Cycles Of Rituximab, Cyclophosphamide, Doxorubicin, Vincristine And Prednisone Research Articles

Zanubrutinib in Combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP) for Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL): Interim Results from a Phase 1b Clinical Trial

Introduction. Although most patients (pts) with DLBCL are cured with R-CHOP, ~40% develop refractory or relapsed disease. Several studies have shown a potential therapeutic role for BTK inhibitors in DLBCL. In the phase 3 PHOENIX trial of pts with DLBCL, the addition of ibrutinib to R-CHOP failed to improve overall outcomes. However, in pts <60 years, ibrutinib plus R-CHOP improved the progression-free (PFS) and overall (OS) survivals. The age-based difference in outcomes with ibrutinib plus R-CHOP may be due to greater toxicity and reduced R-CHOP dose intensity with this combination in older pts. We hypothesized that zanubrutinib, a 2 nd-generation BTK inhibitor with greater selectivity for BTK and improved safety compared with ibrutinib, could be safely combined with R-CHOP and improve outcomes. Methods. This phase Ib investigator-initiated trial is being conducted at 2 US centers. Eligible pts had previously untreated DLBCL, stage II-IV, and International Prognostic Index (IPI) score ≥1. Pts received standard-dose R-CHOP on day 1 and zanubrutinib on days 1-21 for six 21-day cycles. A dose de-escalation design was used to determine the recommended phase 2 dose (RP2D) followed by an expansion cohort. One cycle of R-CHOP off protocol was permitted. Primary prophylaxis with G-CSF was not mandated and followed national guidelines. The primary objective was to determine the RP2D and safety of zanubrutinib plus R-CHOP (ZaR-CHOP). Secondary objectives included overall response rate (ORR), PFS and OS for pts treated at the RP2D, and descriptive data on treatment exposure to zanubrutinib and R-CHOP. Interim results of pts treated with ZaR-CHOP are presented here. Results. From 10/2021 to 5/2023, 16 pts signed consent of whom 2 were ineligible. Data for the 14 eligible and safety-evaluable pts are shown here. The median age was 59 years (range 23-74) and 4 pts (29%) were ≥65 years. Ten pts (71%) had stage IV, 9 (64%) elevated LDH, 6 (43%) high-intermediate or high IPI, and 7 (50%) had bulky (≥10 cm) disease (missing n=3). Cell-of-origin by Hans was germinal center (GC) in 7 pts (50%) and non-GC in 7 (50%); 5 pts (38%) had double-expressor DLBCL (MYC ≥40% and BCL2 ≥50% by immunohistochemistry) (missing n=1). No dose-limiting toxicities occurred and zanubrutinib 160 mg twice daily was selected as the RP2D. Two pts withdrew from trial (1 pt after cycle 5 in the setting of recurrent/persistent COVID19 infection and 1 pt after cycle 2 due to grade (G) 2 stomach pain and G1 diarrhea); both were able to receive 6 cycles of R-CHOP. No dose reductions in cyclophosphamide or doxorubicin occurred. One pt required zanubrutinib dose reduction for febrile neutropenia (FN). The most frequently reported (≥30%) all-grade treatment-emergent adverse events (TEAEs) were lymphopenia 79%, fatigue 57%, leukopenia 50%, sensory peripheral neuropathy 50%, anemia 43% (G1 14%, G2 14%, G3 14%), thrombocytopenia 43% (all G1), hyperglycemia 43%, cough 43%, diarrhea 36% (all G1), nausea 36% (G1 29%, G2 7%), elevated alanine aminotransferase 36% (all G1), neutropenia 36%, hyponatremia 36% (G1 29%, G2 7%), and alopecia 36% (Table). The most frequently reported (≥10%) G≥3 TEAEs were neutropenia 29%, lymphopenia 29%, leukopenia 21%, anemia 14%, and FN 14% (no G4). The most frequently reported serious adverse event (AE) was FN (3 pts (21%) each with 1 G3 event, including 1 event after standard-of-care cycle 1 R-CHOP and 1 after off-protocol cycle 6 R-CHOP in a pt who withdrew from trial). One pt developed G4 sepsis that resolved without sequelae. Bleeding AEs were limited to hematuria (21%, all G1) and bruising (14%, all G1), and cardiac AEs to palpitations (7%, G1). Twelve pts were evaluable for response; 1 pt remains on treatment and 1 awaiting response assessment. The ORR was 91.6% (95% confidence interval 61.5-99.8%) including complete response (CR) in 83.3% and PR in 8.3% (2 pts had positive end-of-treatment (EOT) PET but declared CR based upon follow-up PET and/or biopsy). One pt had progressive disease on EOT PET. With a median follow up of 4.3 months (range 0-15 months) from EOT response assessment, no relapses or deaths occurred on study. Conclusion. The addition of zanubrutinib to R-CHOP is well tolerated and does not compromise R-CHOP delivery. Given the recent approval of polatuzumab in combination with R-CHP in DLBCL, and no additional toxicity concerns identified in this phase Ib trial, the protocol is being amended to substitute polatuzumab for vincristine.

