scholarly journals Upfront Treatment of Pediatric High-Risk Neuroblastoma With Chemotherapy, Surgery, and Radiotherapy Combination: The CCCG-NB-2014 Protocol

2021 ◽  
Vol 11 ◽  
Author(s):  
Dongdong Zhang ◽  
Natasha Mupeta Kaweme ◽  
Peng Duan ◽  
Youhong Dong ◽  
Xiaojun Yuan
Keyword(s):  
High Risk ◽  
Univariate Analysis ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Hazard Ratio ◽  
Hematological Toxicity ◽  
Rapid Progression ◽  
Tumor Mass ◽  
Cancer Group ◽  
Giant Tumor

PurposeThe Chinese Children’s Cancer Group developed the CCCG-NB-2014 study to formulate optimal treatment strategies for high-risk (HR) neuroblastoma (NB). The safety and efficacy of this protocol were evaluated.MethodPatients with newly diagnosed neuroblastoma and defined as HR according to the Children’s Oncology Group study were included. They were treated with a combination of chemotherapy, surgery, and radiotherapy. The treatment-related toxicities, response rate, 3-year progression-free survival (PFS), and overall survival (OS) were analyzed.ResultsOf 159 patients enrolled between 2014 and 2018, 80 were eligible, including 19 girls and 61 boys, with a median age of 3.9 years (range 0.9–11). After a median follow-up of 24 months (range 3–40), the median OS was 31.8 months, and 3-year OS was 83.8%. In multivariate analyses, the OS was affected by N-MYC amplification (hazard ratio 0.212, 95% confidence interval (CI) 0.049–0.910; p = 0.037) and giant tumor mass (hazard ratio 0.197, 95% CI 0.071–0.552; p = 0.002). The median 3-year PFS was 25.8 months, and 3-year PFS was 57.5%. The univariate analysis showed that only the giant tumor mass was associated with the outcome. Of the 13 deaths, 11 died from the rapid progression of the disease and two from treatment-related toxicities. The most common adverse reaction was chemotherapy-induced hematological toxicity.ConclusionThe PFS and OS reported in our study were similar to Western countries. The CCCG-NB-2014 protocol proved to be an efficient regimen with tolerable side-effect for the treatment of pediatric HR-NB.

scholarly journals Overexpression of the OCT-1 Gene Is a Biomarker Associated with Poor Outcomes in Diffuse Large B-Cell Lymphoma (DLBCL) - Data from a Retrospective Cohort from Latin America: Defining a Very High-Risk Clinical-Molecular Subgroup

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 41-42
Author(s):  
Luis Alberto de Padua Covas Lage ◽  
Gisele Rodrigues Gouveia ◽  
Suzete Cleusa Ferreira ◽  
Sheila Aparecida Coelho de Siqueira ◽  
Abrahão Elias Hallack Neto ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Risk ◽  
B Cell ◽  
Univariate Analysis ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Prognostic Impact ◽  
Molecular Subgroup ◽  
Free Survival ◽  
Very High

