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Related HLA-haploidentical blood or marrow transplantation (BMT) with high-dose posttransplantation cyclophosphamide (PTCy) is being increasingly used because of its acceptable safety profile. To better define outcomes of nonmyeloablative (NMA) HLA-haploidentical BMT with PTCy, 372 consecutive adult hematologic malignancy patients who underwent this procedure were retrospectively studied. Risk-stratified outcomes were evaluated using the refined Disease Risk Index (DRI), developed to stratify disease risk across histologies and allogeneic BMT regimens. Patients received uniform conditioning, T-cell-replete allografting, then PTCy, mycophenolate mofetil, and tacrolimus. Six-month probabilities of nonrelapse mortality and severe acute graft-versus-host disease were 8% and 4%. With 4.1-year median follow-up, 3-year probabilities of relapse, progression-free survival (PFS), and overall survival (OS) were 46%, 40%, and 50%, respectively. By refined DRI group, low (n = 71), intermediate (n = 241), and high/very high (n = 60) risk groups had 3-year PFS estimates of 65%, 37%, and 22% (P < .0001), with corresponding 3-year OS estimates of 71%, 48%, and 35% (P = .0001). On multivariable analyses, the DRI was statistically significantly associated with relapse, PFS, and OS (each P < .001). This analysis demonstrates that the DRI effectively risk stratifies recipients of NMA HLA-haploidentical BMT with PTCy and also suggests that this transplantation platform yields similar survivals to those seen with HLA-matched BMT. [ABSTRACT FROM AUTHOR]

High-dose, posttransplantation cyclophosphamide (PTCy) reduces severe graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (alloBMT), but the impact of PTCy on long-term, disease-specific outcomes is unclear. We conducted a retrospective study of 209 consecutive adult patients transplanted for acute myeloid leukemia (AML, n = 138), myelodysplastic syndrome (n = 28), or acute lymphoblastic leukemia (ALL, n = 43) using PTCy as sole GVHD prophylaxis after myeloablative conditioning and HLA-matched-related or -unrelated T-cell-replete allografting. At alloBMT, 30% of patients were not in morphologic complete remission. The cumulative incidences of grades II to IV and III to IV acute GVHD at 100 days and chronic GVHD at 2 years were 45%, 11%, and 13%, respectively. Forty-three percent of patients did not require immunosuppression for any reason beyond PTCy. At 3 years, relapse cumulative incidence was 36%, disease-free survival was 46%, survival free of disease and chronic GVHD was 39%, and overall survival was 58%. Lack of remission at alloBMT, adverse cytogenetics, and low allograft nucleated cell dose were associated with inferior survival for AML patients. Minimal residual disease but not t(9;22) was associated with inferior outcomes for ALL patients. The ability to limit posttransplantation immunosuppression makes PTCy a promising transplantation platform for the integration of postgrafting strategies to prevent relapse. [ABSTRACT FROM AUTHOR]

Abstract: The role of allogeneic blood or marrow transplantation (alloBMT) for peripheral T cell lymphoma (PTCL) remains to be defined. There is growing interest in reduced-intensity conditioning (RIC) regimens and/or utilization of human leukocyte antigen haploidentical (haplo) grafts given concerns about treatment-associated toxicities and donor availability. We reviewed the outcomes of 44 consecutive, related donor alloBMTs for PTCL performed at Johns Hopkins Hospital from 1994 to 2011, including 18 RIC/haplo alloBMTs. Patients receiving RIC (n = 24) were older, with median age of 59 years (range, 24 to 70), than patients receiving myeloablative conditioning (MAC, n = 20), with median age of 46 years (range, 18 to 64), P = .01. The median age at RIC/haplo alloBMT was 60 years. The estimated 2-year progression-free survival (PFS) was 40% (95% confidence interval [CI], 26% to 55%) and overall survival (OS) was 43% (95% CI, 28% to 59%). In older patients (≥60, n = 14), the estimated 2-year PFS and OS were 38% (95% CI, 18% to 79%) and 45% (95% CI, 24% to 86%), respectively. On unadjusted analysis, there was a tendency toward superior outcomes for alloBMT in first remission versus beyond first remission, with an estimated 2-year PFS of 53% (95% CI, 33% to 77%) versus 29% (95% CI, 9% to 45%), P = .08. On competing risk analysis, the 1-year cumulative incidence of relapse was 38% for MAC/HLA-identical alloBMTs and 34% for RIC/haplo alloBMTs. Estimated 1-year nonrelapse mortality was 10% for MAC and 8% for RIC (11% for RIC/haplo alloBMT). On unadjusted landmark analysis, patients with acute grade II-IV or chronic graft-versus-host disease (GVHD) had a 17% probability of relapse (95% CI, 0% to 39%), compared with 66% (95% CI, 48% to 84%) in patients without GVHD, P = .04. Utilization of RIC and alternative donors expands treatment options in PTCL to those who are older and unable to tolerate high-dose conditioning, with outcomes comparable with approaches using myeloablative regimens and HLA-matched donors. AlloBMT may be appropriate in first remission in select high-risk cases. [Copyright &y& Elsevier]

Although some reports have found an association between increasing HLA disparity between donor and recipient and fewer relapses after allogeneic blood or marrow transplantation (BMT), this potential benefit has been offset by more graft-versus-host disease (GVHD) and nonrelapse mortality (NRM). However, the type of GVHD prophylaxis might influence the balance between GVHD toxicity and relapse. The present study analyzed the impact of greater HLA disparity on outcomes of a specific platform for nonmyeloablative (NMA), HLA-haploidentical transplantation. A retrospective analysis was performed of 185 patients with hematologic malignancies enrolled in 3 similar trials of NMA, related donor, haploidentical BMT incorporating high-dose posttransplantation cyclophosphamide for GVHD prophylaxis. No significant association was found between the number of HLA mismatches (HLA-A, -B, -Cw, and -DRB1 combined) and risk of acute grade II-IV GVHD (hazard ratio [HR] = 0.89; P = .68 for 3-4 vs fewer antigen mismatches). More mismatching also had no detrimental effect on event-free survival (on multivariate analysis, HR = 0.60, P = .03 for 3-4 vs fewer antigen mismatches and HR = 0.55, P = .03 for 3-4 vs fewer allele mismatches). Thus, greater HLA disparity does not appear to worsen overall outcome after NMA haploidentical BMT with high-dose posttransplantation cyclophosphamide. [Copyright &y& Elsevier]

