Dose-intensive Cyclophosphamide Research Articles

Assessing the impact of aprepitant on response to dose-intensive cyclophosphamide, etoposide, and cisplatin (DICEP).

Despite evidence demonstrating the effectiveness of aprepitant for chemotherapy-induced nausea and vomiting (CINV), its use in stem cell transplant settings across Canada is not standard. While pharmacokinetic data exists, the clinical significance of cytochrome P450 3A4 (CYP 3A4) inhibition of cyclophosphamide by aprepitant is unclear. Reduced activation of cyclophosphamide may reduce the effectiveness of dose-intensive cyclophosphamide, etoposide, and cisplatin (DICEP). To compare response rates to DICEP in patients with Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL) in the presence and absence of aprepitant. A retrospective review of patients who received full-dose DICEP for relapsed/refractory HL or DLBCL between June 1995 and September 2018 at the Foothills Medical Centre (FMC) in Calgary, Alberta, Canada was conducted. Descriptive statistics were used to assess response rate, as defined by the 2007 International Working Group response criteria. Of the 218 patients included in this study, 87.6% of patients in the control group and 88.5% of patients in the aprepitant group responded to DICEP (difference 0.025 [95% CI, -0.066 to 0.114], p = 0.827). Univariate analyses for age, sex, type of cancer, stage of cancer, number of prior relapses, and relapse status were not significant. No significant differences were observed for secondary outcomes. Response rates to DICEP in relapsed/refractory HL and DLBCL patients were similar regardless of aprepitant use. Considering these results and the effectiveness of aprepitant in CINV, its addition to standard antiemetic therapy in patients receiving DICEP should be given strong consideration in the transplant setting.

Canadian cancer trials group LY.17: A randomized phase II study evaluating novel salvage therapy pre-autologous stem cell transplant in relapsed/refractory diffuse large B-cell lymphoma-outcome of rituximab-dose-intensive cyclophosphamide, etoposide, cisplatin (R-DICEP) versus R-GDP.

The Canadian Cancer Trials Group (CCTG) LY.17 is an ongoing multi-arm randomized phase II trial evaluating novel salvage therapies compared with R-GDP (rituximab, gemcitabine, dexamethasone and cisplatin) in autologous stem cell transplantation (ASCT)-eligible patients with relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL). This component of the LY.17 trial evaluated a dose-intensive chemotherapy approach using a single cycle of inpatient R-DICEP (rituximab, dose-intensive cyclophosphamide, etoposide and cisplatin) to achieve both lymphoma response and stem cell mobilization, shortening time to ASCT. This report is the result of the protocol-specified second interim analysis of the 67 patients who were randomized to either 1 cycle of R-DICEP or to 3 cycles of R-GDP. The overall response rate (ORR) was 65.6% for R-DICEP and 48.6% for R-GDP. The ASCT rate was 71.9% versus 54.3%, and 1-year progression-free survival rate was 42% versus 32%, respectively, for R-DICEP versus R-GDP. Although the improvement in ORR for R-DICEP versus R-GDP exceeded the pre-specified 10% threshold to proceed to full accrual of 64 patients/arm, higher rates of grade 3-5 toxicities, and the need for hospitalization led to the decision to stop this arm of the study. CCTG LY.17 will continue to evaluate different salvage regimens that incorporate novel agents.

Canadian Cancer Trials Group (CCTG) LY.17: A Randomized Phase II Study Evaluating Novel Salvage Therapy Pre-Autologous Stem Cell Transplant (ASCT) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (RR-DLBCL) - Outcome of Rituximab-Dose-Intensive Cyclophosphamide, Etoposide, Cisplatin (R-DICEP) Versus R-GDP

Introduction: The CCTG LY.12 trial established rituximab combined with gemcitabine, dexamethasone and cisplatin (R-GDP) as a standard salvage chemotherapy option prior to ASCT for patients (pts) with relapsed/refractory (RR) DLBCL (Crump JCO 2014). CCTG LY.17 is an ongoing multi-arm randomized phase II "pick a winner" trial evaluating novel salvage therapy compared with R-GDP in ASCT-eligible RR-DLBCL pts. Methods: The primary endpoint of the study is overall response rate (ORR) using CT imaging. According to the protocol futility rule, any treatment arm with an ORR lower than the R-GDP control arm at the first interim analysis (n = 16), or less than 10% higher at the second interim analysis (n=32) would not continue to full target accrual of 64 pts per treatment arm. Encouraging results could then be pursued in a larger phase III trial designed to detect differences in progression-free survival (PFS). This report involves the component of the trial that randomly allocated pts to either 1 cycle of inpatient R-DICEP (Rituximab 375mg/m2 IV or 1400mg sc days 1 and 5 plus dose-intensive Cyclophosphamide 5.25g/m2, Etoposide 1050mg/m2, Cisplatin 105mg/m2 divided over days 2-4, with daily filgrastim starting day 15 until apheresis of blood stem cells approximately between days 20-22) or to 3 cycles of outpatient R-GDP. This report is the result of the protocol-specified second interim analysis. Results: A total of 67 pts were randomized to R-DICEP (n=32) or to R-GDP (n=35) between April 2016 and April 2021. Table 1 lists baseline pt characteristics. Four pts (R-DICEP=2, R-GDP=2) were not evaluable for response. The ORR was 65.6% for R-DICEP (70.0% for evaluable pts), which was 17% greater than the ORR of 48.6% for R-GDP (51.5% for evaluable pts). Additionally, only 1 (3.1%) R-DICEP pts versus (vs) 11 (31.4%) R-GDP pts experienced progressive disease as best response to salvage therapy. Of interest, the ORR to salvage was 40% (14/35) for pts primary refractory to RCHOP (no response to RCHOP or progressive disease during or <3mo post RCHOP) vs 75% (24/32) for those who relapsed >3mo post RCHOP (p=0.006), with ORR to R-DICEP of 50% vs 81.3% and ORR to R-GDP of 31.6% vs 68.8% for primary refractory vs relapse >3mo, respectively. The ORR based on PET-CT scan was 50.0% vs 31.4% for the R-DICEP (n=26) vs R-GDP (n=25) arms, respectively. Overall, 23 (71.9%) R-DICEP pts and 19 (54.3%) R-GDP pts underwent ASCT. In total, 26 out of 27 (96.3%) R-DICEP, and 18 out of 20 (90%) R-GDP pts underwent successful autologous blood stem cell collection (requiring >1 attempt in 0 R-DICEP and 2 R-GDP pts). The median time to neutrophil engraftment post-ASCT was 13 (1-32) and 12 (1-22) days, and to platelet engraftment was 12 (1-50) and 16 (7-22) days for R-DICEP and R-GDP pts, respectively. Regarding adverse events (AEs) of salvage therapy and subsequent ASCT, R-DICEP pts had higher rates of culture positive infection (84% vs 40%), platelet (96.6% vs 60.0%) and red cell (75.0% vs 42.9%) transfusions, diarrhea (44% vs 14%), serious adverse events (50% vs 34.3%), and treatment-related mortality (3.1% vs 0%) but similar rates of other AEs including arrhythmia (6% vs 9%), bleeding (0 vs 0), fungal infections (0 vs 0) and pneumonitis (0 vs 0). At a median duration of follow-up of 26.9 months (R-DICEP 26.4 months and R-GDP 27.4 months), the 1-year PFS rate was 42% for R-DICEP and 32% for R-GDP (HR 0.59, 95%CI: 0.32-1.09, logrank p=0.09), and 1-year OS rate was 65% for R-DICEP and 55% for R-GDP (HR 0.675, 95%CI: 0.333-1.369, logrank p=0.27). Conclusions: Although the 17% improvement in ORR for R-DICEP vs R-GDP in the second interim analysis exceeded the pre-specified 10% threshold required proceed to full accrual of 64 pts in the R-DICEP arm, we decided to stop accrual to the R-DICEP arm of the LY.17 trial due to slow accrual, higher AE rates, and greater utilization of healthcare resources including hospitalization needed to administer treatment, which limits feasibility of R-DICEP at several Canadian centres. The LY.17 trial continues testing other salvage regimens. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Outcomes of Consolidative Autotransplant for High-Risk Large B-Cell Lymphoma

