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Abstract: Although it is evident that standard-dose whole-brain radiotherapy as consolidation is associated with significant neurotoxicity, the optimal consolidative strategy for primary central nervous system lymphoma (PCNSL) is not defined. We performed a randomized phase 2 clinical trial via the US Alliance cancer cooperative group to compare myeloablative consolidation supported by autologous stem cell transplantation with nonmyeloablative consolidation after induction therapy for PCNSL. To our knowledge, this is the first randomized trial to be initiated that eliminates whole-brain radiotherapy as a consolidative approach in newly diagnosed PCNSL. Patients aged 18 to 75 years were randomly assigned in a 1:1 manner to induction therapy (methotrexate, temozolomide, rituximab, and cytarabine) followed by consolidation with either thiotepa plus carmustine and autologous stem cell rescue vs induction followed by nonmyeloablative, infusional etoposide plus cytarabine. The primary end point was progression-free survival (PFS). A total of 113 patients were randomized, and 108 (54 in each arm) were evaluable. More patients in the nonmyeloablative arm experienced progressive disease or death during induction (28% vs 11%; P = .05). Thirty-six patients received autologous stem cell transplant, and 34 received nonmyeloablative consolidation. The estimated 2-year PFS was higher in the myeloablative vs nonmyeloablative arm (73% vs 51%; P = .02). However, a planned secondary analysis, landmarked at start of the consolidation, revealed that the estimated 2-year PFS in those who completed consolidation therapy was not significantly different between the arms (86% vs 71%; P = .21). Both consolidative strategies yielded encouraging efficacy and similar toxicity profiles. This trial was registered at www.clininicals.gov as #NCT01511562., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Purpose: Diffuse large B-cell lymphoma (DLBCL) presents as a limited-stage disease in 25% to 30% of patients, with better overall survival (OS) than that for advanced-stage disease but with continuous relapse regardless of treatment approach. The preferred treatment is abbreviated rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and radiation therapy. On the basis of promising results of positron emission tomography (PET)-directed treatment approaches, we designed a National Clinical Trials Network (NCTN) study to improve outcomes and decrease toxicity., Methods: Patients with nonbulky (< 10 cm) stage I/II untreated DLBCL received 3 cycles of standard R-CHOP therapy and underwent a centrally reviewed interim PET/computed tomography scan (iPET). Those with a negative iPET proceeded with 1 additional cycle of R-CHOP, whereas those with a positive iPET received involved field radiation therapy followed by ibritumomab tiuxetan radioimmunotherapy., Results: Of 158 patients enrolled, 132 were eligible and 128 underwent iPET, which was positive in 14 (11%) of the patients. With a median follow-up of 4.92 years (range, 1.1-7.7 years), only 6 patients progressed and 3 died as a result of lymphoma. Eleven patients died as a result of nonlymphoma causes at a median age of 80 years. The 5-year progression-free survival estimate was 87% (95% CI, 79% to 92%) and the OS estimate was 89% (95% CI, 82% to 94%), with iPET-positive and iPET-negative patients having similar outcomes., Conclusion: To our knowledge, S1001 is the largest prospective study in the United States of limited-stage DLBCL in the rituximab era, with the best NCTN results in this disease subset. With PET-directed therapy, 89% of the patients with a negative iPET received R-CHOP × 4, and only 11% had a positive iPET and required radiation, with both groups having excellent outcomes. The trial establishes R-CHOP × 4 alone as the new standard approach to limited-stage disease for the absolute majority of patients.

Prior to the introduction of rituximab, primary mediastinal B-cell lymphoma (PMBCL) had high rates of treatment failure with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), prompting the use of consolidative mediastinal radiation or more intensive chemotherapy regimens. Cure rates improved dramatically with rituximab, but mediastinal radiation was still commonly employed with R-CHOP. We performed a retrospective review of patients treated with R-CHOP alone without radiation for PMBCL. Of 43 patients with PMBCL, 16 received R-CHOP alone. High-risk factors included 56% with bulky disease, 75% with elevated LDH, 25% with SVC syndrome, and 13% with stage IV disease. Three-year progression-free survival (PFS) and overall survival (OS) were 93% and 100% respectively. These results suggest that R-CHOP alone has a high cure rate in PMBCL while avoiding the side effects of mediastinal radiation.

