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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 -
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 -
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 -
Journal of Clinical Oncology : Official... Sep 2013Concerns regarding neurocognitive toxicity of whole-brain radiotherapy (WBRT) have motivated development of alternative, dose-intensive chemotherapeutic strategies as... (Clinical Trial)
Clinical Trial
PURPOSE
Concerns regarding neurocognitive toxicity of whole-brain radiotherapy (WBRT) have motivated development of alternative, dose-intensive chemotherapeutic strategies as consolidation in primary CNS lymphoma (PCNSL). We performed a multicenter study of high-dose consolidation, without WBRT, in PCNSL. Objectives were to determine: one, rate of complete response (CR) after remission induction therapy with methotrexate, temozolomide, and rituximab (MT-R); two, feasibility of a two-step approach using high-dose consolidation with etoposide plus cytarabine (EA); three, progression-free survival (PFS); and four, correlation between clinical and molecular prognostic factors and outcome.
PATIENTS AND METHODS
Forty-four patients with newly diagnosed PCNSL were treated with induction MT-R, and patients who achieved CR received EA consolidation. We performed a prospective analysis of molecular prognostic biomarkers in PCNSL in the setting of a clinical trial.
RESULTS
The rate of CR to MT-R was 66%. The overall 2-year PFS was 0.57, with median follow-up of 4.9 years. The 2-year time to progression was 0.59, and for patients who completed consolidation, it was 0.77. Patients age > 60 years did as well as younger patients, and the most significant clinical prognostic variable was treatment delay. High BCL6 expression correlated with shorter survival.
CONCLUSION
CALGB 50202 demonstrates for the first time to our knowledge that dose-intensive consolidation for PCNSL is feasible in the multicenter setting and yields rates of PFS and OS at least comparable to those of regimens involving WBRT. On the basis of these encouraging results, an intergroup study has been activated comparing EA consolidation with myeloablative chemotherapy in this randomized trial in PCNSL, in which neither arm involves WBRT.
Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Child; DNA-Binding Proteins; Disease-Free Survival; Female; Humans; Immunotherapy; Lymphoma, Non-Hodgkin; Male; Middle Aged; Prognosis; Prospective Studies; Proto-Oncogene Proteins c-bcl-6
PubMed: 23569323
DOI: 10.1200/JCO.2012.46.9957 -
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... Mar 2019Single-cycle melphalan 200 mg/m and autologous hematopoietic cell transplantation (AHCT) followed by lenalidomide (len) maintenance have improved progression-free... (Comparative Study)
Comparative Study Randomized Controlled Trial
PURPOSE
Single-cycle melphalan 200 mg/m and autologous hematopoietic cell transplantation (AHCT) followed by lenalidomide (len) maintenance have improved progression-free survival (PFS) and overall survival (OS) for transplantation-eligible patients with multiple myeloma (MM). We designed a prospective, randomized, phase III study to test additional interventions to improve PFS by comparing AHCT, tandem AHCT (AHCT/AHCT), and AHCT and four subsequent cycles of len, bortezomib, and dexamethasone (RVD; AHCT + RVD), all followed by len until disease progression.
PATIENTS AND METHODS
Patients with symptomatic MM within 12 months from starting therapy and without progression who were age 70 years or younger were randomly assigned to AHCT/AHCT + len (n = 247), AHCT + RVD + len (n = 254), or AHCT + len (n = 257). The primary end point was 38-month PFS.
RESULTS
The study population had a median age of 56 years (range, 20 to 70 years); 24% of patients had high-risk MM, 73% had a triple-drug regimen as initial therapy, and 18% were in complete response at enrollment. The 38-month PFS rate was 58.5% (95% CI, 51.7% to 64.6%) for AHCT/AHCT + len, 57.8% (95% CI, 51.4% to 63.7%) for AHCT + RVD + len, and 53.9% (95% CI, 47.4% to 60%) for AHCT + len. For AHCT/AHCT + len, AHCT + RVD + len, and AHCT + len, the OS rates were 81.8% (95% CI, 76.2% to 86.2%), 85.4% (95% CI, 80.4% to 89.3%), and 83.7% (95% CI, 78.4% to 87.8%), respectively, and the complete response rates at 1 year were 50.5% (n = 192), 58.4% (n = 209), and 47.1% (n = 208), respectively. Toxicity profiles and development of second primary malignancies were similar across treatment arms.