Background: Although there have been significant recent advances in the treatment of relapsed/refractory (r/r) large B-cell lymphoma (LBCL), there remains a substantial unmet need to optimize the frontline management of high-risk LBCL. Patients with high International Prognostic Index (IPI) scores 4-5 have particularly poor progression-free survival (PFS) rates of ~50% with R-CHOP, and 2-year PFS may be as low as 10-25% for patients with positive interim PET scans. In the phase III DLCL04 and SWOG-9704 trials, the use of upfront consolidative autologous stem cell transplantation (ASCT) after R-CHOP resulted in significant improvements in PFS, with the latter study also demonstrating a significant improvement in overall survival (OS) in the age-adjusted high IPI subgroup. Furthermore, the GAINED trial demonstrated favorable outcomes using an interim PET-adapted strategy, where consolidative ASCT appeared to overcome the poor prognostic impact of a positive interim PET. However, there is only limited and conflicting data from prospective or retrospective studies concerning ASCT consolidation for the highest risk patients with LBCL and IPI score 4-5, particularly those with positive interim PET scans. Methods: This retrospective, multicenter study included consecutive patients with newly diagnosed LBCL and high IPI score 4-5 who received consolidative ASCT as a planned part of first-line therapy at the Tom Baker Cancer Centre and Cross Cancer Institute in Alberta, Canada. Patients were excluded if they had primary central nervous system (CNS) lymphoma, previously treated indolent B-cell lymphoma, or underwent ASCT for r/r LBCL. PFS, OS, and disease-specific survival (DSS) were determined using the Kaplan-Meier method. Results: We included 114 patients with median age 60 years (range 18-73) and median follow-up time 5.6 years. High-risk features at diagnosis included IPI score 4 in 81 (71%), IPI score 5 in 33 (29%), stage IV in 112 (98%), >1 extranodal site in 109 (96%), non-GCB cell of origin by Hans’ algorithm in 32 (28%), double-hit lymphoma in 26 (23%), and secondary CNS involvement in 15 (13%). The most common induction regimen was R-CHOP (n=102) and 25 (22%) patients received 1-3 cycles, 71 (62%) received 4 cycles, and 18 (16%) received 5-6 cycles of induction. Rituximab with dose-intensive cyclophosphamide, etoposide, and cisplatin (R-DICEP) was frequently used (n=69) to intensify induction and for peripheral blood stem cell mobilization. Interim PET was performed during induction for 45 patients and was positive (Deauville 4-5) in 24 (53%) and negative (Deauville 1-3) in 21 (47%). Pre-ASCT disease status was complete response (CR) in 68 (60%), partial response (PR) in 43 (38%), and unknown in 3 (3%) patients. The most common ASCT conditioning regimens were BEAM in 41 (36%), BuMel in 39 (34%), and TBM in 13 (11%) patients. At 2 years, PFS was 82% (95% CI 74-88%), OS was 86% (95% CI 78-91%), and DSS was 87% (95% CI 79-92%). At 5 years, PFS was 72% (95% CI 62-80%), OS was 74% (95% CI 64-81%), and DSS was 80% (95% CI 71-87%). Relapse occurred in 21 (18%) patients at median 284 days (range 168-2229) after ASCT. There was 1 (1%) death due to early transplant-related infection and 3 (3%) late deaths from pulmonary fibrosis and therapy-related myeloid neoplasms. There were no significant differences in DSS for patients with versus without CNS involvement (77% vs. 80%, p=0.62), double-hit lymphoma versus DLBCL NOS (85% vs. 78%, p=0.80), GCB versus non-GCB cell of origin (78% vs. 80%, p=0.89) and positive versus negative interim PET (83% vs. 74%, p=0.51). Discussion: In this study of 114 selected patients with high-risk LBCL with IPI score 4-5, consolidative ASCT was associated with excellent outcomes with long-term disease-specific survival in 80%. Importantly, the efficacy of consolidative ASCT appeared to be independent of adverse prognostic factors including CNS involvement, double-hit status, non-GCB cell of origin, and interim PET positivity. The results of our study are consistent with those of previous clinical trials and provide real-world evidence confirming that consolidative ASCT can be considered a reasonable treatment option for eligible patients with high-risk LBCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

PS1088 A RETROSPECTIVE COHORT STUDY TO EVALUATE THE OUTCOMES OF HIV‐ASSOCIATED HIGH‐GRADE B‐CELL NON‐HODGKIN LYMPHOMA (NHL) TREATED WITH DOSE ADJUSTED R EPOCH REGIMEN

Background:High‐grade B‐cell NHL's are 200‐fold more common in seropositive as compared to seronegative patients. They have a higher incidence of extranodal involvement, advanced stage and chemoresistance. To add to the complexity, social stigma and financial constraints decrease the compliance to therapy. R‐EPOCH is designed to provide a balance between efficacy and safety. We report on our cohort of patients who were treated with this protocol.Aims:The primary objective was the 3‐year overall survival (OS), secondary objectives were response rates, the incidence of grade3/4 toxicities, dose intensity and correlation of OS with CD4 count, IPI, duration of HIV, Cyclophosphamide dose intensity (CDI).Methods:We analysed seropositive de‐novo high‐grade B‐cell NHL patients who were treated at Tata Memorial Centre from 2011 till 2015. Patients aged ≥18 years who had received at least 1 cycle were included in the analysis. Demographic features, HIV related details, histological diagnosis, disease characteristics, treatment details, response, toxicity and status, at last, follow up were recorded. Descriptive statistics were summarised, survival outcomes were analysed with Kaplan Meier method and impact of CD 4 count, CDI, IPI and duration of HIV on survival was assessed using log‐rank test.Results:A total of 40 patients(31males) with a median age of 40 years (24–65 years) were treated. B symptoms were present in 19(48%). The cohort comprised of DLBCL‐19 (48%), BL‐16(40%), High‐grade B‐Cell Lymphoma‐Unclassifiable‐4 (10%) and PBL 1 (2.5%). 16 (40%) patients had co‐morbidities, including co‐existent Hepatitis C in 5 and Hepatitis B in 2. HIV infection was detected at the time of lymphoma diagnosis in 18 (45%). The median CD4+ T cell count was 202 cells/mm3, 6 patients (15%) had count of &lt;100/mm3. All patients received HAART while on chemotherapy. Performance status (ECOG) ≤2 was seen in 36(90%) patients. 38 (95%) had stage III/IV disease and bulky disease (defined as size ≥7 cm) was seen in 29(72%) patients. Extranodal involvement was seen in 36(90%) patients. Haemoglobin level ≤11 g/dL in 10(25%) patients (range‐ 8.2–15.6 g/dL), serum albumin &lt;4 g/dL in 23(58%) patients, serum LDH ≥ upper normal limit −38 (95%) patients. At least 4 cycles of chemotherapy were administered to 35 (93%) patients, with 28 (70%) receiving 6 cycles. CNS prophylaxis was administered with intrathecal methotrexate (median number‐6) to 36(90%) patients. High dose methotrexate was given to 5 patients. Rituximab was not administered to 5 patients (3 due to CD4 count &lt;100, 2 due to CD20 negativity). Responses were assessed using 18FDG PET‐CT scan with complete response‐32(80%), partial response‐1(3%), disease progression‐4(10%) and not evaluable‐ 4 (7%). Grade 3/4 toxicities were seen in 33(83%) patients, with febrile neutropenia‐26(65%), mucositis‐10(25%) and peripheral neuropathy in5(13%) patients. Out of the 210 cycles administered, there were 41(20%) episodes of hospitalization (duration ranged from 2–51 days). There were 11(28%) deaths (progression‐7, toxicity‐2, Not known‐2) and 7(18%) patients had progression (4‐ on treatment progression, 3‐ relapses). With a median follow‐up of 47 months, estimated 4‐year OS is 72% (Figure 1) and 4‐year disease‐free survival is 82%. There was no difference in survival based on IPI, CD 4+ T cell count, CDI or duration of HIV.Summary/Conclusion:R‐EPOCH is a highly effective regimen in seropositive high‐grade B‐cell lymphoma even in the presence of adverse features.image

