High-risk International Prognostic Score Research Articles

Impact of cumulative dose of brentuximab vedotin on outcomes of frontline therapy for advanced-stage Hodgkin lymphoma

AbstractIn the pivotal study ECHELON-1, brentuximab vedotin (BV), doxorubicin, vinblastine, and dacarbazine (A + AVD) demonstrated superior efficacy compared with bleomycin + AVD for the treatment of advanced-stage classic Hodgkin lymphoma (cHL). However, there are minimal available data regarding the frequency of dose reductions or omission of BV during curative therapy and the potential impact on patient outcomes. In a real-world analysis, we retrospectively reviewed the characteristics and outcomes of 179 patients with stage III or IV cHL treated with frontline A + AVD from January 2010 to April 2022. Treatment consisted of up to 1.2 mg/kg of BV and standard dose AVD IV on days 1 and 15 of each 28-day cycle for up to 6 cycles. At the time of treatment, the median patient age was 37 years, and a high-risk International Prognostic Score was observed in 46% of patients. Overall, 91% of patients received 6 cycles of AVD; 55% of patients did not receive the intended cumulative dose of BV (CDB); 28% of patients received two-thirds or less than the planned CDB. At a median follow-up time of 27.4 months (95% confidence interval [CI], 24.8-29), the median progression-free survival (PFS) was not reached, and the 12-month PFS was 90.3% (95% CI, 85.9-95.0). The impact of CDB on PFS was not significant (P = .15), nor was high CDB significantly associated with increased adverse events. In real-world experience, A + AVD is a highly effective treatment for patients with advanced-stage cHL, including for patients with prominent dose reductions of BV.

Trial in Progress: Acalabrutinib Maintenance Following Cellular Therapy for Large B-Cell Lymphoma Patients at High Risk for Relapse

Background Large B-cell lymphoma has been shown to be driven by B-cell receptor signaling, which can be disrupted using Bruton tyrosine kinase (BTK) inhibition. Acalabrutinib has been studied in large B-cell lymphoma in combination with intensive therapies with encouraging results (Davies et al., Blood 2020). Preclinical studies have shown BTK inhibition could improve the effectiveness of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy by improving the tumor microenvironment and delaying T-cell exhaustion (Qin et al., J Immunother 2020). BTK inhibition also has the potential to enhance the T-cell directed graft-versus-malignancy effect of allogeneic stem cell transplantation (alloHCT). This trial seeks to develop an effective therapeutic strategy to prevent relapse following cellular therapy in a specific group of large B-cell lymphoma patients that is high risk for relapse. Design This is a single-arm, open-label, multi-center phase Ib/II clinical trial to evaluate the safety and effectiveness of acalabrutinib as maintenance therapy in a subpopulation of patients with large B-cell lymphoma who are at high risk for relapse after cellular therapy. Inclusion criteria includes 1) patients undergoing autologous stem cell transplant (autoHCT) or any FDA-approved CAR T-cell therapy product for high grade B-cell lymphoma, large B-cell lymphoma with a history of secondary central nervous system (CNS) involvement, histologic transformation of indolent lymphoma to large B-cell lymphoma, or large B-cell lymphoma with high-risk international prognostic index score of 4 or 5 and 2) patients undergoing alloHCT for large B-cell lymphoma. The sample size for this study is 24 patients total, including 12-15 patients treated post-CAR T-cell therapy and 12-15 patients treated post-transplant. Patients will be started on maintenance with acalabrutinib on day +90 following alloHCT, day +60 following autoHCT, or between days +28 and +104 following CAR T-cell therapy. This trial will open at University of California Los Angeles and University of California Davis (two constituent sites of the University of California Hematologic Malignancies Consortium). Objectives The primary objective is to determine the safety and tolerability of maintenance acalabrutinib following cellular therapy in patients with large B-cell lymphoma at high risk for relapse. Secondary objectives include to estimate the effectiveness of maintenance acalabrutinib and to estimate the rates of dose reductions, dose pauses, and permanent discontinuations of acalabrutinib that occur post-cellular therapy. Exploratory objectives include to evaluate CAR T-cell persistence with acalabrutinib maintenance, to determine if there are signs of CNS penetration of acalabrutinib, and to evaluate changes before and after initiation of acalabrutinib in intracellular cytokine and phospho-protein profiling of peripheral blood mononuclear cells. Main Outcomes The primary endpoint is tolerability, determined by permanent discontinuation of acalabrutinib within 12 months from cellular therapy due to intolerance, defined as grade >3 non-hematologic toxicity or grade 4 hematologic toxicity considered related to acalabrutinib that occurs for the third time after previously holding and resuming acalabrutinib. Secondary endpoints include PFS and OS following cellular therapy and the incidence of dose changes and stopping of acalabrutinib. Conclusions This trial will use acalabrutinib as maintenance therapy for large B-cell lymphoma patients at high risk for relapse in the hopes of improving outcomes post-cellular therapy. If there is a PFS benefit in all three groups combined (CAR T-cell therapy, alloHCT, autoHCT), there will be rationale to expand each individual group into a separate larger trial. This study is registered with clinicaltrials.gov: NCT05256641. References Davies A, Caddy J, Mercer K, et al. Acalabrutinib in Combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (R-CHOP) As First Line Therapy for Patients with Diffuse Large B-Cell Lymphoma (DLBCL): The Accept Phase Ib/II Single Arm Study. Blood. 2020;136(Supplement_1):38-39. Qin JS, Johnstone TG, Baturevych A, et al. Antitumor potency of an anti-CD19 chimeric antigen receptor T-cell therapy, lisocabtagene maraleucel in combination with ibrutinib or acalabrutinib. J Immunother. 2020;43(4):107-120. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Predictors of thrombosis and bleeding in 1613 myelofibrosis patients from the Spanish Registry of Myelofibrosis

Available data have proved insufficient to develop consensus recommendations on the prevention of thrombosis and bleeding in myelofibrosis (MF). We evaluated the incidence and risk factors of vascular complications in 1613 patients from the Spanish Myelofibrosis Registry. Over a total of 6981 patient-years at risk, 6.4% of the study population had at least one thrombotic event after MF diagnosis, amounting to an incidence rate of 1.65 per 100 patient-years. Prior history of thrombosis, the JAK2 mutation, and the intermediate-2/high-risk International Prognostic Scoring System (IPSS) categories conferred an increased thrombotic risk after adjustment for the risk-modifying effect of anti-thrombotic and cytoreductive treatments. History of thrombosis and the JAK2 mutation allowed us to pinpoint a group of patients at higher risk of early thrombosis. No decreased incidence of thrombosis was observed while patients were on anti-thrombotic or cytoreductive treatment. An increased risk of venous thrombosis was found during treatment with immunomodulatory agents. A total of 5.3% of patients had at least one episode of major bleeding, resulting in an incidence rate of 1.5 events per 100 patient-years. Patients in the intermediate-2/high-risk IPSS categories treated with anti-coagulants had an almost sevenfold increased risk of major bleeding. These findings should prove useful for guiding decision-making in clinical practice.