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas., (Copyright © 2017 by the National Comprehensive Cancer Network.)

A persistently positive positron emission tomography (PET) scan during therapy for diffuse large B-cell lymphoma (DLBCL) is predictive of treatment failure. A response-adapted strategy consisting of an early treatment change to four cycles of R-ICE (rituximab, ifosfamide, carboplatin, etoposide) was studied in the Eastern Cooperative Oncology Group E3404 trial. Previously untreated patients with DLBCL stage III, IV, or bulky II, were eligible. PET scan was performed after three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and scored as positive or negative by central review during the fourth cycle. PET-positive patients received four cycles of R-ICE, PET-negative patients received two more cycles of R-CHOP. A ≥ 45% 2-year progression-free survival (PFS) for mid-treatment PET-positive patients was viewed as promising. Of 74 patients, 16% were PET positive, 79% negative. The PET positivity rate was much lower than the 33% expected. Two-year PFS was 70%; 42% [90% confidence interval (CI), 19-63%] for PET-positives and 76% (90% CI 65-84%) for PET-negatives. Three-year overall survival (OS) was 69% (90% CI 43-85%) and 93% (90% CI 86-97%) for PET-positive and -negative cases, respectively. The 2-year PFS for mid-treatment PET-positive patients intensified to R-ICE was 42%, with a wide confidence interval due to the low proportion of positive mid-treatment PET scans. Treatment modification based on early PET scanning should remain confined to clinical trials., (© 2015 John Wiley & Sons Ltd.)

Peripheral T-cell lymphoma (PTCL) and natural killer (NK) cell lymphoma have poor survival with conventional cytotoxic chemotherapy. Because angiogenesis plays an important role in the biology of PTCL, a fully humanized anti-vascular endothelial growth factor (VEGF) antibody, bevacizumab (A), was studied in combination with standard cyclosphosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy (ACHOP) to evaluate its potential to improve outcome in these patients. Patients were treated with 6-8 cycles of ACHOP followed by eight doses of maintenance A (15 mg/kg every 21 days). Forty-six patients were enrolled on this phase 2 study from July 2006 through March 2009. Forty-four patients were evaluable for toxicity and 39 were evaluable for response, progression and survival. A total of 324 cycles (range: 2-16, median 7) were administered to 39 evaluable patients and only nine completed all planned treatment. The overall response rate was 90% with 19 (49%) complete response/complete response unconfirmed (CR/CRu) and 16 (41%) a partial response (PR). The 1-year progression-free survival (PFS) rate was 44% at a median follow-up of 3 years. The median PFS and overall survival (OS) rates were 7.7 and 22 months, respectively. Twenty-three patients died (21 from lymphoma, two while in remission). Grade 3 or 4 toxicities included febrile neutropenia (n = 8), anemia (n = 3), thrombocytopenia (n = 5), congestive heart failure (n = 4), venous thrombosis (n = 3), gastrointestinal hemorrhage/perforation (n = 2), infection (n = 8) and fatigue (n = 6). Despite a high overall response rate, the ACHOP regimen failed to result in durable remissions and was associated with significant toxicities. Studies of novel therapeutics are needed for this patient population, whose clinical outcome remains poor.

