Dose-adjusted EPOCH-rituximab Research Articles

Dose-adjusted EPOCH-rituximab or intensified B-NHL therapy for pediatric primary mediastinal large B-cell lymphoma.

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Complications Associated With Dose-adjusted EPOCH-rituximab Therapy for Non-Hodgkin Lymphoma

IntroductionCertain aggressive non-Hodgkin lymphoma subtypes are increasingly being treated with infusional DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab), which requires a central venous catheter. This study aims to identify the rates and predictors of line-associated complications (LACs) associated with DA-EPOCH-R therapy in NHL. Patients and MethodsWe retrospectively identified all patients treated with DA-EPOCH-R at our institution between March 2011 and July 2016. We also identified a concurrent cohort of patients with diffuse large B-cell lymphoma treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). ResultsForty-three patients received DA-EPOCH-R during the study period; 17 (39.5%; 95% confidence interval, 0.25-0.56) patients experienced at least 1 LAC (including venous thromboembolism, chemotherapy extravasation, and line-associated infection). Forty-four patients received R-CHOP during the study period; 8 (18.2%; 95% confidence interval, 0.08-0.32) patients experienced at least 1 complication. Compared with the R-CHOP cohort, patients treated with DA-EPOCH-R experienced a significantly higher rate of these complications (P = .03). In the DA-EPOCH-R cohort, grade 3 toxicity was seen in 41% (7/17). In univariate analysis, body mass index ≥ 35 kg/m2 and using a peripherally inserted central catheter line were significantly associated with an increased risk of venous thromboembolism (P = .04 and P = .02, respectively). ConclusionsForty percent of patients receiving DA-EPOCH-R therapy developed LACs, almost one-half of whom experienced grade 3 toxicities. The complication rate was significantly greater in patients undergoing therapy with DA-EPOCH-R compared with those undergoing R-CHOP therapy. Clinicians need to balance these risks when selecting therapy. Future studies are needed to evaluate prophylactic anticoagulation strategies in this population.

Female fertility following dose-adjusted EPOCH-R chemotherapy in primary mediastinal B-cell lymphomas

We assessed fertility/gonadal function in premenopausal women treated with dose-adjusted EPOCH-Rituximab for untreated primary mediastinal B-cell lymphoma (PMBL). Eligible patents were ≤ 50 years and premenopausal. Serial reproductive histories were obtained and hormonal assays were performed on serum samples before, at the end of treatment and 4–18 months later. Twenty-eight eligible women had a median age (range) of 31 (21–50) years and were followed a median of 7.3 years. Of 23 patients who completed a questionnaire, 19 (83%) were and four were not menstruating prior to chemotherapy. Amenorrhea developed in 12 patients during chemotherapy. At > 1-year follow-up, 14/19 (74%) patients were menstruating, all < 35 years old, and six (43%) of these patients delivered healthy children. Hormonal assays showed ovarian dysfunction during chemotherapy in all patients with varying recovery at 4–18 months after treatment. Fertility was preserved in most women with ovarian failure confined to patients > 40 years old.

Addition of R-HMA to R-DA-EPOCH Favourably Changes the Outcome in Patients with Untreated High-Grade Diffuse Large B-Cell Lymphoma: The First Results of Russian Prospective Multicenter Trial