A Rare B-Myeloid Conversion of Follicular Lymphoma into Clonally Related Acute Myeloid Leukemia: A Case Report

Follicular lymphoma (FL) is a highly prevalent indolent lymphoma, and the risk of histological transformation is approximately 2-3% per year. Transformation of FL generally occurs in the same lineage (B cell lineage). Another rare form of disease progression is the transformation of neoplastic B-cells to another cell lineage such as acute myeloid leukemia (AML). The low incidence of B-myeloid transformation associated with poor prognosis hinders the establishment of model systems to identify molecular mechanisms. A 64-year-old woman was diagnosed with FL and achieved a satisfactory response after six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Approximately one month after treatment terminated, the disease progressed to AML with an increased white blood cell count and abnormal coagulation. Interestingly, nucleotide sequence analysis of the genomic region encoding the immunoglobulin heavy-chain variable domain showed the possibility of homologous transformation from lymphoma to leukemia cells. Although the patient experienced transient improvement after undergoing treatment with one cycle of idarubicin and cytarabine combined with etoposide, she relapsed and died 8 days after venetoclax salvage therapy. Patient with B-myeloid transformation was associated with an aggressive clinical course and poor prognosis. Conventional strategies for treating histologically transformed AML were ineffective. However, treatment with a Bcl-2 inhibitor could serve as an option. Here we review the literature relevant to this rare histological transformation of FL.

Frontmind: A Phase III, Multicenter, Randomized, Double-Blind Study of Tafasitamab + Lenalidomide + R-CHOP Versus R-CHOP Alone for Newly Diagnosed High-Intermediate and High-Risk Diffuse Large B-Cell Lymphoma

Background R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) is the standard of care for newly diagnosed and untreated diffuse large B-cell lymphoma (DLBCL); however, approximately 30-40% of patients relapse or become refractory. Furthermore, the 5-year overall survival (OS) is lower in high-risk DLBCL patients than in low-risk patients. Co-administration of lenalidomide (LEN) with R-CHOP improved both progression-free survival (PFS) and OS in the ECOG-ACRIN E1412 trial but not in the Phase III ROBUST study, in which a lower dose of LEN was used, despite a positive trend in 2-year PFS rate in a subgroup analysis of patients with high-risk disease. POLARIX (NCT03274492) evaluated a modified regimen substituting polatuzumab vedotin for vincristine (pola-R-CHP), showing a modest improvement in PFS without OS benefit between treatment arms, indicating an unmet clinical need remains. Tafasitamab, an Fc-enhanced, humanized, anti-CD19 monoclonal antibody, in combination with LEN was granted accelerated approval in the US (2020) and conditional/accelerated approval by the EMA (2021) and other regulatory authorities for the treatment of adult patients with relapsed/refractory DLBCL not otherwise specified, including DLBCL arising from low-grade lymphoma, and who are ineligible for ASCT. It is a preferred regimen in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for this setting. CD19 and CD20 are broadly expressed on the surface of DLBCL cells, and a treatment strategy targeting both of these B cell surface molecules may limit target evasion in patients exhibiting low CD20 expression and reduce resistance to R-CHOP. Additionally, LEN is an immunomodulatory drug with antineoplastic activity and enhances antibody-dependent cellular cytotoxicity with tafasitamab and rituximab. The addition of tafasitamab + LEN to R-CHOP may provide further therapeutic benefit in patients with newly diagnosed and untreated DLBCL. The Phase Ib First-MIND (NCT04134936), randomized, safety study of R-CHOP + tafasitamab ± LEN in patients with newly diagnosed and untreated DLBCL showed that tafasitamab + LEN does not affect the dosing and scheduling of R-CHOP, with toxicities similar to those expected with R-CHOP alone (ASH 2021; #3556). frontMIND (NCT04824092) will investigate the efficacy and safety of R-CHOP + tafasitamab + LEN versus R-CHOP alone in previously untreated patients with high-intermediate and high-risk DLBCL. Methods frontMIND is a Phase III, multicenter, randomized, double-blind, placebo-controlled study. As of June 2, 2022, more than 350 study sites have been activated in over 25 countries globally (Figure 1). The study is currently enrolling, with a planned sample size of 880 patients; as of June 6, 2022, more than 50% of the planned sample size have been enrolled in the study. Eligible patients include adults aged 18‒80 years with previously untreated, local biopsy-proven CD20+ DLBCL and high-grade B cell lymphoma (double-hit/triple-hit lymphoma if deemed ineligible for a more aggressive treatment) with IPI score 3-5 (age-adjusted IPI 2-3 if ≤60 years), Eastern Cooperative Oncology Group performance status 0-2, and a time from diagnostic biopsy to start of treatment within 28 days (Figure 2). Patients will be randomized 1:1 to receive six 21-day cycles of either R-CHOP + tafasitamab (12 mg/kg IV, Days 1, 8, and 15) + LEN (25 mg orally, Days 1-10) in the experimental arm or R-CHOP + tafasitamab placebo (0.9% saline solution IV, Days 1, 8, and 15) + LEN placebo (orally, Days 1-10) in the control arm. Patients will be followed for safety and efficacy up to 60 months after the treatment ends. The primary endpoint is investigator-assessed PFS. Secondary endpoints include investigator-assessed event-free survival, OS, safety, and tafasitamab serum concentration (trough and Cmax levels). The sensitivity and specificity of minimal residual disease (MRD) for early detection of disease progression is an exploratory endpoint; further MRD parameters may also be investigated. The study is funded by MorphoSys AG and conducted with the scientific support of members of the Fondazione Italiana Linfomi and the German Lymphoma Alliance. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

