-
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... Nov 2022Metastatic retinoblastoma has a poor prognosis when treated with conventional chemotherapy and radiation therapy (RT). Intensified therapy may improve the outcome. (Clinical Trial)
Clinical Trial
PURPOSE
Metastatic retinoblastoma has a poor prognosis when treated with conventional chemotherapy and radiation therapy (RT). Intensified therapy may improve the outcome.
METHODS
A prospective, international trial enrolled patients with extraocular retinoblastoma. Patients with stage II or III (locoregional) retinoblastoma received four cycles of chemotherapy, followed by involved field RT (45 Gy). Patients with stage IVa or IVb (metastatic or trilateral) retinoblastoma also received four cycles of chemotherapy and those with ≥ partial response then received one cycle of high-dose carboplatin, thiotepa, and etoposide with autologous hematopoietic stem-cell support. Patients with stage IVa or IVb with residual tumor postchemotherapy received RT. The proportion of patients who achieved event-free survival would be reported and compared with historical controls separately for each of the three groups of patients.
RESULTS
Fifty-seven eligible patients were included in the analyses. Event-free survival at 1 year was 88.1% (90% CI, 66.6 to 96.2) for stage II-III, 82.6% (90% CI, 61.0 to 92.9) for stage IVa, and 28.3% (90% CI, 12.7 to 46.2) for stage IVb/trilateral. Toxicity was significant as expected and included two therapy-related deaths.
CONCLUSION
Intensive multimodality therapy is highly effective for patients with regional extraocular retinoblastoma and stage IVa metastatic retinoblastoma. Although the study met its aim for stage IVb, more effective therapy is still required for patients with CNS involvement (ClinicalTrials.gov identifier: NCT00554788).
Topics: Child; Humans; Combined Modality Therapy; Prospective Studies; Retinal Neoplasms; Retinoblastoma
PubMed: 35820112
DOI: 10.1200/JCO.21.02337 -
Journal of Clinical Oncology : Official... Feb 2021Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients.
PATIENTS AND METHODS
FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients ≤ 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129).
RESULTS
Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; < .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17; < .0001) and 0.02 (95% CI, < 0.01 to 0.05; = .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively.
CONCLUSION
Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.
Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Chemoradiotherapy; Child; Child, Preschool; Equivalence Trials as Topic; Etoposide; Female; Follow-Up Studies; Humans; International Agencies; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Survival Rate; Thiotepa; Vidarabine; Whole-Body Irradiation
PubMed: 33332189
DOI: 10.1200/JCO.20.02529 -
Haematologica Mar 2023Secondary central nervous system (CNS) lymphoma (SCNSL) is defined by the involvement of the CNS, either at the time of initial diagnosis of systemic lymphoma or in the... (Review)
Review
Secondary central nervous system (CNS) lymphoma (SCNSL) is defined by the involvement of the CNS, either at the time of initial diagnosis of systemic lymphoma or in the setting of relapse, and can be either isolated or with synchronous systemic disease. The risk of CNS involvement in patients with diffuse large B-cell lymphoma is approximately 5%; however, certain clinical and biological features have been associated with a risk of up to 15%. There has been growing interest in improving the definition of patients at increased risk of CNS relapse, as well as identifying effective prophylactic strategies to prevent it. SCNSL often occurs within months of the initial diagnosis of lymphoma, suggesting the presence of occult disease at diagnosis in many cases. The differing presentations of SCNSL create the therapeutic challenge of controlling both the systemic disease and the CNS disease, which uniquely requires agents that penetrate the blood-brain barrier. Outcomes are generally poor with a median overall survival of approximately 6 months in retrospective series, particularly in those patients presenting with SCNSL after prior therapy. Prospective studies of intensive chemotherapy regimens containing high-dose methotrexate, followed by hematopoietic stem cell transplantation have shown the most favorable outcomes, especially for patients receiving thiotepa-based conditioning regimens. However, a proportion of patients will not respond to induction therapies or will subsequently relapse, indicating the need for more effective treatment strategies. In this review we focus on the identification of high-risk patients, prophylactic strategies and recent treatment approaches for SCNSL. The incorporation of novel agents in immunochemotherapy deserves further study in prospective trials.
