Marginal zone lymphoma international prognostic index: a unifying prognostic index for marginal zone lymphomas requiring systemic treatment.

Background: Marginal zone lymphomas (MZL), comprised of three unique but related subtypes, lack a unifying prognostic score applicable to all the patients in need for systemic chemotherapy and/or immunotherapy. Methods: Patients from the prospective NF10 study (NCT02904577) with newly diagnosed MZL and receiving frontline systemic therapy at diagnosis or after observation were used to train a prognostic model. The primary endpoint was progression-free survival (PFS) from start of treatment. The model was externally validated in a pooled analysis of two independent cohorts from the University of Iowa and Mayo Clinic Molecular Epidemiology Resource and the University of Miami. Findings: We identified 501 eligible patients. After multivariable modeling, lactate dehydrogenase (LDH) above upper normal limit, hemoglobin <12 g/dL, absolute lymphocyte count <1 × 109/L, platelets <100 × 109/L, and MZL subtype (nodal or disseminated) were independently associated with inferior PFS. The proposed MZL International Prognostic index (MZL-IPI) combined these 5 factors, and we defined low (LRG, 0 factors, 27%), intermediate (IRG, 1-2 factors, 57%) and high (HRG, 3+ factors, 16%) risk groups with 5-y PFS of 85%, 66%, and 37%, respectively (c-Harrell = 0.64). Compared to the LRG, the IRG (Hazard Ratio [HR] = 2.30, 95% CI 1.39-3.80) and HRG (HR = 5.41, 95% CI 3.12-9.38) had inferior PFS. Applying the MZL-IPI to the pooled US cohort (N = 353), 94 (27%), 192 (54%), and 67 (19%) patients were classified as LRG, IRG, and HRG, respectively, and the model was validated for PFS (log-rank test p = 0.0018; c-Harrell = 0.578, 95% CI 0.54-0.62). The MZL-IPI was also prognostic for OS in both the training and the external validation sets. Interpretation: MZL-IPI is a new prognostic score for use in all patients with MZL considered for systemic treatment. Funding: The MER was supported by P50 CA97274 and U01 CA195568.

Lymphomatoid Papulosis With T-cell Receptor-Gamma Delta Expression: A Clinicopathologic Case-series of 26 Patients of an Underrecognized Immunophenotypic Variant of Lymphomatoid Papulosis.

Lymphomatoid papulosis (LyP) has several histopathologic presentations. LyP featuring gamma-delta (γδ) T-cell receptor expression may masquerade as and may be misdiagnosed as aggressive cutaneous T-cell lymphoma, particularly primary cutaneous γδ T-cell lymphoma (PCGDTL) or γδ mycosis fungoides. We performed a clinicopathologic analysis of the largest series of LyP featuring γδ T-cell expression. We identified 26 patients with a diagnosis of LyP with γδ T cells from our institutions, as well as through a comprehensive review of the literature, and characterized these cases. Most cases were treated with topical steroids or not treated at all. The majority of cases showed a CD4 - CD8 + phenotype and featured at least one cytotoxic marker. Histopathologic features included an intraepidermal or dermal infiltrate with large cells and frequent angiotropism. One case was initially misdiagnosed as PCGDTL, requiring further therapy. Our case series, the largest international cohort of γδ T cell predominant LyP cases, confirms marked clinicopathologic heterogeneity that may contribute to misdiagnosis, reasserting the need to identify classic clinical features, CD30 + T-cell components, and markers of cytotoxicity when dealing with this differential diagnosis. A limitation of this study includes somewhat limited follow-up, histologic, and immunophenotypic information for some cases.

Breast Implant Associated Anaplastic Large Cell Lymphoma: Evidence-Based Consensus Conference Statement From The American Association of Plastic Surgeons.

