3-year Progression-free Survival Estimate Research Articles

Treatment Patterns and Outcomes for Patients with Classic Hodgkin Lymphoma (cHL) and Cardiomyopathy with Low Ejection Fraction (EF): Real-World Evidence (RWE) from 16 US Academic Centers

Introduction The cornerstone for management of newly diagnosed patients (pts) with cHL is an anthracycline (AC) based chemotherapy (chemo) regimen. There are a paucity of data available regarding treatment patterns and outcomes for cHL pts with low EF. Furthermore, cHL pts with low EF are typically excluded from clinical trials limiting our understanding on management of these pts. Methods This was a multicenter retrospective cohort study evaluating pts with newly diagnosed cHL with low EF from 16 US medical centers. Eligible pts included adults diagnosed after 1/1/2010 with pretreatment EF of <50% on echocardiogram. Pts who developed reduced EF during or after first-line treatment were excluded. Based on EF, pts were divided into 2 groups (gp): <45% (gp 1) and 45-49% (gp 2). First-line treatment was categorized into AC based and non-AC based therapies. Primary outcome was progression-free survival (PFS). Secondary outcomes included response rates to first-line therapy and overall survival (OS). Time to event endpoints were evaluated by Kaplan-Meier and Cox proportional hazard methods. Results The study included 69 pts with a median age of 55 yrs (21-88), 74% males, and performance status (PS) of ECOG 0-1 in 65%. There were 37 (54%) pts in gp 1 and 32 (46%) in gp 2. 39 pts received AC and 30 received non-AC based therapies. Pts in the AC group were significantly younger (median age, 46 vs 64 yrs), had higher proportion with EF of 45-49% (72% vs 13%) & ECOG PS of 0-1 (82% vs 54%) compared to non-AC based therapies. Among the 30 pts who received non-AC based therapies, 26 were in gp 1 and 4 in gp 2. Non-AC based therapies included BV monotherapy (n=6), non-AC BV-based therapies (n=11), and other non-AC chemo (n=13). The most common BV based therapy was BV+dacarbazine (n=4) followed by BV+bendamustine (n=3), while the most common other non-AC chemo was MOPP (n=4) followed by ChlVPP (n=3). The overall response rate (ORR) and complete response rate (CRR) to AC based therapy was 77% (30/39) and 69% (27/39), respectively. Among the non-AC therapies, the ORR/CR rates for BV monotherapy, BV based therapies, and other non-AC chemo were 33%/17%, 55%/27%, and 61%/54%, respectively. The median PFS for the entire cohort was 2.7 yrs (95%CI= 0.80-5.01). The median PFS for gp 1 vs gp 2 was 1.55 yrs and 4.20 yrs, respectively (p=0.26). The median PFS was significantly longer in pts receiving AC based compared to non-AC therapies (5.01 yrs vs 0.55 yrs, <0.001, Figure 1) with 3- and 5-yr PFS estimates of 62% vs 27%, and 54% vs 16%, respectively. Among the recipients of non-AC therapies, the 3-year PFS estimates for BV monotherapy, BV based therapies, and other non-AC chemo was 20%, 34%, and 42%, respectively (p=0.25). The median OS for the entire cohort was 5.6 yrs (95% CI=3.47-NR). The median OS for gp 1 vs gp 2 was 5.41 yrs and 5.73 yrs, respectively (p=0.82). The median OS was significantly longer in pts receiving AC based compared to non-AC therapies (7.43 yrs vs 3.20 yrs, p=0.003) with 3- and 5-yr OS estimates of 80% vs 60% and 80% vs 30%, respectively. Among the recipients of non-AC therapies, the 3-year OS estimates for BV monotherapy, BV based therapies and other non-AC chemo were 44%, 78% and 51%, respectively. Univariable Cox models tested baseline pt and disease variables and found increasing age, ECOG PS ≥2, and the presence of geriatric syndrome to be prognostic of inferior PFS and OS but not EF gp. Only increasing age remained associated with significantly inferior PFS and OS in multivariable analysis ( Table 1). After adjusting for these variables together with the inclusion of first-line treatment (AC vs non-AC based therapies), we found first-line treatment with AC-based therapy was associated with superior PFS (aHR= 0.39, 95% CI=0.15-0.97, p=0.04) but not OS (aHR= 0.51 (95% CI=0.16-1.65, p=0.26, Table 1). With inclusion of treatment, only age remained associated with inferior OS in the multivariable adjustment (aHR=1.27, 95%CI=1.04-1.54). Conclusion This first RWE of cHL pts with low EF found that a majority of pts with EF of 45-49% were treated with AC-based therapies. Furthermore, PFS was improved for pts who received AC-based therapies. However, outcomes appeared modest for pts compared with expectant outcomes. Collectively, these data underscore the critical need for prospective interventional studies in this challenging pt population. Further data on AC dosing, safety, risk of AC-induced heart failure, etc. will be presented at the meeting.