First-Mind: Primary Analysis from a Phase Ib, Open-Label, Randomized Study to Assess Safety of Tafasitamab or Tafasitamab + Lenalidomide in Addition to R-CHOP in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma

First-Mind: Primary Analysis from a Phase Ib, Open-Label, Randomized Study to Assess Safety of Tafasitamab or Tafasitamab + Lenalidomide in Addition to R-CHOP in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma

Conversion to Biosimilar Pegfilgrastim-Jmdb from Pegfilgrastim with on-Body Injector Device in Diffuse Large B-Cell Lymphoma: Simulation Modeling of Cost-Savings and Budget-Neutral Expanded Access to Prophylaxis and Anti-Neoplastic Therapy Considering Device Failure Rate

Introduction: Approvals of biosimilar pegfilgrastim products in recent years have reduced the costs of single-dose prophylaxis of chemotherapy-induced (febrile) neutropenia (CIN/FN). While reference pegfilgrastim with on-body injector (PEG-OBI) offers convenience to patients over use of next day pre-filled syringe (PFS), PEG-OBI has a reported failure rate of 1.7-6.9% that predisposes patients to increased risk of CIN/FN episodes. Incremental FN-related hospitalizations (FN-HOSP) associated with PEG-OBI failure contribute to the cost differential between PEG-OBI and assured prophylaxis with biosimilar PEG-PFS. Cost savings generated from conversion to biosimilar PEG-jmdb create opportunities for providing expanded access on a budget-neutral basis to additional CIN/FN prophylaxis or anti-neoplastic treatment. Hence, in a panel of 15,000 patients with diffuse large B-cell lymphoma (DLBCL), we aimed to: 1) quantify the cost-savings from assured prophylaxis with biosimilar PEG-jmdb over PEG-OBI accounting for device failures, 2) simulate the additional CIN/FN prophylaxis that could be achieved from the cost-savings, and 3) model the expanded access to anti-neoplastic treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) that could be provided on a budget-neutral basis through reallocation of cost-savings. Methods: Simulation analysis in a panel of 15,000 DLBCL patients at risk for CIN/FN from the US payer perspective utilized. Costs of medication were based on Q1 2020 average selling price (ASP) for PEG-OBI, PEG-jmdb, and R-CHOP drugs derived from CMS Q3 2020 reimbursement limits; cost of PEG-OBI and PEG-jmdb administration per CMS Outpatient Prospective Payment System; between one and six cycles of prophylaxis; conversion rates from PEG-OBI to biosimilar PEG-jmdb ranging from 10% to 100%; and PEG-OBI failure rates of 1% to 7%. Differential base rate of FN-HOSP in NHL (rate of FN-HOSP without colony-stimulating factor [CSF] minus rate with CSF) was 10.03% over a 6-cycle regimen with 56% occurring in cycle 1 (Chrischilles et al., Cancer Control 2002; 13.25% with CSF, 23.28% without). FN-HOSP costs in 2012 of $25,676 per episode for NHL patients (Tai, J Oncol Pract 2017) were adjusted per the Consumer Price Index for Medical Care to $31,914 for 2020. Results: Conversion from PEG-OBI to biosimilar PEG-jmdb in a panel of 15,000 DLBCL patients generated savings ranging from $379,230 (for one cycle of prophylaxis at 10% conversion) to $22,753,800 (6 cycles at 100%) considering the cost of medication plus administration. These cost-savings could provide access to between 110 (1 cycle at 10% conversion) and 6,623 (6 cycles at 100%) additional cycles of PEG-jmdb on a budget-neutral basis, or between 58 and 3,452 cycles of R-CHOP, respectively. Taking incremental FN-HOSP costs due to PEG-OBI failure into consideration, cost-savings in cycle one from conversion to PEG-jmdb, ranged from $406,118 (at 10% conversion and PEG-OBI failure of 1%) to $5,674,454 (at 100% conversion and 7% PEG-OBI failure). These savings translated into expanded access to between 118 additional cycles of PEG-jmdb or 62 cycles of R-CHOP (at 10% conversion and 1% PEG-OBI failure) and 1,652 cycles of PEG-jmdb or 861 cycles of R-CHOP (at 100% conversion and 7% PEG-OBI failure). Over a 6-cycle regimen, savings increase to $2,323,394 (at 10% conversion and 1% PEG-OBI failure) to $26,114,789 (at 100% conversion and 7% PEG-OBI failure). These additional savings increased expanded access to PEG-jmdb to between 676 additional cycles of PEG-jmdb or 353 cycles of R-CHOP (at 10% conversion and 1% PEG-OBI failure) and 7,601 cycles of PEG-jmdb or 3,962 cycles of R-CHOP (at 100% conversion and 7% PEG-OBI failure). Conclusions: CIN/FN prophylaxis with biosimilar PEG-jmdb generates substantial cost savings compared to PEG-OBI when considering drug and administration costs. Savings further increase when the costs of FN-HOSP related to PEG-OBI failure are taken into account. Reallocation of savings realized through conversion to biosimilar pegfilgrastim-jmdb provide expanded access to additional CIN/FN prophylaxis and anti-neoplastic treatment on a budget-neutral basis while reducing risk and associated hospitalization costs associated with inadequate prophylaxis due to device failure. Disclosures McBride: Coherus BioSciences: Consultancy, Speakers Bureau; Merck: Speakers Bureau; Pfizer: Consultancy; Sandoz: Consultancy; MorphoSys: Consultancy; Bristol-Myers Squibb: Consultancy. MacDonald:Sandoz: Consultancy; Coherus BioSciences: Research Funding; Mylan: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Rockwell Medical: Consultancy; Terumo: Consultancy; Celgene: Consultancy; MorphoSys: Consultancy. Abraham:Sandoz: Consultancy; Mylan: Consultancy; Janssen: Consultancy; Rockwell Medical: Consultancy; Terumo: Consultancy; Celgene: Consultancy; Coherus BioSciences: Research Funding, Speakers Bureau; MorphoSys: Consultancy.