BACKGROUND: In the absence of high-quality evidence, there is a need to provide guidelines and multidisciplinary consensus recommendations on Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL). The purpose of this expert consensus conference was to evaluate the existing evidence regarding the diagnosis, and management of BIA-ALCL caused by textured implants. The aim is to provide evidence-based recommendations regarding the management and prevention of BIA-ALCL. METHODS: A comprehensive search was conducted in the MEDLINE, Cochrane Library, and Embase databases, supplemented by manual searches of relevant English language articles and "related articles" sections. Studies focusing on breast surgery and lymphoma associated with breast implants were included for analysis. Meta-analyses were performed and reviewed by experts selected by the American Association of Plastic Surgeons by a Delphi consensus method. RESULTS: 840 articles between January 2011 and January 2023 were initially identified and screened. Full-text of 188 articles were assessed. An additional 43 articles were excluded for focus, and 145 articles were included in the synthesis of results, with 105 of them being case reports or case series. The analysis encompassed a comprehensive examination of the selected articles to determine the incidence, risk factors, clinical presentation, diagnostic approaches, and treatment modalities related to BIA-ALCL. CONCLUSIONS: Plastic surgeons should be aware of the elevated risks by surface type, implement appropriate patient surveillance, and follow the recommendations outlined in this statement to ensure patient safety and optimize outcomes. Ongoing research on pathogenesis, genetic drivers, and preventative and prophylactic measures is crucial for improving patient care.

Translating prognostic quantification of c-MYC and BCL2 from tissue microarrays to whole slide images in diffuse large B-cell lymphoma using deep learning.

BACKGROUND: c-MYC and BCL2 positivity are important prognostic factors for diffuse large B-cell lymphoma. However, manual quantification is subject to significant intra- and inter-observer variability. We developed an automated method for quantification in whole-slide images of tissue sections where manual quantification requires evaluating large areas of tissue with possibly heterogeneous staining. We train this method using annotations of tumor positivity in smaller tissue microarray cores where expression and staining are more homogeneous and then translate this model to whole-slide images. METHODS: Our method applies a technique called attention-based multiple instance learning to regress the proportion of c-MYC-positive and BCL2-positive tumor cells from pathologist-scored tissue microarray cores. This technique does not require annotation of individual cell nuclei and is trained instead on core-level annotations of percent tumor positivity. We translate this model to scoring of whole-slide images by tessellating the slide into smaller core-sized tissue regions and calculating an aggregate score. Our method was trained on a public tissue microarray dataset from Stanford and applied to whole-slide images from a geographically diverse multi-center cohort produced by the Lymphoma Epidemiology of Outcomes study. RESULTS: In tissue microarrays, the automated method had Pearson correlations of 0.843 and 0.919 with pathologist scores for c-MYC and BCL2, respectively. When utilizing standard clinical thresholds, the sensitivity/specificity of our method was 0.743 / 0.963 for c-MYC and 0.938 / 0.951 for BCL2. For double-expressors, sensitivity and specificity were 0.720 and 0.974. When translated to the external WSI dataset scored by two pathologists, Pearson correlation was 0.753 & 0.883 for c-MYC and 0.749 & 0.765 for BCL2, and sensitivity/specificity was 0.857/0.991 & 0.706/0.930 for c-MYC, 0.856/0.719 & 0.855/0.690 for BCL2, and 0.890/1.00 & 0.598/0.952 for double-expressors. Survival analysis demonstrates that for progression-free survival, model-predicted TMA scores significantly stratify double-expressors and non double-expressors (p = 0.0345), whereas pathologist scores do not (p = 0.128). CONCLUSIONS: We conclude that proportion of positive stains can be regressed using attention-based multiple instance learning, that these models generalize well to whole slide images, and that our models can provide non-inferior stratification of progression-free survival outcomes.

The Lymphoma Epidemiology of Outcomes cohort study: Design, baseline characteristics, and early outcomes.

To address the current and long-term unmet health needs of the growing population of non-Hodgkin lymphoma (NHL) patients, we established the Lymphoma Epidemiology of Outcomes (LEO) cohort study (NCT02736357; https://leocohort.org/). A total of 7735 newly diagnosed patients aged 18 years and older with NHL were prospectively enrolled from 7/1/2015 to 5/31/2020 at 8 academic centers in the United States. The median age at diagnosis was 62 years (range, 18-99). Participants came from 49 US states and included 538 Black/African-Americans (AA), 822 Hispanics (regardless of race), 3386 women, 716 age <40 years, and 1513 rural residents. At study baseline, we abstracted clinical, pathology, and treatment data; banked serum/plasma (N = 5883, 76.0%) and germline DNA (N = 5465, 70.7%); constructed tissue microarrays for four major NHL subtypes (N = 1189); and collected quality of life (N = 5281, 68.3%) and epidemiologic risk factor (N = 4489, 58.0%) data. Through August 2022, there were 1492 deaths. Compared to population-based SEER data (2015-2019), LEO participants had a similar distribution of gender, AA race, Hispanic ethnicity, and NHL subtype, while LEO was underrepresented for patients who were Asian and aged 80 years and above. Observed overall survival rates for LEO at 1 and 2 years were similar to population-based SEER rates for indolent B-cell (follicular and marginal zone) and T-cell lymphomas, but were 10%-15% higher than SEER rates for aggressive B-cell subtypes (diffuse large B-cell and mantle cell). The LEO cohort is a robust and comprehensive national resource to address the role of clinical, tumor, host genetic, epidemiologic, and other biologic factors in NHL prognosis and survivorship.