Abstract: In newly diagnosed aggressive non-Hodgkin lymphoma (NHL), a positive midtreatment fluorine-18 fluorodeoxyglucose positron emission tomography (PET) scan often carries a poor prognosis, with reported 2-year event-free survival (EFS) rates of 0% to 30% after standard therapy. To determine the outcome of early treatment intensification for midtreatment PET-positive disease, a phase II trial of risk-adapted therapy was conducted. Fifty-nine newly diagnosed patients, 98% with B cell lymphoma, had PET/CT performed after 2 or 3 cycles of first-line chemotherapy. Those with negative PET on semiquantitative visual interpretation completed standard therapy. Those with positive PET received platinum-based salvage chemotherapy, high-dose therapy, and autologous stem cell transplantation (ASCT). Midtreatment PET was positive in 33 (56%); 28 received ASCT with an actuarial 2-year EFS of 75% (95% confidence interval, 60%-93%). On intention-to-treat analysis, 2-year EFS was 67% (53%-86%) in all PET-positive patients and 89% (77%-100%) in PET-negative patients. No association was found between the International Prognostic Index category and the midtreatment PET result. The favorable outcome achieved here in historically poor-risk patients warrants further, more definitive investigation of treatment modification based on early PET scanning. [Copyright &y& Elsevier]

Abstract: The results of blood or marrow transplantation in patients with chemorefractory aggressive lymphoma, that is, those not responding to conventional-dose chemotherapy at the time of transplant, have been poor. The relapse rate has been high after autologous bone marrow transplant, whereas allogeneic transplantation has been associated with excessive transplant-related toxicity. Administration of cyclosporine after autologous transplantation can induce an autoreactive syndrome that resembles graft-versus-host disease (GVHD). This syndrome, named autologous graft-versus-host disease, has clear antitumor activity in animal models that can be enhanced by the addition of cytokines such as γ-interferon and interleukin-2. A randomized, prospective study was conducted to evaluate the antitumor effect of autologous graft-versus-host disease induced with cyclosporine, and augmented by the administration of γ-interferon and interleukin-2 in patients with chemorefractory Hodgkin and aggressive non-Hodgkin lymphomas. Fifty-one patients were randomized, 24 to the autologous GVHD induction arm, and 27 to the noninduction arm after autologous transplant using mobilized peripheral blood stem cell (PBSC) grafts. There were no differences in treatment-related mortality, overall and event-free survival (OS, EFS) between both groups; however, in the induction arm, GVHD developed only in 4 patients. The administration of oral cyclosporine followed by interleukin-2 and γ-interferon is generally not well tolerated, and does not appear to be an effective method to induce autologous GVHD in patients receiving autologous PBSC grafts. [Copyright &y& Elsevier]

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.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In 2003, the Eastern Cooperative Oncology Group initiated a randomized phase III clinical trial (E4402) comparing two different rituximab dosing strategies for patients with previously untreated low-tumor burden follicular lymphoma. Rituximab-responsive patients (n = 299) were randomly assigned to either a retreatment rituximab (RR) strategy or a maintenance rituximab (MR) strategy. Each dosing strategy was continued until treatment failure. The primary end point of the study was time to treatment failure (TTF). In the original report, there was no difference in TTF between the two dosing strategies. Here, we report on the long-term outcomes for secondary end points of time to first cytotoxic therapy, duration of response, and overall survival (OS). At 7 years, 83% of MR patients had not required first chemotherapy compared with 63% of RR patients (hazard ratio, 2.37 [95% CI, 1.5 to 3.76]). At 7 years, 71% of MR remained in their first remission compared with 37% of RR patients. Despite the improved first remission length with MR, there was no difference in OS at 10 years (83% v 84%). With mature long-term data, we confirm that prolonged maintenance rituximab does not confer an OS advantage in low-tumor burden follicular lymphoma.

Novel targeted therapies (small molecule inhibitors, antibody-drug conjugates, and CD19-directed therapies) have changed the treatment landscape of relapsed/refractory B-cell lymphomas. Bruton's tyrosine kinase (BTK) inhibitors continue to evolve in the management of mantle cell lymphoma (MCL), in both the relapsed/refractory and the frontline setting. Anti-CD19 CAR T-cell therapies are now effective and approved treatment options for relapsed/refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and MCL. Bispecific T-cell engagers represent a novel immunotherapeutic approach for relapsed FL and DLBCL after multiple lines of therapies, including prior CAR T-cell therapy. These NCCN Guideline Insights highlight the significant updates to the NCCN Guidelines for B-Cell Lymphomas for the treatment of FL, DLBCL, and MCL.