A Retrospective Cohort Study to Evaluate the Outcomes of HIV-Associated High-Grade B-Cell Non-Hodgkin Lymphoma (NHL) Treated with Dose Adjusted R EPOCH Regimen

Background-High grade B-cell NHL's are 200 fold more common in seropositive as compared to seronegative patients. It includes diffuse large B cell lymphoma (DLBCL) (50%), Burkitt's (BL)(40%) and others such as plasmablastic lymphoma(PBL). They are biologically different from their seronegative counterparts with higher incidence of extranodal involvement, advanced stage and poor response to conventional therapy. In addition, they are at a higher risk of chemotherapy side effects and poorly tolerate dose intense regimens. To add to the complexity, social stigma and financial constraints decrease the compliance to therapy. R-EPOCH is designed to provide a balance between efficacy and safety. We report on our cohort of patients who were treated with this protocol.Methods-We retrospectively analysed HIV-associated de-novo high grade B-cell NHL patients who were treated with R EPOCH regimen at Tata Memorial Centre from 2011 till 2015. Patients aged ≥18 years who had received at least 1 cycle were included in the analysis. R EPOCH is an infusional regimen in which the dose of cyclophosphamide is adjusted depending on the baseline CD4+ T cell count and tolerance. The primary objective was the 3-year overall survival(OS), secondary objectives were response rates, the incidence of grade3/4 toxicities, dose intensity and correlation of OS with CD4 count, IPI, duration of HIV, Cyclophosphamide dose intensity (CDI). Demographic features, HIV related details (CD4 count at diagnosis, ART regimen), histological diagnosis, stage, bulky disease, extranodal sites, treatment details (number of cycles, dose administered), response, toxicity and status at last follow up were recorded. Descriptive statistics were summarised with median and range, survival outcomes were analysed with Kaplan meier method and impact of CD 4 count, CDI, IPI and duration of HIV on survival was assessed using log rank test.Results-A total of 40 patients(31males) with a median age-40 years (24-65 years) were treated. B symptoms were present in 19(48%). The cohort comprised of DLBCL-19 (48%), BL-16(40%), High grade B-Cell Lymphoma-Unclassifiable-4 (10%) and PBL 1 (2.5%). 16 (40%) patients had co-morbidities, including co-existent Hepatitis C in 5 and Hepatitis B in 2. HIV infection was detected at the time of lymphoma diagnosis in 18 (45%). The median CD4+ T cell count was 202 cells/mm3, 6 patients (15%)had count of <100/mm3 All patients received HAART while on chemotherapy, NNRTI plus 2 NRTI combination being the commonest regimen-33(82%) patients. Performance status (ECOG) ≤2 was seen in 36(90%) patients. 38 (95%) had stage III/IV disease and bulky disease (defined as size ≥7cm) was seen in 29(72%) patients. Extranodal involvement was seen in 36(90%) patients. Haemoglobin level ≤11g/dL in 10(25%) patients (range- 8.2-15.6 g/dL), serum albumin <4g/dL in 23(58%) patients, serum LDH ≥ upper normal limit -38 (95%)patients. Atleast 4 cycles of chemotherapy were administered to 35 (93%)patients, with 28 (70%) receiving 6 cycles. Cyclophosphamide dose escalation was possible in 18(45%) patients. CNS prophylaxis was administered with intrathecal methotrexate (median number-6) to 36(90%) patients. High dose methotrexate was given to 5 patients. Rituximab was not administered to 5 patients (3 due to CD4 count <100, 2 due to CD20 negativity). Responses were assessed using 18FDG PET-CT scan with complete response-32(80%), partial response-1(3%), disease progression-4(10%) and not evaluable- 4 (7%). Grade ¾ toxicities were seen in 33(83%) patients, with febrile neutropenia-26(65%), mucositis-10(25%) and peripheral neuropathy in5(13%) patients. Out of the 210 cycles administered, there were 41(20%) episodes of hospitalisation (duration ranged from 2-51 days). There were 11(28%) deaths (progression-7, toxicity-2, Not known-2) and 7(18%) patients had progression (4- on treatment progression, 3- relapses). With a median follow-up of 29 months, estimated 3-year OS is 71% (Figure 1) and 3-year progression free survival is 79%. There was no difference in survival based on IPI, CD 4+ T cell count, CDI or duration of HIV.Conclusions-R-EPOCH is a highly effective regimen in seropositive high-grade B-cell lymphoma even in the presence of adverse features (advanced stage, extranodal sites, CNS involvement, low CD4+ T cell count). The emphasis should now be on further reducing the toxicities. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Abstract P1-14-08: Prediction of pathological response (pCR) to neoadjuvant dose dense and intense cyclophosphamide and anthracycline in a prospective series of triple negative locally advanced breast cancers (TNLABC)