Topics: Humans; Prospective Studies; Retrospective Studies; Neoplasm Recurrence, Local; Central Nervous System Neoplasms; Lymphoma, Large B-Cell, Diffuse; Methotrexate; Central Nervous System; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36384246
DOI: 10.3324/haematol.2022.281457 -
JAMA Oncology Jul 2021Primary central nervous system lymphoma (PCNSL) requires induction and consolidation to achieve potential cure. High-dose therapy and autologous hematopoietic cell... (Observational Study)
Observational Study
IMPORTANCE
Primary central nervous system lymphoma (PCNSL) requires induction and consolidation to achieve potential cure. High-dose therapy and autologous hematopoietic cell transplant (AHCT) is an accepted and effective consolidation strategy for PCNSL, but no consensus exists on the optimal conditioning regimens.
OBJECTIVE
To assess the outcomes in patients with PCNSL undergoing AHCT with the 3 most commonly used conditioning regimens: thiotepa/busulfan/cyclophosphamide (TBC), thiotepa/carmustine (TT-BCNU), and carmustine/etoposide/cytarabine/melphalan (BEAM).
DESIGN, SETTING, AND PARTICIPANTS
This observational cohort study used registry data from the Center for International Blood and Marrow Transplant Research registry. The Center is a working group of more than 380 transplantation centers worldwide that contributed detailed data on HCT to a statistical center at the Medical College of Wisconsin, Milwaukee. The participant data were from 603 adult patients with PCNSL who underwent AHCT as initial, or subsequent, consolidation between January 2010 and December 2018. Patients were excluded if they had a non-Hodgkin lymphoma subtype other than diffuse large B-cell lymphoma, systemic non-Hodgkin lymphoma, or HIV; received an uncommon conditioning regimen; or were not in partial remission or complete remission prior to AHCT. Statistical analysis was performed from July 5, 2020, to March 1, 2021.
INTERVENTIONS
Patients received 1 of 3 conditioning regimens: TBC (n = 263), TT-BCNU (n = 275), and BEAM (n = 65).
MAIN OUTCOMES AND MEASURES
The primary outcome was progression-free survival. Secondary outcomes included hematopoietic recovery, incidence of relapse, nonrelapse mortality, and overall survival.
RESULTS
Of 603 patients, the mean age was 57 (range, 19-77) years and 318 (53%) were male. The 3-year adjusted progression-free survival rates were higher in the TBC cohort (75%) and TT-BCNU cohort (76%) compared with the BEAM cohort (58%) (P = .03) owing to a higher relapse risk in the BEAM cohort (hazard ratio [HR], 4.34; 95% CI, 2.45-7.70; P < .001). In a multivariable regression analysis, compared with the TBC cohort, patients who received TT-BCNU had a higher relapse risk (HR, 1.79; 95% CI, 1.07-2.98; P = .03), lower risk of nonrelapse mortality (NRM) (HR, 0.50; 95% CI, 0.29-0.87; P = .01), and similar risk of all-cause mortality more than 6 months after HCT (HR, 1.54; 95% CI, 0.93-2.55; P = .10). Age of 60 years or older, Karnofsky performance status less than 90, and an HCT-comorbidity index greater than or equal to 3 were associated with lower rates of survival across all 3 cohorts. Subgroup analyses demonstrated that patients aged 60 years and older had considerably higher NRM with TBC.
