.01780