Abstract Background: Stage II-III TNBC retains a poor outcome despite high chemosensitivity. Patients (pts) with pCR after neoadjuvant chemotherapy have a good prognosis whereas non-responding pts have a 25-40% risk of distant relapse at 5 years. pCR is thus a major goal in TNBC. We previously reported that TNLABC benefit the most of dose dense dose intense cyclophosphamide (C)-epirubicin (E) (S.Giacchetti; BJC, 2014) Aim: To confirm these results prospectively and analyze the predictive factors of response to high dose chemotherapy in TNBC. Patients and methods: From january 2009 to april 2015 non inflammatory TNLABC received high dose C (1200 mg/m2 d1 qw 2) with E (75 mg/m2/ d1 qw2) for 6 cycles. The pts had a breast biopsy with frozen tissue. We performed molecular studies: qRT-PCR for AR, FOXA1, PI3K and FASAY technic for p53 mutation.The percentage of stromal Tumor-infiltrating lymphocytes (TILs) was also evaluated by two independent pathologists and assessed as a continuous variable. A18F-FDG PET/CT was performed initially and after 2 courses of chemotherapy and the metabolic answer assessed as a variation of the tumor uptake (ΔSUVmax). We report here the pathological complete response (pCR) (absence of infiltrative carcinomas in the breast and in the lymph nodes) and the factors associated with pCR. Results: The characteristics of the 74 pts are listed in table 1. The median age is 48 years old, 48 pts (65.8%) are premenopausal and 79% did not have any family history of breast cancers. TIL was divided in 3 groups &amp;lt; 10 % (26 pts, 40 %); 10-50 % (30 pts, 46 %) &amp;gt; 50% (9 pts, 14 %). Pathological response was assessed in 66 pts, one pt progressed during chemotherapy and 6 pts did not undergo surgery yet. 28 pts were in pCR (42.4 %). With a median follow up of 25 months, 13 pts (17.8 %) progressed and 8 (11%) died. Table 1: Patients characteristics and pCR according to tumor features and metabolic responseCharacteristicsNumber of pts (%)N of pts evaluated for pCRpCR (%)OR [IC 95%]p-valueTumor size T2363519 (54)10.04T337319 (29)0.34 [0.12 ; 0.96]Nodal status N0363315 (46)10.62N1/N2/N3 24/11/33313 (39)0.78 [0.29 ; 2.07]Histological grade: 2660 (0) 0.04*3676028 (47)TILs &amp;lt;10 %26 (40)2510 (40)10.02610-50 %30 (46)267 (27)0.55 [0.17 ; 1.80]≥ 509 (14)9 7 (78)5.25 [0.90 ; 30.62]P53 Mutated54 (89)5121 (41)10.43WT7 (12)53 (60)2.14 [0.33; 13.96]AR Negative43 (83)4318 (42)10.46Positive 9 (17)95 (56)1.74 [0.41 ; 7.38]FOXA1 Negative40 (77)4015 (38)10.08Positive 12 (23)128 (60) 3.33 [0.86 ; 12.99]Molecular Apocrine8 (17)85 (63)10.19TN38 (83)3814 (37)0.35 [0.07 ; 1.69]PI3K Non mutated44 (88)4419 (43)10.75Mutated6 (12)63 (50)1.31 [0.24 ; 7.26]SUVmax at 2 courses0.0001&amp;lt; 70 %27 (53)221 (5)1≥ 70 %24 (47)2318 (78)79.2 [8.48 ; 739.82]* Measured with a Fisher Test Tumor size, tumor grade, percentage of TILs, the change in 18F-fluorodeoxyglucose tumor uptake (ΔSUVmax) were significantly associated with pCR at univariate analysis. Only one factor remained significant at multivariate analysis, the ΔSUVmax, OR: 0.04 [0.007- 0.27], p = 0.0008. Conclusion: In this prospective phase III trial we confirm the efficacy of a dose dense EC in TNBC. The metabolic response evaluated with 18 F-FDG PET/CT is a strong and reliable predictor of pCR and could allow an early change of treatment for the non responders. A clinical trial is planned to test this strategy. Citation Format: Giacchetti S, De Roquancourt A, Groheux D, Piron P, Lehmann-che J, Cuvier C, Resche-rigon M, Albiter M, Roche B, Frank S, Hamy A-S, Teixeira L, Marty M, Lalloum M, Espié M. Prediction of pathological response (pCR) to neoadjuvant dose dense and intense cyclophosphamide and anthracycline in a prospective series of triple negative locally advanced breast cancers (TNLABC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-08.

Abstract 4525: The impact of chemoimmunotherapy dose intensity in diffuse large b-cell lymphoma

Abstract Introduction Chemotherapy dose intensity (DI) impacts outcomes across tumor subtypes. In diffuse large B-cell lymphoma (DLBCL), DI played a large role prior to rituximab, but is still a subject of investigation. Research into intensifying treatment for poorer prognostic lymphoma subtypes has yielded dose-adjusted EPOCH-R where etoposide is added to standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Though, R-CHOP given every 14 vs. 21 days has not been found to improve survival, this study examines if delays in treatment or reductions in R-CHOP21 DI impact patient outcomes. Methods In this single institution review, DLBCL patients (pts) treated with first-line R-CHOP between 2004 and 2010 were included. After factoring in covariates such as revised International Prognostic Index (R-IPI) and gender, pts were compared by DI (ratio of actual total dose received vs. prescribed dose) of cyclophosphamide, doxorubicin, and treatment duration as a whole for their impact on progression-free (PFS) and overall survival (OS). Results Of 232 pts identified, 224 were included in final review. Median age and ECOG performance status was 62 years and 1, respectively. Majority had stage IV disease (46%). 124 patients were male with pts evenly distributed between R-IPI 0-1 (low, 28%), 2 (low-intermediate, 21%), 3 (high-intermediate, 26%), and 4-5 (high, 25%). A median DI of both cyclophosphamide and doxorubicin was 97%. 118 pts had &amp;gt;/ = 1 week delay during treatment duration. Cutpoint analysis found that DI was more important at 85% for both cyclophosphamide and doxorubicin. Median PFS for patients who received / = 85% cyclophosphamide DI was 27.2 vs. 55.0 months (hazard ratio [HR] 2.48, p = 0.03). Similarly, median OS was 41.8 months vs. not reached (HR 2.79 p = 0.02), respectively. PFS and OS for doxorubicin was similar at 27.6 vs. 53.7 months (HR 2.25, p = 0.04) and 40.9 months vs. not reached (HR 2.54, p = 0.02), respectively. Actual treatment durations that differed &amp;lt;15% of the planned durations were protective for PFS (HR 0.44, p = 0.008), but less so for OS (HR 0.63, p = 0.18). Taking R-IPI scores and gender in multivariate Cox proportional hazards modeling found the impact of cyclophosphamide and doxorubicin DI on PFS and OS maintained significance but not treatment duration. Though multiple reasons for reduced DI exist, growth factor support use trended towards higher DI pts (32 vs. 19%, p = 0.10). Conclusions While intensifying R-CHOP by shortening cycles to every 14 days has not been beneficial, this study suggests that delays and dose reductions in R-CHOP21 substantially impact outcomes. In doing so, it highlights that maintaining pts on schedule is important and that more accurate methods of determining appropriate chemotherapeutic doses may affect both survival and toxicity. Although it is our standard to only use growth factor support with delays it may be beneficial to starting all patients up front on growth factor support. Citation Format: Michael P. Chu, Sunita Ghosh, Andrew Belch, Neil S. Chua, Amelie Fontaine, Randeep Sangha, Robert Turner, Christopher Venner, Vickie Baracos, Michael B. Sawyer. The impact of chemoimmunotherapy dose intensity in diffuse large b-cell lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4525. doi:10.1158/1538-7445.AM2015-4525

Long-term survival of advanced triple-negative breast cancers with a dose-intense cyclophosphamide/anthracycline neoadjuvant regimen

