Immune checkpoint inhibitors in advanced and relapsed/refractory Hodgkin lymphoma: current applications and future prospects.

Classic Hodgkin lymphoma (cHL) treatment paradigms are undergoing a shift with the integration of immune checkpoint inhibitors (ICIs) into both first-line and relapsed/refractory (R/R) regimens. In first-line therapy, the synergy between ICIs and chemotherapy may surpass the previous standards of ABVD and BV-AVD established by landmark trials including RATHL and ECHELON-1. In R/R disease, the combination of ICIs with chemotherapy has begun to challenge the paradigm of chemotherapy as a bridge to consolidative autologous stem cell transplantation. The clinical advances heralded by ICI offer unique challenges to management. ICI treatment and the associated inflammatory response can make the traditional timing and modalities of treatment response assessment difficult to interpret. In contrast to ABVD and BV-AVD, pembrolizumab-AVD results in PET2 positivity rates that are higher and less predictive of treatment response even when ultimate outcomes may be superior. This suggests that the predictive value of PET2 may be less reliable in the ICI era, prompting a reevaluation of response assessment strategies. Looking forward, circulating tumor DNA (ctDNA) may be a promising tool in response-adapted therapy. Its potential to complement or even supersede PET scans in predicting response to ICIs represents a critical advancement. The integration of ctDNA analysis holds the promise of refining response-adapted approaches and enhancing precision in therapeutic decision-making for patients with cHL. This review navigates the evolving landscape of cHL therapy, emphasizing the paradigmatic shift brought about by ICIs. This article explores the impact of combining ICIs with chemotherapy in both relapsed/refractory and first-line settings, scrutinizes the challenges posed to response-adapted therapy by ICIs, and highlights the potential role of ctDNA as an adjunct in refining response-adapted strategies for cHL.

Progression-free survival is a weakly predictive surrogate end-point for overall survival in follicular lymphoma: A systematic review and meta-analysis.

Although progression-free survival (PFS) is a commonly used surrogate end-point for clinical trials of follicular lymphoma (FL), no analyses have evaluated the strength of surrogacy for PFS with overall survival (OS). A systematic review was performed and 20 studies (total participants, 10 724) met final inclusion criteria. PFS was weakly associated with OS (correlation coefficient; 0.383, p < 0.001). The coefficient of determination was 0.15 (95% CI: 0.002-0.35) suggesting 15% of OS variance could be explained by changes in PFS. This challenges the role for PFS as a surrogate end-point for clinical trials and drug approvals.

Impact of race and social determinants of health on outcomes in patients with aggressive B-cell NHL treated with CAR-T therapy.

ABSTRACT: Chimeric antigen receptor (CAR) T-cell (CAR-T) immunotherapy is an effective therapy for relapsed/refractory B-cell non-Hodgkin lymphoma (r/r B-NHL). However, data are limited on the impact of the convergence of race and social determinants of health on outcomes for patients treated with CAR-T therapy. We examined the impact of interactions between race and insurance type on health care use and outcomes in patients treated with CAR-T therapy for aggressive B-NHL. Adult patients with r/r B-NHL treated with CD19 CAR-Ts were identified between 2015 and 2021 across 13 US academic centers. Insurance type, demographic, and clinical data were collected and analyzed. In total, 466 adult patients were included in our analysis. Median follow-up after CAR-T therapy was 12.7 months. Median progression-free survival (mPFS) was longer for Caucasians (11.5 months) than for African Americans (3.5 months; hazard ratio [HR], 1.56 [1.03-2.4]; P = .04) or Asians (2.7 months; HR, 1.7 [1.02-2.67]; P = .04). Differences in median overall survival (mOS) were not significant. For Medicare (n = 206) vs Medicaid (n = 33) vs private insurance (n = 219) vs self-pay (n = 7): mPFS was 15.9 vs 4.2 vs 6.0 vs 0.9 months (P < .001), respectively; and mOS was 31.2 vs 12.8 vs 21.5 vs 3.2 months (P < .001), respectively. Our multicenter retrospective analysis showed that race and insurance status can affect outcomes for patients treated with CAR-T therapy.