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoid malignancy, representing 30-40% of all non-Hodgkin's lymphomas (NHLs). They comprise a group of aggressive and heterogeneous neoplasms in terms of clinical presentation, response to therapy and prognosis. The OCT-1 gene is a member of the homodomain-POU family of transcriptional regulators of B-lymphoid differentiation. OCT-1 acts by controlling the expression of specific B-cell genes, such as BCL-2, a potent inhibitor of apoptosis that is essential for the differentiation of B-cells in the germinal center. These genes can be expressed in DLBCL, but the role of BCL-2 in its prognosis has been contradictory and the prognostic impact of the OCT-1 gene has not yet been tested in this lymphoma. Methods: In this observational, retrospective, single-center study, we investigated the prognostic impact of BCL-2 and OCT-1 gene expression in Brazilian patients with DLCBL treated with immunopolychemotherapy R-CHOP in a real-world context. The BCL-2 and OCT-1 genes were assessed in 78.5% (77/98) DLBCL patients, and the RNA for quantitative real-time PCR (qRT-PCR) was isolated from formalin-fixed and paraffin-embedded (FFPE) samples. The values obtained for gene expression were transformed into categorical variables according to their medians (6.27 for BCL-2 and 24.5 for OCT-1). The association between clinical and laboratory variables and results of gene expression was verified by the Fischer test. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Univariate analysis was performed using Cox's bivariate regression method and multivariate analysis using Cox multiple regression methodology. Results: The median age of the cohort was 54.5 years (15-84), 50% (49/98) were male, 49.4% (38/77) and 51.4% (40/77) showed expression of OCT-1 and BCL- 2 ≥ median, respectively. The clinical characteristics of the 98 Brazilian patients with DLBCL that comprised our cohort are summarized in Table 1. The overall response rate (ORR) in all patients was 68.4% (67/98), 65.3% (64/98) showed a complete response (CR), and 3.1% (3/98) showed partial response (PR), while 6.1% (6/98) were primary refractory. With a median follow-up of 3.77 years (95% CI: 3.2-4.1), the median overall survival (OS) was 5.43 years (95% CI: 2.2-NR) and the median progression-free survival (PFS) was 5.15 years (95% CI: 2.9-NR). The 5-year OS and PFS was 54.2% (42.2% -64.8%) and 52.0% (40.1-62.6%), respectively. In the univariate analysis OCT-1 ≥ median was associated with shortened OS (HR: 2.45, 95% CI: 1.21-4.96, p = 0.013) and PFS (HR: 2.27, 95% CI: 1.14-4.51, p = 0.019). Overexpression of BCL-2 was associated with worse PFS (HR: 2.00, 95% CI: 1.02-3.95, p = 0.043). Subgroup analysis showed that OCT-1 overexpression predominated in elderly individuals (≥ 60 years) in a statistically significant mode (29/38 cases - 76.3%, p = 0.029). It was also observed that overexpression of OCT-1 was associated with worse OS in the high-risk adjusted International Prognostic Index (aIPI) subgroup (p = 0.048) - Figure 1, and worse PFS in patients ≥ 60 years old (p = 0.025) - Figure 2. In the multivariate analysis, overexpression of OCT-1 was associated with poor PFS (HR: 2.22, 95% CI: 1.06-4.76, p = 0.035). Conclusion: In this study, we demonstrated that overexpression of the OCT-1 gene was an independent prognostic factor associated with adverse outcomes in Brazilian patients with DLCBL. We also show that in patients with unfavorable risk, such as the elderly and those with intermediate-high and high-risk IPI, overexpression of OCT-1 contributed to the identification of a very high-risk clinical-molecular subgroup, where the results with standard R-CHOP therapy are unsatisfactory, and they may benefit from intensified therapeutic strategies. Our results are preliminary and need to be validated in subsequent studies of prospective nature and with an expanded sample. Disclosures No relevant conflicts of interest to declare.

Factors influencing survival in inflammatory breast cancer.

2014 ◽  
Vol 32 (26_suppl) ◽  
pp. 136-136
Author(s):  
Julie A. Cupp ◽  
Diane Liu ◽  
Yu Shen ◽  
Naoto T. Ueno ◽  
Ricardo H. Alvarez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Inflammatory Breast Cancer ◽  
Poor Prognosis ◽  
Cox Model ◽  
Univariate Analysis ◽  
Progression Free Survival ◽  
Rank Test ◽  
Rapid Progression ◽  
Progression Of Disease ◽  
Delay In Treatment

136 Background: Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer associated with poor prognosis, characterized by rapidly growing mass, skin changes, and regional adenopathy. The objective of this study was to determine if delay in treatment influenced survival in IBC patients. Methods: A prospective IBC database identified 93 women with stage III IBC who received care at MD Anderson from 2007 - 2012 and were retrospectively reviewed. All patients received neoadjuvant chemotherapy followed by surgery, unless progression of disease was noted, and postmastectomy radiation. Impact of time from onset of symptoms to chemotherapy or to surgery on overall survival (OS) and progression free survival (PFS) were evaluated after adjusting for the baseline covariates in the Cox model. Results: A majority of patients were white (77.4%) with an average age of 54 years. Average days from onset of symptoms to first chemo is 95 (range 16 – 387) and to surgery is 283 (range 184 – 585). Four patients had progression while on chemo. There were 14 deaths with median follow up of 2.6 years from diagnosis. In univariate analysis, delay in treatment, > 90 days from onset of symptoms to chemo, did not affect OS or PFS. Obtaining negative margins was statistically significant for OS and PFS measured from first chemo (p=0.005 and p=0.007). Positive HER-2 status was associated with longer PFS time from chemo (p=0.02, log-rank test) and from surgery (p=0.009). Positive progesterone receptor (PR) was found to be statistically significantly associated with longer OS time from chemo (p=0.01) and from surgery (p=0.03). Clinical and imaging response to chemo were associated with better OS (p=0.007 and p=0.005) and pathologic response was marginally associated with improved OS and PFS (p=0.07 and p=0.06), both measured from surgery. In multivariate Cox model, adjusting for PR or HER2, days from onset of symptoms to chemo or surgery did not have significant impact on OS or PFS. Conclusions: While traditionally delay diagnosis and treatment is considered one of the factors associated with poor prognosis, our study suggests otherwise. However, due to such rapid progression of disease, early diagnosis is still important in the overall management of patients diagnosed with IBC.