Background:Triple-negative (TN) breast cancers exhibit major initial responses to neoadjuvant chemotherapy, but generally have a poor outcome. Because of the lack of validated drug targets, chemotherapy remains an important therapeutic tool in these cancers.Methods:We report the survival of two consecutive series of 267 locally advanced breast cancers (LABC) treated with two different neoadjuvant regimens, either a dose-dense and dose-intense cyclophosphamide–anthracycline (AC) association (historically called SIM) or a conventional sequential association of cyclophosphamide and anthracycline, followed by taxanes (EC-T). We compared pathological responses and survival rates of these two groups and studied their association with tumours features.Results:Although the two regimens showed equivalent pathological complete response (pCR) in the whole population (16 and 12%), the SIM regimen yielded a non-statistically higher pCR rate than EC-T (48% vs 24%, P=0.087) in TN tumours. In the SIM protocol, DFS was statistically higher for TN than for non-TN patients (P=0.019), although we showed that the TN status was associated with an increased initial risk of recurrence in both regimens. This effect gradually decreased and after 2 years, TN was associated with a significantly decreased likelihood of relapse in SIM-treated LABC (hazard ratio (HR)=0.25 (95% CI: 0.07–0.86), P=0.028).Conclusions:AC dose intensification treatment is associated with a very favourable long-term survival rate in TN breast cancers. These observations call for a prospective assessment of such dose-intense AC-based regimens in locally advanced TN tumours.

A phase III randomized trial of high‐dose CEOP + filgrastim versus standard‐dose CEOP in patients with non‐Hodgkin lymphoma: 10‐year follow‐up data: Australasian Leukaemia and Lymphoma Group (ALLG) NHL07 trial

Increasing dose intensity (DI) of chemotherapy for patients with aggressive non-Hodgkin lymphoma (NHL) may improve outcomes at the cost of increased toxicity. This issue was addressed in a randomized trial aiming to double the DI of myelosuppressive drugs. Between 1994 and 1999, 250 patients with previously untreated aggressive NHL were randomized to treatment with six cycles of 3-weekly standard (s) or intensive (i) chemotherapy: s-CEOP-cyclophosphamide 750, epirubicin 75, vincristine 1.4 mg/m(2) all on day 1, and prednisolone 100 mg days 1-5; i-CEOP-cyclophosphamide 1,500, epirubicin 150, vincristine 1.4 mg/m(2) all on day 1, and prednisolone 100 mg days 1-5. Primary endpoint was 5-year overall survival (OS). Relative to s-CEOP patients, i-CEOP patients achieved a 78% increase in the DI of cyclophosphamide and epirubicin. Despite this, there was no significant difference in any outcome: 5-year OS (56.7% i-CEOP; 55.1% s-CEOP; P = 0.80), 5-year progression free survival (PFS; 41% i-CEOP; 43% s-CEOP; P = 0.73), 5-year time to progression (TTP; 44% i-CEOP; 47% s-CEOP; P = 0.72), or complete remission (CR) + unconfirmed CR (CRu) rates (53% i-CEOP; 59% s-CEOP; P = 0.64). Long-term follow up at 10 years also showed no significant differences in OS, PFS, or TTP. The i-CEOP arm had higher rates of febrile neutropenia (70 vs. 26%), hospitalisations, blood product utilisation, haematological and gastrointestinal toxicities, and lower quality of life scores during treatment, although without significant differences 6-month later. In the treatment of aggressive NHL in the prerituximab era, increasing DI did not result in improved outcomes, while at the same time lead to increased toxicity.

High dose salvage therapy with dose intensive cyclophosphamide, etoposide and cisplatin may increase transplant rates for relapsed/refractory aggressive non-Hodgkin lymphoma

Only one-quarter to one-third of patients with relapsed/refractory aggressive non-Hodgkin lymphoma (r/r-aNHL) treated with common salvage chemotherapy regimens and autologous stem cell transplant (ASCT) achieve 5-year progression-free survival (PFS). Worse outcomes have been reported after failure of prior rituximab-containing induction, initial time to progression (TTP) < 1 year or age-adjusted International Prognostic Index (aaIPI) = 2–3 at relapse. In Calgary, we have treated patients with r/r-aNHL with dose-intensive cyclophosphamide 5.25 g/m2, etoposide 1.05 g/m2 and cisplatin 105 mg/m2 (DICEP) for both re-induction therapy and autologous blood stem cell mobilization. In this study we retrospectively analyzed 113 consecutive transplant-eligible patients with r/r-aNHL who received one cycle of DICEP (n = 93) or R-DICEP (n = 20) from 1995 to 2009. Patient characteristics included: median age = 49 years (22–69); TTP < 1 year = 85; elevated lactate dehydrogenase (LDH) = 60; Eastern Cooperative Oncology Group performance status (ECOG) 2–4 = 42; aaIPI 2–3 = 59; bulk > 10 cm = 26, prior rituximab = 27. The median number of CD34 + cells collected was 19 × 106/kg (0.3–142), 83.5% responded and 90% (102) proceeded to ASCT. The 5-year PFS rate was 42% for all patients, 32% for those with relapse aaIPI = 2–3, 35% for initial TTP < 1 year and 56% for those who failed initial rituximab induction. In conclusion, (R)DICEP is an effective re-induction regimen for r/r-aNHL, leading to excellent stem cell mobilization, a high chance of proceeding to ASCT and encouraging long-term PFS rates.

Necrosis After Craniospinal Irradiation: Results From a Prospective Series of Children With Central Nervous System Embryonal Tumors

Necrosis of the central nervous system (CNS) is a known complication of craniospinal irradiation (CSI) in children with medulloblastoma and similar tumors. We reviewed the incidence of necrosis in our prospective treatment series. Between 1996 and 2009, 236 children with medulloblastoma (n = 185) or other CNS embryonal tumors (n = 51) received postoperative CSI followed by dose-intense cyclophosphamide, vincristine, and cisplatin. Average risk cases (n = 148) received 23.4 Gy CSI, 36 Gy to the posterior fossa, and 55.8 Gy to the primary; after 2003, the treatment was 23.4 Gy CSI and 55.8 Gy to the primary. All high-risk cases (n = 88) received 36-39.6 Gy CSI and 55.8 Gy primary. The primary site clinical target volume margin was 2 cm (pre-2003) or 1 cm (post-2003). With competing risk of death by any cause, we determined the cumulative incidence of necrosis. With a median follow-up of 52 months (range, 4-163 months), eight cases of necrosis were documented. One death was attributed. The median time to the imaging evidence was 4.8 months and to symptoms 6.0 months. The cumulative incidence at 5 years was 3.7% ± 1.3% (n = 236) for the entire cohort and 4.4% ± 1.5% (n = 196) for infratentorial tumor location. The mean relative volume of infratentorial brain receiving high-dose irradiation was significantly greater for patients with necrosis than for those without: ≥ 50 Gy (92.12% ± 4.58% vs 72.89% ± 1.96%; P=.0337), ≥ 52 Gy (88.95% ± 5.50% vs 69.16% ± 1.97%; P=.0275), and ≥ 54 Gy (82.28% ± 7.06% vs 63.37% ± 1.96%; P=.0488), respectively. Necrosis in patients with CNS embryonal tumors is uncommon. When competing risks are considered, the incidence is 3.7% at 5 years. The volume of infratentorial brain receiving greater than 50, 52, and 54 Gy, respectively, is predictive for necrosis.

Dose-intensive cyclophosphamide, etoposide, cisplatin reinduction for relapsed/refractory aggressive non-Hodgkin lymphoma (r/r-aNHL).