RADT-40. FINAL RESULTS OF THE PROSPECTIVE PHASE 2 MARCIE TRIAL: EFFICACY AND TOXICITY OF POSTOPERATIVE BIMODAL RADIOTHERAPY WITH C12-BOOST IN PATIENTS WITH ATYPICAL MENINGIOMAS FOLLOWING SUBTOTAL RESECTION

Abstract Radiotherapy is recommended by current EANO guidelines for patients with atypical meningiomas (WHO grade 2) following subtotal resection. While meningiomas are generally considered radioresistant, novel radiotherapeutic modalities using carbon ions present an increased relative biological effectiveness (RBE) compared to photons, while reducing the radiation exposure for adjacent organs at risk by exploiting the Bragg peak. Our prospective phase 2 trial investigated bimodal radiotherapy using a carbon-ion boost in patients with atypical meningiomas following subtotal resection. A total of 33 patients were enrolled from 07/2012 until 07/2020. The study was prematurely terminated in 07/2020 after recruiting 33 of the initially planned 40 patients due to one grade 5 toxicity. Study treatment comprised a carbon ion boost (18 Gy [RBE] in 6 fractions) targeted to the macroscopic tumor in combination with photon radiotherapy (50 Gy in 25 fractions). The primary endpoint was progression-free survival, and secondary endpoints included overall survival, safety and toxicities. With a median follow-up of 42 months, the 3-year estimates of progression-free survival (PFS), local PFS and overall survival were 80.3%, 86.7% and 89.8%, respectively. Radiation-induced contrast enhancements (RICE) was encountered in 45%, particularly in cases of periventricularly-located meningiomas. Patients exhibiting (transient) RICE were either asymptomatic (40%) or presented immediate improvement (47%) after the administration of corticosteroids or/and bevacizumab. Treatment-associated complications were encountered in 2 patients with radiation necrosis: 1 patient died due to postoperative complications in an external center after resection of radiation necrosis, and the other received an aggregated 21 cycles of bevacizumab. As a result, the study was prematurely terminated. Post-hoc integrated molecular-morphologic scoring identified patients at risk of tumor progression. Study treatment may be considered for selected patients with molecular high-risk meningiomas to achieve high tumor control rates. Patients’ risk to develop radiation-induced side effects depends on the location of the treatment volume.

DA.R-EPOCH Vs. R-CHOP for High-Risk Diffuse Large B- Cell Lymphoma: The Mayo Clinic Florida Experience

▪BACKGROUNDDiffuse large B cell lymphoma (DLBCL) is a heterogeneous entity with varied outcomes. A subset of DLBCL with high-risk features carries poor prognosis with an increased relapse rate when treated with chemoimmunotherapy regimen incorporating rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (DA.R-EPOCH) regimen is a high intensity regimen commonly used for the upfront treatment of high-risk DLBCL, especially DLBCL with c-Myc ± BCL2/BCL6 translocation. A phase 3 study (CALGB 50303) comparing R-CHOP and DA.R-EPOCH in untreated DLBCL did not show any difference in progression free survival (PFS) or overall survival (OS), however specific outcomes of high-risk DLBCL are unknown. (Wilson et al. ASH 2016) In this study, we analyzed the clinical outcomes in a longitudinal cohort of patients with high-risk DLBCL who received DA.R-EPOCH, and compared it to the similar group of patients who received R-CHOP during the same period at our institute.METHODPatients diagnosed with DLBCL who received chemo-immunotherapy at our center between January 2011 to December 2016 were included in the analysis. High-risk DLBCL was defined by the presence of any of the following features at the time of diagnosis: International prognostic index (IPI) score >/= 4, tumor measuring >/=5 cm, c-Myc ± BCL2/BCL6 translocation by FISH or overexpression by immunohistochemistry, Ki-67 index >/= 80% and activated B-cell (ABC) phenotype by Han's algorithm. Patients without these features were deemed to have standard risk-DLBCL. Clinical characteristics, grade 3/4 toxicities (CTCAE v4) and need for hospitalization and transfusion support were reviewed. Responses were evaluated at middle and end of chemotherapy. Overall (OS) and progression free survival (PFS) were calculated. Cox proportional hazard regression was performed to assess influence of clinical and treatment variables on OS and PFS.RESULTSA longitudinal cohort of 95 patients was included in this analysis. All standard risk DLBCL (N=15) patients were treated with R-CHOP. Eighty patients with high-risk DLBCL were treated with R-CHOP (N= 52, 65%) and DA.R-EPOCH (N= 28, 35%) respectively. Table 1 shows baseline clinical characteristics of all high-risk DLBCL patients. DA.R-EPOCH cohort had more patients with higher Ann Arbor stage, ABC phenotype and BCL2/BCL6 expression. Rate of treatment completion and complete response rate at the end of treatment were similar in both groups. DA.R-EPOCH was associated with increased grade 3/4 neutropenia and need for transfusions during treatment. The median follow up was 13.3 months and 10.9 months for DA.R-EPOCH and R-CHOP group respectively. There was no significant difference in OS and PFS among high-risk DLBCL patients treated with DA.R-EPOCH compared to R-CHOP: 3-year estimates of PFS with DA.R-EPOCH vs. R-CHOP was 77% and 71% respectively, while the 3-year estimates of OS was 80% and 66% respectively. The hazard ratio (HR) for PFS was 0.79 (95% CI- 0.28-2.29, P=0.67) and OS was 0.86 (95% CI- 0.26-2.78, P- 0.80). (Figure 1) Low baseline serum albumin levels, ECOG performance status >/=2, elevated LDH and high IPI were associated with poor OS and PFS.CONCLUSIONIn our retrospective analysis, treatment of patients with high-risk DLBCL with DA.R-EPOCH resulted in similar clinical outcomes, but was associated with increased incidence of grade 3/4 neutropenia and need for transfusions during treatment when compared to those receiving R-CHOP regimen. Patients receiving DA.R-EPOCH regimen had more adverse features in terms of disease stage and phenotype. A prospective randomized comparison is warranted between these two regimens for high-risk DLBCL. Until such prospective studies show benefit in any sub-set of DLBCL, DA.R-EPOCH should be used with judicious clinical discretion. [Display omitted] DisclosuresAilawadhi:Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pharmacyclics: Research Funding; Novartis: Consultancy, Honoraria.

