Cancer is the leading cause of death for HIV-infected persons in economically developed countries, even in the era of antiretroviral therapy (ART). Lymphomas remain a leading cause of cancer ...morbidity and mortality for HIV-infected patients and have increased incidence even in patients optimally treated with ART. Even limited interruptions of ART can lead to CD4 cell nadirs and HIV viremia, and increase the risk of lymphoma. The treatment of lymphoma is now similar for HIV-infected patients and the general population: patients with good HIV control can withstand intensive therapies appropriate to the lymphoma, including autologous and even allogeneic hematopoietic stem cell transplantation. Nonetheless, HIV-related lymphomas have unique aspects, including differences in lymphoma pathogenesis, driven by the presence of HIV, in addition to coinfection with oncogenic viruses. These differences might be exploited in the future to inform therapies. The relative incidences of lymphoma subtypes also differ in the HIV-infected population, and the propensity to advanced stage, aggressive presentation, and extranodal disease is higher. Other unique aspects include the need to avoid potential interactions between ART and chemotherapeutic agents, and the need for HIV-specific supportive care, such as infection prophylaxis. Despite these specific challenges for cancer treatment in the setting of HIV infection, the care of these patients has progressed sufficiently that recent guidelines from the American Society of Clinical Oncology advocate the inclusion of HIV-infected patients alongside HIV− patients in cancer clinical trials when appropriate.
Chromosomal integrity is vital to the life span of the dividing cell. Telomeres are tandem sequences at chromosome ends that provide protection for the genetic coding material. Erosion of those ends ...leads to cell death. Does stabilization promote cancer?
Summary Background Pre-transplantation18 F-fluorodeoxyglucose (FDG) PET-negativity is one of the strongest predictors of outcome after high-dose therapy and autologous stem-cell transplant (HDT/ASCT) ...for patients with relapsed or refractory Hodgkin's lymphoma. In this study, we assessed the feasibility and activity of PET-adapted salvage therapy with brentuximab vedotin, followed by augmented ifosfamide, carboplatin, and etoposide (ICE). Methods In this non-randomised, open-label, single-centre, phase 2 trial, we enrolled patients with relapsed or refractory Hodgkin's lymphoma who had failed one previous doxorubicin-containing chemotherapy regimen. All patients received weekly infusions of 1·2 mg/kg brentuximab vedotin on days 1, 8, and 15 for two 28 day cycles. After completion of brentuximab vedotin treatment, patients received a PET scan. Patients who achieved PET-negative status (a Deauville score of 1 or 2) proceeded directly to HDT/ASCT; those with persistent abnormalities on PET received two cycles of augmented ICE (augICE; two doses of ifosfamide 5000 mg/m2 in combination with mesna 5000 mg/m2 continuous infusion over 24 h, days 1 and 2; one dose of carboplatin AUC 5, day 3; three doses of etoposide 200 mg/m2 every 12 h, day 1) before consideration for HDT/ASCT. Only patients with persistent abnormalities on PET after brentuximab vedotin received augICE; however, all patients in the intention-to-treat population were assessed for the primary outcome, which was the proportion of patients who were PET-negative after brentuximab vedotin alone or brentuximab vedotin followed by augICE. This study is registered with ClinicalTrials.gov , number NCT01508312 , and is no longer accruing patients. Findings Between Jan 5, 2012, and Oct 4, 2013, we enrolled 46 patients. One patient was deemed ineligible, and not evaluable, before treatment initiation owing to having nodular, lymphocyte-predominant Hodgkin's lymphoma and thus 45 patients received treatment. After brentuximab vedotin, 12 patients (27%, 95% CI 13–40) were PET-negative and proceeded to HDT/ASCT. 33 (73%, 95% CI 60–86) patients were PET-positive after brentuximab vedotin; one PET-positive patient withdrew consent, therefore 32 PET-positive patients received augICE, 22 (69%, 95% CI 53–85) of whom were PET-negative. Overall, 34 patients (76%, 95% CI 62–89) achieved PET-negativity. All 44 patients who completed treatment as per protocol proceeded to receive HDT/ASCT. Brentuximab vedotin was well tolerated and associated with few grade 3–4 adverse events including hyperglycaemia (two 4% patients, grade 3), nausea (one 2%, grade 3), hypoglycaemia (one 2%, grade 3 and one 2%, grade 4), and hypocalcaemia (one 2%, grade 3 and one 2%, grade 4). Interpretation PET-adapted sequential salvage therapy with brentuximab vedotin followed by augICE resulted in a high proportion of patients with relapsed or refractory Hodgkin's lymphoma achieving PET-negativity, and therefore could optimise the chance of cure after HDT/ASCT. Funding Seattle Genetics.
Although methotrexate (MTX) is the most widely used therapy for central nervous system (CNS) prophylaxis in patients with diffuse large B-cell lymphoma (DLBCL), the optimal regimen remains unclear. ...We examined the efficacy of different prophylactic regimens in 585 patients with newly diagnosed DLBCL and high-risk for CNS relapse, treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or R-CHOP-like regimens from 2001 to 2017, of whom 295 (50%) received prophylaxis. Intrathecal (IT) MTX was given to 253 (86%) and high-dose MTX (HD-MTX) to 42 (14%). After a median follow-up of 6.8 years, 36 of 585 patients relapsed in the CNS, of whom 14 had received prophylaxis. The CNS relapse risk at 1 year was lower for patients who received prophylaxis than patients who did not: 2% vs. 7.1%. However, the difference became less significant over time (5-year risk 5.6% vs. 7.5%), indicating prophylaxis tended to delay CNS relapse rather than prevent it. Furthermore, the CNS relapse risk was similar in patients who received IT and HD-MTX (5-year risk 5.6% vs. 5.2%). Collectively, our data indicate the benefit of MTX for CNS prophylaxis is transient, highlighting the need for more effective prophylactic regimens. In addition, our results failed to demonstrate a clinical advantage for the HD-MTX regimen.