Severe aplastic anemia (SAA) is a marrow failure disorder with high morbidity and mortality. It is treated with bone marrow transplantation (BMT) for those with fully matched donors, or immunosuppressive therapy (IST) for those who lack such a donor, which is often the case for underrepresented minorities. We conducted a prospective phase 2 trial of reduced-intensity conditioning HLA-haploidentical BMT and posttransplantation cyclophosphamide (PTCy)-based graft-versus-host (GVHD) prophylaxis as initial therapy for patients with SAA. The median patient age was 25 years (range, 3-63 years), and the median follow-up time was 40.9 months (95% confidence interval [CI], 29.4-55.7). More than 35% of enrollment was from underrepresented racial/ethnic groups. The cumulative incidence of grade 2 or 4 acute GVHD on day 100 was 7% (95% CI, not applicable [NA]-17), and chronic GVHD at 2 years was 4% (95% CI, NA-11). The overall survival of 27 patients was 92% (95% CI, 83-100) at 1, 2, and 3 years. The first 7 patients received lower dose total body irradiation (200 vs 400 cGy), but these patients were more likely to have graft failure (3 of 7) compared with 0 of 20 patients in the higher dose group (P = .01; Fisher exact test). HLA-haploidentical BMT with PTCy using 400 cGy total body irradiation resulted in 100% overall survival with minimal GVHD in 20 consecutive patients. Not only does this approach avoid any adverse ramifications of IST and its low failure-free survival, but the use of haploidentical donors also expands access to BMT across all populations. This trial was registered at www.clinicaltrials.gov as NCT02833805., (© 2023 by The American Society of Hematology.)

The use of post-transplantation cyclophosphamide (PTCy) for graft-versus host-disease (GVHD) prophylaxis has revolutionized allogeneic blood or marrow transplantation (alloBMT), but there is limited published experience in peripheral T cell lymphoma (PTCL). We sought to assess outcomes in patients with PTCL who underwent alloBMT with PTCy. We reviewed the charts of all adult patients age ≥18 years who underwent alloBMT with nonmyeloablative conditioning and PTCy-based GVHD prophylaxis at the Sidney Kimmel Comprehensive Cancer Center between January 2004 and December 2020. Sixty-five patients were identified. The median age was 59 years (range, 24 to 75 years). Lymphoma histology included PTCL not otherwise specified (n = 24), anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (n = 14), angioimmunoblastic T cell lymphoma (n = 7), enteropathy-associated T cell lymphoma (n = 6), hepatosplenic T cell lymphoma (n = 4), and others (n = 10). Eleven patients were in first complete remission (17%); the remaining patients were in first partial remission or underwent salvage therapy to at least PR prior to transplantation. Forty-eight patients underwent alloBMT from a haploidentical related donor (74%), 10 from a fully matched donor (15%), and 7 from a mismatched unrelated donor (11%). All patients received fludarabine, cyclophosphamide, and total body irradiation (TBI). The graft source was bone marrow (BM) in 46 patients (71%) and peripheral blood (PB) in 19 patients (29%); all patients in the BM cohort received 200 cGy TBI, and most patients in the PB cohort (15 of 19) received 400 cGy TBI. GVHD prophylaxis comprised PTCy, mycophenolate mofetil, and a calcineurin inhibitor or sirolimus. With a median follow-up of 2.8 years (range, 290 days to 14.2 years), the 2-year progression-free survival (PFS) for the entire cohort was 49% (95% confidence interval [CI], 38% to 64%), and the 2-year overall survival (OS) was 55% (95% CI, 44% to 69%). Outcomes were significantly improved in those receiving PB compared to those receiving BM, including a 2-year PFS of 79% (95% CI 63% to 100%) versus 39% (95% CI, 27% to 56%), 2-year OS of 84% (95% CI, 69% to 100%) versus 46% (95% CI, 33% to 63%), and 1-year cumulative incidence of relapse of 5% (95% CI, 0 to 16%) versus 33% (95% CI, 19% to 46%), with no difference in GVHD and nonrelapse mortality. AlloBMT with PTCy is safe and well-tolerated in patients with PTCL. Our data suggest that increasing the TBI dose to 400 cGy and using PB allografts may offer improved disease control and better survival outcomes, though additional studies are needed to confirm these findings., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2-3 oligodendroglioma [1p19q codeleted, IDH-mutant], WHO grade 2-4 IDH-mutant astrocytoma, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non-AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers are designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding molecular profiling of gliomas.

High-dose post-transplantation cyclophosphamide (PTCy) is an effective platform for prevention of severe graft-versus-host disease (GVHD) after allogeneic bone marrow (BM) transplantation with mismatched unrelated donors (mMUDs). Previous studies evaluating PTCy with mMUDs favored BM allografts over peripheral blood stem cell transplantation (PBSCT) due to concerns that PBSCT may be associated with an increased risk of acute and chronic GVHD. In addition, haploidentical PBSCT is associated with high rates of cytokine release syndrome (CRS), which is another concern with mMUD PBSCT. This study was conducted to determine the feasibility and safety of using mMUD PBSCT with PTCy as GVHD prophylaxis. Patients who received mMUD PBSCT using a PTCy-based GVHD prophylaxis at Johns Hopkins Hospital as part of a prospective clinical trial of mMUD and non-first-degree relative haploidentical transplantation with PTCy (ClinicalTrials.gov identifier NCT01203722) were included. All patients underwent T cell-replete PBSCT between November 2012 and August 2020. Statistical analyses were performed using the Kaplan-Meier method and proportional subdistribution hazard regression model for competing risks. The 29 patients in the study had a median age of 54 years, with 10 patients (34%) age ≥60 years. Nineteen grafts (66%) were matched for 9/10 HLA loci, 6 (21%) were match for 8/10, and 4 (14%) were matched for 7/10. No primary or secondary graft failure occurred. The median time to neutrophil recovery (≥500/µL) was 17 days, and that to platelet recovery (≥20,000/µL) was 28 days. Full donor chimerism was achieved in all patients by day +60. The cumulative incidence (CuI) of grade II-IV acute GVHD at 180 days was 15% (90% confidence interval [CI], 3% to 26%). There were no cases of severe chronic GVHD, 3 cases of mild chronic GVHD, and 1 case of moderate chronic GVHD. The CuI of nonrelapse mortality (NRM) was 7% (90% CI, NA to 18%) at 1 year. Eighteen patients (62%) experienced mild CRS (grade 1-2), and 1 patient (3%) experienced severe CRS (grade 3-5). At 1 year, the CuI of relapse was 29% (90% CI, 8% to 50%), overall survival was 93% (90% CI, 85% to 100%), progression-free survival was 64% (90% CI, 46% to 88%), GVHD-free relapse-free survival was 41% (90% CI, 23% to 73%), and chronic GVHD-free relapse-free survival was 64% (90% CI, 46% to 88%). Our data indicate that mMUD PBSCT using PTCy-based GVHD prophylaxis is safe and feasible. All patients engrafted, and rates of NRM (7%) and acute GVHD (15%) at 1 year were low. There was only 1 case (3%) of severe CRS. Compared with previously published outcomes, mMUD PBSCT using PTCy-based GVHD prophylaxis has a safety and efficacy profile that may not be different from that of PBSCT from matched donors. These results further solidify that all patients who require blood or BM transplantation should be able to find an acceptable donor., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