Switching Fractioned R-CHOP Cycles to Standard R-CHOP Cycles Guided by Endoscopic Ultrasonography in Treating Patients with Primary Gastric Diffuse Large B-Cell Lymphoma.

BackgroundPrimary gastric diffuse large B-cell lymphoma (PG-DLBCL) is a common subtype of extranodal non-Hodgkin lymphoma (NHL), with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) as the commonly used treatment regimen. However, full cycles of standard R-CHOP present the risk of severe bleeding or perforation, even leading to emergency surgery, especially for those with deep lesions in their first 1–2 cycles of treatment. This study aims to explore the safety and efficacy of fractioned R-CHOP (rituximab d0, 50% dose of CHOP d1 and d5) followed by standard R-CHOP cycles in PG-DLBCL patients guided by endoscopic ultrasonography (EUS).Patients and MethodsThirty-one PG-DLBCL patients were analyzed in this retrospective study. All patients had lesions infiltrated to at least the 3rd layer of the stomach under EUS at baseline. Patients switched to standard R-CHOP if they showed the reduced infiltrated layers and restricted lesions after fractioned R-CHOP cycles.ResultsThe overall response rate, 5-year progression-free survival (PFS) and overall survival (OS) of patients in our study were 93.5%, 75% and 84%, respectively. No treatment delay or dosage reduction from gastric adverse event was observed. None of the patients in our study suffered from severe bleeding or perforation during the treatment. Kaplan–Meier analyses showed that PG-DLBCL patients characterized by multiple localization, lesions ≥3cm, having B symptoms, lower serum albumin level, and elevated LDH level were associated with worse PFS and OS.ConclusionOur data indicate that it might be an effective approach in treating deeply infiltrated PG-DLBCL patients by switching fractioned R-CHOP to standard R-CHOP cycles guided by EUS.

Treatment of primary gastric lymphoma

Stomach is the most common location of lymphoma in digestive tract, accounting for 50%-60% of gastrointestinal lymphomas. The most common histological types are low malignant mucosa-associated lymphoid tissue (MALT) lymphoma from non-Hodgkin lymphoma (NHL) and diffuse large B-cell and marginal zone B-cell lymphoma (DLBCL) from NHL. Chronic gastritis secondary to Helicobacter pylori(HP) infection has been considered a major predisposing factor for MALT lymphoma. At present, the most widely accepted initial therapy for localized disease is aimed at the eradication of HP using regimens combining antibiotics and proton-pump inhibitors. The irradiation has become the therapy of choice for patients with early stage MALT lymphoma without HP infection or with persistent lymphoma following antibiotic therapy. In all the patients with advanced disease, treatment options include chemotherapy and the use of monoclonal antibodies. Treatment of DLBCL in stomach is based on aggressive poly-chemotherapy that is usually combined with rituximab. The same guidelines followed for nodal aggressive lymphoma can also be applied to gastric lymphoma with aggressive histology as DLBCL. For localized stages (stages I( and II(), these guidelines suggest front-line therapy with 3 to 4 cycles of standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) followed by radiotherapy. Advanced stage patients (stage IIII() usually undergo only 6 to 8 cycles of R-CHOP in order to obtain a complete remission rate. Nowadays surgery is limited to rare cases and radiotherapy combined or not with chemotherapy represents an effective therapeutic option ensuring long-term, organ-salvage benefits mainly in aggressive histological types.

Prognostic analysis of DLBCL patients and the role of upfront ASCT in high-intermediate and high-risk patients.