6548 Background: Approximately 2/3 r/r-aNHL patients (pts) respond to salvage R-ICE or R-DHAP, 1/2 proceed to autologous stem cell transplantation (ASCT), and 1/3 achieve 3 year (yr) progression-free survival (PFS); however, PFS is only 20% if prior Rituximab, time to progression (TTP)&lt;1yr, or age-adjusted International Prognostic Index (aaIPI)=2-3 [JCO 2010;28: 4184-90]. Since 1995, we re-induced poor prognosis r/r-aNHL with dose-intensive Cyclophosphamide 5.25g/m2, Etoposide 1.05g/m2 and Cisplatin 105mg/m2 (DICEP), G-CSF days (d) 14-19, and apheresis d19,20, or 21. Rituximab was added d0,7 after 2006. Methods: We retrospectively analyzed 113 consecutive transplant eligible r/r-aNHL pts [diffuse large B-cell=95, transformed=9, peripheral T-cell=6, other=3] who received one cycle of DICEP (n=93) or R-DICEP (n=20) from 1995-2009. Patient characteristics included: median age=49yr (22-69); primary refractory=68; TTP&lt;1yr=85; elevated LDH=60; ECOG 2-4=42; aaIPI 2-3=59; bulk&gt;10cm=26. Results: Of 113 pts, 77% responded to DICEP and 90% (102) proceeded to ASCT. The median CD34+ cells collected was 19x106/kg (0.3-142). Early treatment-related mortality (TRM) occurred in 3 pts (2.7%), and 4 others developed late second cancers (MDS/AML=2). With 94 months median follow-up (26-194), 5 and 10yr OS rates for all 113pts are 48% and 41%, and PFS rates are 42% and 37%, respectively. 5 year PFS rates for ASCT vs no-ASCT are 46% vs 9%, for relapse aaIPI=0-1 vs aaIPI=2-3 are 53.3% vs 32.1% (p=0.01), and for TTP&gt;1yr vs &lt;1yr are 63.9% vs 35.2% (p=0.009). Other predictors of inferior PFS in univariate analysis were elevated LDH, ECOG 2-4, no response to DICEP; however, PFS for 27 pts who failed prior Rituximab-chemotherapy (56%) was similar to other 86 pts (38%) (logrank p=0.09). Predictors of PFS and OS in multivariate analysis include: TTP&lt;1yr, elevated LDH, bulk, no response to DICEP. Conclusions: (R)DICEP is an effective re-induction regimen for r/r-aNHL, leading to excellent stem cell mobilization and a high chance of proceeding to ASCT. Long-term PFS and OS rates compare favourably to reports of other re-induction regimens, and a prospective multicentre trial is warranted.

Biweekly regimen of nonpegylated liposomal doxorubicin with cyclophosphamide, vincristine, and prednisone plus rituximab (R-COMP-14) as primary treatment for diffuse large B-cell lymphoma (DLBCL): Long-term follow-up of a phase II study.

8062 Background: To evaluate the efficacy and toxicity of dose-dense biweekly schedule of (R-COMP-14) in patients newly diagnosed of agrressive diffuse B cell lymphomas (DLBCL). Methods: In this single-arm, open-label, multicenter trial, 60 pts were included between 2004 to 2008. Received rituximab (375 mg/m2) D1 + cyclophosphamide (750 mg/m2)D1 + vincristine (1.4 mg/m2; max. 2 mg)D1 + prednisone (100 mg/d D1 and D5) and non-pegylated liposomal doxorubicin (50 mg/m2) every two weeks. Response was assessed at cycle 3, and patients with complete or partial response received 5 additional courses. Granulocyte colony-stimulating factor (G-CSF). Pegfilgrastim was administered on day 2. The primary efficacy endpoint was (CR) and objective response rate (ORR). Survival follow-up data were updated. Results: 59 evaluable patients with a median age of 50 years (21-65) were analyzed. Clinical Characteristics: 22 Pts stage I-II (aaIPI≥1 (37%), 17 (29%) stage III, and 19 (32%) in stage IV. aaIPI=1 41(67%), aaIPI2/3= 18(33%).LVEF basal: 65,5[50-93]. Extra-nodal disease: 42%. B symptoms: 44.1%. The mean calculated dose intensities of cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and rituximab were 98,7%, 98,7%, 76,1% and 98,3% respectively. Among 60 eligible patients (96,7% completed six cycles and 74,4% completed all eight cycles. ORR was 81%, and CR rate of 54,2%. IC 95% [40,7-67,8]. The main toxicity was neutropenia Gr=III-IV/ and febrile neutropenia in 20% of patients. Neurotoxicity Gr=III-IV in 3,4%. No cardiac toxicity Gr: III-IV was reported. No toxic deaths. After a median follow-up of 25-64m(44m) the 5-year overall survival (OS), event-free survival, (EFS) and disease free survival (DFS) were 80%, 67%, and 77% respectively. Forty two patients (71%) had (&lt;60 y) and med. OS(p=0,017) and med EFS(p=0,014) was 72,3% and 68,1 in aaIPI=1 and 50,4% and 33,8 in aaIPI&gt;1. Conclusions: Dose dense R-COMP-14 is an effective regimen in patients with (DLBCL) comparable o R- CHOP-14. Good tolerability profile with no Gr: III-IV cardiac toxicity or reduction of LVEF.

Double high-dose therapy with dose-intensive cyclophosphamide, etoposide, cisplatin (DICEP) followed by high-dose melphalan and autologous stem cell transplantation for relapsed/refractory Hodgkin lymphoma

The purpose of the present study was to review retrospectively our results of double high-dose therapy with DICEP (dose-intensified cyclophosphamide 5.25 g/m2, etoposide 1.05 g/m2, and cisplatin 105 mg/m2) re-induction followed by high dose melphalan 200 mg/m2 (HDM) and autologous stem cell transplantation (ASCT) for 73 consecutive patients with relapsed (n = 43) or refractory (n = 30) classical Hodgkin lymphoma (HL) treated between June 1995 and November 2009. DICEP chemotherapy resulted in successful stem cell mobilization in 71 patients (97%), with a median CD34 + cell collection of 15.6 × 106/kg. With a median follow-up of 56 months post-DICEP, the 5-year progression free survival (PFS) and overall survival (OS) rates were 61% [95%CI = 49–72%] and 80% [95%CI = 69–89%], respectively. The 5-year PFS was 65% vs. 30% for DICEP responders vs. nonresponders (logrank p = 0.003) and 89% for International Prognostic Score (IPS) = 0–1, 56% for IPS = 2–3, and 24% for IPS = 4–7 (logrank p < 0.001). Response to DICEP and IPS at relapse were the only two factors that independently predicted PFS and OS in multivariate analyses. Treatment-related mortality was 1%. In conclusion, DICEP-HDM/ASCT is well tolerated double high-dose therapy associated with excellent stem cell mobilization and favorable PFS and OS outcomes for relapsed as well as primary refractory HL.