The asymptomatic follicular lymphoma (AFL) trial: single-agent rituximab immunotherapy versus 90Y-ibritumomab tiuxetan radioimmunotherapy (RIT) for patients with new, untreated follicular lymphoma.

Patients with asymptomatic follicular lymphoma (AFL) are candidates for observation or immunotherapy. Given the effectiveness of radiation therapy in FL, another option is 90Yttrium-ibritumomab tiuxetan radioimmunotherapy (RIT). We conducted a trial where untreated AFL patients were randomized to rituximab 375 mg/m2 weekly × 4 or rituximab 250 mg/m2 days 1, 8, and 0.4 mCi/kg (maximum 32 mCi) of RIT day 8. Twenty patients were enrolled before the study was halted due to unavailability of RIT. The ORR for rituximab and RIT were 90% and 80%, respectively; the CR rate at 6 months was 30% and 60%, respectively. After a median follow-up of 67 months, eight patients have progressed-three in the rituximab arm and five in the RIT arm and five have required systemic therapy. All patients remain alive. Both agents are highly active for AFL. The 1-week treatment with RIT and sparing of T-cells make combination therapy with newer agents attractive.

Molecular and clinicopathological features of granzyme B-negative extranodal NK/T-cell lymphoma.

Extranodal NK/T-cell lymphoma (ENKTL) generally expresses cytotoxic molecules, including granzyme B (GZMB), T-cell-restricted intracellular antigen-1 (TIA-1), and perforin; however, the expression of these molecules varies across cases. We performed gene expression profiling and identified unique biological and clinicopathological features of GZMB-negative ENKTL. We reviewed the clinicopathological characteristics of 71 ENKTL samples. Gene expression profiling on nine ENKTLs using multiplexed, direct, and digital mRNA quantification divided ENKTLs into Groups A (n = 7) and B (n = 2) through hierarchical clustering and t-distributed stochastic neighbor embedding. Group B was characterized by downregulation of genes associated with IL6-JAK-STAT3 signaling and inflammatory responses. GZMB mRNA expression was significantly downregulated in Group B. GZMB protein expression was evaluated with immunohistochemistry in all 71 ENKTLs, and expression data of Tyr705-phosphorylated STAT3 (pSTAT3) and MYC from our previous study was utilized. T-cell receptor gamma (TRG) gene rearrangement in the selected samples was also assessed using PCR. GZMB expression was higher in pSTAT3-positive (p = 0.028) and MYC-positive (p = 0.014) ENKTLs. Eighteen percent (13/71) of all ENKTLs were negative for GZMB (defined by positivity <10 %); patients with GZMB-negative ENKTLs were often in a higher clinical stage (p = 0.016). We observed no other correlations with clinical parameters or TRG rearrangement and no significant association between GZMB expression and survival. In conclusion, GZMB expression is highly heterogeneous in ENKTLs and is associated with the activation of the JAK-STAT3 pathway and higher MYC expression. GZMB-negative ENKTLs correlate with an advanced clinical stage, suggesting the potential utility of GZMB immunohistochemistry as a biomarker of ENKTL.

Updates in the Classification of T-cell Lymphomas and Lymphoproliferative Disorders.