The role of autologous stem cell transplantation (ASCT) as a frontline treatment in patients with diffuse large B cell lymphoma (DLBCL) who are in their first remission has not been fully elucidated in the rituximab era. We analyzed 272 DLBCL patients who received 4–6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) or R-CHOP followed by ASCT, from January 2005 to June 2013 in our institution. Multivariate analysis showed the none germinal center B cell (non-GCB) subtype (P=0.014, P=0.012) and International Prognostic Index (IPI) (3–5) (P=0.004, P=0.016) were independent unfavorable predictors of overall survival (OS) and progression-free survival (PFS), respectively. To investigate the treatment effect of upfront ASCT, we selected 94 high-intermediate and high-risk DLBCL patients who achieved complete remission after R-CHOP, with 41 in the ASCT and 53 in the non-ASCT groups. Survival analysis revealed patients who received upfront ASCT compared with those who did not had better OS (3-year OS: 74.5% vs. 50.4%, P=0.029) or PFS (3-year PFS: 59.6% vs. 32.1%, P=0.004), suggesting up-front ASCT following R-CHOP could improve the outcome of high-intermediate and high-risk DLBCL patients.

B-cell Function Gene Mutations in Diffuse Large B-cell Lymphoma: A Retrospective Cohort Study

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous subtype of non-Hodgkin lymphoma. In addition to clinical and immunophenotypic characteristics, recurrent gene mutations have recently been identified in patients with DLBCL using next-generation sequencing technologies. The aim of this study is to investigate the clinical relevance of B-cell function gene mutations in DLBCL. Clinical analysis was performed on 680 Chinese DLBCL patients (146 non-CR and 534 CR cases) treated with six cycles of 21-day R-CHOP (Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), alone or followed by two additional doses of rituximab consolidation on patients' own intention. Somatic mutations of B-cell function genes were further screened on 275 (71 non-CR and 204 CR) cases with available tumor samples by targeted sequencing, including genes involved in B-cell receptors (BCRs) pathway (CARD11, LYN, CD79A, and CD79B), Toll-like receptors (TLRs) pathway (MYD88), and tumor necrotic factor receptor (TNFR) pathway (TRAF2 and TNFAIP3). B-cell function gene mutations occurred in 44.0% (121/275) of DLBCL patients. The TLRs and TNFR related gene mutations were more frequently observed in non-CR patients (p=0.019 and p=0.032, respectively). BCRs related gene mutations, as well as revised IPI (R-IPI) and double BCL-2/MYC expression, were independently related to short progression-free survival in DLBCL after CR. The adverse prognostic effect of BCRs related gene mutations could be overcome by two additional doses of rituximab consolidation. These results highlight the molecular heterogeneity of DLBCL and identify a significant role of B-cell function gene mutations on lymphoma progression and response to rituximab in DLBCL.

The Diverse Clinical Presentations of Adrenal Lymphoma

ABSTRACT Objective: Adrenal lymphoma is a rare and aggressive form of non-Hodgkin lymphoma (NHL). We report 2 cases of adrenal lymphoma: one with typical symptoms of adrenal insufficiency, the other with the unusual presentation of symptomatic hypercalcemia from 1,25-dihydroxyvitamin D (1,25-[OH]2-D) excess. Methods: A comparison of the clinical presentation of 2 patients diagnosed with primary adrenal diffuse large B cell lymphoma (DLBCL) treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) is reported. Results: The first patient was a 72-year-old man who presented with weight loss, hypotension, and bilateral adrenal masses. He was diagnosed with adrenal insufficiency from stage IVB DLBCL with primarily adrenal involvement. Treatment with 6 cycles of R-CHOP led to near-complete regression of adrenal masses and clinical remission, but with continued need for adrenocortical hormone replacement. He eventually succumbed to recurrent DLBCL with brain metastasis. The seco...

Addition of Intermediate-Dose Methotrexate Is Beneficial in Terms of Both Progression-Free Survival and Overall Survival for Patients with Diffuse Large B Cell Lymphoma Receiving Either R-CHOP or CHOP