Clinical and Epidemiological Profile of Elderly Hodgkin's Lymphoma in India.

BackgroundHodgkin’s lymphoma (HL) is a curable malignancy that commonly involves the younger population. However, HL can rarely occur in the elderly population (≥60 years) and probably has different biology as compared to the younger counterparts. There was a paucity of data on the clinical and epidemiological profile of the elderly subset with HL in Indian patients who are misdiagnosed and empirically treated as tuberculosis. We have done an analysis of this subset of elderly patients who were registered at our institute.MethodsA retrospective chart analysis of HL patients who presented to our center from 2008 to 2016 was conducted. Twenty-eight patients with HL of age ≥60 years were included in this study.ResultsElderly HL comprised 18.67% of the total HL patients registered during this period. The majority were male patients, and the mean age of presentation was 65.9±5.6 years. A Charlson Comorbidity Index (CCI) of ≥2 was seen in 30.77% of the patients. Among these, 84.62% of the patients presented with advanced-stage disease, and 57.69% of the patients presented with B symptoms, which was significantly associated with a high-risk international prognostic score (IPS). Histology-wise, mixed cellularity classical Hodgkin’s lymphoma (MCCHL) and nodular sclerosis classical Hodgkin’s lymphoma (NSCHL) were equally represented (30.76%). Of the patients, 50% had extranodal disease, with the liver being the most frequent site involved. One patient each had bone marrow involvement and bulky disease. CD30, CD15, and CD20 positivity was seen in 84.61%, 50%, and 26.92% of cases, respectively.ConclusionAmong elderly HL patients, males were more commonly represented than females, and patients more often presented with advanced disease and B symptoms and less often with bulky disease and mediastinal mass. Mixed cellularity classical HL is more common in the elderly subset, and significant comorbidities are present in a higher number of elderly HL patients.

Prognostic Role of the Expression of Latent-Membrane Protein 1 of Epstein-Barr Virus in Classical Hodgkin Lymphoma.

The prognostic impact of the presence of Epstein–Barr virus (EBV) in classical Hodgkin lymphoma (cHL) is controversial. Previous studies reported heterogeneous results, rendering difficult the clinical validation of EBV as a prognostic biomarker in this lymphoma. The objective of this study was to evaluate the survival impact of the expression of EBV Latent-Membrane Protein 1 (EBV-LMP1) in tumoral Hodgkin–Reed–Sternberg (HRS) cells of primary diagnostic samples of cHL. Formalin-Fixed Paraffin-Embedded (FFPE) lymph node samples from 88 patients with cHL were analyzed. Patients were treated with the standard first-line chemotherapy (CT) with Adriamycin, Bleomycin, Vinblastine and Dacarbazine (ABVD) followed by radiotherapy. The Kaplan–Meier method and the Cox proportional hazards model were used for carrying out the survival analysis. In order to investigate whether the influence of EBV was age-dependent, analyses were performed both for patients of all ages and for age-stratified subgroups. In bivariate analysis, the expression of EBV was associated with older age (p = 0.011), mixed cellularity subtype cHL (p < 0.001) and high risk International Prognostic Score (IPS) (p = 0.023). Overall survival (OS) and progression-free survival (PFS) were associated with the presence of bulky disease (p = 0.009) and advanced disease at diagnosis (p = 0.016). EBV-positive cases did not present a significantly lower OS and PFS in comparison with EBV-negative cases, for all ages and when stratifying for age. When adjusted for covariates, absence of bulky disease at diagnosis (HR: 0.102, 95% CI: 0.02–0.48, p = 0.004) and limited disease stages (I–II) (HR: 0.074, 95% CI: 0.01–0.47, p = 0.006) were associated with a significant better OS. For PFS, limited-disease stages also retained prognostic impact in the multivariate Cox regression (HR: 0.145, 95% CI: 0.04–0.57, p = 0.006). These results are of importance as the early identification of prognostic biomarkers in cHL is critical for guiding and personalizing therapeutic decisions. The prognostic role of EBV in cHL could be modulated by the type of CT protocol employed and interact with the rest of presenting features.

Fit older adults with advanced myelodysplastic syndromes: who is most likely to benefit from transplant?

We conducted a prospective observational study of fit adults aged 60 to 75 with advanced MDS, enrolled hierarchically for adverse MDS risk (intermediate-2 or high-risk international prognostic score [IPSS], low or intermediate-1 IPSS with poor-risk cytogenetics, or therapy-related MDS) or standard risk with severe cytopenia. A total of 290 patients enrolled at two centers: 175 for adverse risk and 115 for standard risk with severe cytopenia. 113 underwent HCT after a median of 5 months; median follow-up for all was 39.5 months. In univariable analyses, the hazard ratio (HR) for death comparing HCT with no HCT was 0.84 (p=0.30). The HR for death was 0.64 (p=0.04) for HCT ≤5 months after enrollment and 1.20 (p=0.39) for HCT >5 months. In multivariable analyses controlling for age, gender, ECOG performance status, cytogenetic risk, and IPSS risk group, HR for death was 0.75 (p=0.13) for HCT compared to no HCT, 0.57 (p=0.01) for adverse MDS risk and 1.33 (p=0.36) for standard risk with severe cytopenia. In this large, prospective cohort of fit older adults with advanced MDS, we found that survival was significantly improved if HCT was performed early or for adverse risk disease but not for standard risk disease with severe cytopenia.

Real-World Evidence of Tisagenlecleucel for the Treatment of Relapsed or Refractory Large B-Cell Lymphoma