Outcomes of patients with secondary central nervous system lymphoma following CAR T-cell therapy: a multicenter cohort study.

Chimeric antigen receptor T-cell therapy (CAR-T) has been successful in treating relapsed/refractory B-cell lymphomas. However, its role in the treatment of diseases involving the central nervous system (CNS) is not well studied. We performed a multicenter retrospective cohort study to evaluate the outcomes of patients with secondary CNS lymphoma (SCNSL) who received CAR-T. Eligibility required active CNSL at the time of apheresis. The objectives included evaluation of overall survival (OS), progression-free survival (PFS), identification of predictors of complete response (CR) post-CAR-T, and assessment of risk factors for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Sixty-one patients were included in the analysis. The overall response rate was 68% with a CR rate of 57%. In the multivariable analysis, patients who experienced any grade CRS had higher odds of achieving CR (OR = 3.9, 95% CI = 1.01-15.39, p = 0.047). The median PFS was 3.3 months (95% CI = 2.6-6.0 months) with 6- and 12-month PFS rates of 35% and 16%, respectively. The median OS was 7.6 months (95% CI = 5.0-13.5 months) with 6- and 12-month OS rates of 59% and 41%, respectively. Any grade CRS and ICANS were 70% (n = 43) and 57% (n = 34), respectively with grade ≥ 3 CRS and ICANS rates of 16% and 44%. Factors associated with increased risk of CRS and ICANS included receiving axi-cel or having leptomeningeal ± parenchymal + CNS involvement, respectively. Despite achieving high response rates, most patients experience early relapse or death following CAR-T in SCNSL. The current study provides a benchmark for future trials exploring novel therapeutic options in SCNSL.

Advances in Immunotherapy for the Treatment of Cutaneous T-Cell Lymphoma.

Cutaneous T-Cell Lymphoma (CTCL) is a heterogenous disease that consists of distinct clinicopathologic entities and presentations requiring a unique and expert approach to management. The most common subtype is mycosis fungoides, in which local disease has an excellent prognosis and is often managed with topical therapy alone. More extensive cutaneous involvement as well as involvement of lymph nodes and the peripheral blood (Sezary syndrome) require systemic therapies. Recent years have brought an expansion of therapeutic options, specifically with immune-based approaches that were developed using the knowledge gained regarding the biology and molecular pathology of CTCL. Previous systemic therapies such as retinoids, histone deacetylase inhibitors, and chemotherapeutic agents come with significant toxicity and only short-term response. Newer agents such as mogamulizumab and brentuximab vedotin use a targeted immune-based approach leading to longer periods of response with less systemic toxicity. While still in its infancy, the use of immune checkpoint inhibitors such as nivolumab and pembrolizumab appears promising, and while their current clinical application is limited, early data suggest possible future areas for research of immune manipulation to treat CTCL. Herein, we review these novel immune-based treatment strategies, their superiority over prior systemic options, and the ongoing need for further research and clinical trial enrollment.

Immunochemotherapy or chemotherapy alone in primary central nervous system lymphoma: a National Cancer Database analysis.

Debate remains over the role of rituximab, a large molecule with reduced central nervous system (CNS) penetration, in therapy for primary CNS lymphoma (PCNSL). Since 2013, the National Cancer Database has distinguished between chemotherapy and immunotherapy for frontline treatment. In this setting, rituximab would be the only standard frontline immunotherapy. We examined factors associated with the receipt of immunotherapy using a multivariate regression model for relative risk, with a random intercept to account for the hospital-specific treatment selection process. Patients were matched using a 1:1 propensity score to limit possible confounders, and overall survival (OS) was compared in the matched cohort. We identified 4691 patients with PCNSL diagnosed between 2013 and 2018. The use of immunotherapy has increased from 45% in 2013 to 76% in 2018. Immunotherapy use was associated with sociodemographic variables and local (hospital level) preference rather than clinical factors. The main factors associated with reduced use of immunotherapy included male sex, Black race or Hispanic ethnicity (compared with White non-Hispanic), HIV+ status, treatment in a lower-volume hospital, and earlier year of diagnosis. We matched 2830 patients for the survival analysis. Receipt of immunotherapy was associated with a significantly better OS (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.67-0.83). There was heterogeneity according to age, because the advantage of immunotherapy was more pronounced for patients aged ≤75 years (HR, 0.71; 95% CI, 0.63-0.80) than for those older than 75 years (HR, 0.87; 95% CI, 0.70-1.08). Overall, our findings support the current trend toward rituximab use, although a nuanced approach should be adopted when treating older patients.