Introduction: Patients with diffuse large B cell lymphoma (DLBCL) and high International Prognostic Index (IPI) or extra-nodal disease are at an increased risk of systemic and central nervous system (CNS) relapse. Presently, the management of DLBCL patients at the Rambam Health Care Campus (Haifa, Israel) and Hadassah Medical Center (Jerusalem, Israel) includes 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) along with 4 doses of intrathecal (IT) methotrexate (MTX), which may be followed by 2 additional cycles of an intermediate dose (3 g/m2) of intravenousMTX (ID-MTX). The current study compared progression-free survival (PFS), overall survival (OS) and CNS relapse rate in a cohort of DLBCL patients with risk factors for CNS relapse who did or did not undergo prophylactic therapy with ID-MTX.Methods: Four hundred and eighty DLBCL patients treated at two tertiary care centers (Rambam and Hadassah) between the years 1991 and 2013 were retrospectively evaluated. The cohort included 224 females and 256 males at a median age of 58 years (range18-76). OS, PFS and CNS involvement at relapse were analyzed. The study incorporated all patients with the primary diagnosis of DLBCL and risk factors for CNS relapse, i.e., Waldeyer ring (2%), breast (1%), testicular (3%) or orbita (1%) involvement, bone marrow involvement (21%), stage IV disease (64%), LDH higher than normal (70%), ≥1 extra-nodal site (28%), IPI ≥3 (36%). Eight percent of patients had stage I-IE disease, 17% - stage II-IIE, 11% - stage III, 64% - stage IV, 29% had B symptoms. Patients with CNS involvement at diagnosis were excluded from the analysis.Results: Four hundred and seventy three patients (99%) were treated with either CHOP or CHOP-like regimen, and 384 (80%) patients received rituximab (R). In the R-CHOP cohort, 23% of patients with IPI 0/1, 28% with IPI 2 and 42% with IPI ≥3 were given prophylaxis. One hundred and thirty patients received ID-MTX (27%), 35 patients (7%) received IT-MTX only, while no prophylaxis was administered to 315 patients (66%). The cumulative incidence of CNS relapse at 5 years was 6%, with no difference in the incidence between the patients who received prophylaxis with ID-MTX, IT-MTX or were given no prophylaxis at all. Patients with IPI ≥3 treated with ID-MTX had a decreased overall relapse rate and significantly superior OS and PFS (Table 1; Figure 1).Conclusion: In the current study, the addition of two cycles of ID-MTX to the standard R-CHOP regimen resulted in improved 5-year PFS and OS of DLBCL patients with IPI ≥3. These data need to be further confirmed in a randomized controlled study. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Intermediate Dose Methotrexate Improves Overall Survival and Progression-Free Survival of Patients with Diffuse Large B Cell Lymphoma Treated with the R-CHOP or CHOP Regimen

Introduction: Patients (pts) with diffuse large B cell lymphoma (DLBCL) and high International Prognostic Index (IPI) or extra-nodal localization are at a higher risk for relapse with central nervous system (CNS) involvement. The current policy at the Rambam Health Care Campus (Haifa, Israel) is to give DLBCL pts 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) together with 4 doses of intrathecal (IT) methotrexate (MTX), which may be followed by 2 additional cycles of an intermediate dose (3 g/m2) of intravenous MTX (ID-MTX). The present study aimed to compare the outcome of DLBCL pts with risk factors for CNS relapse who did or did not receive prophylaxis with ID-MTX.Methods: We retrospectively evaluated a cohort of DLBCL pts treated at Rambam between the years 1991 and 2012. Overall survival (OS), progression-free survival (PFS) and CNS involvement at relapse were estimated in 203 of 355 pts [96 females, 107 males; median age 59 (range18-90) years]. The study included all pts with the primary diagnosis of DLBCL and risk factors for CNS relapse, i.e., Waldeyer ring (5%), breast (2%), testicular (3%), orbital (1%) involvement, bone marrow involvement (25%), stage IV disease (63%), LDH > normal (68%), ≥1 extra-nodal site (26%), IPI ≥3 (41%). Ten percent of pts had stage I-IE disease, 15% - stage II-IIE, 12% - stage III, 63% - stage IV, 38% had B symptoms. Pts with CNS involvement at diagnosis were excluded from the study.Results: One hundred and fifty patients (74%) were treated with R-CHOP. In this group, 40% of pts with IPI=0/1, 29% with IPI=2 and 47% with IPI ≥3 received ID-MTX prophylaxis. Sixty four pts received ID-MTX (32%), 14 pts (7%) received IT MTX only, 125 pts had no prophylaxis (62%). At a median follow-up of 92 months, 5% of pts had CNS relapse with no difference in incidence between the study groups. Pts with IPI≥3 treated with ID-MTX had a reduced overall relapse rate and significantly better PFS and OS (table 1).Conclusion: The addition of 2 cycles of ID-MTX to the R-CHOP regimen improved both PFS and OS of DLBCL pts with IPI≥3. A randomized controlled study is warranted to provide stronger evidence.Table 1All patientsPts No.PFS %P*HR95% CIPOS %#HR95% CIID-MTX65601881IT MTX15560.091.920.9-4.10.008433.271.4-7.8No prophylaxis123420.041.581.0-2.490.002512.491.4-4.4R-CHOP DataIPI≥3 no prophylaxis35201261IPI≥3 +ID-MTX31580.0040.380.29-0.850.001670.290.14-0.6No.: number; *HR: hazard ratio for progression; #HR for mortality; CI: confidential interval DisclosuresNo relevant conflicts of interest to declare.