Introduction Tisagenlecleucel (tisa-cel) is a second generation, CD19-targeted Chimeric Antigen Receptor (CAR) T-cell therapy for relapsed or refractory (R/R) large B-cell lymphoma (LBCL). The pivotal phase 2 trial JULIET included 93 patients and reported an overall response rate (ORR) of 52% and a complete response rate of 40% among treated patients. However, very little is known regarding its safety and efficacy in the commercial or real-world setting as well as from an intention-to-treat perspective. In our study, we report clinical outcomes of patients with R/R LBCL treated with commercial tisa-cel in 10 Spanish institutions. Methods Data were collected retrospectively from all consecutive patients with R/R LBCL who underwent apheresis for tisa-cel at a Spanish site from December 2018 until June 2020. Evaluable patients included those who received a CAR-T infusion and had at least 1 month of follow-up. Adverse events after infusion were graded according to the ASTCT consensus and efficacy outcomes were assessed according to the Lugano criteria. Efficacy outcomes were calculated in the patients who received a CAR T-cell infusion and in all patients who underwent apheresis for tisa-cel (intention-to-treat). Results During the study period 91 patients with R/R LBCL underwent apheresis for tisa-cel. At the study cutoff, 69 (76%) patients had received a CAR T-cell infusion whereas 22 (24%) had not due to progressive disease (n=10, 45%), pending manufacturing process (n=7, 32%), out of specification (OOS) or manufacturing failure (n=4, 18%), or others (n=1, 5%). Sixty-one patients had at least the first disease response evaluation at 1-month post-infusion. Baseline characteristics of the whole cohort and the infused patients are summarized in Table 1. Among infused patients, median age was 57 years (range 24-77) and 65% were male. Most of the patients had a high-risk International Prognostic Index score (62%), an advanced stage at diagnosis (91%) and were refractory to the previous therapy (80%). Median follow-up after CAR T-cell infusion was 4 months (1-16). Fifty-six patients (81%) received bridging therapy before infusion, including chemotherapy in most cases (n=51, 91%). All patients received fludarabine and cyclophosphamide as lymphodepleting chemotherapy. Median time from apheresis to infusion was 53 days (range 29-225). Median infused cell dose was 2.2 x 108 CAR positive viable T-cells (range 0.4-4.2 x 108). Eleven (16%) products were considered OOS although 45% of them were infused. Among the infused patients, 47 (68%) and 9 (13%) developed any grade of cytokine release syndrome (CRS) and neurotoxicity, respectively. Grade &amp;gt;2 CRS and neurotoxicity events occurred in 3 (4%) and 0 patients, respectively. Tocilizumab was administered to 21 (30%) patients and steroids to 13 (19%) patients. Nine (13%) patients required admission to the Intensive Care Unit. By day 100, 2 (3%) patients experienced non-relapse mortality. Other adverse events including infections and tumor lysis syndrome are summarized in table 2. Best response achieved among the infused patients included complete remission in 17 (28%) patients and partial remission in 22 (36%) patients, with an ORR of 64%. Stable disease and progressive disease were the best response in 4 (7%) and 18 (29%) patients, respectively. Considering all patients who underwent apheresis, CR and PR were obtained in 19% and 24% (ORR 43%), respectively. Median progression-free survival (PFS) and overall survival (OS) for infused patients were 3 months (95%CI 2.1-3.4) and 8 months (95%CI 5.7-10.8), respectively. In the univariate analysis, patients with ECOG score &amp;gt;1 (HR 4.3 95%CI 1.5 - 40.9) (p &amp;lt; 0.001) and IPI score &amp;gt;2 (HR 4.8 95%CI 1.6 - 14.4) (p = 0.002) were associated with lower PFS while an ECOG score &amp;gt;1 was also associated with lower OS (HR 3.4 95%CI 1.15 - 34.4) (p = 0.04). In the intention-to-treat analysis for all patients who underwent apheresis, median PFS and OS from apheresis were 4 months (95%CI 2.8-5.8) and 9 months (95%CI 5.8-11.8), respectively. Conclusions Treatment with tisa-cel was able to induce disease response with a good toxicity profile in a population of patients with LBCL treated in a European country. Poor performance status at the time of CAR T-cell infusion was associated with lower PFS and OS. Disclosures Iacoboni: Novartis, Gilead, Celgene, Roche: Honoraria. Guerreiro:Novartis: Honoraria. Mussetti:Novartis, Gilead: Honoraria, Research Funding. Sancho:Roche, Janssen, Celgene, Novartis, Gilead, Sandoz, Mundipharma y Takeda; Advisory y/o consultor para Roche, Janssen, Celgene, Novartis, Gilead, Sandoz, Celltrion y Kern-Pharma.: Honoraria. Hernani:Gilead: Honoraria. Sureda Balari:Takeda: Consultancy, Honoraria, Speakers Bureau; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Celgene: Consultancy, Honoraria; BMS: Speakers Bureau; Roche: Honoraria. Martin Garcia-Sancho:Celgene, Eusa Pharma, Gilead, iQuone, Kyowa Kirin, Roche, Morphosys: Consultancy; Roche, Celgene, Janssen, Servier, Gilead: Honoraria. Kwon:Jazz: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Reguera:Celgene, Novartis: Consultancy; Novartis, Gilead: Honoraria. Barba:Novartis, Celgene, Gilead, Pfizer, Amgen, Roche: Honoraria.

Decitabine/Cedazuridine: First Approval

A fixed dose oral combination (FDC) of decitabine and cedazuridine (Inqovi®), is being developed by Astex Pharmaceuticals (a subsidiary of Otsuka Pharmaceuticals) for the treatment of various cancers like myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemia (AML), glioma and solid tumours. Decitabine, a DNA methyltransferase inhibitor approved for the treatment of MDS and CMML, is degraded by cytidine deaminase in the gastrointestinal tract and liver, thereby limiting oral bioavailability. Cedazuridine is a proprietary, patented cytidine deaminase inhibitor that, when added to decitabine, increases oral bioavailability of the drug. In July 2020, decitabine/cedazuridine received its first approval in the USA and Canada for the treatment of MDS and CMML. In the USA, it is indicated for use in adults with MDS and CMML, including previously treated and untreated, de novo and secondary MDS with the following French–American–British subtypes (refractory anaemia, refractory anaemia with ringed sideroblasts, refractory anaemia with excess blasts and CMML) and intermediate-1, intermediate-2 and high-risk International Prognostic Scoring System groups. Clinical studies for AML, glioma and solid tumours are underway in several countries worldwide. This article summarizes the milestones in the development of decitabine/cedazuridine leading to this first approval for the treatment of MDS and CMML.

The critical role of RasGRP4 in the growth of diffuse large B cell lymphoma

BackgroundThis study aimed to confirm that blocking RasGRP4 can effectively slow down the growth of DLBCL both in vitro and in vivo and ascertain the role of RasGRP4 in the prognosis of DLBCL clinically.MethodsRasGRP4 expression levels were examined in benign tissues and lymphomas. In order to verify somatic mutation in RasGRP4 gene, cDNA sequencing was performed in DLBCL patients. RasGRP4-dependent cell proliferation, mitochondrial membrane potential, oxidative stress levels and signaling pathway changes were measured by knockdown of RasGRP4. Tumor growth was monitored in xenografted lymphoma model. Clinical data were collected to confirm the role of RasGRP4 in DLBCL.ResultsRasGRP4 expression was significantly elevated in DLBCL while no somatic mutations were detected of this gene in DLBCL patients. Decreased RasGRP4 significantly inhibited cell proliferation by simultaneously reducing mitosis and promoting apoptosis and increased the oxidative stress levels. Mechanistically, reduced expression of RasGRP4 decreased ERK while increased JNK expression in SUDHL-4 cells. Knockdown of RasGRP4 also significantly inhibited tumor formation in vivo. Furthermore, RasGRP4 expression levels were significantly higher in patients with larger DLBCL lesions (P = 0.0004), high-risk international prognostic index score groups (P = 0.0042), and its expression was positively correlated with maximum standardized uptake value in DLBCL (P = 0.0004).ConclusionsThese findings indicate the oncogenic role of RasGRP4 in DLBCL, suggesting it as a prognostic biomarker and potential therapeutic target in DLBCL.