EBV-positive PCNSL in older patients: incidence, characteristics, tumor pathology, and outcomes across a large multicenter cohort.

The objective of this multicenter retrospective study was to examine the incidence, patient characteristics, pathology, and outcomes associated with Epstein-Barr virus (EBV)-related CNS lymphoma (CNSL) in older patients. Among 309 CNSL patients aged ≥60, 11.7% had EBV + tumors of which 72.2% were solid organ transplant (SOT)-related post-transplant lymphoproliferative disorders (PTLD). Younger age, SOT or autoimmune disease, and immunosuppressive treatment correlated highly with EBV-positivity. EBV + tumors were associated with absent C-MYC and BCL6 expression. EBV + PTLD was more likely to be associated with the absence of CD5 expression. EBV + non-PTLD had better median OS (not reached) compared to EBV + PTLD (10.8 months) and EBV-negative patients (43 months). Multivariable Cox regression analysis showed that age, performance status, and PTLD were negative predictors of OS. EBV status and immunosuppressive treatment were not correlated with OS. Our findings merit further investigation of EBV + PCNSL tumors and EBV-directed therapies.

Older patients with primary central nervous system lymphoma: Survival and prognostication across 20 U.S. cancer centers.

There is a paucity of large-scale data delineating outcomes and prognostication of older patients with primary central nervous system lymphoma (PCNSL). We retrospectively analyzed 539 newly-diagnosed PCNSL patients ages ≥60 years across 20 U.S. academic centers. The median age was 70 years (range 60-88); at least one geriatric syndrome was present in 46%; the median Cumulative Index Ratings Scale-Geriatrics (CIRS-G) score was 6 (range, 0-27); and 36% had impairment in activities of daily living (ADL). The most common induction regimens were high-dose methotrexate (HD-MTX) ± rituximab; methotrexate, temozolomide, rituximab (MTR); and rituximab, methotrexate, procarbazine, vincristine (R-MPV). Overall, 70% of patients achieved remission, with 14% undergoing consolidative autologous stem cell transplant (ASCT) and 24% receiving maintenance. With 58-month median follow-up, median progression-free survival (PFS) and overall survival (OS) were 17 months (95% CI 13-22 months) and 43 months (95% CI 31-56 months), respectively. Three-year PFS and OS were highest with MTR (55% and 74%, respectively). With single-agent methotrexate ± rituximab, 3-year PFS and OS were 30% (p = .0002) and 47% (p = .0072). On multivariate analysis, increasing age at diagnosis and Cooperative Oncology Group (ECOG) performance status (PS) was associated with inferior PFS; age, hypoalbuminemia, higher CIRS-G score, and ECOG PS adversely affected OS. Among patients receiving maintenance, 3-year PFS was 65% versus 45% without maintenance (p = 0.02), with 3-year OS of 84% versus 61%, respectively (p = .0003). Altogether, outcomes in older PCNSL patients appeared optimized with HD-MTX combination induction regimens and maintenance therapy. Furthermore, several prognostic factors, including geriatric measures, were associated with inferior outcomes.

Testicular Relapse of Primary Diffuse Large B-cell Lymphoma of the Central Nervous System - a Rare Occurrence.