scholarly journals Smoldering multiple myeloma: evolving diagnostic criteria and treatment strategies

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 673-681
Author(s):  
Alissa Visram ◽  
Joselle Cook ◽  
Rahma Warsame
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Risk Stratification ◽  
Risk Model ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Free Survival ◽  
Smoldering Myeloma ◽  
Insight Into ◽  
Made In

Abstract The adage for smoldering myeloma (SMM) has been to observe without treatment, until criteria for active multiple myeloma were satisfied. Definitions and risk stratification models have become more sophisticated, with prognostication tailored to include high-risk cytogenetics as per the most recent International Myeloma Working Group 2020 risk model. Moreover, progress in defining genomic evolution and changes in the bone marrow microenvironment through the monoclonal continuum have given insight into the complexities underlying the different patterns of progression observed in SMM. Given recent data showing improved progression-free survival with early intervention in high-risk SMM, the current dilemma is focused on how these patients should be treated. This case-based article maps the significant advancements made in the diagnosis and risk stratification of SMM. Data from landmark clinical trials will also be discussed, and ongoing trials are summarized. Ultimately, we outline our approach to SMM and hope to impart to the reader a sound concept of the current clinical management of SMM.

Relation Between Cereblon Expression and Survival in Patients with Newly Diagnosed Multiple Myeloma Treated with Thalidomide

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3973-3973
Author(s):  
Annemiek Broyl ◽  
Rowan Kuiper ◽  
Mark van Duin ◽  
Bronno van der Holt ◽  
Laila el Jarari ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Hazard Ratio ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Cox Regression Analysis ◽  
Kaplan Meier ◽  
Hazard Ratios

Abstract Abstract 3973 Introduction: Cereblon (CRBN) expression has been described to be essential for the activity of Thalidomide and Lenalidomide. This suggests that presence and possibly increased level of CRBN expression would be associated with better outcome in Thalidomide/Lenalidomide treated patients. The aim of this study was to evaluate CRBN expression in relation to outcome in patients receiving Thalidomide maintenance. Patients and methods: The HOVON-65/GMMG-HD4 trial is a multi-center, phase III trial, comparing Bortezomib in induction and post-intensification vs. conventional chemotherapy and daily Thalidomide 50 mg for 2 years post-intensification in newly diagnosed MM patients. This trial demonstrated that Bortezomib during induction and maintenance improved CR and achieved superior PFS and OS (Sonneveld et al., JCO, July 16, 2012). Gene expression profiling was performed at the start of the trial by Affymetrix U133 Plus 2.0 GeneChip, and was available for 96 patients which started Thalidomide maintenance. CRBN expression levels were based on a combined value of probe sets 218142_s_at and 222533_at. CRBN expression was validated using real-time PCR. All survival analyses were performed in SPSS, with survival time taken from the start of maintenance. Results: In patients receiving Thalidomide maintenance, increased CRBN expression was significantly associated with longer progression free survival (p=0.005, hazard ratio = 0.7) and longer overall survival (p=0.04, hazard ratio= 0.7). Using Kaplan-Meier analysis for visualization and using the median expression to define high and low expression, a significant separation was found for PFS (Log rank p=0.009) but not for OS (Log rank p=0.13). No association was observed between CRBN expression and PFS/OS after Bortezomib maintenance (PFS, p=0.4, hazard ratio=1.1; OS, p=0.7, hazard ratio=1.1). Multivariate Cox regression analysis was performed using the covariates ISS, CRBN and high-risk cytogenetics, defined as having del(17p) and/or 1q gain and/or t(4;14). Higher CRBN levels remained significantly related to longer PFS (hazard ratio 0.7, p=0.03), but not OS (hazard ratio of 0.8, p=0.3). High-risk cytogenetics and ISS were both significant in both PFS and OS multivariate models, with hazard ratios of 2.8 and 3.6, for high-risk cytogenetics and 2.5 and 5.5, for ISS stage 3, respectively (p=0.0004, p=0.003, high-risk cytogenetics and p=0.01 and p=0.005, ISS stage 3, respectively). Conclusion: These data suggest use of CRBN as a biomarker for thalidomide outcome, but further analysis in other Thalidomide trials is required to validate this finding. Disclosures: Lokhorst: Genmab: Consultancy. Sonneveld:Onyx: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; celgene: Honoraria, Research Funding.