CONCLUSIONS AND RELEVANCE
In this cohort study, thiotepa-based conditioning regimen was associated with higher rates of survival compared with BEAM, despite higher rates of early toxic effects and NRM; these findings may assist clinicians in choosing between TBC or TT-BCNU based on patient and disease characteristics.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System; Cohort Studies; Cyclophosphamide; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Neoplasm Recurrence, Local; Thiotepa
PubMed: 33956047
DOI: 10.1001/jamaoncol.2021.1074 -
JAMA Aug 2019Induction chemotherapy followed by high-dose therapy with autologous stem cell transplant and subsequent antidisialoganglioside antibody immunotherapy is standard of... (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
Induction chemotherapy followed by high-dose therapy with autologous stem cell transplant and subsequent antidisialoganglioside antibody immunotherapy is standard of care for patients with high-risk neuroblastoma, but survival rate among these patients remains low.
OBJECTIVE
To determine if tandem autologous transplant improves event-free survival (EFS) compared with single transplant.
DESIGN, SETTING, AND PARTICIPANTS
Patients were enrolled in this randomized clinical trial from November 2007 to February 2012 at 142 Children's Oncology Group centers in the United States, Canada, Switzerland, Australia, and New Zealand. A total of 652 eligible patients aged 30 years or younger with protocol-defined high-risk neuroblastoma were enrolled and 355 were randomized. The final date of follow-up was June 29, 2017, and the data analyses cut-off date was June 30, 2017.
INTERVENTIONS
Patients were randomized to receive tandem transplant with thiotepa/cyclophosphamide followed by dose-reduced carboplatin/etoposide/melphalan (n = 176) or single transplant with carboplatin/etoposide/melphalan (n = 179).
MAIN OUTCOMES AND MEASURES
The primary outcome was EFS from randomization to the occurrence of the first event (relapse, progression, secondary malignancy, or death from any cause). The study was designed to test the 1-sided hypothesis of superiority of tandem transplant compared with single transplant.
RESULTS
Among the 652 eligible patients enrolled, 297 did not undergo randomization because they were nonrandomly assigned (n = 27), ineligible for randomization (n = 62), had no therapy (n = 1), or because of physician/parent preference (n = 207). Among 355 patients randomized (median diagnosis age, 36.1 months; 152 [42.8%] female), 297 patients (83.7%) completed the study and 21 (5.9%) were lost to follow-up after completing protocol therapy. Three-year EFS from the time of randomization was 61.6% (95% CI, 54.3%-68.9%) in the tandem transplant group and 48.4% (95% CI, 41.0%-55.7%) in the single transplant group (1-sided log-rank P=.006). The median (range) duration of follow-up after randomization for 181 patients without an event was 5.6 (0.6-8.9) years. The most common significant toxicities following tandem vs single transplant were mucosal (11.7% vs 15.4%) and infectious (17.9% vs 18.3%).
CONCLUSIONS AND RELEVANCE
Among patients aged 30 years or younger with high-risk neuroblastoma, tandem transplant resulted in a significantly better EFS than single transplant. However, because of the low randomization rate, the findings may not be representative of all patients with high-risk neuroblastoma.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT00567567.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Combined Modality Therapy; Consolidation Chemotherapy; Disease-Free Survival; Female; Humans; Induction Chemotherapy; Infant; Intention to Treat Analysis; Male; Neuroblastoma; Proportional Hazards Models; Risk; Stem Cell Transplantation; Transplantation, Autologous; Young Adult
PubMed: 31454045
DOI: 10.1001/jama.2019.11642 -
The Lancet. Haematology Feb 2021Secondary CNS lymphoma is a rare but potentially lethal event in patients with diffuse large B-cell lymphoma. We aimed to assess the activity and safety of an intensive,...
MATRix-RICE therapy and autologous haematopoietic stem-cell transplantation in diffuse large B-cell lymphoma with secondary CNS involvement (MARIETTA): an international, single-arm, phase 2 trial.
BACKGROUND
Secondary CNS lymphoma is a rare but potentially lethal event in patients with diffuse large B-cell lymphoma. We aimed to assess the activity and safety of an intensive, CNS-directed chemoimmunotherapy consolidated by autologous haematopoietic stem-cell transplantation (HSCT) in patients with secondary CNS lymphoma.