Among diffuse large b-cell lymphoma (DLBCL) subtypes, primary testicular lymphoma (PTL) has one of the highest risks of central nervous system (CNS) relapse. The converse, primary CNS lymphoma (PCNSL) relapse outside the CNS is rare. Molecular analysis has illustrated a genetic similarity between PTL and PCNSL. Here we present a case of a 64-year-old man with testicular relapse of PCNSL 20 months after a complete response to high dose methotrexate-based chemotherapy. His tumor demonstrated a molecular profile similar to both PCNSL and PTL on next generation sequencing, and molecular analysis confirmed common clonal origin of his CNS and testicular lesions. We review prior cases of testicular relapse of PCNSL, which lacked molecular investigations, and discuss the implications of the genomic findings in our patient, including future treatment options.

Peri-CAR-T practice patterns and survival predictors for all CAR-T patients and post-CAR-T failure in aggressive B-NHL.

Most patients receiving chimeric antigen receptor T-cell therapy (CAR-T) for aggressive B-cell non-Hodgkin lymphoma (B-NHL) do not experience a durable remission. Several novel agents are approved to treat relapsed, refractory aggressive B-NHL; however, it remains unclear how to sequence these therapies pre- and post-CAR-T. We conducted a multicenter retrospective analysis to describe peri-CAR-T practice patterns and survival predictors for patients receiving CD19-directed CAR-T. Patients (n = 514) from 13 centers treated with CAR-T for B-NHL between 2015-2021 were included in the study. Survival curves were constructed using Kaplan-Meier method. Multivariate Cox regression analysis was used to determine the impact of the variables on survival outcomes. For all patients receiving CAR-T, a greater number of lines of therapy pre-CAR-T apheresis and bridging therapy were predictive of inferior progression-free survival (PFS) and overall survival (OS). The median PFS and OS from the time of CAR-T cell infusion were 7.6 and 25.6 months, respectively. From the time of progression post-CAR-T, the median OS was 5.5 months. The median PFS of treatments administered in the first-line post-CAR-T failure was 2.8 months. Patients with refractory disease on day 30 had inferior OS and were less likely to receive subsequent treatment(s) than other patients with CAR-T failure. Allogeneic hematopoietic cell transplantation for selected patients at any time following CAR-T failure led to durable responses in over half of patients at 1 year. These data provide a benchmark for future clinical trials in patients with post-CAR-T cell progression, which remains an unmet clinical need.

Seroconversion and outcomes after initial and booster COVID-19 vaccination in adults with hematologic malignancies.

BACKGROUND: Patients with hematologic malignancies have impaired humoral immunity secondary to their malignancy and its treatment, placing them at risk of severe coronavirus disease-19 (COVID-19) infection and reduced response to vaccination. METHODS: The authors retrospectively analyzed serologic responses to initial and booster COVID-19 vaccination in 378 patients with hematologic malignancy and subsequently tracked COVID-19-related outcomes. RESULTS: Seroconversion occurred in 181 patients (48%) after initial vaccination; patients who had active malignancy or those who were recently treated with a B-cell-depleting monoclonal antibody had the lowest rates of seroconversion. For initial nonresponders to vaccination, seroconversion after a booster dose occurred in 48 of 85 patients (56%). The seroconversion rate after the booster was similar for patients on (53%) and off (58%) active therapy (p = .82). Thirty-three patients (8.8%) developed a COVID-19 infection, and there were three COVID-19-related deaths (0.8%). Although no significant association was observed between postvaccination seroconversion and the incidence of COVID-19 infection, no patient with seroconversion died from COVID-19, and no patient who received tixagevimab/cilgavimab (N = 25) was diagnosed with a COVID-19 infection. CONCLUSIONS: Booster vaccinations can promote seroconversion in a significant proportion of patients who are seronegative after the initial vaccination course regardless of the specific vaccine or on/off treatment status at the time of revaccination. Although postvaccination seroconversion may not be associated with a decrease in any (including asymptomatic) COVID-19 infection, the authors' experience suggested that effective vaccination (including a booster), supplemented by passive immunization using tixagevimab/cilgavimab in case of lack of seroconversion, effectively eliminated the risk of COVID-19 death in the otherwise high-risk population. LAY SUMMARY: Patients with hematologic malignancy, especially lymphoma, have an impaired response to coronavirus disease 2019 (COVID-19) vaccination. In this single-institution review, less than one half of the patients studied made detectable antibodies. For those who did not make detectable antibodies after initial vaccination, over one half (65%) were able to produce antibodies after booster vaccination. By the end of February 2022, 33 of the original 378 patients had a documented COVID-19 infection. The only deaths from COVID-19 were in those who had undetectable antibodies, and no patient who received prophylactic antibody therapy developed a COVID-19 infection.