Risk and Prognostic Factors of Extra-Nodal Hodgkin Lymphoma: Single Jordanian Center Experience

BackgroundHodgkin lymphoma (HL) is a clonal B-cell hematologic malignancy usually affecting only the lymphoid tissue, as extra-nodal (EN) involvement (e.g., bone, lung or liver) is seen only in ~15% of cases, much less than what is observed in non-Hodgkin lymphomas. To date, a small number of studies worldwide have investigated the epidemiology and clinical characteristics associated with HL with EN manifestations.AimTo describe risk factors and prognosis of EN involvement in HL patients.MethodsPatients diagnosed with HL at King Abdullah University hospital (KAUH) between January 2004 and April 2018 were retrospectively reviewed for EN involvement, confirmed by histopathology of involved tissues. Risk factors assessed in our cohort of EN HL patients were: age, gender, presenting symptoms, B Symptoms, LDH levels, histological subtypes, CBC with differential, CT scans and PET/CT scans. International prognostic score (IPS) was also calculated.ResultsAmong 140 HL patients included in our study, 16 of them (11.4%) had EN involvement. The mean age at diagnosis was 30 years old, ranging from 14-59. As in classic HL, men with EN involvement were slightly more affected than female (M/F, 10/6; 62.5% vs. 37.5%). Most of patients (N=8; 50%) had HL with mixed cellularity (MC); 6 patients (37.5%) had nodular sclerosing (NS); and 2 patients (12.5%) were classified as lymphocyte depleted (LD) subtype. Bone was the most compromised extra-nodal tissue as shown by the observation that 8 patients (50%) had bone involvement. Lungs pleura were affected in 7 patients (43.8%) and liver in 4 (25%) patients. The remaining subjects (N=4; 25%) showed involvement in other sites (skin, CNS and muscles). Out of our 16 EN HL patients, 6 of them (37.5%) had two EN tissues involved.EN HL patients were younger than patients without EN involvement (mean age, 30 vs. 37 years old respectively, P=.036 by unpaired t-test).EN HL patients with bone involvement were younger than those with liver or lung localization (mean age, 23.1 vs. 30.8 vs. 30.6 years old, respectively; P = 0.018 by unpaired t-test).We also observed a significant association between liver involvement and MC subtype. (P =0.032 by chi-square test).There was significant association between positive B symptoms and EN involvement. (P=.006 by chi-square test). There was no significant association between gender, high LDH levels, anemia, leukocytosis, lymphocytosis, monocytopenia, low albumin levels and EN involvement.There was significant association between IPS and EN involvement (56.25% of patients with EN involvement have high risk IPS, P=.00002 by chi-square test).All patients received ABVD as a first-line treatment. Seven patients (43.75%) experienced disease relapse during the follow-up period. There was a significant relationship between disease relapse and the type of HL, as 6 patients who experienced relapse had NS (P=0.0004 by chi-square), while only one MC.Overall survival rate was 75%, and 5-years survival rate was 45%. Four out of 7 patients who had disease relapse (57.1%) died, suggesting that disease relapse in EN HL might be a poor prognostic factor (P =0.045 by Kaplan Meier). There was no significant association between EN involvement and overall survival rate (P=.35 by Kaplan Meier).ConclusionPrevalence of EN involvement in patient with HL in Jordan is 11.4%, higher than that in Western countries and United States. In our cohort, EN involvement frequently presented as MC histological subtype; however, patients with NS showed the highest relapse rate. According to previous observations, bone and lungs were the most involved sites in our cohort, and patients with bone involvement were younger than those with other extra-nodal sites. Of note, our study might suggest some differences in the primary disease site in patients with HL possibly due to some geographic and ethnic variations. We also showed that risk and prognostic factors of classic HL are well applicable to EN HL, highlighting possible roles of histological subtypes in prognostication of EN HL. However, our preliminary findings need further validation in larger prospective studies. DisclosuresNo relevant conflicts of interest to declare.

Prognostic impact of elevated pretreatment serum ferritin in patients with high-risk MDS treated with azacitidine

Iron overload has been associated with poor overall survival in patients with higher-risk myelodysplastic syndromes after allogeneic hematopoietic stem cell transplantation, but has not been investigated in higher-risk MDS patients treated with hypomethylating agents. We evaluated the prognostic value of serum ferritin levels at diagnosis in a retrospective analysis of 48 patients with an intermediate 2 or high-risk International Prognostic Scoring System (IPSS) score treated with azacytidine. overall survival probability at 1 and 2 years was 58% and 42%, respectively. When stratifying according to serum ferritin level at azacytidine initiation, patients with serum ferritin level <725 ng/mL had significantly better OS than those with serum ferritin level ≥725 ng/mL, with an overall survival probability of 74% (95% confidence interval [CI]: 58-94) versus 44% (95% CI: 28-68) at 1 year and 57% (95% CI: 39-81) versus 28% (95% CI: 15-52) at 2 years, respectively (p = 0.034). Median progression-free survival was 16.15 months (range: 9-26) for the entire cohort. Progression-free survival probabilities according to serum ferritin cut-off level <725 ng/mL or ≥725 ng/mL at 1 and 2 years were 70% (95% CI: 53-91) versus 44 (95% CI: 28-68) and 52% (95% CI: 35-77) versus 24% (95% CI: 12-48), respectively (p = 0.031). We have demonstrated that an serum ferritin level ≥725 ng/mL was associated with worse overall survival and progression-free survival when adjusting for other covariables in multivariate analysis, in addition, unfavorable karyotype led to worse outcome. In conclusion, we believe that that negative effect of serum ferritin level on overall survival is not only related to the iron toxicity, but most probably may also be considered as a surrogate marker for very ineffective erythropoiesis leading to marked anemia.

Options for patients with myelodysplastic syndromes after the treatment failure of hypomethylating agent

The treatment of patients with myelodysplastic syndromes (MDS) has included primarily supportive care (blood transfusions, colony stimulating agents, iron chelation, etc.) and new drugs, including 5-azacytidine, deoxyazacytidine, and lenalidomide. For those who are no longer benefiting from these agents, there is nearly nothing to do with effective therapies. When those drugs are ineffective, what the doctors could do is optimizing the delivery of hypomethylating agents (HMT) by dosing appropriately, sequencing appropriately, and using thoughtful combinations; as well as improving drug formulations (oral formulations and/or novel formulations) and working toward better selection of patients for best upfront mutation-directed therapy. Hopefully, the drug targeting and patient selection for optimal HMT treatment of MDS will be improved. Furthermore, ongoing research is focused on identifying unique agents to rescue MDS patients who have progressed despite HMT. Agents such as rigosertib are now focused on its application in specific MDS populations who might most likely benefit from this therapeutic approach [primary refractory and high-risk international prognostic scoring system (IPSS) patients]. Doctors eagerly await results of single-agent programmed death 1 (PD-1) and its inhibitors, or combination with HMT to the upfront and relapsed MDS setting. For the minority of patients who have specific targetable mutations, the selective agents (IDH1/2) are highly promising. Bone marrow transplantation remains the only offer for cure, but is depressingly unrealistic given the majority of the elderly and frail patients at the time of MDS progression. Key words: Myelodysplastic syndromes; Hypomethylating agent; Treatment failure

Treatment outcomes for Hodgkin lymphoma: First report from the Brazilian Prospective Registry.