Interim Restaging PET/CT-Guided High Dose Sequential Induction Therapy with Autologous Stem Cell Transplantation (ASCT) Does Not Improve Outcome for Poor Prognosis Diffuse Large B-Cell Lymphoma (DLBCL). ClinicalTrials.Gov Identifier: NCT00530179

Abstract 500 Purpose:Approximately 55% of patients (pts) with stage 3–4 DLBCL and elevated serum LDH achieve long-term progression-free survival (PFS) following R-CHOP chemotherapy. A prospective, multicentre, phase II clinical trial was designed to evaluate the use of high dose sequential therapy with RDICEP (Rituximab, Dose-Intensive Cyclophosphamide, Etoposide, Cisplatin) then RBEAM/ASCT (Rituximab, BCNU, Etoposide, Ara-C, Melphalan) for such pts who have unfavorable interim restaging FDG-PET/CT scans after 2 cycles of RCHOP. The trial was designed to minimize false positive interim restaging PET scans by only enrolling poor prognosis pts, and modifying response interpretation criteria such that unfavorable PET response required more than 1 site with uptake more intense than background liver. The use of RDICEP-RBEAM/ASCT built on our prior encouraging experience with DICEP-BEAM/ASCT for poor prognosis aggressive lymphoma (Blood 2006; 107: 4623–4627). The hypothesis was that interim PET response would stratify pts into good RCHOP responders who should avoid upfront ASCT, and poor RCHOP responders who may benefit from upfront ASCT, resulting in an overall PFS rate of 80%. Patients and Methods: Pts were eligible if they were HIV negative, 18–65 years of age, with stage 3–4 DLBCL and elevated serum LDH. An FDG-PET/CT scan was performed 10–15 days following the second cycle of R-CHOP. Pts with favorable interim PET response completed 4 further cycles of RCHOP, whereas pts with unfavorable PET response received one cycle of RDICEP (Rituximab 375mg/m2 day 1 and 8, C 1.75g/m2 d2-4, E 350mg/m2 d2-4 P 35mg/m2 d2-4, G-CSF d15-21 and autologous blood stem cell collection by apheresis d21or 22) followed by one cycle of RBEAM/ASCT (R 375mg/m2 day −6 and +14, B 300mg/m2 d-6, E 200mg/m2 d-5to-2, A 400mg/m2 d-5to-2, M 140mg/m2 d-1). Both groups could receive intrathecal (IT) chemotherapy or involved field radiation (IFRT) to a single site of disease at physician discretion. The sample size of 70–80pts assumed at least 33pts would be assigned to each of the favorable and unfavorable PET response groups, providing a lower limit of 66% for the 95% confidence interval around the expected 80% PFS rate. Results: Target accrual of 70 pts was achieved 5/2007–7/2011, and 67 pts have thus far undergone interim PET/CT restaging following 2 cycles RCHOP (favorable PET=32, unfavorable PET=35). The median IPI score was 3 (IPI 3–5=60pts) and median age was 54 years (range19–65) with 15 pts (21%) older than 60 years. Although there were no statistically significant differences in pt characteristics between PET response groups, the unfavorable PET response pts numerically had more ECOG 2–4 (51% vs 44%), stage IV (86% vs 69%), >1 extranodal site (60% vs 41%), bulk>10cm (54% vs 34%), B symptoms (63% vs 41%), involved marrow (40% vs 28%). IFRT was used for 8 and 5 pts, and IT chemo used for 0 and 3 pts in unfavorable and favorable PET response groups, respectively. At a median follow-up of 24mo, the 2 year OS and PFS rates for all 67 pts are 71% (95%CI 56%, 82%), and 60% (95%CI 46%, 72%), respectively (see figure). The PFS rates for the 35 unfavorable and 32 favorable PET pts were 66% (95%CI 46, 79) and 53% (95%CI 32, 71), respectively (logrank p=0.57). Of the 35 unfavorable PET pts, 3 refused assigned ASCT, 9 (25.7%) relapsed (1 in brain), and 3 (8.6%) experienced non-relapse mortality (NRM) (day+5 post-ASCT from sepsis, 12months post-ASCT from pneumonia, and 30months post-ASCT from recurrent pneumonia and heart failure). Of the 32 favorable PET pts, 12 (37.5%) relapsed (3 in brain); 9 relapses occurred in pts with completely negative PET scans, with no uptake above blood pool. Conclusions: 1) Favorable Interim PET/CT response as defined in this study does not identify good prognosis DLBCL following RCHOPx2, 2) RDICEP-RBEAM/ASCT may decrease relapse for poor prognosis DLBCL pts with unfavorable PET response, but is associated with risks of early and delayed NRM from infection, 3) a phase III trial evaluating this PET-guided RDICEP-RBEAM/ASCT approach compared to standard RCHOP alone is probably not warranted. [Display omitted] Disclosures:Stewart:Hoffmann La Roche: Honoraria, Research Funding. Off Label Use: Rituximab with High Dose Chemotherapy and Autologous Stem Cell Transplantation for DLBCL. Bence-Bruckler:Hoffmann La Roche: Honoraria, Research Funding.

Clinical prognostic factors of diffuse large B cell non-Hodgkin lymphoma: A retrospective study

BackgroundDiffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL in Egypt. It represents about 49% of NHL presenting to the National Cancer Institute (NCI), Cairo University. CHOP regimen is the standard treatment used for NHL since the 1970s with only 30–40% overall survival. Recently, integration of Rituximab became a standard of care for patients with DLBCL. However, its widespread use in developing countries is still limited by the lack of financial coverage. Clinical prognostic factors, as well as the pathological markers, are mandatory to individualize treatment. AimThe aim of the study was to evaluate the clinical risk stratification models including the age adjusted International prognostic index (aaIPI), patients profile and dose intensity (DI) of Cyclophosphamide and Doxorubicin as effective tools for predicting the outcome and prognosis of our DLBCL patients treated with first line CHOP regimen. Patients and methodsThis retrospective study included 224 patients with diffuse large B cell lymphoma who were treated with 3–8 cycles of CHOP regimen at the Medical Oncology Department, NCI, Cairo University during the time period from 1999 to 2006. ResultsOne hundred and seventy-eight patients (79.5%) achieved CR after the CHOP regimen with an observation period of 51months. The median survival time was 12months. The OS and DFS at 2years were 82% and 68.8%, respectively. The univariate analysis of predictive factors for response to treatment showed that the CR rate was significantly affected by aa-IPI and its elements (performance status, stage & LDH), extranodal lesions and DI of Cyclophosphamide and Doxorubicin. The CR rate was 96.9%, 91.2%, 73.9% and 55.6% in cases with aa-IPI 0, 1, 2 and 3, respectively (p<0.001) and it was 82.4%, 81.9% versus 50% in cases with no extranodal site, one extranodal site and two extranodal sites, respectively (p=0.01). As regard DI of Cyclophosphamide, with DI below or equal to the median (249mg/m2/week) the CR rate was 69%, while with DI above the median the CR rate was 87.7% (p=0.001). For Doxorubicin, the CR rate was 72.3% with DI below or equal to the median (16.5mg/m2/week), however, it was 86.6% with DI above the median (p=0.008). The OS rate was significantly affected by aa-IPI as it was 89.8% in cases of aa-IPI 0+1 versus 75.8% in those of aa-IPI 2+3 (p=0.03). DI of Cyclophosphamide and Doxorubicin significantly influenced the OS. The OS rate was 74% with DI of Doxorubicin below or equal to the median versus 96% in cases with DI above the median (p=0.02). For Cyclophosphamide the OS rate was 72.7% with DI below or equal to the median versus 96.3% in cases with DI above the median (p=0.01). The tumor bulk (with a median tumor size of 5cm) affected the OS, which was 91.23% versus 86.8% in the tumor bulk less than and more than or equal to the median, respectively (p=0.05). By multivariate analysis of predictive factors for response to treatment, the CR rate was significantly affected by the number of extranodal sites and the clinical staging of diffuse large B cell lymphoma. However, OS rate was strongly associated with the bulk of the tumor and the clinical staging of diffuse large B cell lymphoma. ConclusionDI of Cyclophosphamide and Doxorubicin is important in the future treatment regimen plan for DLBCL especially in high risk cases. In addition to aa-IPI and its elements, extra nodal sites and bulk of the tumor proved to be significant predictors and prognostic factors for DLBCL treatment outcome.