Vincristine Sulfate Liposome Injection with Bendamustine and Rituximab as First-Line Therapy for B-Cell Lymphomas: A Phase I Study.

BACKGROUND: We conducted an investigator-initiated, phase I trial of vincristine sulfate liposomal injection (VSLI) in combination with bendamustine and rituximab (BR) for indolent B-cell (BCL) or mantle cell lymphoma. METHODS: Participants received 6 cycles of standard BR with VSLI at patient-specific dose determined by the Escalation with Overdose Control (EWOC) model targeting 33% probability of dose-limiting toxicity (DLT). Maximum tolerated dose (MTD) was the primary endpoint; secondary endpoints included rates of adverse events (AEs), overall response rate (ORR), and complete response (CR). Vincristine sulfate liposomal injection is FDA approved for the treatment of patients with recurrent Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL). RESULTS: Among 10 enrolled patients, VSLI was escalated from 1.80 to 2.24 mg/m2, with one DLT (ileus) at 2.04 mg/m2. Two patients discontinued VSLI early. The most common AE included lymphopenia (100%), constipation, nausea, infusion reaction (each 60%), neutropenia, and peripheral neuropathy (50%). Grade 3/4 AE included lymphopenia (90%), neutropenia (20%), and ileus (10%), with prolonged grade ≥2 lymphopenia observed in most patients. Calculated MTD for VSLI was 2.25 mg/m2 (95% Bayesian credible interval: 2.00-2.40). Overall response was 100% with 50% CR. With median follow-up 26 months, 4/10 patients experienced recurrence and 1 died. CONCLUSION: Vincristine sulfate liposomal injection at 2.25 mg/m2 can be safely combined with BR for indolent B-cell lymphoma, but given observed toxicities and recurrences, we did not pursue an expanded cohort.Clinical Trials Registration Number: ClinicalTrials.gov identifier NCT02257242.

Analysis of Hematology and Oncology Fellowship Website Content and Diversity Representation.

PURPOSE: Hematology and oncology (HO) lags behind all medicine subspecialties in fellows under-represented in medicine (URM) despite a growing minority patient population. Websites have been effectively used in URM recruitment. We evaluated all US HO program websites to facilitate a more informed and URM-considerate recruitment. We also performed a stratified analysis on programs affiliated with National Cancer Institute (NCI) Designated Cancer Centers, National Comprehensive Cancer Center Network (NCCN) member institutions, and ranked as a top 50 cancer hospital by US News, given their stated commitment to outreach. MATERIALS AND METHODS: Websites of all 2019-2020 Accreditation Council for Graduate Medical Education-accredited HO programs were assessed for 28 informational and three diversity categories. Websites with > 70% of categories were comprehensive. Affiliation with NCI, NCCN, and US News was noted. RESULTS: One hundred fifty-six websites were analyzed: 20% were comprehensive and 22% had any diversity information. Inclusion of diversity content and being comprehensive were significantly associated (P = .001). NCI, NCCN, and US News ranking were significantly associated with inclusion of more information in univariate analyses (P < .001, P = .008, and P < .001, respectively). Multivariate analyses showed that US News ranking was significantly associated with more information (P = .005). Diversity-related univariate and multivariate analyses showed a significant association with US News ranking (P = .006 and P = .029, respectively). CONCLUSION: Most HO fellowship websites are not comprehensive and lack diversity content. Given COVID-19 travel restrictions limit in-person interviews, digital program presence remains an important opportunity. HO programs should offer comprehensive and inclusive websites to better inform applicants, including URM. This may increase institutional diversity and potentially improve URM representation in the HO workforce.

Single-route CNS prophylaxis for aggressive non-Hodgkin lymphomas: real-world outcomes from 21 US academic institutions.