PURPOSE OF REVIEW: Mature T/NK-cell neoplasms comprise a heterogeneous group of diseases with diverse clinical, histopathologic, immunophenotypic, and molecular features. A clinically relevant, comprehensive, and reproducible classification system for T/NK-cell neoplasms is essential for optimal management, risk stratification, and advancing understanding of these diseases. Two classification systems for lymphoid neoplasms were recently introduced: the 5th edition of World Health Organization classification (WHO-HAEM5) and the 2022 International Consensus Classification (ICC). In this review, we summarize the basic framework and updates in the classification of mature T/NK-cell neoplasms. RECENT FINDINGS: WHO-HAEM5 and ICC share basic concepts in classification of T/NK-cell neoplasms, emphasizing integration of clinical presentation, pathology, immunophenotype, and genetics. Major updates in both classifications include unifying nodal T-follicular helper-cell lymphomas into a single entity and establishing EBV-positive nodal T/NK-cell lymphoma as a distinct entity. However, some differences exist in taxonomy, terminology, and disease definitions. The recent classifications of mature T/NK-cell neoplasms are largely similar and provide new insights into taxonomy based on integrated clinicopathologic features.

Spinal Meningeal Mass Lesion: A Rare Presentation of Primary Dural Follicular Lymphoma.

INTRODUCTION: The differential diagnosis of a spinal intradural extramedullary mass lesion is broad and includes meningioma, schwannoma, neurofibroma, leptomeningeal metastasis, and myxopapillary ependymoma. Though rare, lymphoma should be included in the differential diagnosis of a dural mass lesion. CASE REPORT: A 38-year-old man presented with back pain that progressed over 1 month with associated focal tenderness over his mid to lower thoracic spine. He developed intermittent numbness of the bilateral lower extremities, nuchal rigidity, difficulty sleeping, and night sweats. A magnetic resonance imaging of the thoracic spine demonstrated a dorsal intradural extramedullary enhancing lesion from T7 to T10 extending outside the spinal canal. Dural thickening across the entire circumference of the spinal cord was noted. Computed tomography (CT)-guided biopsy of the thoracic lesion was performed, and pathology was consistent with follicular lymphoma. Fluorodeoxyglucose positron emission tomography:CT demonstrated no systemic disease. Bone marrow biopsy was negative for malignancy. Symptoms resolved with dexamethasone therapy. He was treated with bendamustine and rituximab with follow-up positron emission tomography:CT 2 months later demonstrating a complete response. CONCLUSIONS: Lymphoma can rarely present as an isolated dural lesion and should be considered in the differential diagnosis of intradural extramedullary spinal mass lesions. Prompt diagnosis and initiation of treatment can lead to complete response and resolution of symptoms.

TP63 fusions drive multicomplex enhancer rewiring, lymphomagenesis, and EZH2 dependence.

Gene fusions involving tumor protein p63 gene (TP63) occur in multiple T and B cell lymphomas and portend a dismal prognosis for patients. The function and mechanisms of TP63 fusions remain unclear, and there is no target therapy for patients with lymphoma harboring TP63 fusions. Here, we show that TP63 fusions act as bona fide oncogenes and are essential for fusion-positive lymphomas. Transgenic mice expressing TBL1XR1::TP63, the most common TP63 fusion, develop diverse lymphomas that recapitulate multiple human T and B cell lymphomas. Here, we identify that TP63 fusions coordinate the recruitment of two epigenetic modifying complexes, the nuclear receptor corepressor (NCoR)-histone deacetylase 3 (HDAC3) by the N-terminal TP63 fusion partner and the lysine methyltransferase 2D (KMT2D) by the C-terminal TP63 component, which are both required for fusion-dependent survival. TBL1XR1::TP63 localization at enhancers drives a unique cell state that involves up-regulation of MYC and the polycomb repressor complex 2 (PRC2) components EED and EZH2. Inhibiting EZH2 with the therapeutic agent valemetostat is highly effective at treating transgenic lymphoma murine models, xenografts, and patient-derived xenografts harboring TP63 fusions. One patient with TP63-rearranged lymphoma showed a rapid response to valemetostat treatment. In summary, TP63 fusions link partner components that, together, coordinate multiple epigenetic complexes, resulting in therapeutic vulnerability to EZH2 inhibition.

Anaplastic large cell lymphomas with equivocal DUSP22 FISH results: recommendations for clinical reporting and diagnostic evaluation.