Data about Hodgkin lymphoma (HL) in developing countries are scarce and suggest the existence of substantial disparities in healthcare and outcomes in large areas of the world. In 2009, a prospective registry of HL was implemented in Brazil. Web-based data were contributed by 20 institutions across the country participating in the Brazilian Prospective Hodgkin's Lymphoma Registry. The aim of this study was to present the clinical features and outcomes of newly diagnosed patients with HL aged 13 to 90years. Multivariate Cox regression models were used to estimate progression-free (PFS) and overall survival (OS) by clinical factors. A total of 674 patients with classical HL were analysed, with a median follow-up of 37months. Median age was 30years (13-90). The median time from the onset of symptoms to diagnosis was 6months (0-60). Only 6% of patients had early favourable disease, while 65% had advanced disease. Stage IVB was present in 26% and a high-risk International Prognostic Score in 38%. Doxorubicin, bleomycin, vinblastine, and dacarbazine was used in 93%. The median dose of radiotherapy was 36Gy for localized disease and 32Gy for advanced disease. The 3year PFS in early favourable, early unfavourable, and advanced disease were 95%, 88%, and 66%, respectively. High-risk International Prognostic Score, advanced disease, and age greater than or equal to 60 were independently associated with poorer PFS and OS; performance status greater than or equal to 2 was also associated with a poorer OS. Poor-risk patients predominated. Radiation doses for localized disease appear higher than current recommendations. Outcomes appear inferior in developing countries than in developed countries. Delayed diagnosis is probably a major factor underlying these findings. Scattered reports from developing nations suggest that many aspects of standard care in developed countries remain unmet needs for populations living in developing countries. The present report contributes to this body of data, with a proper description of what is currently achieved in urban areas in Brazil.

Collagen Fibers Structure Detected By Second-Harmonic Generation Microscopy: A Potential Prognostic Marker for High-Risk Nodular Sclerosis

Introduction: Second-Harmonic Generation microscopy (SHG) has provided progresses in extracellular matrix research, mainly regarding automated analysis of collagen fibers. Nodular sclerosis-classical Hodgkin lymphoma (NS) often has a rich collagen deposition, which remains poorly explored in its biological significance and potential prognostic role. The aim of this study was to characterize the collagen component of NS using SHG, and to investigate its clinical value.Methods: Hematoxylin and eosin stained slides from 53 consecutive samples of paraffin embedded NS tissue were analyzed by SHG imaging in an Inverted Zeiss LSM 780-NLO. HIV-positive individuals were excluded. For comparative purposes, 11 reactive lymph nodes (RL) were also randomly selected. In each slide, 3 capsular areas and 3 sclerotic regions (perinodular septa - PS - in NS and fibrotic foci around germinal centers in RL) were chosen. Collagen near blood vessels was not considered. We evaluated quantity, uniformity and organization of the fibers with ImageJ and OrientationJ plug-in in 4 hotspots from each image. Shapiro-Wilk test was used to assess data normality, while t-tests and Pearson correlations were performed to analyze collagen parameters between two groups. Overall survival (OS) was defined as time from diagnosis until death from the disease or last follow-up. Event-free survival (EFS) was set as time from diagnosis until progressive disease, death from the disease or last follow-up. Collagen data were used in survival analyses as continuous variables (in Cox-hazards model) or categorical ones (by choosing the mean value as a threshold for Kaplan-Meier curves and log-rank test). Significance was set at p<0.05.Results: NS patients were mostly female (58.5%). The mean and median values of age at diagnosis were, respectively, 33 and 29 years (range: 14-82 years). Forty-two patients (79.2%) had B-symptoms, while bulky disease was seen in 23 cases (43.3%). Bone marrow was infiltrated in 4 patients (7.5%). Based on the International Prognostic Score (IPS), patients were stratified as follows: 39 (73.5%) as low-risk (IPS ≤ 3) and 14 (26.5%) as high-risk (IPS > 3). The first-line treatment was ABVD in 40 cases (75.5%) and BEACOPP in 13 patients (24.5%). Radiotherapy was performed in 27 (50.9%) patients.Tumor PS presented more dense (p<0.01), organized (p<0.01) and uniform (p=0.02) fibers than sclerosis in RL. NS capsule had only a more organized collagen than RL (p=0.02). Considering solely NS, we found significant correlations of collagen fibers quantity (r=0.67), uniformity (r=0.78) and organization (r=0.49) between capsule and PS, suggesting a proportional deposition of collagen in these compartments. When clinical data were analyzed in the entire patient group, the presence of more organized PS collagen was associated with low-risk IPS (p=0.03), grade 2 tumors (p= 0.04), extranodal disease (p=0.003) and a higher risk of death (p=0.02). On the other hand, a higher fiber organization in NS capsule was only associated with low-risk IPS (p=0.03).The presence of high-risk IPS was associated with a shorter EFS (p=0.002), but had no relationship to OS. Collagen parameters had no impact on EFS. However, in univariate Cox regression, higher collagen quantity (p=0.04) in PS was the only factor associated with a worse OS. When only high-risk IPS cases were analyzed in Cox regression model, PS collagen had association with unfavorable OS regarding higher collagen quantity (p=0.03) and uniformity (p<0.01). In this setting, a higher quantity of capsular collagen was also associated with a worse OS (p=0.02). We did not perform multivariate analysis in this group due to the small amount of patients (14). Also in the high-risk cases, using the mean value of PS collagen quantity (15.19) as a threshold to binarize data, we found a trend to worse OS in cases with a higher collagen quantity (p=0.05, figure 1). Considering only low-risk IPS cases, collagen factors had no association with OS.Conclusion: Collagen parameters in NS have distinct features than in RL and affect clinical presentation of the tumor. Moreover, collagen quantity and uniformity in cases with high-risk IPS were associated with survival, which indicates that incorporation of collagen information might be relevant in the prognostication of NS. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Methylation of miR124a-1, miR124a-2, and miR124a-3 in Hodgkin lymphoma.