Older patients with Burkitt lymphoma/leukemia (BL) have inferior outcomes. Because cyclophosphamide is highly active in BL and can be dose-escalated without stem-cell rescue, we designed a short, cyclophosphamide-intensive regimen without anthracyclines for patients aged ≥ 30 with untreated, non-HIV-associated BL/atypical BL. Two cycles involving cyclophosphamide 1500 mg/m(2), vincristine, rituximab, prednisone, methotrexate 3 g/m(2), and intrathecal cytarabine were delivered 2 weeks apart, followed by intensification with high-dose cyclophosphamide (50 mg/kg/day for 4 days) and rituximab. Of 21 patients, median age 53 (range, 34-75), 71% had stage IV, 95% were high-risk and 29% had performance status 3-4. Response occurred in all evaluable patients post-cycle 2 and in 76% post-intensification. Five non-relapse deaths occurred (four before intensification). The estimated 1-year and 3-year event-free survival was 52%; 1-year and 3-year overall survival was 57%. Seventeen (81%) received intensification (median 30 days to intensification). Brief, anthracycline-sparing, intensive cyclophosphamide (BASIC) therapy yields durable remissions in poorer-risk BL/atypical BL.

In classical Hodgkin lymphoma, circulating clonotypic malignant cells express CD20, which potentially explains the observed activity of rituximab. This multicenter phase 2 study investigated the combination of rituximab-ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) for stage II-IV untreated classical Hodgkin lymphoma. A goal was to assess the behavior of circulating clonotypic B cells clinically. Of 49 evaluable patients, 69% had stage IIB-IV disease; 8% had CD20(+) Hodgkin and Reed-Sternberg cells. Rituximab-ABVD was generally well tolerated. Delivered relative dose intensity was 94% for AVD and 79% for bleomycin. After 6 cycles, 81% of patients were in complete remission. Only 8% received radiation therapy. The actuarial 3-year event-free and overall survival rates were 83% and 98%, respectively. EBV copy number in plasma fell dramatically during cycle 1 in patients with EBV(+) tumors. Persistence of detectable circulating clonotypic B cells was associated with a greater relapse frequency (P < .05). Rituximab-ABVD and clonotypic B cells warrant additional study in classical Hodgkin lymphoma.

Relapse after autologous stem cell transplant for low grade B-cell lymphoma is common secondary to ineffective conditioning and/or tumor autograft contamination. We investigated high-dose cyclophosphamide and rituximab without stem cell rescue as first-line or salvage therapy in lymphomas. After establishing safety, accrual was increased to evaluate event-free survival (EFS). Eighty-one adults received rituximab (375 mg/m(2) days 1, 4, 8, 11, 45, 52), cyclophosphamide (50 mg/kg days 15-18), and pegfilgrastim (day 20). Forty-two patients had low grade B-cell lymphoma [grade I/II follicular (69%), transformed lymphoma (17%), other (15%)]: 45% were treated without measurable disease. Thirty-nine patients had mantle cell lymphoma: 82% were treated without measurable disease. All achieved hematopoietic recovery; 46% required brief hospitalizations. The 5-year EFS and overall survival (OS) for patients with low grade B-cell and transformed lymphoma were 40% and 72%, respectively. The 5-year EFS and OS for patients with MCL were 39% and 62%, respectively. This low-toxicity therapeutic approach obviates the need for stem cell products and establishes a platform for future therapies.

Purpose of Review: Functional metabolic imaging through fluorine-18 fluorodeoxyglucose positron emission tomography has recently come to the forefront in the management of various solid and hematologic malignancies. This review summarizes the developments in risk assessment through positron emission tomography in patients with lymphoma and the implications for management., Recent Findings: In addition to improving staging and response assessment, positron emission tomography has emerged as a strong prognostic tool in patients with aggressive lymphomas. A positron emission tomographic scan performed after only a few cycles of chemotherapy can accurately predict relapse risk, and most studied patients with abnormal positron emission tomographic scans have had distinctly poorer clinical outcomes than patients with negative scans., Summary: With confirmation of these findings, a more individualized, risk-adapted approach to the treatment of aggressive lymphomas will be feasible. Early identification of high-risk patients through the combination of positron emission tomography and existing prognostic indices could lead to earlier implementation of intensive therapies and improved clinical outcomes.