Background: Approximately 50% of diffuse large B-cell lymphomas (DLBCL) are defined as high-grade by IPI. They are characterized by aggressive course and poor response to standard chemotherapy (CT): 5-years overall survival (OS) rate of less than 30%. R-DA-EPOCH has demonstrated very optimistic results (overall and progression-free survival (PFS) were 90%), but high-risk patients (IPI 3-4) showed only 43% of OS and PFS [1]. The addition of high-dose AraC (12 g/m2) to the upfront therapy of high-risk DLBCL has significantly improved the outcome on Hyper-CVAD/HMA and mNHL-BFM-90 protocols [2, 3]. But high toxicity of these protocols restricts their application. We suggested that addition of courses R-HMA in rotation with R-DA-EPOCH could improve the treatment outcome and decrease toxicity.Aim: To evaluate the efficacy and toxicity of R-DA-EPOCH/R-HMA protocol in patients with untreated high-grade diffuse large B-cell lymphoma.Patients and Methods: 33 untreated DLBCL patients from 4 centers were enrolled in a prospective study between August 2013 - July 2015; stage II-IV; ECOG 0-3; median age 55 years (27-76); age ≥60y/<60y 50%/50%; M/F 60%/40%; IPI: 48% high-intermediate and 52% high risk; 15% with bone marrow involvement. All patients underwent 4-8 courses (2-4 cycles) of chemotherapy: R-DA-EPOCH (standard dose and scheme), R-HMA (R 375 mg/m2 d1, MTX 1000 mg/m2 24 hours d 2, AraC 3000 mg/m2 q 12 hrs d 3-4). For patients older than 60 year dose of R-HMA was reduced (R 375 mg/m2 d1, MTX 500 mg/m2 24 hours d 2, AraC 1000 mg/m2 q 12 hrs d 3-4). In 4 cases of DLBCL with bone marrow involvement BEAM conditioning and autologous stem cell transplantation were applied.Results: The median follow-up is 12 months (4-24). There was no mortality associated with toxicity. The main non-hematological toxicities of R-HMA were infections (mucositis, pneumonia, sepsis, enteropathy) grades 1-2 and 3-4 in 90% and 10%, respectively. Hematological toxicity grade 4 for less than 4 days we observed only after courses R-HMA. Complete remission (CR) was achieved in 29 (88%) patients. In 2 patients we observed progression of the disease after first cycle of chemotherapy, in another 2 cases - partial remission after 2-3 cycles and following progression of disease. In patients older than 60 years with doses reduction in R-HMA failures were absent, except one later relapse after 13 month CR.With a median follow 12 months overall and disease-free survival of 33 patients constituted 90,5% and 74% , respectively. In a group of patients older than 60 years results of therapy seemed to be better than in young patients: OS were 100% vs 85,6% (p=0,1), DFS were 80% vs 74,9% (p=0,2), respectively. So the combination of R-DA-EPOCH/R-HMA may be considered as optimal intensive approach in the older patients.Conclusions: TheR-DA-EPOCH/R-HMA protocol demonstrated acceptable toxicity and high efficacy in patients with high-grade DLBCL. This protocol has shown optimistic results in the elderly patients and it could be recommended for further investigation in that group.Ññûëêè:1. Salit RB, Fowler DH, Wilson WH, et al. Dose-adjusted EPOCH-rituximab combined with fludarabine provides an effective bridge to reduced-intensity allogeneic hematopoietic stem-cell transplantation in patients with lymphoid malignancies.J Clin Oncol. 2012. 10;30(8):830-6.2. Oki Y, Westin JR, Vega F, et al. Prospective phase II study of rituximab with alternating cycles of hyper-CVAD and high-dose methotrexate with cytarabine for young patients with high-risk diffuse large B-cell lymphoma. Br J Haematol 2013; 163(5):611-20.3. Magomedova AU, Kravchenko SK, Kremenetskaia AM, et al. Nine-year experience in the treatment of patients with diffuse large B-cell lymphosarcoma. Ter Arkh. 2011;83(7):5-10. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Study On The Fertility Status Of Females With Primary Mediastinal B-Cell Lymphoma Following Treatment With Dose-Adjusted EPOCH-Rituximab