Deregulation of the microRNA miR124a by DNA methylation has been implicated in various malignancies, but no study reported its methylation status in Hodgkin lymphoma (HL). We evaluated the methylation of the three loci encoding for miR124a using methylation-specific PCR in 64 HL patients and 15 reactive lymph nodes obtained from patients with nonmalignant diseases. Results were correlated with clinicopathological parameters. Methylation rates of miR124a-1, miR124a-2, and miR124a-3 in HL were 17, 50, and 28%, respectively. None of the nontumoral samples showed aberrant hypermethylation in any of the miR tested. In HL cases, we found that miR124a-1 methylation correlates with high-risk International Prognostic Score (IPS) (score >3, p = 0.04) and that miR124a-2 methylation was more frequent in children (82.3%, p = 0.006) and men (63.9%, p = 0.01). Methylation of miR124a-3 was associated with advanced Ann-Arbor stages (p = 0.007). The survival analysis showed that methylation of at least one of the miR124a genes was associated with shortened event-free survival in univariate (p = 0.03) and multivariate (p = 0.02) analyses. These results suggest that miR124a methylation is associated with aggressive HL disease and may be an interesting factor for predicting treatment response.

Peripheral Neuropathy in Sézary Syndrome: Coincidence or a Part of the Syndrome?

Waldenstrom macroglobulinemia (WM) is a rare and incurable B cell malignancy. Most WM cells express CD20, which enables the use of anti-CD20 monoclonal antibody rituximab-based strategies. Rituximab has been evaluated in WM for about 10 years as a single agent with major response rates of 30% to 40%, whereas the combination of rituximab with chemotherapy has resulted in response rates of 70% to 90% [1,2,3]. However, the extent to which achievement of complete response (CR) confers clinical benefit is still debatable. As such, we administered rituximab (375 mg/m2, day 0) combined with fludarabine (40 mg, days 1-3) or cyclophosphamide (200 mg, days 1-2) in WM patients naive to rituximab and report herein the toxicities and effects of these combinations. A total of 4 elderly patients (ages older than 80) were identified with WM diagnoses from 2007 to 2012 in our department. According to recommendations for assessing response from the Third International Workshop on WM, 2 of 4 (50%) patients achieved complete response, 2 (50%) had major or minor response, and the overall response rate was 100% at the end of the treatment [4]. The individual changes in serum IgM, IgM paraprotein, and hemoglobin levels for all patients are shown in Figure 1. Figure 1 Individual changes in A) IgM, B) IgM paraprotein, and C) HB serum levels Hematologic toxicity was one of the major side effects of this regimen. Neutropenia and thrombocytopenia were found in 2 patients at the end of the treatment. Pulmonary infection was observed in one patient. With a median follow-up of 27 months, all 4 patients died. Two patients with sustainable CR died of pulmonary infection or heart failure, respectively, after follow-up for 11 and 36 months. One patient who achieved a major response duration of 34 months died of duodenal squamous adenocarcinoma. The last patient with minor response had progression of disease in 2 months and died of WM after 10 months of follow-up. Gruson et al. assigned a rituximab and fludarabine combination in a treatment cycle that was repeated every month for 6 months. Five patients aged 52-85 years with IgM achieved overall and complete response at 80% and 40%, respectively [5]. Several analyses have identified age as a major adverse factor [6]. Our results showed that 2 patients with sustainable CR were older than 80 years old and had high-risk International Prognostic Scoring System for WM scores. Therefore, with this combination regimen, age is no longer a major risk factor. In a study by Dimopoulos et al., which combined rituximab and fludarabine or cyclophosphamide in 11 patients with WM, combination treatment was used monthly for 4 cycles. The partial response rate was only 55% and no patients achieved complete response [7]. The 4-cycle combination therapy was thus not enough for WM patients and 5-6 cycles were necessary. In conclusion, rituximab in association with fludarabine or cyclophosphamide is well tolerated and effective for elderly WM patients.

Outcome of Patients with Lower-Risk Myelodysplastic Syndrome (MDS) After Azacitidine (AZA) Treatment Failure.

AbstractAbstract 2815▪▪This icon denotes a clinically relevant abstract Background:Azacitidine has emerged as the standard of care for treatment of higher risk MDS based upon results of the AZA-001 study. Several groups reported poor outcomes after AZA failure in patients with int-2 or high risk International Prognostic Scoring System (IPSS) risk groups with a median overall survival (OS) ranging from 4–8 months (mo). In the USA, AZA is approved for all FAB types and risk groups and is as first or second line therapy for anemia after erythroid stimulating agents in low /int-1 risk non-deletion 5q MDS and is the treatment of choice for thrombocytopenia. The outcome of patients with lower risk myelodysplastic syndrome (MDS) after AZA failure has not been characterized. We report our experience in a large cohort of low/int-1 (lower risk) MDS patients after AZA failure. Methods:Patients were identified through the Moffitt Cancer Center (MCC) MDS database. Individual charts were reviewed and relevant clinical data was extracted. Patients with low or intermediate-1 (int-1) risk disease as defined by IPSS who had received AZA treatment were identified. These patients were also risk stratified based on Global MD Anderson Score (MDAS). The primary objective was to estimate OS in these patients after AZA failure. AZA failure was defined as failure to respond after 4 or more treatment courses, loss of response, or disease progression while on therapy. All responses were defined according to the International Working Group (IWG) 2006 criteria. The Kaplan–Meier method was used to estimate median overall survival. Results:Two hundred eighty MDS patients with low/int-1 IPSS risk who had received AZA treatment were identified. Most patients (81%) were greater than 60 years of age (median, 69 years), and 90% of AZA treated patients were RBC transfusion dependent. Refractory cytopenia with multilineage dysplasia (RCMD) was the most common WHO subtype (44%), and 81% of patients had good risk cytogenetics (Table-1).The median time from MDS diagnosis to AZA treatment was 12.3 months; median number of AZA cycles received was six. At the time of AZA treatment, 241 patients (86 %) were risk stratified as int-1 versus 39 patients (14 %) who were stratified as low risk IPSS. The IWG 2006 responses to AZA treatment included 4% CR (n=10 ), 1% marrow CR (n=2), 4% PR (n=10), 27% Hematological improvement (HI) (n=75), whereas 52% (n=146) had stable disease with no HI (n=146) and 10% had progressive disease (n=10); 6 patients (2%) died on therapy, and responses were missing in 2 patients (<1%). The overall best response (HI or better) was 36%.The median OS for the entire cohort after AZA failure was 18.5 months (95% CI [13.5–23.5 mo], Figure 1A). The median OS for patients with low risk IPSS disease from time of AZA failure was 46 months versus 15 mo for int-1 patients (p<0.005, Figure 1B). When utilizing MDAS, median OS was 33.3 months for low risk patients, 21 months for int-1, 11 months for int-2, and 7.5 months for poor risk patients (p=0.005). Conclusions:To our knowledge this is the first report describing the outcome of lower risk MDS patients after AZA treatment failure. Outcome is particularly poor for those patients with int-1 risk MDS, with a median OS of 15 mo. Global MDAS identified patients upstaged to int-2 or high risk with less than one year OS. There is unmet need for effective novel therapies for lower risk MDS patients after AZA failure.Table 1Baseline characteristicsVariableN (%)N=280Age>60227 (81%)GenderMale74 (64%)WHO subtypeRA26 (9%)RARS33 (12%)RCMD123 (43%)Del5 q9 (3%)RAEB-155 (20%)RAEB-26 (2%)MDS-U7 (3%)CMML8 (3%)MDS/MPN-U13 (5%)IPSSDiagnosis Prior AZALow61 (22%) 39 (14%)Int-1219 (78%) 241 (86%)MDASLow47 (17%)Int-1159 (57%)Int-261 (22%)High13 (5%)CytogeneticsGood227 (81%)Intermediate43 (15%)Poor8 (3%) [Display omitted] Disclosures:List:Celgene: Consultancy. Komrokji:Celgene: Speakers Bureau.