Double Autologous Stem Cell Transplantation Significantly Prolongs Progression-Free Survival and Overall Survival in Comparison with Single Autotransplantation in Newly Diagnosed Multiple Myeloma: An Analysis of Phase 3 EMN02/HO95 Study

Background The role of single vs double autologous stem cell transplantation (ASCT) for newly diagnosed (ND) multiple myeloma (MM) continues to be debated in the novel agent era. Methods The phase III EMN02/HO95 study was designed to administer 3-4 cycles of bortezomib-cyclophosphamide-dexamethasone as induction therapy for NDMM and afterwards to randomize eligible patients to receive (randomization 1, R1) standard-dose intensification treatment with bortezomib-melphalan-prednisone (VMP) for four 42-day cycles or high-dose intensification treatment with melphalan at 200 mg/m2 (HDM) plus ASCT. A second randomization to receive or not receive consolidation therapy was planned after the intensification phase, followed by lenalidomide maintenance in both arms. In centers committed to a double ASCT policy, patients were randomized (1:1:1) to receive VMP or single ASCT (ASCT-1) or two sequential courses of HDM (administered 2 to 3 months apart) plus double ASCT (ASCT-2) in order to prospectively compare ASCT-1 vs ASCT-2, which was an additional study objective. For this purpose, and for consistency with the primary study end point, progression-free survival (PFS) from R1 was evaluated. Results A total of 1503 patients aged ≤65 years were registered and 1192 were eligible for R1. By study design, 618 patients who received the diagnosis of MM in centers with a double ASCT policy were randomly assigned to VMP (n=203) or ASCT-1 (n=208) or ASCT-2 (n=207). 415 of these patients who were randomized to receive ASCT-1 or ASCT-2 were included in the current pre-specified analysis. Median age was 58 years for patients in the ASCT-1 group and 57 years for those in the ASCT-2 group. The frequency of ISS stage III was 19% in both groups. According to IMWG criteria, a high-risk (HiR) cytogenetic profile defined by t(4;14) ± t(14;16) ± del(17p) positivity (HiR-cyto-3) was detected in 26% and 21% of patients who were evaluable in ASCT-1 (80%) and ASCT-2 (86%) groups. The presence of amp(1q) ± del(1p) ± 1 or more of t(4;14), t(14;16) and del(17p) identified a HiR cytogenetic profile (HiR-cyto-5) which was detected in 55% of patients in ASCT-1 arm and 50% of those in ASCT-2 arm. Median follow-up from R1 was 38 (IQR: 29-47) months for the overall patient population (36 and 39 months for patients randomized to ASCT-1 and ASCT-2, respectively). On an intention-to-treat basis, 3-year estimate of PFS was 73% (95% CI=66-79) for ASCT-2 group vs 64% (CI=57-71) for ASCT-1 group (HR=0.70; CI=0.50-0.98; P=0.040), which represented a 30% reduced risk of progression or death in the ASCT-2 group compared with the ASCT-1 group (Fig. 1a). PFS benefit associated with ASCT-2 was confirmed in subgroups of patients with HiR-cyto-3 (HR=0.42; CI=0.21-0.84; P=0.014), revised ISS (R-ISS) stage II+III (HR=0.64; CI=0.43-0.97; P=0.034), age >55 years (HR=0.64; CI=0.43-0.96; P=0.033); HiR-cyto-5 (HR=0.65; CI=0.42-1.01; P=0.059) and best ≥VGPR (HR=0.64; CI=0.44-0.94; P=0.023). Importantly, ASCT-2 overcame the adverse prognosis conferred by HiR-cyto-3 (3-year PFS: 76% vs 69% for patients with standard-risk cytogenetic profile; P=0.482) (Fig. 1b). In particular, 3-year PFS estimate for patients randomized to ASCT-2 and carrying or lacking del(17p) was 72% vs 73%, respectively (P=0.534). The corresponding PFS values in the ASCT-1 group were 43% vs 67%, respectively (P=0.014). In a multivariate Cox regression analysis, randomization to ASCT-2 (HR=0.65; CI=0.44-0.95; P=0.029), R-ISS I (HR=0.60; CI=037-0.98; P=0.042), absence of HiR-cyto-5 (HR=0.35; CI=0.22-0.55; P Conclusions Randomization to ASCT-2 was superior over ASCT-1 in terms of prolonged PFS and OS for the overall patient population and for poor prognosis subgroups of patients with advanced R-ISS disease stage and HiR cytogenetic profile. Incorporation of bortezomib into ASCT-2 abrogated the increased risk of progression or death imparted by t(4;14) ± t(14;16) ± del(17p), and in particular by del(17p) positivity. Disclosures Gay: Amgen: Honoraria; Mundipharma: Membership on an entity9s Board of Directors or advisory committees; Roche: Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Honoraria; Seattle Genetics: Membership on an entity9s Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria. Bringhen: Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Amgen: Membership on an entity9s Board of Directors or advisory committees; Mundipharma: Membership on an entity9s Board of Directors or advisory committees; Karyipharm: Membership on an entity9s Board of Directors or advisory committees. Musto: janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria. Palumbo: Takeda: Consultancy, Employment, Equity Ownership, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding; Binding Site: Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Genmab A/S: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Sonneveld: Celgene Corporation, Amgen, Janssen, Karyopharm, PharmaMar, SkylineDx: Honoraria; Celgene, Amgen, Janssen, Karyopharm, Takeda: Consultancy, Honoraria, Research Funding; Celgene Corporation, Amgen, Janssen, Karyopharm, SkylineDx, PharmaMar: Consultancy.

Burkitt Lymphoma International Prognostic Index.