BackgroundIn young females with lymphoma, the impact of immunochemotherapy on fertility status has been poorly studied. Primary mediastinal B-cell lymphoma (PMBL) predominantly affects young females and is highly curable with the dose-adjusted EPOCH-rituximab (DA-EPOCH-R) regimen (Dunleavy et al., NEJM 2013:368;1408). We therefore identified this group of PMBL patients as an excellent population to study fertility status and evaluated the impact of DA-EPOCH-R on gonadal function of females aged 50 years or less. MethodsA questionnaire was first mailed to 27 patients, and this was followed by a semi-structured phone interview to obtain information on patients' medical and gynecologic/obstetric histories before PMBL diagnosis, during treatment and after its completion. Serum estradiol (E2), luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels were analyzed before commencing chemotherapy, following 5-6 cycles of DA-EPOCH-R, and 10-18 months after treatment completion. ResultsAll patients included in the study completed 6-8 cycles of DA-EPOCH-R and were in complete remission from PMBL at a median follow-up of 63 months. Median age at diagnosis was 30.5 years (r 21-50). Twenty-three patients participated in the questionnaire. Prior to chemotherapy, twenty of twenty-three were menstruating, three patients were not. Of the twenty menstruating patients treated with DA-EPOCH-R three were unsure of their menstrual histories during chemotherapy, fourteen (70%) developed amenorrhea and three (15%), all younger than 25 years, continued to menstruate. After completion of chemotherapy, fifteen of the twenty patients (75%) had menstrual periods. All were 35 years or younger. Five patients (25%) remained amenorrheic following completion of chemotherapy, however one had a hysterectomy shortly after treatment completion. To date six of twenty (30%) patients have conceived naturally and delivered healthy children with nine not yet desiring motherhood.On laboratory evaluations performed before treatment, after 5-6 cycles of DA-EPOCH-R and 10-18 months after completion of chemotherapy, median serum LH levels were 2.5, 33.4 and 4.6 U/L respectively, median FSH values at the same time points were 3.6, 69.5 and 8 U/L, while median E2 levels were 24.4, <5 and 16.7 pg/mL, time courses consistent with transient ovarian damage from chemotherapy, but with recovery at a median follow-up of 12 months. Eight patients, who were 40 years or older were treated with DA-EPOCH-R. The median endocrine laboratory parameters of six of these patients, who had clinically normal ovarian function prior to treatment were examined at the indicated time points and were as follows: LH: 2.6, 36.4, 26.7 U/L; FSH: 6.4, 102.8, 83.9 U/L; E2: 68.8, <5, <5 pg/mL, a pattern consistent with premature menopause. ConclusionFertility appears to be preserved in female PMBL patients receiving DA-EPOCH-R, particularly in those less than 40 years old. The risk of premature menopause seems to be confined to patients over 40 years of age. Further analysis of ovarian reserve in patient younger than 40 years, measuring Anti-Muellerian hormone and inhibin-B pre- and post-treatment, is ongoing. Disclosures:No relevant conflicts of interest to declare.

Dose-Adjusted EPOCH-Rituximab Combined With Fludarabine Provides an Effective Bridge to Reduced-Intensity Allogeneic Hematopoietic Stem-Cell Transplantation in Patients With Lymphoid Malignancies

There is currently no standard chemotherapy regimen for patients with lymphoid malignancies being considered for reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation (RIC-alloHSCT). The ideal regimen would provide disease control and result in lymphocyte depletion to facilitate engraftment. To this end, we developed a novel regimen by adding fludarabine to dose-adjusted continuous-infusion etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus with or without rituximab (DA-EPOCH-F/R). One hundred forty-seven patients with lymphoid malignancy (median age, 50 years) who had heavily pretreated (median prior regimens, three) and chemo-refractory (47%) disease were treated with DA-EPOCH-F/R before RIC-alloHSCT. Patients received one to three consecutive cycles until achieving lymphocyte depletion (CD4(+) count < 200/μL) or progressive disease. Overall response rate was 41%; 39% of patients had stable disease. Toxicity included grade 4 neutropenia in 65% and thrombocytopenia in 25% of patients. DA-EPOCH-F/R resulted in lymphocyte depletion (P < .001), which was inversely associated with serum interleukin (IL) 7 and IL-15 levels. Of 147 patients, 143 patients proceeded to RIC-alloHSCT. Patients with lower CD3(+) (P < .001), CD4(+) (P < .001), and CD8(+) (P < .001) T-cell counts after DA-EPOCH-F/R were more likely to achieve full donor lymphoid chimerism by day +14 after transplant. Relative to nonresponders to DA-EPOCH-F/R, patients with complete and partial response had increased event-free survival (77.4 v 4.8 months; P < .001) and overall survival (98.5 v 16.2 months; P < .001). DA-EPOCH-F/R safely provides tumor cytoreduction and lymphocyte depletion, thereby offering a bridge to RIC-alloHSCT in patients with aggressive lymphoid malignancies.