Limited data exist regarding the activity of bendamustine in Hodgkin lymphoma (HL). This phase II study evaluated the efficacy of bendamustine in relapsed and refractory HL.
Patients with relapsed ...and refractory HL who were ineligible for autologous stem-cell transplantation (ASCT), or for whom this treatment failed, received bendamustine 120 mg/m(2) as a 30-minute infusion on days 1 and 2 every 28 days with growth factor support. The primary end point was overall response rate (ORR). A secondary end point was referral rate to allogeneic stem-cell transplantation (alloSCT) for patients deemed eligible for alloSCT at the time of enrollment.
Of the 36 patients enrolled, 34 were evaluable for response. Patients had received a median of four prior treatments, and 75% had relapsed after ASCT. The ORR by intent-to-treat analysis was 53%, including 12 complete responses (33%) and seven partial responses (19%). The response rate among evaluable patients was 56%. Responses were seen in patients with prior refractory disease, prior ASCT, and prior alloSCT; however, no responses were seen in patients who relapsed within 3 months of ASCT. The median response duration was 5 months. Five patients (20% of those eligible) proceeded to alloSCT after treatment with bendamustine. Grade ≥ 3 adverse events were infrequent and most commonly included thrombocytopenia (20%), anemia (14%), and infection (14%).
This study confirms the efficacy of bendamustine in heavily pretreated patients with HL. These results support current and future studies evaluating bendamustine combinations in relapsed and refractory HL.
Patients with follicular lymphoma (FL) frequently require multiple treatments during their disease course; however, survival based on lines of treatment remains poorly described in the post-rituximab ...era. Also, the Follicular Lymphoma International Prognostic Index (FLIPI) score was developed to predict survival at diagnosis, yet it remains unknown whether increase in FLIPI score following an initial observation period is associated with less-favorable outcomes. To address these knowledge gaps, we retrospectively studied 1088 patients with FL grade 1-3A managed between 1998 and 2009 at our institution. Median overall survival (OS) and progression-free survival (PFS) after first-line treatment were not reached and 4.73 years, respectively. Following successive lines of treatment, years of median OS and PFS were, respectively: after second-line, 11.7 and 1.5; third-line, 8.8 and 1.1; fourth-line, 5.3 and 0.9; fifth-line, 3.1 and 0.6; sixth-line, 1.9 and 0.5. In initially observed, subsequently treated patients, FLIPI score increase after observation was associated with inferior survival following first-line treatment. The reduced survival we observed after second-line and later therapy supports the development of new treatments for relapsed patients and benchmarks historical targets for clinical endpoints. This study also highlights the utility of changes in FLIPI score at diagnosis and after observation in identifying patients likely to have worse outcomes.
Limited comparative data exist for the treatment of HIV-associated non-Hodgkin lymphoma. We analyzed pooled individual patient data for 1546 patients from 19 prospective clinical trials to assess ...treatment-specific factors (type of chemotherapy, rituximab, and concurrent combination antiretroviral cART use) and their influence on the outcomes complete response (CR), progression free survival (PFS), and overall survival (OS). In our analysis, rituximab was associated with a higher CR rate (odds ratio OR 2.89; P < .001), improved PFS (hazard ratio HR 0.50; P < .001), and OS (HR 0.51; P < .0001). Compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), initial therapy with more dose-intense regimens resulted in better CR rates (ACVBP doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisolone: OR 1.70; P < .04), PFS (ACVBP: HR 0.72; P = .049; “intensive regimens”: HR 0.35; P < .001) and OS (“intensive regimens”: HR 0.54; P < .001). Infusional etoposide, prednisone, infusional vincristine, infusional doxorubicin, and cyclophosphamide (EPOCH) was associated with significantly better OS in diffuse large B-cell lymphoma (HR 0.33; P = .03). Concurrent use of cART was associated with improved CR rates (OR 1.89; P = .005) and trended toward improved OS (HR 0.78; P = .07). These findings provide supporting evidence for current patterns of care where definitive evidence is unavailable.
•Rituximab use is associated with significant improvement in all outcomes for patients with HIV-associated CD20-positive lymphomas.•Infusional EPOCH chemotherapy is associated with better overall survival in patients with AIDS-related diffuse large B-cell lymphoma (DLBCL).
As the survival of patients with mantle cell lymphoma (MCL) continues to improve, patients are increasingly being treated with multiple regimens. However, outcome after each line remains poorly ...characterized in the modern era. To address this knowledge gap, we retrospectively studied 404 consecutive MCL patients who were managed between 2000 and 2014 at Memorial Sloan Kettering Cancer Center. Histologic diagnosis was centrally confirmed, and patients were followed longitudinally from diagnosis throughout their disease course. Progression-free survival (PFS) and overall survival (OS) were determined by Kaplan-Meier method. The median OS and PFS after first-line treatment were 9.7 and 4.0 years, respectively. After second-line therapy, the median OS and PFS were 41.1 and 14.0 months, third line were 25.2 and 6.5 months, and fourth line were 14.4 and 5.0 months. In patients less than 65 years, stem cell transplant (SCT)-based frontline regimens were associated with improved PFS compared with non-SCT regimens (median PFS: 86.2 versus 40.0 months; P < 0.01), with a trend toward longer OS (median OS: 165.0 versus 120.0 months; P = 0.06). Early treatment failure after first-line regimens was associated with worse OS (5.9 versus 2.5 years; P < 0.01). Our study should facilitate establishing proper endpoints for future clinical trials using novel treatment approaches.
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