Burkitt lymphoma (BL) has unique biology and clinical course but lacks a standardized prognostic model. We developed and validated a novel prognostic index specific for BL to aid risk stratification, interpretation of clinical trials, and targeted development of novel treatment approaches. We derived the BL International Prognostic Index (BL-IPI) from a real-world data set of adult patients with BL treated with immunochemotherapy in the United States between 2009 and 2018, identifying candidate variables that showed the strongest prognostic association with progression-free survival (PFS). The index was validated in an external data set of patients treated in Europe, Canada, and Australia between 2004 and 2019. In the derivation cohort of 633 patients with BL, age ≥ 40 years, performance status ≥ 2, serum lactate dehydrogenase > 3× upper limit of normal, and CNS involvement were selected as equally weighted factors with an independent prognostic value. The resulting BL-IPI identified groups with low (zero risk factors, 18% of patients), intermediate (one factor, 36% of patients), and high risk (≥ 2 factors, 46% of patients) with 3-year PFS estimates of 92%, 72%, and 53%, respectively, and 3-year overall survival estimates of 96%, 76%, and 59%, respectively. The index discriminated outcomes regardless of HIV status, stage, or first-line chemotherapy regimen. Patient characteristics, relative size of the BL-IPI groupings, and outcome discrimination were consistent in the validation cohort of 457 patients, with 3-year PFS estimates of 96%, 82%, and 63% for low-, intermediate-, and high-risk BL-IPI, respectively. The BL-IPI provides robust discrimination of survival in adult BL, suitable for use as prognostication and stratification in trials. The high-risk group has suboptimal outcomes with standard therapy and should be considered for innovative treatment approaches.

Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables

AbstractTo define the efficacy of venetoclax with extended follow-up and identify clinical or biological treatment effect modifiers, updated data for previously treated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) enrolled in 4 early-phase trials were pooled. Rates of response, complete remission (CR/CRi), and undetectable minimal residual disease (U-MRD) were analyzed for all patients (n = 436) and for those patients who were planned to receive 400 mg/day monotherapy (n = 347). Univariate and multiple regression analyses were performed to identify the pretreatment factors associated with response rates and duration of response (DoR). Objective responses were documented in 75% of all patients, including 22% CR/CRi. Overall, 27% and 16% of the patients achieved U-MRD in blood and marrow, respectively. Estimated median progression-free survival (PFS), DoR, and time to progression were 30.2, 38.4, and 36.9 months, respectively. Similar efficacy outcomes were observed within the 400 mg/day monotherapy subset. For those who achieved CR/CRi, the 3-year PFS estimate was 83%. DoR was superior for patients achieving CR/CRi or U-MRD in landmark analyses. In multiple regression analyses, bulky lymphadenopathy (≥5 cm) and refractoriness to B-cell receptor inhibitor (BCRi) therapy were significantly associated with lower CR rate and shorter DoR. Fewer prior therapies were associated with higher CR rate, but not DoR. Chromosome 17p deletion and/or TP53 mutation and NOTCH1 mutation were consistently associated with shorter DoR, but not probability of response. Thus, both pretreatment factors and depth of response correlated with DoR with venetoclax. Patients without bulky lymphadenopathy, BCRi-refractory CLL, or an adverse mutation profile had the most durable benefit.

Upfront Single Versus Double Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma: An Intergroup, Multicenter, Phase III Study of the European Myeloma Network (EMN02/HO95 MM Trial)

▪BackgroundThe role of single vs double autologous stem cell transplantation (ASCT) in patients with newly diagnosed (ND) multiple myeloma (MM) needs to be prospectively investigated in the novel agent era.MethodsThe phase III EMN02/HO95 study was designed to compare (first randomization, R1) (stratification according to ISS stage) standard-dose intensification therapy with bortezomib-melphalan-prednisone (VMP) vs high-dose intensification therapy with melphalan at 200 mg/m2 (HDM) followed by ASCT after 3-4 cycles of bortezomib-cyclophosphamide-dexamethasone as induction therapy. A second randomization to consolidation therapy vs no consolidation was performed after intensification therapy, to be followed by lenalidomide maintenance until progression or toxicity in both arms. A primary study endpoint was progression-free survival (PFS) from R1. In centers with a policy of double ASCT, patients were randomized in a 1:1:1 ratio to either VMP or single ASCT (ASCT-1) or two sequential courses (administered 2 to 3 months apart) of HDM and double ASCT (ASCT-2) in order to prospectively compare ASCT-1 with ASCT-2, which was an additional study objective.ResultsFrom February 2011 to April 2014, 1510 pts aged ≤65 years with symptomatic NDMM were registered and 1192 of these were eligible for R1. According to the design of the study, 614 eligible patients who received the diagnosis of MM in centers with a double intensification policy were randomly assigned to either VMP (n=199) or ASCT-1 (n=208) or ASCT-2 (n=207). Patients randomized to ASCT-1 or ASCT-2 were included in the current pre-specified analysis. Median age was 59 years for patients in the ASCT-1 group and 57 years for those in the ASCT-2 group. The frequency of ISS stage III was 18% and 19%, while revised ISS stage III was 9% and 11%, respectively. Cytogenetic abnormalities were detected by FISH analysis of CD138+ plasma cells. A high-risk (HR) cytogenetic profile, defined by t(4;14) and/or del(17p) and/or t(14;16) (HR cyto-3), was observed in 26% of evaluable patients who were randomized to ASCT-1 and in 21% of those randomly assigned to ASCT-2. If amp(1q) and/or del(1p) were added for the definition of high-risk disease, a HR cytogenetic profile that included at least 1 of the 5 above mentioned chromosomal abnormalities (HR cyto-5) was reported in 55% of evaluable patients in the ASCT-1 group and in 54% of those in the ASCT-2 group. Median follow-up from R1 was 27 (IQR: 20-35) months. On an intention-to-treat basis, the median PFS was 45 months in the ASCT-1 arm and was not yet reached for patients in the ASCT-2 arm; 3-year estimates of PFS were 60% and 73%, respectively (HR=0.66; 95% CI=0.45-0.96; P=0.030). PFS benefit with ASCT-2 was retained across predefined subgroups, including patients with β2-microglobulin >3.5 mg/L (HR=0.59; CI=0.34-0.99; P=0.005), bone marrow plasma cells >60% (HR=0.41; CI=0.22-0.77; P=0.006), LDH values above the upper limits (HR=0.52; CI=0.28-095; P=0.034), revised ISS stage II (HR=0.50; CI=0.31-0.80; p=0.004), HR cyto-3 (HR=0.49; CI=0.24-1.02; P=0.057) and HR cyto-5 (HR=0.57; CI=0.35-0.93; P=0.024). In a multivariate Cox regression analysis stratified by ISS stage, randomization to ASCT-2 (HR=0.62; CI=0.40-0.95; P=0.027) and HR cyto-5 (HR=2.63; CI=1.63-4.16; P<0.001) were the leading independent predictors of PFS. Overall survival was not yet mature and no difference between the two treatment groups was evident.ConclusionsUpfront double ASCT after bortezomib-based induction therapy for newly diagnosed MM was superior over a single ASCT in terms of prolonged PFS. Clinical benefits of double ASCT were mostly seen in patients with disease-related factors predicting for poor prognosis. DisclosuresCavo:Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria. Offidani:Janssen: Honoraria; Celgene: Honoraria, Research Funding. Boccadoro:Janssen: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding; Mundipharma: Research Funding; Amgen: Honoraria, Research Funding; SANOFI: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbivie: Honoraria.