Bortezomib-Based Therapy for Newly Diagnosed Mantle-Cell Lymphoma

BackgroundThe proteasome inhibitor bortezomib was initially approved for the treatment of relapsed mantle-cell lymphoma. We investigated whether substituting bortezomib for vincristine in frontline therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) could improve outcomes in patients with newly diagnosed mantle-cell lymphoma.MethodsIn this phase 3 trial, we randomly assigned 487 adults with newly diagnosed mantle-cell lymphoma who were ineligible or not considered for stem-cell transplantation to receive six to eight 21-day cycles of R-CHOP intravenously on day 1 (with prednisone administered orally on days 1 to 5) or VR-CAP (R-CHOP regimen, but replacing vincristine with bortezomib at a dose of 1.3 mg per square meter of body-surface area on days 1, 4, 8, and 11). The primary end point was progression-free survival.ResultsAfter a median follow-up of 40 months, median progression-free survival (according to independent radiologic review) was 14.4 months in the R-CHOP group versus 24.7 months in the VR-CAP group (hazard ratio favoring the VR-CAP group, 0.63; P<0.001), a relative improvement of 59%. On the basis of investigator assessment, the median durations of progression-free survival were 16.1 months and 30.7 months, respectively (hazard ratio, 0.51; P<0.001), a relative improvement of 96%. Secondary end points were consistently improved in the VR-CAP group, including the complete response rate (42% vs. 53%), the median duration of complete response (18.0 months vs. 42.1 months), the median treatment-free interval (20.5 months vs. 40.6 months), and the 4-year overall survival rate (54% vs. 64%). Rates of neutropenia and thrombocytopenia were higher in the VR-CAP group.ConclusionsVR-CAP was more effective than R-CHOP in patients with newly diagnosed mantle-cell lymphoma but at the cost of increased hematologic toxicity. (Funded by Janssen Research and Development and Millennium Pharmaceuticals; LYM-3002 ClinicalTrials.gov number, NCT00722137.)

PP-082 DELAYED ENGRAFTMENT DUE TO CANDIDA NORVEGENSIS IN HDC AND SCT PATIENT

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous subtype of non-Hodgkin lymphoma. In addition to clinical and immunophenotypic characteristics, recurrent gene mutations have recently been identified in patients with DLBCL using next-generation sequencing technologies. The aim of this study is to investigate the clinical relevance of B-cell function gene mutations in DLBCL. Clinical analysis was performed on 680 Chinese DLBCL patients (146 non-CR and 534 CR cases) treated with six cycles of 21-day R-CHOP (Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), alone or followed by two additional doses of rituximab consolidation on patients' own intention. Somatic mutations of B-cell function genes were further screened on 275 (71 non-CR and 204 CR) cases with available tumor samples by targeted sequencing, including genes involved in B-cell receptors (BCRs) pathway (CARD11, LYN, CD79A, and CD79B), Toll-like receptors (TLRs) pathway (MYD88), and tumor necrotic factor receptor (TNFR) pathway (TRAF2 and TNFAIP3). B-cell function gene mutations occurred in 44.0% (121/275) of DLBCL patients. The TLRs and TNFR related gene mutations were more frequently observed in non-CR patients (p = 0.019 and p = 0.032, respectively). BCRs related gene mutations, as well as revised IPI (R-IPI) and double BCL-2/MYC expression, were independently related to short progression-free survival in DLBCL after CR. The adverse prognostic effect of BCRs related gene mutations could be overcome by two additional doses of rituximab consolidation. These results highlight the molecular heterogeneity of DLBCL and identify a significant role of B-cell function gene mutations on lymphoma progression and response to rituximab in DLBCL.

PP-083 SECONDARY ALL IN MULTIPLE MYELOMA PATIENT WHO UNDERWENT HDC AND SCT

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous subtype of non-Hodgkin lymphoma. In addition to clinical and immunophenotypic characteristics, recurrent gene mutations have recently been identified in patients with DLBCL using next-generation sequencing technologies. The aim of this study is to investigate the clinical relevance of B-cell function gene mutations in DLBCL. Clinical analysis was performed on 680 Chinese DLBCL patients (146 non-CR and 534 CR cases) treated with six cycles of 21-day R-CHOP (Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), alone or followed by two additional doses of rituximab consolidation on patients' own intention. Somatic mutations of B-cell function genes were further screened on 275 (71 non-CR and 204 CR) cases with available tumor samples by targeted sequencing, including genes involved in B-cell receptors (BCRs) pathway (CARD11, LYN, CD79A, and CD79B), Toll-like receptors (TLRs) pathway (MYD88), and tumor necrotic factor receptor (TNFR) pathway (TRAF2 and TNFAIP3). B-cell function gene mutations occurred in 44.0% (121/275) of DLBCL patients. The TLRs and TNFR related gene mutations were more frequently observed in non-CR patients (p = 0.019 and p = 0.032, respectively). BCRs related gene mutations, as well as revised IPI (R-IPI) and double BCL-2/MYC expression, were independently related to short progression-free survival in DLBCL after CR. The adverse prognostic effect of BCRs related gene mutations could be overcome by two additional doses of rituximab consolidation. These results highlight the molecular heterogeneity of DLBCL and identify a significant role of B-cell function gene mutations on lymphoma progression and response to rituximab in DLBCL.