Multicenter Phase II Study of the CyclOBEAP Regimen for Patients with Peripheral T-Cell Lymphoma with Analysis of Biomakers.

AbstractAbstract 2795Peripheral T-cell lymphoma (PTCL) is more aggressive and has a poorer prognosis than diffuse large B-cell lymphoma (DLBCL). In particular, PTCL, not otherwise specified (PTCL, NOS) is not responsive to conventional chemotherapies. The usefulness of high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation has been reported, although a recent study did not confirm this result. More recent study, however, suggested that intensified regimens may indeed yield superior results to CHOP. We previously administered the CyclOBEAP (cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, prednisolone) regimen to patients with DLBCL, and reported its safety and efficacy.nm23-H1 was originally identified as a protein that was expressed at a lower level in metastatic cancer cells. The nm23 genes play critical roles in cellular proliferation, differentiation, oncogenesis, and tumor metastasis. We previously reported that the serum nm23-H1 level was significantly higher in patients with aggressive lymphoma than in healthy controls, and that a high nm23-H1 level was associated with poor prognosis in patients with aggressive lymphoma. We previously examined cytoplasmic nm23-H1 expression in DLBCLs and found that the serum and cytoplasmic nm23-H1 levels were significant prognostic factors in DLBCLs.Here, we report the results of a multicenter phase II study of the CyclOBEAP regimen for patients with PTCLs [anaplastic large-cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AILT), and PTCL, NOS]. This was a prospective, single-arm phase II trial in the Adult Lymphoma Treatment Study Group (ALTSG) in Japan. Patients were enrolled in the study between April 1998 and March 2006. Patients aged between 18 and 60 years who were in the low-intermediate (L-I), high-intermediate (H-I), or high (H) risk groups, were eligible for this study. The CyclOBEAP regimen was administered over a total period of 12 weeks. In the CyclOBEAP regimen, the dose intensities of cyclophosphamide, doxorubicin, and vincristine are equal to or higher than those in the CHOP regimen, and etoposide and bleomycin were added to the CHOP regimen. There were 84 eligible patients and the median age was 54 years. The median follow-up period was 82 months. A complete response was achieved in 77 patients (92%). The 5-year overall survival (OS) rate was 72% and progression-free survival (PFS) rate was 69%. The 5-year OS was 93% among the ALCL patients, 74% among the AILT patients, and 63% among the PTCL,NOS patients. Further evaluation of the 5-year PFS among the PTCL, NOS and AILT patients (n=70) according to the international prognostic index showed that the 5-year PFS in patients with L-I, H-I or H risk was 77.4%, 48.6% and 25%, respectively (P=0.011). When the patients were divided according to the prognostic index for PTCL (PIT), the 5-year OS and PFS rates did not significantly differ among the risk groups. We next examined the survival curve of patients with PTCL in whom soluble interleukin-2 receptor data were available. The 5-year survival rates of the high (≧2000 IU/ml) and low soluble interleukin-2 receptor groups (<2000 IU/ml) were 60.2 and 69.5%, respectively (p=0.75), with PFS rates of 51.1 and 70.5% (p=0.25). As for nm23-H1 expression in the PTCL, NOS and AILT patients in the present study, the 5-year OS of the nm23-H1-positive group was 46.7% and that of the nm23-H1-negative group was 83.3%, indicating that the nm23-H1-positive group showed significantly poorer prognosis (p = 0.0007). Univariate analysis showed that bone marrow involvement, bulky lesion, serum LDH level, serum albumin level and nm23-H1expression were significant prognostic factors, and in multivariate analysis, nm23-H1 expression was a significant independent prognostic factor. Grade 4 neutropenia was observed in 80 patients and thrombocytopenia in 9 patients.Our results suggest that the CyclOBEAP therapy is safe and effective for the treatment of PTCLs. Furthermore, nm23-H1 protein expression may be an important prognostic factor in PTCLs. Disclosures:No relevant conflicts of interest to declare.

Comparison of two high-dose cyclophosphamide, doxorubicin, vincristine, and prednisone derived regimens in patients aged under 60 years with low–intermediate risk aggressive lymphoma: a final analysis of the multicenter LNH93-2 protocol

One-third of patients aged ≤60 years with aggressive lymphoma are at low–intermediate risk (LIR). Before the rituximab era, we prospectively compared ACVBP with ECVBP, a similar regimen including epirubicin instead of doxorubicin and increased dose intensity of cyclophosphamide, followed by conventional consolidation with an increased amount and dose intensity of cytosine-arabinoside, methotrexate, etoposide, and ifosfamide, in 652 patients with LIR aggressive lymphoma. The overall response rate, 5-year event-free survival (EFS), and survival were estimated to be 86%, 60%, and 74%, respectively, with no differences between the two arms. In patients with diffuse large B-cell lymphoma (DLBCL) who received ACVBP, the 5-year EFS and survival were estimated at 69% and 82%. These findings do not support the use of a chemotherapy regimen more intensive than ACVBP in patients aged ≤60 years with LIR aggressive lymphoma. The results in the control arm, without rituximab, have led to a randomized comparison of R-ACVBP and R-CHOP in this patient population.

Cyclophosphamide Dose Intensification May Circumvent Anthracycline Resistance of p53 Mutant Breast Cancers

The predictive value of p53 for the efficacy of front-line anthracycline-based chemotherapy regimens has been a matter of significant controversy. Anthracyclines are usually combined with widely different doses of alkylating agents, which may significantly modulate tumor response to these combinations. We analyzed three series of de novo stage II-III breast cancer patients treated front line with anthracycline-based regimens of various cyclophosphamide dose intensities: 65 patients with estrogen receptor (ER)(-) tumors treated with anthracyclines alone (Institut Jules Bordet, Brussels), 51 unselected breast cancer patients treated with intermediate doses of cyclophosphamide (MD Anderson Cancer Center, Houston, TX), and 128 others treated with a dose-dense anthracycline-cyclophosphamide combination (St. Louis, Paris). After chemotherapy and surgery, pathologic complete response (pCR) was evaluated. p53 status was determined by a yeast functional assay on the pretreatment tumor sample. In a multivariate analysis of the pooled results, a lack of ER expression and high-dose cyclophosphamide administration were associated with a higher likelihood of pCR. A sharp statistical interaction was detected between p53 status and cyclophosphamide dose intensity. Indeed, when restricting our analysis to patients with ER(-) tumors, we confirmed that a mutant p53 status was associated with anthracycline resistance, but found that p53 inactivation was required for response to the dose-intense alkylating regimen. The latter allowed very high levels of pCR in triple-negative tumors. Thus, our data strongly suggest that cyclophosphamide dose intensification in ER(-) p53-mutated breast cancer patients could significantly improve their response.