Intensification Therapy with Bortezomib-Melphalan-Prednisone Versus Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma: An Intergroup, Multicenter, Phase III Study of the European Myeloma Network (EMN02/HO95 MM Trial)

▪BackgroundThe role of upfront autologous stem cell transplantation (ASCT) for younger patients with newly diagnosed (ND) multiple myeloma (MM) has been questioned in the novel agent era.MethodsA prospective, multicenter, phase III study was designed to compare (first randomization, R1) (1:1 ratio; stratification according to ISS stage) four 42-day cycles of bortezomib-melphalan-prednisone (VMP) given at the same dosing schedule reported in the VISTA study (NEJM 2008; 359:906-17) vs either a single course or two sequential courses of melphalan at 200 mg/m2 (HDM) followed by single or double ASCT, respectively, as intensification therapy after three to four 21-day cycles of induction therapy with bortezomib-cyclophosphamide-dexamethasone and subsequent collection of peripheral blood stem cells. A second randomization (R2) to consolidation therapy with bortezomib-lenalidomide-dexamethasone vs no consolidation was performed after intensification, to be followed by lenalidomide maintenance until progression or toxicity in both arms. A primary study end point was progression-free survival (PFS) from R1.ResultsFrom February 2011 to April 2014, 1510 patients aged ≤65 years with symptomatic NDMM were registered. Of these, 1192 were eligible for R1 and were randomly assigned to receive either VMP (n=497 patients) or HDM (1±2 courses) (n=695 patients). Median age was 58 years in both groups, ISS stage III was 21% in VMP and 20% in HDM, while revised ISS stage III was 9% in both groups. Data on cytogenetic abnormalities, as detected by FISH analysis of CD138+ plasma cells, were available in 71% of patients (n=354) randomized to VMP and in 76% of those (n=529) assigned to HDM. The frequency of conventionally defined high-risk cytogenetic changes, including t(4;14) and/or del(17p) and/or t(14;16), was 25% in both arms. Median follow-up from R1 was 26 (IQR: 19-37) months. On an intention-to-treat basis, median PFS was 44 months in the VMP arm and was not yet reached in the HDM arm; 3-year estimates of PFS were 57.5% and 66%, respectively (HR=0.73; 95% CI=0.59-0.90; P=0.003). PFS benefit with HDM was retained across predefined subgroups, including patients with ISS stage I (HR=0.69; CI=0.48-0.98; P=0.037), revised ISS stage II (HR=0.70; CI=0.54-0.91; P=0.008), revised ISS stage III (HR=0.54; CI=0.30-0.97; P=0.040), standard-risk cytogenetics (HR=0.75, CI=0.56-1.01; P=0.055) and a high-risk cytogenetic profile (HR=0.54; CI=0.37-0.80; P=0.002). The probability of achieving a very good partial response or higher quality response was 85.5% in the HDM group vs 74% in the VMP group (odds ratio=1.90; CI=1.42-2.54; P<0.001). In a multivariate Cox regression analysis stratified by ISS, randomization to HDM (HR=0.67; CI=0.53-0.85; P=0.001) and absence of high-risk cytogenetic abnormalities (0.71; CI=0.53-0.95; P=0.021) were the leading independent predictors of prolonged PFS. Overall survival was not yet mature and no difference between the two treatment groups was evident. Detection of minimal residual disease (MRD) after intensification therapy was performed by multiparameter flow cytometry and PET/CT in a subgroup of patients, and details are provided in a separate abstract (E. Zamagni et al). Overall, MRD negativity favorably affected PFS and OS.ConclusionsIn comparison with VMP as standard-dose intensification therapy, upfront HDM and ASCT significantly improved PFS and increased the rate of high quality responses. An updated analysis with a longer follow-up will be reported at the meeting. Results of this phase III study, the largest so far reported, support the conclusion that upfront ASCT still continues to be the reference treatment for fit patients with NDMM, even in the novel agent era. DisclosuresCavo:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria. Beksac:Celgene, Janssen Cilag Amgen, Novartis, Takeda: Honoraria, Speakers Bureau. Dimopoulos:Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Gay:Celgene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria, Other: Advisory Board; Janssen-Cilag: Other: Advisory Board; Mundipharma: Other: Advisory Board. Hájek:Janssen: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; BMS: Honoraria; Celgene: Consultancy, Research Funding. Mellqvist:Mundipharma: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Takeda: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Galli:Celgene: Honoraria; Janssen: Honoraria; Sigma-tau: Honoraria. Ludwig:Janssen: Speakers Bureau; BMS: Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau. Zweegman:Janssen: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria.