In the last decade, a better understanding of the molecular pathogenesis of B-cell non-Hodgkin lymphomas has resulted in the development of novel targeted therapies, such as small molecule inhibitors of select kinases in the B-cell receptor pathway, antibody-drug conjugates, and small molecules that target a variety of proteins (eg, CD-19, EZH2, and XPO-1-mediated nuclear export). Anti-CD19 CAR T-cell therapy, first approved for relapsed/refractory (R/R) diffuse large B-cell lymphoma, has also emerged as a novel treatment option for R/R follicular lymphoma and mantle cell lymphoma. These NCCN Guideline Insights highlight the new targeted therapy options included in the NCCN Guidelines for B-Cell Lymphomas for the treatment of R/R disease.

Secondary central nervous system (CNS) lymphoma is a rare and often fatal complication of non-Hodgkin lymphoma (NHL). Treatment options include radiation therapy, high-dose systemic chemotherapy, intrathecal chemotherapy, and high-dose chemotherapy with autologous stem cell rescue, but outcomes remain poor. Allogeneic blood or marrow transplantation (alloBMT) is widely used in patients with relapsed/refractory systemic NHL. We sought to understand whether a graft-versus-lymphoma effect could maintain remission in CNS disease. We reviewed outcomes in 20 consecutive patients with secondary CNS lymphoma who underwent alloBMT with nonmyeloablative conditioning using fludarabine, cyclophosphamide, and 200 cGy total body irradiation. For graft-versus-host disease prophylaxis, all patients received post-transplantation cyclophosphamide, mycophenolate mofetil, and a calcineurin inhibitor. With a median follow up of 4.1 years, the median overall survival for the entire cohort was not reached. Median progression-free survival was 3.8 years (95% confidence interval [CI], 5.3 months to not reached). The cumulative incidence of relapse was 25% (95% CI, 5% to 45%), and nonrelapse mortality was 30% (95% CI, 5% to 54%) at 4 years. Of the 5 patients who relapsed, 2 were CNS only, 1 was systemic only, and 2 were combined CNS/systemic. The use of alloBMT in CNS lymphoma merits further investigation., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice. This article describes NCCN Guidelines recommendations for WHO grade I, II, III, and IV gliomas. Treatment of brain metastases, the most common intracranial tumors in adults, is also described.

Primary central nervous system lymphomas (PCNSLs) are rare cancers of the central nervous system (CNS) and are predominantly diffuse large B-cell lymphomas of the activated B-cell (ABC) subtype. They typically present in the sixth and seventh decade of life, with the highest incidence among patients aged >75 years. Although many different regimens have demonstrated efficacy in newly diagnosed and relapsed or refractory PCNSL, there have been few randomized prospective trials, and most recommendations and treatment decisions are based on single-arm phase II trials or even retrospective studies. High-dose methotrexate (HD-MTX; 3-8 g/m2) is the backbone of preferred standard induction regimens. Various effective regimens with different toxicity profiles can be considered that combine other chemotherapies and/or rituximab with HD-MTX, but there is currently no consensus for a single preferred regimen. There is controversy about the role of various consolidation therapies for patients who respond to HD-MTX-based induction therapy. For patients with relapsed or refractory PCNSL who previously experienced response to HD-MTX, repeat treatment with HD-MTX-based therapy can be considered depending on the timing of recurrence. Other more novel and less toxic regimens have been developed that show efficacy in recurrent disease, including ibrutinib, or lenalidomide ± rituximab. There is uniform agreement to delay or avoid whole-brain radiation therapy due to concerns for significant neurotoxicity if a reasonable systemic treatment option exists. This article aims to provide a clinically practical approach to PCNSL, including special considerations for older patients and those with impaired renal function. The benefits and risks of HD-MTX or high-dose chemotherapy with autologous stem cell transplantation versus other, better tolerated strategies are also discussed. In all settings, the preferred treatment is always enrollment in a clinical trial if one is available.

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.

Severe aplastic anemia (SAA) is a stem cell disorder often treated with bone marrow transplantation (BMT) to reconstitute hematopoiesis. Outcomes of related HLA-haploidentical (haplo) donors after reduced-intensity conditioning with intensive graft-versus-host disease (GVHD) prophylaxis including posttransplantation cyclophosphamide are presented here from 37 SAA, 20 relapsed/refractory (R/R), and 17 treatment-naïve (TN) SAA patients. Median follow-up is 32 months (90% confidence interval [CI], 29-44). The median age was 25 (range, 4-69) years. The median time to neutrophil recovery was 17 days (range, 15-88). Four of 37 patients (11%) experienced graft failure (GF). There was 1 primary GF of 20 patients in the R/R group and 3 of 17 in the TN group at 200 cGy (1 primary, 2 secondary), but none in the 10 patients who received 400 cGy total body irradiation. Two patients with GF succumbed to infection and 2 were rescued with second haplo BMT. The overall survival for all patients is 94% (90% CI, 88-100) at 1 and 2 years. The cumulative incidence of grade II-IV acute GVHD at day 100 is 11%. The cumulative index of chronic GVHD at 2 years is 8%. Similar results were seen in 10 SAA patients who received the identical nonmyeloablative regimen with posttransplant cyclophosphamide but matched donor transplants. Haplo BMT with posttransplant cyclophosphamide represents a potential cure in SAA, with all 20 R/R currently alive, disease-free, and with no evidence of active GVHD. Extending this approach to TN patients was associated with higher GF rates, but an increase in total body irradiation dose to 400 cGy was associated with durable engraftment without greater early toxicity. Nonmyeloablative haplo BMT in TN SAA could lead to a paradigm shift, such that essentially all patients can proceed quickly to safe, curative BMT. These trials were registered at www.cincialtrials.gov as #NCT02224872) and #NCT02833805., (© 2020 by The American Society of Hematology.)