Prophylaxis is commonly used to prevent central nervous sy stem (CNS) relapse in diffuse large B-cell lymphoma (DLBCL), with no clear standard of care. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline therapy between 2013 and 2019. Prophylaxis was administered intrathecally(IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7%) had CNS relapse after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4% vs 6.8%, P = .4), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected vs observed CNS relapse rates were nearly identical (5.8% vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated, and reconsideration of prophylaxis strategies in DLBCL is of critical need.

Detection of clonotypic DNA in the cerebrospinal fluid as a marker of central nervous system invasion in lymphoma.

The diagnosis of parenchymal central nervous system (CNS) invasion and prediction of risk for future CNS recurrence are major challenges in the management of aggressive lymphomas, and accurate biomarkers are needed to supplement clinical risk predictors. For this purpose, we studied the results of a next-generation sequencing (NGS)-based assay that detects tumor-derived DNA for clonotypic immunoglobulin gene rearrangements in the cerebrospinal fluid (CSF) of patients with lymphomas. Used as a diagnostic tool, the NGS-minimal residual disease (NGS-MRD) assay detected clonotypic DNA in 100% of CSF samples from 13 patients with known CNS involvement. They included 7 patients with parenchymal brain disease only, whose CSF tested negative by standard cytology and flow cytometry, and 6 historical DNA aliquots collected from patients at a median of 39 months before accession, which had failed to show clonal rearrangements using standard polymerase chain reaction. For risk prognostication, we prospectively collected CSF from 22 patients with newly diagnosed B-cell lymphomas at high clinical risk of CNS recurrence, of whom 8 (36%) had detectable clonotypic DNA in the CSF. Despite intrathecal prophylaxis, a positive assay of CSF was associated with a 29% cumulative risk of CNS recurrence within 12 months of diagnosis, in contrast with a 0% risk among patients with negative CSF (P = .045). These observations suggest that detection of clonotypic DNA can aid in the diagnosis of suspected parenchymal brain recurrence in aggressive lymphoma. Furthermore, the NGS-MRD assay may enhance clinical risk assessment for CNS recurrence among patients with newly diagnosed lymphomas and help select those who may benefit most from novel approaches to CNS-directed prophylaxis.

Chemotherapy-Free Management of Follicular and Marginal Zone Lymphoma.

Many patients with follicular (FL) or marginal zone lymphoma (MZL) are not eligible to receive immunochemotherapy due to advanced age or comorbidities. Recent innovations in the treatment of these indolent lymphomas provide options for multiple lines of chemotherapy-free management. More research is needed to determine which older patients are best served by a chemotherapy-free approach in the context of geriatric vulnerabilities. In the first line, regardless of disease burden, rituximab monotherapy can provide high rates of disease control with minimal toxicity, while judicious use of brief maintenance extends the duration of response. Radioimmunotherapy using ibritumomab tiuxetan is an effective and safe post-rituximab consolidation for older patients who have <25% bone marrow involvement. The combination of rituximab and lenalidomide, although "chemotherapy-free", does not improve tolerability over immunochemotherapy. However, studies support lower doses and shorter duration of lenalidomide exposure as a means to improve safety without materially compromising efficacy for older individuals. Extranodal MZL can often be effectively controlled with low-dose radiation therapy, and splenic MZL has excellent outcomes with rituximab monotherapy. For many patients with relapsed FL/MZL, simple retreatment with anti-CD20 antibodies will prove sufficient. Other currently available options for relapsed/refractory disease include ibritumomab tiuxetan, lenalidomide with rituximab, umbralisib as a potentially less toxic PI3K inhibitor, ibrutinib (for MZL), and tazemetostat (for FL, especially with EZH2 mutation). Emerging data with novel forms of immunotherapy (antibody-drug conjugates like polatuzumab vedotin or loncastuximab tesirine; T-cell-engaging bispecific antibodies like mosunetuzumab or epcoritamab; and chimeric antigen receptor CAR T-cells like axicabtagene ciloleucel) suggest that immune-directed approaches can produce very high and potentially durable responses in FL/MZL with limited toxicities, further obviating the need for chemotherapy.