Bfr (bendamustine, fludarabine, rituximab) Nonmyeloablative Allogeneic Conditioning Improves Survival in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL).

Background: Bendamustine is a novel active agent in CLL with favorable safety profile. We recently reported the preliminary results of allogeneic stem cell transplantation (alloSCT) in lymphoma/CLL patients (pts) after BFR conditioning (Khouri et al. Blood 2014; 124:2306). Herein, we report more mature outcomes in CLL pts. Results and safety were compared with a previous regimen using FCR (fludarabine, cyclophosphamide, rituximab).Patients and Methods: We studied 89 CLL pts treated on 3 trials (one includes FCR later changed to BFR) at our center. Twenty-six (29%) pts received BFR and 63 (71%) received FCR. The BFR regimen consisted of bendamustine 130 mg/m2 IV daily on days -5 to - 3 prior to transplantation, thus substituting the cyclophosphamide in the FCR regimen. The dose and schedule of fludarabine (30 mg/m2 IV daily on days -5 to -3) and rituximab (375 mg/m2 IV on day -13 and 1000 mg/m2 on days -6, +1, +8) were similar in both regimens. Tacrolimus and mini-methotrexate were used for GVHD prophylaxis. In addition, thymoglobulin 1 mg/kg IV was given on days -2, and -1 in patients receiving a matched unrelated donor (MUD) transplant.Results: Patient characteristics were similar in both groups. This included median age (58 years in both), sex distribution, and median number of prior therapies (3 in both), % pts with β2-microglobulin >3 mg/L at study entry, refractory disease (38% in BFR vs. 48% in FCR, P=0.4), presence of 17p deletion [27% in BFR vs. (8/33) 24% in FCR], unmutated status [19/21 (90%) of BFR vs 22/24 (92%) in FCR] and peripheral blood stem cell source (92% in BFR vs. 87% in FCR). Donor/recipient CMV and sex-mismatched distributions were not significantly different between the groups. However, more patients received their transplants from unrelated donors in the BFR group than the FCR group (54% vs. 32%, P=0.05). Ten (38%) BFR pts vs 2 (3%) FCR pts did not experience severe neutropenia (P <0.001) and 21 (81%) vs 39 (63%), respectively, did not require platelet transfusions (P=0.08). Median follow-up times for BFR and FCR groups were 29 (range 19-60), and 104 (range, 34-195) months. The 3-year overall survival (OS) estimates in the BFR and FCR groups were 82% vs. 51% (P=0.03) and the 3-year progression-free survival estimates were 63% vs. 27% (P=0.001). The 3-year OS improvements were seen across the prognostic factors studied for BFR and FCR respectively: MUD (93% vs 30%), presence of 17p deletion (86% vs 50%), and age >50 years (79% vs 50%), β2-microglobulin >3 mg/L (73% vs 45%), >3 prior lines of therapy (70% vs 43%) and recent years of transplant (82% vs 47%). Treatment-related mortality was 11% and 27% (P=0.05) at 2-year. The incidence of acute grade 3 GVHD was 4% and 10% in the BFR and FCR groups, respectively, despite the higher % of MUD transplants in BFR. Grade 4 acute GVHD was not observed in either group. The 3-year incidence of extensive chronic GVHD in BFR vs FCR was 45% vs 58% (P=0.01). This difference in GVHD incidence may in part be explained by a lower absolute blood level of CD8+ T cells in BFR patients compared to the FCR group at 6 months (median 343 vs 538, respectively) and 9 months (median 208 vs 406, respectively) post alloSCT.Conclusions: This is the first study to show that conditioning in alloSCT for CLL impacts outcomes with an improved survival after BFR when compared to the FCR regimen. DisclosuresNo relevant conflicts of interest to declare.

Risk-stratified outcomes of nonmyeloablative HLA-haploidentical BMT with high-dose posttransplantation cyclophosphamide

AbstractRelated HLA-haploidentical blood or marrow transplantation (BMT) with high-dose posttransplantation cyclophosphamide (PTCy) is being increasingly used because of its acceptable safety profile. To better define outcomes of nonmyeloablative (NMA) HLA-haploidentical BMT with PTCy, 372 consecutive adult hematologic malignancy patients who underwent this procedure were retrospectively studied. Risk-stratified outcomes were evaluated using the refined Disease Risk Index (DRI), developed to stratify disease risk across histologies and allogeneic BMT regimens. Patients received uniform conditioning, T-cell–replete allografting, then PTCy, mycophenolate mofetil, and tacrolimus. Six-month probabilities of nonrelapse mortality and severe acute graft-versus-host disease were 8% and 4%. With 4.1-year median follow-up, 3-year probabilities of relapse, progression-free survival (PFS), and overall survival (OS) were 46%, 40%, and 50%, respectively. By refined DRI group, low (n = 71), intermediate (n = 241), and high/very high (n = 60) risk groups had 3-year PFS estimates of 65%, 37%, and 22% (P < .0001), with corresponding 3-year OS estimates of 71%, 48%, and 35% (P = .0001). On multivariable analyses, the DRI was statistically significantly associated with relapse, PFS, and OS (each P < .001). This analysis demonstrates that the DRI effectively risk stratifies recipients of NMA HLA-haploidentical BMT with PTCy and also suggests that this transplantation platform yields similar survivals to those seen with HLA-matched BMT.

Pretherapy metabolic tumour volume is an independent predictor of outcome in patients with diffuse large B-cell lymphoma.