Hematologic malignancies in older people are unlikely to be cured with chemotherapy alone. Advances in allogeneic blood or marrow transplantation (alloBMT), especially nonmyeloablative (NMA) conditioning and the use of haploidentical donors, now make this therapy available to older people; however, long-term outcomes and predictors of success are unclear. We reviewed the outcomes of 93 consecutive patients aged 70 and older (median, 72; range, 70-78), who underwent haploidentical BMT at Johns Hopkins Hospital between 1 September 2009 and 1 April 2018. All patients received NMA conditioning and posttransplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis. The 2-year overall survival was 53%, and 2-year event-free survival was 43%. The 180-day cumulative incidence (CuI) of nonrelapse mortality (NRM) was 14%, and the 2-year CuI was 27%. The 2-year CuI of relapse was 30%. Of 78 patients who were alive and had their weight recorded on day 180, weight loss predicted subsequent NRM (subdistribution hazard ratio, 1.0; 95% CI, 1-1.13; P = .048). In conclusion, haploidentical BMT with PTCy is feasible and relatively safe in septuagenarians. Although early, 6-month NRM was relatively low at 14%, but overall NRM continued to climb to 27% at 2 years, at least in part because of late deaths that appeared to be somewhat age related. Further studies to elucidate predictors of NRM are warranted., (© 2019 by The American Society of Hematology.)

Diffuse large B-cell lymphomas (DLBCLs) and follicular lymphoma (FL) are the most common subtypes of B-cell non-Hodgkin's lymphomas in adults. Histologic transformation of FL to DLBCL (TFL) occurs in approximately 15% of patients and is generally associated with a poor clinical outcome. Phosphatidylinositol 3-kinase (PI3K) inhibitors have shown promising results in the treatment of relapsed/refractory FL. CAR T-cell therapy (axicabtagene ciloleucel and tisagenlecleucel) has emerged as a novel treatment option for relapsed/refractory DLBCL and TFL. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines for B-Cell Lymphomas regarding the treatment of TFL and relapsed/refractory FL and DLBCL.

Background: Although severe haemoglobinopathies can be cured with allogeneic blood or bone marrow transplantation, availability of matched donors and toxic effects can be problematic. We previously found that non-myeloablative haploidentical related bone marrow transplantation with post-transplantation cyclophosphamide expanded the donor pool while limiting graft-versus-host disease (GVHD). However, graft failure-albeit with full host haemopoietic recovery-occurred in 50% of patients. In this study, we investigated whether increasing total body irradiation from 200 cGy to 400 cGy would improve engraftment while maintaining the safety profile., Methods: This study was done at Johns Hopkins Hospital (Baltimore, MD, USA). Patients aged 2-70 years receiving their first bone marrow transplant were eligible for inclusion in the study. Patients received rabbit-derived intravenous anti-thymocyte globulin 0·5 mg/kg on day -9 and 2 mg/kg on days -8 and -7, intravenous fludarabine 30 mg/m 2 on days -6 to -2, intravenous cyclophosphamide 14·5 mg/kg on days -6 and -5, and total body irradiation 400 cGy administered as a single fraction on day -1. We collected unmanipulated bone marrow and infused on day 0. GVHD prophylaxis comprised intravenous cyclophosphamide 50 mg/kg per day on days 3 and 4 after transplantation, oral mycophenolate mofetil 15 mg/kg per dose (maximum 1 g) every 8 h on days 5 to 35, and oral sirolimus to maintain a level of 5-15 ng/dL for at least 1 year starting on day 5. The original planned primary objectives of this phase 2 clinical trial were transplant-related mortality and progression-free survival. However, the coverage decision by the Centers for Medicare and Medicaid Services to only provide payment for allogeneic bone marrow transplantation for patients with sickle cell disease on a clinical trial that had a comparison arm with patients not receiving bone marrow transplantation prompted the closure of this trial to accrual in 2017. Therefore, as we were unable to perform our planned statistical analysis, the primary objective was modified to evaluate engraftment, assessed by chimerism. This trial is registered with ClinicalTrials.gov, number NCT00489281. The study is closed to new participants and this is the primary analysis., Findings: Between Sept 24, 2014, and Aug 1, 2017, we enrolled 17 consecutive patients: 12 (71%) with sickle cell disease and 5 (29%) with β-thalassaemia major. The median patient age was 16 years (range 6-31, IQR 7·7-27·5). One (6%) of 17 patients had primary graft failure with recovery of host haemopoiesis. 13 (76%) of 17 patients achieved full donor chimerism and three (18%) had mixed donor-host chimerism. Five (29%) of 17 patients developed grade 2-4 acute GVHD, including four (24%) with maximal grade 2 GVHD and one (6%) with grade 3 GVHD. Chronic GVHD developed in three (18%) patients. As of their last follow-up visit, GVHD had resolved in all patients and no patients were receiving systemic GVHD therapy. All patients remained alive as of Aug 4, 2019, and the median follow-up duration was 705 days (range 355-1294; IQR 398-943). Only one (6%) of the 16 engrafted patients remained transfusion dependent, and 14 (88%) discontinued immunosuppression., Interpretation: Increasing total body irradiation to 400 cGy substantially reduced graft failure while maintaining the safety of haploidentical bone marrow transplantation with post-transplantation cyclophosphamide. These results suggest that engraftment after haploidentical bone marrow transplantation for haemoglobinopathies is possible, and primary graft failure-the main problem previously reported-might be addressed by this strategy. Therefore, this curative approach should no longer be restricted to patients with HLA-matched donors., Funding: Maryland Stem Cell Research Fund and US National Institutes of Health., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Published reports suggest that immune checkpoint inhibitors (ICIs) before allogeneic blood or marrow transplantation (alloBMT) may increase the incidence of graft-versus-host disease (GvHD), immune-related adverse events, and nonrelapse mortality (NRM); this led to the US Food and Drug Administration issuing a "Warning and Precaution" regarding the potential for life-threatening immune-mediated complications associated with alloBMT after nivolumab and pembrolizumab. We retrospectively reviewed the outcomes of 14 consecutive patients who received ICIs as their final salvage therapy before T-cell-replete alloBMT using reduced-intensity conditioning. All patients received posttransplant cyclophosphamide (PTCy), which significantly limits severe GvHD, even in the mismatched-donor setting. There was no grade 3-4 acute GvHD (aGvHD), and all 6 cases of grade 2 aGvHD readily resolved with immunosuppression. No patient experienced veno-occlusive disease of the liver, other immune-related adverse events, chronic GvHD, or NRM. There have been 2 relapses (15-month median follow-up), with 12 of 14 patients remaining alive, well, and progression-free. The only death was a result of disease relapse. Although more experience is needed, our data suggest that concerns over immunologic complications associated with ICIs should not preclude allogeneic bone marrow transplantation with PTCy as GvHD prophylaxis., (© 2018 by The American Society of Hematology.)