Recommendation of CHOP-Rituximab/More Intensive Regimen Such as Dose-Adjusted EPOCH-Rituximab for Cyclin D1 Expression in DLBCL

Recommendation of CHOP-Rituximab/More Intensive Regimen Such as Dose-Adjusted EPOCH-Rituximab for Cyclin D1 Expression in DLBCL

Efficacy and toxicity of dose-adjusted EPOCH-rituximab in adults with newly diagnosed Burkitt lymphoma

8035 Background: Burkitt Lymphoma (BL) is a rare and highly aggressive lymphoma, characterized by a high tumor proliferation rate. While the standard therapy of BL is highly effective, it involves intensive, multi-agent chemotherapy that is associated with considerable treatment-related toxicity and mortality, especially in older patients. We hypothesized that the regimen DA-EPOCH may be effective in BL, based on the observation that it overcomes the adverse effect of high proliferation in diffuse large B-cell lymphoma. Methods: We investigated DA-EPOCH-rituximab (R) in untreated BL in an attempt to maintain the high cure rates of standard therapy with minimal treatment related toxicity. Eligible patients had a diagnosis of untreated BL and could be HIV negative or positive with HIV negative patients (n=13) receiving 6 cycles of DA-EPOCH-R as previously described (Blood 99: 2685, 2002) and HIV positive (n=6) patients receiving 3–6 cycles of DA- EPOCH-R for 1 cycle beyond CR for a minimum of 3 cycles. All patients received intrathecal methotrexate prophylaxis and outpatient therapy where possible. Results: The characteristics of 19 enrolled patients are: median age (range) 29 (18–66) and ECOG PS 1(1–3); stage III/IV 10 (53%); LDH &gt; N 11 (61%); male sex 15 (79%); extranodal sites 13 (68%) and ileocecal disease 13 (68%). No patients so far had CNS involvement at diagnosis. Response is CR/CRu in 100% of patients with one patient receiving consolidative radiotherapy to a site of residual disease. OS and PFS are both 100% and EFS 93.3% at a median potential follow-up time of 29 months. Toxicities were fever/neutropenia in 16%, grade 4 neutropenia in 47% and grade 3/4 thrombocytopenia in 22% of cycles. There was one case of tumor lysis syndrome and no treatment related deaths. Conclusions: DA-EPOCH-R is highly effective in BL. It appears to be associated with much lower toxicity compared to standard high-dose regimens and may significantly advance the therapeutic index of BL treatment. Accrual continues. No significant financial relationships to disclose.

Novel Treatment of Burkitt Lymphoma with Dose-Adjusted EPOCH-Rituximab: Preliminary Results Showing Excellent Outcome.

Burkitt Lymphoma (BL) is a highly proliferative lymphoma with a propensity to present in extranodal sites. Standard treatment for BL involves intensive, multi-agent chemotherapy that is highly effective but associated with considerable toxicity and treatment-related mortality, particularly in older patients. Based on the observation that DA-EPOCH overcomes the adverse effect of high proliferation in diffuse large B-cell lymphomas, we hypothesized it may be effective in BL. We have undertaken a study of DA-EPOCH-Rituximab in untreated BL in an attempt to maintain a high cure rate with low treatment related toxicity. Eligible patients had untreated BL and could be HIV positive or negative. HIV negative patients (n=13) received 6 cycles of DA-EPOCH-R as previously described (Blood 99: 2685, 2002). Patients with HIV-associated BL (n=4) received 3–6 cycles of DA-EPOCH-R for 1 cycle beyond CR for a minimum of 3 cycles. All patients received intrathecal methotrexate prophylaxis and therapy was administered in the outpatient clinic where possible. Characteristics of 17 patients include median age (range) 27 (18–66) and ECOG PS 1 (1–3); stage III/IV 9 (53%); LDH > N 9 (53%); male sex 13 (76%) and; extranodal sites 11 (65%). All 11 (65%) patients with extranodal disease had abdominal or pelvic involvement at diagnosis. No patients had central nervous system disease on presentation. Response is CR/CRu in 100% of patients. One patient received consolidative radiotherapy to a single site of residual disease. At a median potential follow-up of 28 months, OS and PFS are both 100% and EFS is 92.3%. Significant toxicities include fever/neutropenia in 16%, grade 4 neutropenia in 47% and grade 3/4 thrombocytopenia in 22% of cycles. There were no treatment related deaths and no tumor lysis syndrome. In conclusion, DA-EPOCH-R appears to be highly effective with relatively low toxicity compared to standard intensive high-dose regimens for BL. Infusional chemotherapy may reduce or eliminate the risk of tumor lysis syndrome. Accrual continues. [Display omitted]