Multivariate and Subgroup Analyses of a Multinational Phase III Trial of Decitabine in Older Patients with Newly Diagnosed Acute Myeloid Leukemia

AbstractAbstract 3618 Introduction:A recent phase III trial compared efficacy and safety of decitabine with those of patient's treatment choice (TC) of supportive care or low-dose cytarabine in older patients with newly diagnosed acute myeloid leukemia (AML) and poor- or intermediate-risk cytogenetics (Kantarjian et al. J Clin Oncol 2012;30:2760; NCT00260832). At the planned clinical cutoff date in 2009 (396 deaths), a nonsignificant trend toward increased median overall survival (OS) was seen with decitabine (7.7 months; 95% confidence interval [CI] 6.2, 9.2 months) vs TC (5.0 months; 95% CI: 4.3, 6.3 months); estimated hazard ratio (HR) 0.85 (P=.108). A 2010 post hoc analysis of mature data (446 deaths) from this study showed that the median OS had not changed but HR had improved (0.82; 95% CI 0.68, 0.99; nominal P=.037) and favored decitabine versus TC. At the 2009 cutoff, remission rates (complete response [CR] or CR with incomplete platelet recovery [CRp] were significantly improved with decitabine (17.8%) vs TC (7.8%; P=.001). Decitabine was generally well tolerated. A multivariate analysis was conducted using the mature (2010) data to identify potential predictors of OS in this older population with AML. Methods:Eligible patients were aged ≥65 years with newly diagnosed de novo or secondary AML (≥20% blasts), poor- or intermediate-risk cytogenetics, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2. Patients were randomized 1:1 to receive decitabine (20 mg/m2 intravenously once daily for 5 consecutive days every 4 weeks) or TC (supportive care or cytarabine 20 mg/m2 subcutaneously once daily for 10 days every 4 weeks), stratified by age, cytogenetic risk, and ECOG PS. A multivariate Cox proportional hazards model was used to investigate the effects of the following demographic and baseline characteristics on OS in addition to treatment effect: sex, age (<70, 70–<75, or ≥75 years), baseline cytogenetic risk (intermediate vs poor), AML type (de novo vs secondary), baseline ECOG PS (0/1 vs 2), geographic region (North America/Australia, Western Europe, Eastern Europe, Asia), baseline bone marrow blasts (>50% vs ≤50%), baseline platelet count (analyzed at each unit of 100 × 109/L) and baseline white blood cell (WBC) count (analyzed at each unit of 25 × 109/L). These potential prognostic factors were evaluated simultaneously, and values were not adjusted for multiple testing. Results:Of 485 randomized patients, 242 received decitabine and 243 received TC (cytarabine, n=215; supportive care, n=28). Baseline patient demographics and clinical characteristics were similar between groups and indicated a high-risk population: 71% of patients were aged ≥70 years, 35.3% had secondary AML, 36.0% had poor-risk cytogenetics, and 25.8% had ECOG PS 2 or higher; median baseline proportion of blasts in bone marrow was 46.0%. Patient characteristics that appeared to adversely affect OS at the 0.05 level included more advanced age, poorer baseline ECOG PS, poor cytogenetics, higher bone marrow blast count, low baseline platelet count, high WBC count, and geographic region (Western vs Eastern Europe) (Table). Conclusions:In older patients with AML, OS was associated with prognostic factors of age, ECOG PS, cytogenetic risk, baseline bone marrow blasts, baseline platelet counts, and baseline WBC in addition to responding differently to decitabine vs TC (supportive care or cytarabine). Treatment response is related both to patient and disease status in older patients with AML.TableMultivariate Analysis of Effects of Baseline Patient Demographics and Clinical Characteristics on Overall SurvivalVariableHR95% CIP valueTreatment: decitabine vs TC0.80(0.65, 0.98).030Age group70–74 vs <70 years1.31(1.00, 1.71).047≥75 vs <70 years1.56(1.20, 2.03).001Baseline cytogenetic risk: intermediate vs poor0.70(0.57, 0.87).001Baseline ECOG PS: 0 or 1 vs 20.77(0.61, 0.98).032Geographic region: Eastern vs Western Europe0.65(0.48, 0.88).005Baseline bone marrow blast: >50% vs ≤50%1.36(1.10, 1.67).005Baseline platelets (109/L)0.78a(0.66, 0.91).002Baseline WBC (109/L)1.26b(1.05, 1.51).015aHR <1 = lower risk associated with each additional 100 × 109/L in baseline platelet counts.bHR >1 = higher risk associated with each additional 25 × 109/L in baseline WBC counts. Disclosures:Mayer:Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Decitabine is a nucleoside metabolic inhibitor indicated for treatment of patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups. Delaunay:Novartis, Genzyme: Consultancy. Jones:Eisai Inc: Employment. Berrak:Eisai Inc: Employment. Kantarjian:Eisai: Research Funding.