Anaplastic large cell lymphoma (ALCL), one of the most common T-cell lymphomas, shows unifying pathological features but is clinically and genetically heterogeneous. One genetic subgroup, characterized by recurrent DUSP22 rearrangements (R), has distinct morphologic, immunophenotypic, and molecular features and can be identified in routine pathology practice using a breakapart (BAP) fluorescence in situ hybridization (FISH) probe. However, some cases show equivocal BAP-FISH findings (BAP-FISHEQ) and the features of these cases are poorly understood. Here, we sought to characterize DUSP22 BAP-FISHEQ ALCLs further. First, we applied an immunohistochemistry (IHC) algorithm using TIA1, pSTAT3Y705, and LEF1, which can predict DUSP22-R with high accuracy. Among 37 BAP-FISHEQ ALCLs, 18 (49%) were IHC-algorithm positive (IHCPOS), 8 (21%) were IHC-algorithm negative (IHCNEG), and 11 (30%) were IHCEQ. In 32 BAP-FISHEQ cases, we also applied a dual-color, dual-fusion (D-FISH) probe for t(6;7)(p25.3;q32.3), which accounts for 45% of DUSP22-R ALCLs. Among BAP-FISHEQ cases, D-FISH was positive in 10/18 IHCPOS cases (56%), 0/9 IHCEQ cases (0%), and 0/5 IHCNEG cases (0%). Median survival in BAP-FISHEQ ALCLs was 105 months, intermediate between BAP-FISHPOS ALCLs (median survival not reached) and BAP-FISHNEG ALCLs (19 months). Thus, DUSP22 BAP-FISHEQ ALCLs are clinicopathologically heterogeneous, likely due to an admixture of cases with an unbalanced DUSP22-R and cases with focal deletions without rearrangement. For clinical reporting, we recommend that DUSP22 BAP-FISHEQ ALCLs be reported as equivocal, and not be grouped with BAP-FISHPOS ALCLs. Clinical adoption of an IHC algorithm, possibly supplemented by t(6; 7) D-FISH, could facilitate genetic subtyping in about two-thirds of BAP-FISHEQ ALCLs.

Epithelioid inflammatory myofibroblastic sarcoma: a pitfall in the differential diagnosis of ALK-positive anaplastic large cell lymphoma.

An 18-year-old female presented with a 4.5 cm abdominal mass. Biopsy showed sheet-like growth of large tumor cells with round to oval nuclei, 1-2 nucleoli, and abundant cytoplasm. Immunohistochemistry showed strong, uniform CD30 staining and cytoplasmic ALK staining. B-cell markers (CD20, CD79a, PAX5, kappa/lambda) and T-cell markers (CD2, CD3, CD4, CD5, CD43, granzyme B, T-cell receptor-ß) were negative. Other hematopoietic markers (CD45, CD34, CD117, CD56, CD163, EBV) were negative, but CD138 was positive. Non-hematopoietic markers showed desmin positivity and negativity for S100, melan A, HBM45, PAX8, PAX2, WT1, MYO-D1, myogenin, pancytokeratin, and CAM5.2. Sequencing identified PRRC2B::ALK fusion. A diagnosis of epithelioid inflammatory myofibroblastic sarcoma (EIMS) was made. EIMS is a rare, aggressive form of inflammatory myofibroblastic tumor typically presenting in children and young adults. The tumor comprises large epithelioid cells that express ALK and often CD30. ALK-positive ALCL has a similar age range and also is a large-cell tumor expressing CD30 and ALK. Other ALK-positive neoplasms (e.g., carcinomas, ALK-positive large B-cell lymphoma, ALK-positive histiocytosis) typically lack CD30 and have distinct clinicopathologic features that aid diagnosis. Hematopathologists need to distinguish EIMS from ALK-positive ALCL, which frequently shows loss of pan-T-cell antigens. Careful morphologic evaluation for the hallmark cells of ALCL and comprehensive phenotyping are critical to avoid this diagnostic pitfall. If known, the ALK rearrangement partner gene may also provide diagnostic clues; for example PRRC2B::ALK and RANBP2::ALK occur in EIMS but not ALCL.

Multiomic Analysis Identifies a High-Risk Metabolic and TME Depleted Signature that Predicts Early Clinical Failure in DLBCL.