METHODS
This international, single-arm, phase 2 trial was done in 24 hospitals in Italy, the UK, the Netherlands, and Switzerland. Adults (aged 18-70 years) with histologically diagnosed diffuse large B-cell lymphoma and CNS involvement at the time of primary diagnosis or at relapse and Eastern Cooperative Oncology Group Performance Status of 3 or less were enrolled and received three courses of MATRix (rituximab 375 mg/m, intravenous infusion, day 0; methotrexate 3·5 g/m, the first 0·5 g/m in 15 min followed by 3 g/m in a 3 h intravenous infusion, day 1; cytarabine 2 g/m every 12 h, in 1 h intravenous infusions, days 2 and 3; thiotepa 30 mg/m, 30 min intravenous infusion, day 4) followed by three courses of RICE (rituximab 375 mg/m, day 1; etoposide 100 mg/m per day in 500-1000 mL over a 60 min intravenous infusion, days 1, 2, and 3; ifosfamide 5 g/m in 1000 mL in a 24 h intravenous infusion with mesna support, day 2; carboplatin area under the curve of 5 in 500 mL in a 1 h intravenous infusion, day 2) and carmustine-thiotepa and autologous HSCT (carmustine 400 mg/m in 500 mL glucose 5% solution in a 1-2 h infusion, day -6; thiotepa 5 mg/kg in saline solution in a 2 h infusion every 12 h, days -5 and -4). The primary endpoint was progression-free survival at 1 year. Overall and complete response rates before autologous HSCT, duration of response, overall survival, and safety were the secondary endpoints. Analyses were in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02329080. The trial ended after accrual completion; the database lock was Dec 31, 2019.
FINDINGS
Between March 30, 2015, and Aug 3, 2018, 79 patients were enrolled. 75 patients were assessable. 319 (71%) of the 450 planned courses were delivered. At 1 year from enrolment the primary endpoint was met, 42 patients were progression free (progression-free survival 58%; 95% CI 55-61). 49 patients (65%; 95% CI 54-76) had an objective response after MATRix-RICE, 29 (39%) of whom had a complete response. 37 patients who responded had autologous HSCT. At the end of the programme, 46 patients (61%; 95% CI 51-71) had an objective response, with a median duration of objective response of 26 months (IQR 16-37). At a median follow-up of 29 months (IQR 20-40), 35 patients were progression-free and 33 were alive, with a 2-year overall survival of 46% (95% CI 39-53). Grade 3-4 toxicity was most commonly haematological: neutropenia in 46 (61%) of 75 patients, thrombocytopenia in 45 (60%), and anaemia in 26 (35%). 79 serious adverse events were recorded in 42 (56%) patients; four (5%) of those 79 were lethal due to sepsis caused by Gram-negative bacteria (treatment-related mortality 5%; 95% CI 0·07-9·93).
INTERPRETATION
MATRix-RICE plus autologous HSCT was active in this population of patients with very poor prognosis, and had an acceptable toxicity profile.
FUNDING
Stand Up To Cancer Campaign for Cancer Research UK, the Swiss Cancer Research foundation, and the Swiss Cancer League.
Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Cytarabine; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Kaplan-Meier Estimate; Lymphoma, Large B-Cell, Diffuse; Male; Methotrexate; Middle Aged; Neutropenia; Rituximab; Severity of Illness Index; Transplantation, Autologous; Young Adult
PubMed: 33513372
DOI: 10.1016/S2352-3026(20)30366-5 -
Transplantation and Cellular Therapy Sep 2023Autologous hematopoietic cell transplantation (auto-HCT) has long been the standard approach for patients with relapsed/refractory (R/R) chemosensitive diffuse large B...