CONCLUSION
Second AHCT or RVD consolidation as post-AHCT interventions for the up-front treatment of transplantation-eligible patients with MM did not improve PFS or OS. Single AHCT and len should remain as the standard approach for this population.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Consolidation Chemotherapy; Dexamethasone; Disease Progression; Female; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Maintenance Chemotherapy; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Progression-Free Survival; Prospective Studies; Remission Induction; Reoperation; Time Factors; Transplantation, Autologous; United States; Young Adult
PubMed: 30653422
DOI: 10.1200/JCO.18.00685 -
Biology of Blood and Marrow... May 2014Hematopoietic stem cell transplantation (HCT) is a potentially life-saving therapy for patients with malignant and nonmalignant disease states. This article reviews the... (Review)
Review
Conditioning chemotherapy dose adjustment in obese patients: a review and position statement by the American Society for Blood and Marrow Transplantation practice guideline committee.
Hematopoietic stem cell transplantation (HCT) is a potentially life-saving therapy for patients with malignant and nonmalignant disease states. This article reviews the current published literature on the dosing of pharmacologic agents used for HCT preparative regimens with specific focus on the obese patient population. The review found that dose adjustments for obesity have, to date, been based empirically or extrapolated from published data in the nontransplantation patient population. As a result, the Committee determined that clear standards or dosing guidelines are unable to be made for the obese population because Level I and II evidence are unavailable at this time. Instead, the Committee provides a current published literature review to serve as a platform for conditioning agent dose selection in the setting of obesity. A necessary goal should be to encourage future prospective trials in this patient population because further information is needed to enhance our knowledge of the pharmacokinetics and pharmacodynamics of conditioning agents in the setting of obesity.
Topics: Humans; Antilymphocyte Serum; Bone Marrow Transplantation; Busulfan; Cyclophosphamide; Cytarabine; Drug Administration Schedule; Drug Dosage Calculations; Etoposide; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Melphalan; Myeloablative Agonists; Obesity; Transplantation Conditioning
PubMed: 24462742
DOI: 10.1016/j.bbmt.2014.01.019 -
Blood Oct 2008Mantle cell lymphoma (MCL) is considered incurable. Intensive immunochemotherapy with stem cell support has not been tested in large, prospective series. In the 2nd...
Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group.
Mantle cell lymphoma (MCL) is considered incurable. Intensive immunochemotherapy with stem cell support has not been tested in large, prospective series. In the 2nd Nordic MCL trial, we treated 160 consecutive, untreated patients younger than 66 years in a phase 2 protocol with dose-intensified induction immunochemotherapy with rituximab (R) + cyclophosphamide, vincristine, doxorubicin, prednisone (maxi-CHOP), alternating with R + high-dose cytarabine. Responders received high-dose chemotherapy with BEAM or BEAC (carmustine, etoposide, cytarabine, and melphalan/cyclophosphamide) with R-in vivo purged autologous stem cell support. Overall and complete response was achieved in 96% and 54%, respectively. The 6-year overall, event-free, and progression-free survival were 70%, 56%, and 66%, respectively, with no relapses occurring after 5 years. Multivariate analysis showed Ki-67 to be the sole independent predictor of event-free survival. The nonrelapse mortality was 5%. The majority of stem cell products and patients assessed with polymerase chain reaction (PCR) after transplantation were negative. Compared with our historical control, the Nordic MCL-1 trial, the event-free, overall, and progression-free survival, the duration of molecular remission, and the proportion of PCR-negative stem cell products were significantly increased (P < .001). Intensive immunochemotherapy with in vivo purged stem cell support can lead to long-term progression-free survival of MCL and perhaps cure. Registered at www.isrctn.org as #ISRCTN 87866680.
Topics: Adult; Aged; Bone Marrow Purging; Combined Modality Therapy; Disease-Free Survival; Female; Humans; Immunotherapy; Ki-67 Antigen; Lymphoma, Mantle-Cell; Male; Middle Aged; Multivariate Analysis; Stem Cells; Time Factors; Treatment Outcome
PubMed: 18625886
DOI: 10.1182/blood-2008-03-147025