PURPOSE: 60-70% of newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients avoid events within 24 months of diagnosis (EFS24) and the remainder have poor outcomes. Recent genetic and molecular classification of DLBCL has advanced our knowledge of disease biology, yet were not designed to predict early events and guide anticipatory selection of novel therapies. To address this unmet need, we used an integrative multiomic approach to identify a signature at diagnosis that will identify DLBCL at high risk of early clinical failure. PATIENTS AND METHODS: Tumor biopsies from 444 newly diagnosed DLBCL were analyzed by WES and RNAseq. A combination of weighted gene correlation network analysis and differential gene expression analysis followed by integration with clinical and genomic data was used to identify a multiomic signature associated with high risk of early clinical failure. RESULTS: Current DLBCL classifiers are unable to discriminate cases who fail EFS24. We identified a high risk RNA signature that had a hazard ratio (HR, 18.46 [95% CI 6.51-52.31] P < .001) in a univariate model, which did not attenuate after adjustment for age, IPI and COO (HR, 20.8 [95% CI, 7.14-61.09] P < .001). Further analysis revealed the signature was associated with metabolic reprogramming and a depleted immune microenvironment. Finally, WES data was integrated into the signature and we found that inclusion of ARID1A mutations resulted in identification of 45% of cases with an early clinical failure which was validated in external DLBCL cohorts. CONCLUSION: This novel and integrative approach is the first to identify a signature at diagnosis that will identify DLBCL at high risk for early clinical failure and may have significant implications for design of therapeutic options.

Current Concepts in Nodal Peripheral T-Cell Lymphomas.

This review summarizes the current understanding of mature T-cell neoplasms predominantly involving lymph nodes, including ALK-positive and ALK-negative anaplastic large cell lymphomas, nodal T-follicular helper cell lymphoma, Epstein-Barr virus-positive nodal T/NK-cell lymphoma, and peripheral T-cell lymphoma (PTCL), not otherwise specified. These PTCLs are clinically, pathologically, and genetically heterogeneous, and the diagnosis is made by a combination of clinical information, morphology, immunophenotype, viral positivity, and genetic abnormalities. This review summarizes the pathologic features of common nodal PTCLs, highlighting updates in the fifth edition of the World Health Organization classification and the 2022 International Consensus Classification.

Relationship between BCL2 mutations and follicular lymphoma outcome in the chemoimmunotherapy era.

How to identify follicular lymphoma (FL) patients with low disease burden but high risk for early progression is unclear. Building on a prior study demonstrating the early transformation of FLs with high variant allele frequency (VAF) BCL2 mutations at activation-induced cytidine deaminase (AICDA) sites, we examined 11 AICDA mutational targets, including BCL2, BCL6, PAX5, PIM1, RHOH, SOCS, and MYC, in 199 newly diagnosed grade 1 and 2 FLs. BCL2 mutations with VAF ≥20% occurred in 52% of cases. Among 97 FL patients who did not initially receive rituximab-containing therapy, nonsynonymous BCL2 mutations at VAF ≥20% were associated with increased transformation risk (HR 3.01, 95% CI 1.04-8.78, p = 0.043) and a trend toward shorter event-free survival (EFS, median 20 months with mutations versus 54 months without, p = 0.052). Other sequenced genes were less frequently mutated and did not increase the prognostic value of the panel. Across the entire population, nonsynonymous BCL2 mutations at VAF ≥20% were associated with decreased EFS (HR 1.55, 95% CI 1.02-2.35, p = 0.043 after correction for FLIPI and treatment) and decreased overall survival after median 14-year follow-up (HR 1.82, 95% CI 1.05-3.17, p = 0.034). Thus, high VAF nonsynonymous BCL2 mutations remain prognostic even in the chemoimmunotherapy era.

An Effective Combination Therapy for the Treatment of Pediatric Monomorphic Post-transplant Lymphoproliferative Disorder With Plasmacytic Differentiation.

Post-transplant lymphoproliferative disorder (PTLD) is a complication of immunosuppressive therapy following solid organ or hematopoietic cell transplantation. Initial treatment typically includes a reduction of immunosuppression with or without rituximab. However, the optimal therapy for PTLD with plasmacytic differentiation is unclear. We present 3 cases of pediatric patients with plasmacytic PTLD. Two patients received a standard rituximab-based approach and relapsed, prompting additional chemotherapy. The third patient was treated with a novel regimen of bortezomib, dexamethasone, and daratumumab. This regimen was safe, well-tolerated, and resulted in a 2-year remission. Larger studies are needed to further explore this regimen.