Background: Therapy of primary CNS lymphoma (PCNSL) has focused on multi-agent chemotherapy designed to cross the blood brain barrier. Rituximab has demonstrated activity in PCNSL. E1F05 is an ECOG-ACRIN multicenter phase 2 prospective trial of rituximab with high-dose methotrexate (HD-MTX)-based chemotherapy similar to the RTOG 93-10 regimen, omitting radiotherapy., Methods: Immunocompetent patients with newly diagnosed PCNSL received HD-MTX 3.5g/m2 with vincristine every two weeks for 5 doses; procarbazine for 7 days in weeks 1, 5, and 9; cytarabine 3g/m2/day IV for 2 days in weeks 11 and 14; a dexamethasone taper over 6 weeks; and rituximab 375mg/m2 IV infusion 3 times per week for weeks 1-4. Subjects with CSF involvement received intrathecal methotrexate 12mg every two weeks., Results: Twenty-six patients were enrolled; median age was 57. Sixteen subjects (65%) completed treatment per protocol; the most common reason for discontinuation was adverse events, and 2 subjects discontinued due to progressive disease (PD). Complete response (CR) + unconfirmed CR (CRu) was 16/25 (64%), overall response rate was 20/25 (80%), and 4/25(16%) had PD as best response. Median progression free survival (PFS) was 34 months, and median overall survival has not been reached at 40 months' median follow up. Two year PFS was 63%. The most common grade 3-4 toxicities were hematologic., Conclusion: The addition of rituximab to multi-agent chemotherapy is well tolerated. Outcomes are comparable to or better than those seen in RTOG 93-10, which included RT. These and other results suggest rituximab has activity in the CNS. [ECOG-ACRIN E1F05]., Clinical Trial Registration: NCT00335140, clinicaltrials.gov., Competing Interests: CONFLICTS OF INTEREST Advani: Seattle Genetics, Inc.: Research Funding; Genentech: Consultancy. Swinnen: Genentech, Pharmacyclics, consultancy.

Composite endpoints that not only encompass mortality and relapse, but other critical post-transplant events such as graft-versus-host disease, are being increasingly utilized to quantify survival without significant morbidity after allogeneic blood or marrow transplantation. High-dose, post-transplantation cyclophosphamide reduces severe graft-versus-host disease with allogeneic marrow transplantation, making composite endpoints after this management particularly interesting. We retrospectively analyzed 684 adults with hematologic malignancies who received T-cell-replete bone marrow grafts and cyclophosphamide after myeloablative HLA-matched related (n=192) or unrelated (n=120), or non-myeloablative HLA-haploidentical (n=372) donor transplantation. The median follow up was 4 (range, 0.02-11.4) years. Graft-versus-host disease-free, relapse-free survival was defined as the time after transplantation without grade III-IV acute graft-versus-host disease, chronic graft-versus-host disease requiring systemic treatment, relapse, or death. Chronic graft-versus-host disease-free, relapse-free survival was defined as the time after transplantation without moderate or severe chronic graft-versus-host disease, relapse, or death. One-year graft-versus-host disease-free, relapse-free survival and chronic graft-versus-host disease-free, relapse-free survival estimates were, respectively, 47% (95% CI: 41-55%) and 53% (95% CI: 46-61%) after myeloablative HLA-matched related, 42% (95% CI: 34-52%) and 52% (95% CI: 44-62%) after myeloablative HLA-matched unrelated, and 45% (95% CI: 40-50%) and 50% (95% CI: 45-55%) after non-myeloablative HLA-haploidentical donor transplantation. In multivariable models, there were no differences in graft-versus-host disease-free, or chronic graft-versus-host disease-free, relapse-free survival after either myeloablative HLA-matched unrelated or non-myeloablative HLA-haploidentical, compared with myeloablative HLA-matched related donor transplantation. Although limited by inclusion of dissimilar cohorts, we found that post-transplantation cyclophosphamide-based platforms yield comparable composite endpoints across conditioning intensity, donor type, and HLA match., (Copyright© Ferrata Storti Foundation.)

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.)