Non-Hodgkin's Lymphoma in Job's Syndrome: A Case Report and Literature Review

Job's or hyper immunoglobulin E recurrent infection syndrome (Hyper-IgE syndrome) is a rare, often inherited multisystem disorder, characterized by cutaneous abscesses, pneumonia, elevated IgE levels and skeletal defects. We report a case of a 22-year-old man with Job's syndrome who presented with back pain. He was found to have diffuse large B-cell lymphoma involving his second lumbar vertebrae and spleen. Treatment with dose-adjusted EPOCH-rituximab (DA-EPOCH-R) chemotherapy achieved a complete remission after 4 cycles. A review of reported cases of lymphoma in Job's syndrome indicates an increase in relative risk of 259 (95% confidence interval 102, 416). The cause of the increased risk has yet to be defined but has similarities to a pathogenetic model of AIDS related lymphoma. In previous reports of lymphoma in Job's syndrome, patients presented with extranodal disease and had poor outcomes. With appropriate chemotherapy and hematological support, lymphoma associated with Job's syndrome can achieve complete remission.

Dose-Adjusted EPOCH-Rituximab Is Highly Effective in the GCB and ABC Subtypes of Untreated Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is subdivided by microarray into germinal center B-cell (GCB) and activated B-cell (ABC) subtypes. These subtypes have distinct pathways of lymphomagenesis and outcome with 5-year survival of 59% and 31%, respectively, using CHOP. A molecular predictor showed high tumor proliferation and the ABC subtype are associated with a poor outcome. We showed DA-EPOCH overcomes the adverse effects of high tumor proliferation (BLOOD 99:2685, 2002) and rituximab overcomes the adverse effects of BCL-2, which is associated with the ABC subtype (Proc Am Soc Heme 102:abstr 356, 2003). To assess DA-EPOCH-R with G-CSF in GCB and ABC subtypes, we employed a validated immunohistochemistry (IHC) algorithm (BLOOD: 103:275, 2004). GCB was defined as CD10+ or BCL-6+ and MUM1-. ABC was defined as CD10- and BCL-6- or CD10-, BCL-6+ and MUM1+. Eligibility includes de novo DLBCL, no prior chemotherapy, any PS, HIV- and stage I thymic DLBCL > 5 cm and all stage II-IV. Characteristics of 77 enrolled pts include median (range) age 48 (12-85) and PS 1 (0-3); stage III/IV 48 (62%); and LDH > nl 42 (55%); extranodal sites >1 27 (35%); and HI/H IPI 26 (34%). Including all 77 pts, response is CR/CRu 72 (94%). At the median (range) follow-up of 28 (4-60) mos, PFS is 82% and OS is 83% (Fig 1). DFS is 87% at 28 mos with no relapses beyond 18 mos. PFS at 28 mos according to IPI risk is 95% for 0-2 factors and 54% for 3-5 factors. Using IHC, 44 pts were subdivided in GCB (35) and ABC (9) subtypes. The proportion of the ABC subtype vs. GCS is low and likely due to incomplete IHC for the ABC subtype. Specifically, 16 cases that were CD10- did not have adequate BCL-6 and/or MUM1 IHC for categorization. PFS at 28 mos for the GCB and ABC subgroups were 84% and 62%, respectively (Fig 2). DA-EPOCH-R employs a pharmacodynamic design where doses of doxorubicin, etoposide and cyclophosphamide are adjusted (i.e. normalized) to achieve neutrophil nadirs < 500/mm3. PK analysis shows that clearance of doxorubicin and etoposide varies by up to 1 log and that dose-adjustment compensates for these differences. This approach increases dose intensity in pts with high drug clearance while limiting toxicity. Based on 451 cycles, the target nadir ANC < 500/mm3 was achieved on 277 (61%) cycles but with 67 (15%) episodes of fever/neutropenia. Non-hematological toxicity was low and there were 2 treatment related deaths. These results suggest DA-EPOCH-R is highly effective in all subtypes of de novo DLBCL. A phase III study comparing R-CHOP and DA-EPOCH-R with microarray analysis of tumor biopsies is under development. [Display omitted] [Display omitted]