We investigated the prognostic value of total metabolic tumour volume (TMTV) in diffuse large B-cell lymphoma (DLBCL). TMTV was measured in 114 patients with newly diagnosed DLBCL who underwent (18)F-FDG PET/CT at baseline before immunochemotherapy. TMTV was computed by summing the volumes of all lymphomatous lesions after applying the local SUVmax threshold of 41% using semiautomatic software. Prognostic value was assessed by Kaplan-Meier estimates of progression-free survival (PFS) and overall survival (OS). Median follow-up was 39 months. Average pretherapy TMTV was 509 ± 568 cm(3). The 3-year estimates of PFS were 77 % in the low metabolic burden group (TMTV ≤550 cm(3)) and 60% in the high metabolic burden group (TMTV >550 cm(3), p = 0.04), and prediction of OS was even better (87% vs. 60%, p = 0.0003). Cox regression showed independence of TMTV for OS prediction (p = 0.002) compared with other pretherapy indices of tumour burden, such as tumour bulk and the International Prognostic Index. Pretherapy TMTV is an independent predictor of outcome in patients with DLBCL.

An international confirmatory study of the prognostic value of early PET/CT in diffuse large B-cell lymphoma: comparison between Deauville criteria and ΔSUVmax

The role of interim PET/CT in guiding therapeutic strategies in diffuse large B-cell lymphoma (DLBCL) is debated, mainly because interpretation rules vary among centres. This study aimed to explore the reproducibility and confirm the prognostic value of early PET/CT using the Deauville criteria and ΔSUVmax. This international confirmatory study retrospectively evaluated 114 patients with newly diagnosed DLBCL treated with a rituximab-containing regimen. All patients underwent ¹⁸F-FDG PET/CT at baseline (PET0) and after two cycles (PET2), with no therapy change based on the latter. Scans were interpreted by three observers using the Deauville five-point scale and ΔSUVmax between PET0 and PET2 was calculated. Interpretations were evaluated for interobserver agreement and for progression-free survival (PFS) prediction. Median follow-up was 39 months. Early PET/CT was predictive of outcome when interpreted with the Deauville criteria and ΔSUVmax. Using the five-point scale, the overall kappa value was 0.66 with the reference background set in the liver (score ≥4) and interobserver agreement was even better using a 66% ΔSUVmax cut-off (κ = 0.83). Moreover, the prognostic value of interim PET was slightly inferior when using a Deauville score ≥4 than when using a 66% ΔSUVmax cut-off: for the Deauville score the 3-year PFS estimate was 59% (45-73%) in PET2-positive patients vs. 81% (71-91%) in PET2-negative patients (P = 0.003); for the 66% ΔSUVmax cut-off the 3-year PFS estimate was 44% (23-65%) in PET2-positive patients vs. 79% (70-88%) in PET2-negative patients (P = 0.0002). Although the Deauville criteria are valid for assessing the prognostic value of early PET/CT in DLBCL, computation of the ΔSUVmax leads to better performance and interobserver reproducibility, and should be preferred when a baseline scan is available.

A Retrospective Study to Evaluate the Survival Rates in R-CHOP Chemotherapy Followed by Autologous Stem Cell Transplantation for the Treatment of Diffuse Large B Cell Lymphoma

AbstractAbstract 4517Prognosis in diffuse large B cell lymphoma (DLBCL) is highly associated with the International Prognostic Index (IPI) score, which was proposed to assign prognosis to patients with aggressive non-Hodgkin lymphoma undergoing treatment with doxorubicin-containing chemotherapy. The addition of rituximab to CHOP or CHOP-like regimens has resulted in significant improvements in the overall survival (OS) rate of CD20 positive DLBCL. In addition, the original IPI scoring system has been validated even in patients receiving rituximab-based chemotherapy. However, OS and progression-free survival (PFS) in patients with high-intermediate or high IPI DLBCL were not satisfactory, and the upfront autologous stem cell transplantation (ASCT) was reported to improve the survival rates in these patients subset. Therefore, we retrospectively evaluated the survival rates in patients with DLBCL with CD20+, who were treated with R-CHOP followed by ASCT.We analyzed 40 DLBCL patients who underwent an ASCT, reported to the Korean Blood and Marrow Transplant Registry between 2005 and 2011 by 12 centers. Patients characteristics at diagnosis: 60% male, 5% stage II with bulky disease, 95% stage III or IV, 42.5% bone marrow involvement, 65% high-intermediate or high risk by IPI score. Patients characteristics at ASCT: median age 47 years (range, 23–66) and 82.5% of patients received ≥6 cycles of R-CHOP. Response to R-CHOP: 62.5% CR and 37.5% PR. 17.5% of patients received involved field radiotherapy prior to ASCT for bulky disease or residual lymphoma. Disease status at ASCT: 72.5% CR and 27.5% PR. Median time from diagnosis to ASCT was 7.85 months (range, 4.4–16.1).Median follow-up period from diagnosis was 36.2 months (range, 6.3–84.8). 2-year estimates of PFS, OS and relapse from diagnosis were 73.8%, 86.4% and 24.3%, respectively. 5-year estimates of PFS, OS and relapse were 70.8%, 68.3% and 27.4%, respectively. 3-year estimates of PFS and OS according to IPI score were not significantly different among 4 risk groups (P=0.890 and P=0.855, respectively).The upfront ASCT following R-CHOP induction therapy may improve survival for patients with advanced high risk DLBCL. Prospective evaluation of the treatment outcome of R-CHOP followed by ASCT is needed for high risk DLBCL on a large scale. Disclosures:No relevant conflicts of interest to declare.

Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial

The outcome of diffuse large B-cell lymphoma has been substantially improved by the addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy regimens. We aimed to assess, in patients aged 18-59 years, the potential survival benefit provided by a dose-intensive immunochemotherapy regimen plus rituximab compared with standard treatment plus rituximab. We did an open-label randomised trial comparing dose-intensive rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) with subsequent consolidation versus standard rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone (R-CHOP). Random assignment was done with a computer-assisted randomisation-allocation sequence with a block size of four. Patients were aged 18-59 years with untreated diffuse large B-cell lymphoma and an age-adjusted international prognostic index equal to 1. Our primary endpoint was event-free survival. Our analyses of efficacy and safety were of the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00140595. One patient withdrew consent before treatment and 54 did not complete treatment. After a median follow-up of 44 months, our 3-year estimate of event-free survival was 81% (95% CI 75-86) in the R-ACVBP group and 67% (59-73) in the R-CHOP group (hazard ratio [HR] 0·56, 95% CI 0·38-0·83; p=0·0035). 3-year estimates of progression-free survival (87% [95% CI, 81-91] vs 73% [66-79]; HR 0·48 [0·30-0·76]; p=0·0015) and overall survival (92% [87-95] vs 84% [77-89]; HR 0·44 [0·28-0·81]; p=0·0071) were also increased in the R-ACVBP group. 82 (42%) of 196 patients in the R-ACVBP group experienced a serious adverse event compared with 28 (15%) of 183 in the R-CHOP group. Grade 3-4 haematological toxic effects were more common in the R-ACVBP group, with a higher proportion of patients experiencing a febrile neutropenic episode (38% [75 of 196] vs 9% [16 of 183]). Compared with standard R-CHOP, intensified immunochemotherapy with R-ACVBP significantly improves survival of patients aged 18-59 years with diffuse large B-cell lymphoma with low-intermediate risk according to the International Prognostic Index. Haematological toxic effects of the intensive regimen were raised but manageable. Groupe d'Etudes des Lymphomes de l'Adulte and Amgen.

Bortezomib-Melphalan-Prednisone-Thalidomide Followed by Maintenance With Bortezomib-Thalidomide Compared With Bortezomib-Melphalan-Prednisone for Initial Treatment of Multiple Myeloma: A Randomized Controlled Trial

The combination of bortezomib-melphalan-prednisone (VMP) is a new standard of care for newly diagnosed multiple myeloma. This phase III study examined the efficacy of the four-drug combination of bortezomib-melphalan-prednisone-thalidomide (VMPT) followed by maintenance with bortezomib-thalidomide (VMPT-VT) compared with VMP treatment alone in untreated multiple myeloma patients who are ineligible for autologous stem-cell transplantation. A total of 511 patients were randomly assigned to receive nine cycles of VMPT followed by continuous VT as maintenance, or nine cycles of VMP at the same doses with no additional therapy. The primary end point was progression-free survival. The 3-year estimates of progression-free survival were 56% in patients receiving VMPT-VT and 41% in those receiving VMP (hazard ratio [HR], 0.67; 95% CI, 0.50 to 0.90; P = .008). At 3 years, the cumulative proportions of patients who did not go on to the next therapy were 72% with VMPT-VT and 60% with VMP (HR, 0.58; 95% CI, 0.50 to 0.90; P = .007). Complete response rates were 38% in the VMPT-VT group and 24% in the VMP group (P < .001). The 3-year overall survival was 89% with VMPT-VT and 87% with VMP (HR, 0.92; 95% CI, 0.53 to 1.60; P = .77). Grade 3 to 4 neutropenia (38% v 28%; P = .02), cardiologic events (10% v 5%; P = .04), and thromboembolic events (5% v 2%; P = .08) were more frequent among patients assigned to the VMPT-VT group than among those assigned to the VMP group; treatment-related deaths were 4% with VMPT-VT and 3% with VMP. VMPT followed by VT as maintenance was superior to VMP alone in patients with multiple myeloma who are ineligible for autologous stem-cell transplantation.

Influence of tumor grade on time to progression after irradiation for localized ependymoma in children

Purpose: To investigate the influence of histologic grade on progression-free survival (PFS) after irradiation (RT) for pediatric patients with localized ependymoma. Methods and Materials: Fifty patients with localized ependymoma (median age 3.6 years, range 1–18 years at the time of RT) were treated with RT between December 1982 and June 1999. Anaplastic features were identified in 14 of 50 patients. The extent of resection was characterized as gross-total in 36 patients, near-total in 5, and subtotal in 9. The median dose to the primary site was 54 Gy. Of the 50 patients, 23 received pre-RT chemotherapy. Results: Thirty-nine patients were alive at a median follow-up of 46 months (range 21–214) from diagnosis. Thirty-four patients remained progression free at a median follow-up of 35 months (range 13–183) after the initiation of RT. Progression occurred in 16 patients (12 local and 4 local and distant), with a median time to failure of 21.2 months (range 4.6–65.0). The tumor grade significantly influenced the PFS after RT ( p < 0.0005). The estimated 3-year PFS rate was 28% ± 14% for patients with anaplastic ependymoma compared with 84% ± 8% for patients with differentiated ependymoma. These results remained significant when corrected for age at diagnosis (<3 years), pre-RT chemotherapy, and extent of resection. Patients who received pre-RT chemotherapy had an inferior 3-year PFS estimate after RT (49 ± 12%) compared with those who did not (84% ± 10%; p = 0.056). Anaplastic ependymoma was found more frequently in the supratentorial brain ( p = 0.002). Six of 12 patients with supratentorial tumor developed recurrence; recurrence was restricted to patients with anaplastic ependymoma. Conclusion: Tumor grade influences outcome for patients with ependymoma independent of other factors and should be considered in the design and analysis of prospective trials involving pediatric patients treated with RT. Chemotherapy before RT influences the PFS and overall survival after RT. The effect is more pronounced when progression occurs during chemotherapy.