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease, which are managed in the same way. The advent of novel monoclonal antibodies (ofatumumab and obinutuzumab) led to the development of effective chemoimmunotherapy regimens. The recently approved small molecule kinase inhibitors (ibrutinib and idelalisib) are effective treatment options for CLL in elderly patients with decreased tolerance for aggressive regimens and in patients with poor prognostic features who do not benefit from conventional chemoimmunotherapy regimens. This portion of the NCCN Guidelines for Non-Hodgkin's Lymphomas describes the recent specific to the incorporation of recently approved targeted therapies for the management of patients with newly diagnosed and relapsed or refractory CLL/SLL., (Copyright © 2015 by the National Comprehensive Cancer Network.)

High-dose, posttransplantation cyclophosphamide (PTCy) reduces severe graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (alloBMT), but the impact of PTCy on long-term, disease-specific outcomes is unclear. We conducted a retrospective study of 209 consecutive adult patients transplanted for acute myeloid leukemia (AML, n = 138), myelodysplastic syndrome (n = 28), or acute lymphoblastic leukemia (ALL, n = 43) using PTCy as sole GVHD prophylaxis after myeloablative conditioning and HLA-matched-related or -unrelated T-cell-replete allografting. At alloBMT, 30% of patients were not in morphologic complete remission. The cumulative incidences of grades II to IV and III to IV acute GVHD at 100 days and chronic GVHD at 2 years were 45%, 11%, and 13%, respectively. Forty-three percent of patients did not require immunosuppression for any reason beyond PTCy. At 3 years, relapse cumulative incidence was 36%, disease-free survival was 46%, survival free of disease and chronic GVHD was 39%, and overall survival was 58%. Lack of remission at alloBMT, adverse cytogenetics, and low allograft nucleated cell dose were associated with inferior survival for AML patients. Minimal residual disease but not t(9;22) was associated with inferior outcomes for ALL patients. The ability to limit posttransplantation immunosuppression makes PTCy a promising transplantation platform for the integration of postgrafting strategies to prevent relapse., (© 2014 by The American Society of Hematology.)

The NCCN Guidelines for Central Nervous System Cancers provide multidisciplinary recommendations for the clinical management of patients with cancers of the central nervous system. These NCCN Guidelines Insights highlight recent updates regarding the management of metastatic brain tumors using radiation therapy. Use of stereotactic radiosurgery (SRS) is no longer limited to patients with 3 or fewer lesions, because data suggest that total disease burden, rather than number of lesions, is predictive of survival benefits associated with the technique. SRS is increasingly becoming an integral part of management of patients with controlled, low-volume brain metastases., (Copyright © 2014 by the National Comprehensive Cancer Network.)

Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer cells. Mantle cell lymphoma (MCL) accounts for approximately 6% of all newly diagnosed NHL cases. Radiation therapy with or without systemic therapy is a reasonable approach for the few patients who present with early-stage disease. Rituximab-based chemoimmunotherapy followed by high-dose therapy and autologous stem cell rescue (HDT/ASCR) is recommended for patients presenting with advanced-stage disease. Induction therapy followed by rituximab maintenance may provide extended disease control for those who are not candidates for HDT/ASCR. Ibrutinib, a Bruton tyrosine kinase inhibitor, was recently approved for the treatment of relapsed or refractory disease. This manuscript discusses the recommendations outlined in the NCCN Guidelines for NHL regarding the diagnosis and management of patients with MCL., (Copyright © 2014 by the National Comprehensive Cancer Network.)

Positive interim positron emission tomography (PET) scans are thought to be associated with inferior outcomes in diffuse large B-cell lymphoma. In the E3404 diffuse large B-cell lymphoma study, PET scans at baseline and after 3 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone were centrally reviewed by a single reader. To determine the reproducibility of interim PET interpretation, an expert panel of 3 external nuclear medicine physicians visually scored baseline and interim PET scans independently and were blinded to clinical information. The binary Eastern Cooperative Oncology Group (ECOG) study criteria were based on modifications of the Harmonization Criteria; the London criteria were also applied. Of 38 interim scans, agreement was complete in 68% and 71% by ECOG and London criteria, respectively. The range of PET(+) interim scans was 16% to 34% (P = not significant) by reviewer. Moderate consistency of reviews was observed: kappa statistic = 0.445 using ECOG criteria, and kappa statistic = 0.502 using London criteria. These data, showing only moderate reproducibility among nuclear medicine experts, indicate the need to standardize PET interpretation in research and practice. This trial was registered at www.clinicaltrials.gov as #NCT00274924 [corrected].

Inhibition of DNA excision repair can modulate resistance to cisplatin. Cytosine arabinoside (Ara-C) and hydroxyurea (HU), in combination, inhibit the excision-repair system and removal of platinum-DNA adducts. Marked cytotoxic synergy had been demonstrated in vitro at clinically achievable levels. The three-drug regimen was found to be feasible in clinical pilot studies. A Phase II study in patients with relapsed or progressive anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM) was performed in the Southwest Oncology Group. The primary end point was 6 month survival, historically about 42%. A loading dose of HU 1,260 mg/m2 IV over 1 h was followed by Ara-C 1,200 mg/m2 plus HU 5,040 mg/m2 IV over 12 h, followed by cisplatin 100 mg/m2 IV over 1 h. A total of 76 patients were registered. The GBM stratum registered 56 patients in a two-stage accrual. Among 51 eligible GBM patients, the 6-month survival probability was 41% (95% CI 28-55%), and median overall survival was 5 months (95% CI 4-6 months). The 6-month progression-free survival probability was 25% (95% CI 14-37%), and median progression-free survival was 2 months (95% CI 2-4 months). One patient achieved a partial response (2%, 95% CI 0-10%), 13 patients had stable disease (25%, 95% CI 14-39%). Twenty-two patients progressed, and 14 were not assessable for response. The AA stratum was closed early after 20 patients due to slow accrual. Among 19 eligible patients, the 6-month survival probability was 58% (95% CI 36-80%), and median overall survival was 7 months (95% CI 7-14 months). The 6-month progression-free survival probability was 26% (95% CI 6-46%), and median progression-free survival was 3 months (95% CI 2-5 months). No responses were seen. Six patients (32%) had stable disease (95% CI 13-57%), 11 progressed, and 2 were not assessable for response. Of the 70 patients evaluable for toxicity, two died of infection. Twenty-three patients (33%) experienced Grade 4 toxicities, primarily hematological. Cisplatin combined with HU and Ara-C did not improve the 6 month survival rate in patients with relapsed or progressive AA or GBM. Significantly more hematological toxicity was seen than expected from cisplatin alone. Although benefit might be possible in a more platinum-sensitive tumor type, further clinical trials with this regimen for patients with glioblastoma multiforme or anaplastic astrocytoma are not justified.