Autologous hematopoietic cell transplantation (auto-HCT) has long been the standard approach for patients with relapsed/refractory (R/R) chemosensitive diffuse large B cell lymphoma (DLBCL). However, the advent of chimeric antigen receptor (CAR) T cell therapy has caused a paradigm shift in the management of R/R DLBCL patients, especially with the recent approval of CD19-directed CAR-T therapy in the second-line setting in high-risk groups (primary refractory and early relapse [≤12 months]). Consensus on the contemporary role, optimal timing, and sequencing of HCT and cellular therapies in DLBCL is lacking; therefore, the American Society of Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines undertook this project to formulate consensus recommendations to address this unmet need. The RAND-modified Delphi method was used to generate 20 consensus statements with a few key statements as follows: (1) in the first-line setting, there is no role for auto-HCT consolidation for patients achieving complete remission (CR) following R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone) or similar therapy in non-double-hit/triple-hit cases (DHL/THL) and in DHL/THL cases receiving intensive induction therapies, but auto-HCT may be considered in eligible patients receiving R-CHOP or similar therapies in DHL/THL cases; (2) auto-HCT consolidation with thiotepa-based conditioning is standard of care for eligible patients with primary central nervous system lymphoma achieving CR with first-line therapy; and (3) in the primary refractory and early relapse setting, the preferred option is CAR-T therapy, whereas in late relapse (>12 months), consolidation with auto-HCT is recommended for patients achieving chemosensitivity to salvage therapy (complete or partial response), and CAR-T therapy is recommended for those not achieving remission. These clinical practice recommendations will serve as a tool to guide clinicians managing patients with newly diagnosed and R/R DLBCL.
Topics: Humans; Receptors, Chimeric Antigen; Neoplasm Recurrence, Local; Lymphoma, Large B-Cell, Diffuse; Hematopoietic Stem Cell Transplantation; Rituximab; Lymphoma, Non-Hodgkin; Cyclophosphamide; Vincristine; Prednisone; Doxorubicin; Recurrence
PubMed: 37419325
DOI: 10.1016/j.jtct.2023.06.012 -
Neuro-oncology Jul 2022Embryonal tumors of the CNS are the most common malignant tumors occurring in the first years of life. This study evaluated the feasibility and safety of incorporating... (Clinical Trial)
Clinical Trial
BACKGROUND
Embryonal tumors of the CNS are the most common malignant tumors occurring in the first years of life. This study evaluated the feasibility and safety of incorporating novel non-cytotoxic therapy with vorinostat and isotretinoin to an intensive cytotoxic chemotherapy backbone.
METHODS
PBTC-026 was a prospective multi-institutional clinical trial for children <48 months of age with newly diagnosed embryonal tumors of the CNS. Treatment included three 21-day cycles of induction therapy with vorinostat and isotretinoin, cisplatin, vincristine, cyclophosphamide, and etoposide; three 28-day cycles of consolidation therapy with carboplatin and thiotepa followed by stem cell rescue; and twelve 28-day cycles of maintenance therapy with vorinostat and isotretinoin. Patients with M0 medulloblastoma (MB) received focal radiation following consolidation therapy. Molecular classification was by DNA methylation array.
RESULTS
Thirty-one patients with median age of 26 months (range 6-46) received treatment on study; 19 (61%) were male. Diagnosis was MB in 20 and supratentorial CNS embryonal tumor in 11. 24/31 patients completed induction therapy within a pre-specified feasibility window of 98 days. Five-year progression-free survival (PFS) and overall survival (OS) for all 31 patients were 55 ± 15 and 61 ± 13, respectively. Five-year PFS was 42 ± 13 for group 3 MB (n = 12); 80 ± 25 for SHH MB (n = 5); 33 ± 19 for embryonal tumor with multilayered rosettes (ETMR, n = 6).
CONCLUSION
It was safe and feasible to incorporate vorinostat and isotretinoin into an intensive chemotherapy regimen. Further study to define efficacy in this high-risk group of patients is warranted.
Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cerebellar Neoplasms; Child; Child, Preschool; Cyclophosphamide; Etoposide; Female; Humans; Infant; Isotretinoin; Male; Medulloblastoma; Neoplasms, Germ Cell and Embryonal; Neuroectodermal Tumors, Primitive; Prospective Studies; Vincristine; Vorinostat
PubMed: 34935967
DOI: 10.1093/neuonc/noab293