A Post Hoc Landmark Analysis of Survival Probabilities in a Multinational Phase III Trial of Decitabine in Older Patients with Newly Diagnosed Acute Myeloid Leukemia

AbstractAbstract ▪3623▪This icon denotes a clinically relevant abstract Introduction:In a recent large, international, multicenter, randomized phase III trial (NCT00260832), the hypomethylating agent decitabine elicited a significantly greater response rate (complete remission [CR] rate plus CR without platelet recovery [CRp]) of 17.8%, with an odds ratio of 2.5 (95% CI: 1.4, 4.8; P=.001), at the time of the primary analysis (clinical cut-off [CCO] date October 28, 2009, at which time 396 deaths had occurred) compared with a response rate of 7.8% for patient's treatment choice (TC), with physician's advice, of low-dose cytarabine or supportive care (SC) in older patients with newly diagnosed acute myeloid leukemia (AML). A nonsignificant trend toward an overall survival (OS) benefit was observed with decitabine (median 7.7 months) versus TC (5.0 months). A subsequent analysis on a more mature data set (CCO date October 29, 2010; 446 deaths) confirmed this trend, finding that the median OS data were the same (Kantarjian et al. J Clin Oncol 2012;30:2760). This post hoc analysis aimed to further delineate the OS trend seen with decitabine by conducting a landmark analysis to determine OS for each treatment group in the trial at fixed time points based on the mature data set. Methods:In this multicenter, randomized, open-label phase III study, patients aged ≥65 years with de novo or secondary AML received decitabine 20 mg/m2 intravenously once daily for 5 days every 4 weeks or TC (SC or cytarabine 20 mg/m2 subcutaneously once daily for 10 days every 4 weeks). The primary efficacy population comprised all randomized patients. In the landmark analysis, OS at 3, 6, 12, 18, and 24 months postrandomization was estimated for each treatment group using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using a Cox regression model; P values for the difference between the decitabine and TC arms were calculated using a 2-sided log-rank test. Results:In total, 485 patients were randomized to receive decitabine (n=242) or TC (n=243: 215 cytarabine; 28 SC). This was a high-risk AML population: at baseline, median patient age was 73.0 years (range, 64.0–91.0; 70.9% were ≥70 years), 59.4% were men, 35.3% had secondary AML, 36.0% had poor-risk AML, 25.8% had ECOG PS of 2 or higher, and median baseline blasts in bone marrow were 46.0%. In the post hoc landmark analysis using the mature data set (2010 CCO), a survival advantage was seen with decitabine at each time point (Table), with significant differences in OS at 6, 18, and 24 months (P=.009, .027, and .019, respectively). Conclusions:At fixed time points over 2 years, treatment with decitabine showed a trend toward improved OS compared with TC.TableLandmark Analysis of Overall Survival RatesTreatment Choice (n = 243)Decitabine (n = 242)Hazard ratio (P value)Overall Survival Rate, % (95% CI)*3 months67.0 (60.7, 72.6)71.5 (65.3, 76.7)0.83 (.261)6 months44.3 (38.0, 50.4)56.9 (50.4, 62.9)0.71 (.009)12 months28.1 (22.6, 33.9)32.4 (26.6, 38.4)0.83 (.088)18 months14.5 (10.4, 19.2)20.8 (15.9, 26.1)0.80 (.027)24 months9.9 (6.6, 14.1)14.9 (10.7, 19.8)0.79 (.019)CI, confidence interval. <>*Survival rates based on Kaplan-Meier product limit estimates.Three patients with no prerandomization choice available and later randomized to the decitabine group were excluded from the analysis.Note: Analysis based on the mature data set (2010 CCO). Disclosures:Off Label Use: Decitabine is a nucleoside metabolic inhibitor indicated for treatment of patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups. Delaunay:Novartis, Genzyme: Consultancy. Jones:Eisai Inc: Employment. Barrak:Eisai Inc.: Employment. Kantarjian:Eisai: Research Funding.

Interim Report of a Randomized, Open-Label, Multicenter Study to Evaluate the Safety and Efficacy of Decitabine As an Epigenetic Priming Agent When Combined with Induction Chemotherapy in Pediatric Patients (pts) with Newly Diagnosed Acute Myelogenous Leukemia (AML)

AbstractAbstract 1517 Purpose:Decitabine, a deoxycytidine nucleoside derivative, is an inhibitor of DNA-methyltransferases indicated for treatment of myelodysplastic syndrome (MDS) including previously treated and untreated, de novo or secondary MDS of all French-American-British (FAB) subtypes, Intermediate-1, Intermediate-2, and High-Risk International Prognostic Scoring System (IPSS) groups. Laboratory evidence shows that pretreatment of AML cell lines can sensitize leukemia cells to chemotherapy as well as inhibit clonogenic potential. The purpose of this study is to evaluate the safety, pharmacokinetics, and efficacy of decitabine when used as priming before induction therapy in children with newly diagnosed AML. Exploratory analyses of genomic methylation and RNA expression patterns and minimal residual disease (MRD) are embedded correlative studies. Methods:This multicenter, randomized, two-arm, open-label study enrolls pediatric pts ages 1–16 with newly diagnosed AML to either Arm A: daunorubicin, cytarabine, etoposide (D-ADE) preceded by a 5-day course of decitabine (experimental arm) or Arm B: daunorubicin, cytarabine, etoposide (ADE; control arm). Following completion of induction on study, post-induction therapy is at the treating physician’s discretion. To date, 20 pts, 10 in each arm (1–16 yrs, median 9.4 yrs in both arms) have been enrolled. Results:At the protocol-specified bone marrow sampling time 3 weeks post-induction, there were 2 CRs, 6 CRi (CR with incomplete hematopoietic recovery), 1 leukemia not in remission and 1 pt who discontinued due to an AE in Arm A. In Arm B, 6 CRs, 2CRi, 1 PR and 1 pt with marrow aplasia have been confirmed. Decitabine PK in all arm A pts (100%) were characterized by mean+SD Cmax, 297+109 ng/mL, AUC0-t, 216+73.7 ng*h/mL, CL, 136+93.9L/h, Vdss 93.1+70.7 L, t1/2 0.456+0.073 h, and median tmax0.925 h.All pts had at least one AE. Grade 3 and 4 non-hematologic AEs in Arm A that were not seen in Arm B were caecitis in 2 (20%), anorexia in 3 (30%), and hypophosphatemia in 2 (20%) of pts. All pts experienced neutropenia and thrombocytopenia as expected. One pt in Arm A had appendicitis and colon perforation on Day 6 that led to study discontinuation, later determined to have been leukemic infiltrate. Two pts have died to date (both in Arm A), one of necrotic bowel, Pseudomonas sepsis and multisystem organ failure 6 months after completing study induction therapy. One pt died 5 months following study treatment from multisystem organ failure after stem cell transplant. Epigenetic changes associated with decitabine pretreatment were analyzed and will be presented. Conclusions:Decitabine in combination with ADE chemotherapy is well tolerated in children with newly diagnosed AML. There were no AEs that had not been previously identified in adults with MDS or AML. No differences have been observed between treatment arms in hematologic toxicities based on the current sample size. To date, the decitabine-treated pts in this study may have more gastrointestinal toxicity and hypophosphatemia. Decitabine-treated pts achieved PK exposures that were similar to those observed in adults treated with decitabine. Preliminary responses by CR/CRi were similar between treatment arms; expected adverse events of neutropenia and thrombocytopenia were similar between both Arms. Molecular changes associated with decitabine pretreatment may be important in the sensitization of clonogenic AML cells. Total accrual of 40 subjects is planned. Disclosures:Off Label Use: AC220 in relapsed/refractory pediatric acute leukemia. Tarassoff:Eisai, Inc.: Employment. Jones:Eisai Inc: Employment.