Although cytogenetic analysis advanced the understanding of the pathogenesis of primary non-Hodgkin lymphoma and led to improved clinical management, there have been no large cytogenetic studies of post-transplant lymphoproliferative disorder (PTLD). We examined the karyotypes of 36 PTLD cases and correlated them with clinical, laboratory, and pathologic findings. The cases included 2 early lesions, 13 polymorphic PTLDs, and 21 monomorphic PTLDs (18 B-cell and 3 T-cell proliferations). Cytogenetic abnormalities were identified in 72% of monomorphic B-cell PTLDs and in all T-cell PTLDs, but in only 15% of polymorphic PTLDs and in no early lesions. The most frequent clonal abnormalities in monomorphic PTLD were trisomies 9 and/or 11 (5 cases), followed by rearrangements of 8q24.1 (4 cases), 3q27 (2 cases), and 14q32 (2 cases). MYC rearrangement (8q24.1) and T-cell-associated chromosomal abnormalities correlated with poor outcome and short survival. PTLD with trisomy 9 and/or 11 developed early after transplant, presenting as Epstein-Barr virus-positive large B-cell lymphoma with prolonged survival.

Lymphoproliferative disorders associated with Epstein--Barr virus (EBV) after bone-marrow or organ transplantation express all the immunogenic EBV antigens, and reduction in immunosuppressive treatment can result in permanent resolution. As such, the disease lends itself to EBV-directed immune-cell therapy. Successes have been achieved with both manipulated and unmanipulated T-cell infusions for lymphoproliferations occurring after bone-marrow transplantation. Several practical challenges have been overcome in applying EBV-specific T-cell therapy to the setting of organ-transplant-related lymphoproliferations. These include the generation of autologous cytotoxic T lymphocytes (CTLs), the creation of a partially HLA-matched cryopreserved allogeneic CTL bank, and the generation of autologous EBV-specific CTLs from EBV-naïve pediatric patients. The efficacy of immune-cell therapy in the setting of solid-organ transplantation is less well established than it is after T-cell-depleted allogeneic bone-marrow transplantation, and it is as yet not clear how to best to integrate CTL therapy with the anti-B-cell antibody rituximab, which has significant activity against these lymphoproliferations.

Epstein-Barr virus (EBV) is implicated in the pathogenesis of acquired immunodeficiency syndrome (AIDS) lymphoma, and viral DNA is present within the malignant cells in about half of affected patients. We examined the extent to which EBV viral load is elevated in the plasma of AIDS lymphoma patients compared to AIDS patients with opportunistic infections. Sixty-one AIDS patients were studied including 35 with lymphoma (24 non-Hodgkin, six Hodgkin, and five brain lymphoma) and 26 with various opportunistic infections. In situ hybridization revealed EBV encoded RNA (EBER) expression in the malignant cells of 17/28 AIDS lymphomas (61%). In 232 serial plasma samples from 35 lymphoma patients and in 128 samples from AIDS controls, EBV viral load was assayed by quantitative-polymerase chain reaction (Q-PCR) using a TaqMan probe targeting the BamH1W sequence. EBV was detected in plasma from all 17 EBER-positive AIDS lymphoma patients, with viral loads ranging from 34 to 1,500,000 copies per ml (median 3,210). Viral load usually fell rapidly upon initiation of lymphoma therapy and remained undetectable except in two patients with persistent tumor. In 11 AIDS patients, whose lymphoma lacked EBER expression, and in 26 control patients without lymphoma, levels of EBV in plasma were usually low or undetectable (range 0-1,995 and 0-2,409, median 0 and 0, respectively). There was no association between EBV viral load and human immunodeficiency virus (HIV) load or CD4 count. In conclusion, EBV viral load shows promise as a tool to assist in diagnosis and management of EBV-related lymphoma patients., (Copyright 2005 Wiley-Liss, Inc.)

Drugs currently available for intrathecal administration are cleared rapidly from the CSF. DepoCyt is a slow-release formulation of cytarabine that maintains cytotoxic concentrations of free cytarabine in the CSF for >14 days following a single injection. DepoCyt was administered to 110 patients with a diagnosis of neoplastic meningitis based on either a positive CSF cytology (76) or neurologic and CT or MRI scan findings sufficient to document neoplastic meningitis (34). Patients were treated with DepoCyt 50mg every 2 weeks for 1 month of induction therapy by either lumbar puncture (LP) or intraventricular (IVT) injection. Patients without neurologic progression were candidates to receive an additional 3 months of consolidation therapy. All patients received dexamethasone 4 mg BID on days 1-5 of each cycle. Median time to neurologic progression was 55 days; median overall survival was 95 days. Among the 76 patients with a positive CSF cytology at baseline, 70 were evaluable for response, and of this group 19 (27%) attained the criteria for response (cytologic response in the absence of neurologic progression). The most important adverse events were headache and arachnoiditis. When drug-related, these were largely low grade, transient, and reversible. Drug-related grade 3 headache occurred on 4% of cycles; grade 3 or 4 arachnoiditis occurred on 6% of cycles. No cumulative toxicity was observed. DepoCyt injected once every 2 weeks produced a response-rate comparable to that previously reported for methotrexate given twice a week. The once in every 2-week-dosing interval offers an advantage over conventional schedules (2-3 doses/week) used for other agents available for intrathecal injection.