Rituximab-induced pneumonitis mimicking miliary tuberculosis

To the Editor: Rituximab, a chimeric anti-CD20 monoclonal antibody, is commonly being used in combination with chemotherapy regimens in the standard treatment of B-cell non-Hodgkin lymphoma (NHL) [1]. Rituximab is considered to be a relatively safe drug but recently, severe and fatal interstitial lung disease (ILD) was noted with an occurrence rate of 0.01–0.03% [2]. Computed tomography (CT) patterns of rituximab-induced ILD include focal (54%) or diffused (9%) alveolar patterns and macronodules (3%), or ground-glass patterns (34%) [2]. In this regard, we report a patient with NHL in whom ILD developed after six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) therapy with diffused micronodules mimicking miliary tuberculosis (TB). …

Radioimmunotherapy with (131)i-rituximab in a patient with diffuse large B-cell lymphoma relapsed after treatment with (90)y-ibritumomab tiuxetan.

We report a case that demonstrates the efficacy of radioimmunotherapy (RIT) with radioiodinated rituximab ((131)I-rituximab) for relapsed diffuse large B-cell lymphoma (DLBCL). A 79-year-old male patient with DLBCL initially achieved a complete response (CR) after six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) therapy. However, the lymphoma relapsed 20months later. Although the patient had achieved a second and a third CR after two cycles of (90)Y-ibritumomab tiuxetan, he experienced a third relapse approximately 3years later. Between March and June 2011, the patient received three cycles of (131)I-rituximab. Although he had achieved partial response after the second cycle, the disease progressed after the third cycle, and the total progression-free survival was thus 5months. The patient suffered only relatively mild toxicity (grade 1 thrombocytopenia) during treatment. RIT with (131)I-rituximab is therefore potentially effective in patients with relapsed DLBCL, even after the failure of (90)Y-ibritumomab tiuxetan therapy.

Anti-Myelin Associated Glycoprotein Polyneuropathy in a Patient With Lymphoma and its Resolution After Chemotherapy

Anti-myelin associated glycoprotein (anti-MAG) antibody associated polyneuropathy is a chronic distal symmetric sensorimotor neuropathy. The rarity of this condition precludes establishment of a standard of care. It has been treated with steroids, intravenous immunoglobulin (IVIG) and Rituximab. We present a case of a 72 years old man presenting with 1 year history of neuropathic pain in lower extremities and hands bilaterally, right cervical lymphadenopathy on physical exam, and the anti-MAG antibody ELISA was positive. An excisional biopsy of the cervical lymph node showed diffuse large B cell lymphoma. The staging bone marrow examination did not show lymphoma involvement, the PET/CT did only demonstrated neck and mediastinal lymphadenopathy. The patient received four cycles of R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone) for Stage IIA disease with complete response, and complete resolution of polyneuropathy after the first cycle of chemotherapy. The case report highlights the successful treatment of a rare presentation of anti-MAG polyneuropathy associated with early stage diffuse large B-cell lymphoma. J Med Cases. 2013;4(8):557-559 doi: https://doi.org/10.4021/jmc1399w

Neurolymphomatosis of Brachial Plexus in Patients with Non-Hodgkin's Lymphoma

Neurolymphomatosis (NL) is a rare clinical disease where neoplastic cells invade the cranial nerves and peripheral nerve roots, plexus, or other nerves in patients with hematologic malignancy. Most NL cases are caused by B-cell non-Hodgkin's lymphoma (NHL). Diagnosis can be made by imaging with positron emission tomography (PET) and magnetic resonance imaging (MRI). We experienced two cases of NL involving the brachial plexus in patients with NHL. One patient, who had NHL with central nervous system (CNS) involvement, experienced complete remission after 8 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy but relapsed into NL of the brachial plexus 5 months later. The other patient, who suffered from primary central nervous system lymphoma (PCNSL), had been undergoing chemoradiotherapy but progressed to NL of the brachial plexus.

Impact of [18F]Fluorodeoxyglucose Positron Emission Tomography Response Evaluation in Patients With High–Tumor Burden Follicular Lymphoma Treated With Immunochemotherapy: A Prospective Study From the Groupe d'Etudes des Lymphomes de l'Adulte and GOELAMS

[(18)F]Fluorodeoxyglucose positron emission tomography (PET) is widely used for the staging and restaging of patients with aggressive lymphoma, but less is known about the utility of PET in patients with follicular lymphoma (FL). In a prospective study, we evaluated the prognostic value of PET performed during treatment and at the end of treatment in 121 patients with FL treated with first-line immunochemotherapy. Patients with previously untreated high-tumor burden FL were treated with six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) plus two cycles of rituximab, without rituximab maintenance. PET was performed before treatment, after four cycles of R-CHOP (interim PET), and at the end of treatment (final PET). PET scans were centrally reviewed. The total number of patients included was 121. Median age was 57 years. After central review, interim PET (n = 111) was negative in 76% of patients, and final PET (n = 106) was negative in 78%. With a median follow-up of 23 months, 2-year progression-free survival rates were 86% for interim PET-negative versus 61% for interim PET-positive patients (P = .0046) and 87% for final PET-negative versus 51% for final PET-positive patients (P < .001), respectively. Two-year overall survival also significantly differed according to final PET results: 100% versus 88% (P = .0128). PET performed either after four cycles of R-CHOP or at the end of therapy was strongly predictive of outcome in this prospective study. Therapeutic intervention based on PET results during or after inductive treatment should be evaluated.