Post Induction Minimal Residual Disease Levels Identifies a Group of High Risk Relapsed Childhood Acute Lymphoblastic Leukemia (rALL) with a Favorable Outcome Independent of Induction Therapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1294-1294
Author(s):  
Catriona Anne Parker ◽  
Marie Reeves ◽  
Sharon Love ◽  
Jeremy Hancock ◽  
Peter M Hoogerbrugge ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Induction Therapy ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Favorable Outcome ◽  
Childhood All ◽  
Post Induction

Abstract BACKGROUND: The determinants of outcome in children with rALL are the duration of first remission (CR1), site of relapse and immunophenotype. High risk (HR) relapses are defined as those occurring with a CR1 of <18 months; B-cell precursor (BCP) with bone marrow (BM) relapse within 6 months of stopping therapy and T-cell BM or combined relapses at any time. All other relapses are defined as standard risk (SR). In the UKALLR3 clinical trial for rALL, HR patients had a lower CR2 rate, higher post induction MRD and inferior survival when compared to SR patients treated in identical fashion. We investigated the effect of further intensifying induction therapy with clofarabine in HR patients. METHODS: Clofarabine was added to the UKALLR3 consolidation block of cyclophosphamide, etoposide (CCE) and used as induction therapy, with dexamethasone and PEG-Asparaginase for HR patients. The previous induction block with mitoxantrone (M) was given as consolidation and all patients were eligible for stem cell transplantation (SCT) with any donor after a third intensification block. The outcomes assessed were improvements in CR2, MRD and progression-free survival (PFS) when compared to historical controls of patients receiving idarubicin (I) or M induction in UKALLR3. A Fleming-style design, based on observed response and toxicity, was incorporated to allow an increase in the dose of cyclophosphamide from 300 mg/m2 to 440 mg/m2. RESULTS: 61, 39 at lower and 22 at the higher dose of cyclophosphamide, CCE patients were compared to 30 I and 69 M patients with HR rALL. Patients in the CCE group had a lower median age at presentation, but other prognostic variables were comparable. CR2 rates of 73%, 83%, 71% and low MRD (≤10-4) was seen in 32%, 0%, 25% of CCE, I and M groups. The higher cyclophosphamide dose was associated with improved CR rates, lower MRD but also increased toxicity levels in CCE compared to M group patients. The proportions of patients reaching transplantation were 43%, 60% and 55% of CCE, I and M patients respectively. 73/82 eligible patients received a SCT, 48 (66%) with matched and 25 (34%) with mismatched donors. The 2-year PFS with CCE, M and I regimens were 17% (11,23), 27% (19,34) and 30% (25,36) respectively (p=0.08). Outcomes of matched sibling, matched unrelated and mismatched SCT were comparable (p=0.9). Seventeen patients with a post induction MRD<10-4, had a 2-year PFS of 63% (50,75), compared to 21% (15,27) for 53 patients with MRD≥10-4 and 21% (17, 25) for the 90 patients with unknown MRD (p=0.005). All 4 patients with MRD≥10-3 prior to SCT and 8/9 not transplanted suffered a second relapse. Overall outcomes of BCP (2-year PFS 21% (15,28)) and T-cell ALL (2-year PFS 26% (16,35)) were comparable (p=0.9). PFS in BCP-ALL was 31% (24,38) and 13% (6,20) (p=0.1) for those receiving M and CCE respectively. CONCLUSIONS: We define two groups of HR rALL patients based on MRD levels attained post induction, independent of the induction regimen. Approximately a quarter of HR patients continue to have chemosensitive disease as evidenced by rapid MRD clearance (<10-4 at week 5). This group includes high-risk cytogenetics and T-cell rALL with MRD as the single discriminatory factor for outcome. These patients have a favorable outcome after SCT with any donor. In the other group (MRD≥10-4) over half of HR patients do not reach SCT primarily due to refractory disease (27%) or disease recurrence (14%). One third of patients relapse post SCT. For this group novel agents and newer treatment strategies are urgently required. Disclosures Off Label Use: Clofarabine 1st relapse childhood ALL.

scholarly journals FOLLICULAR LYMPHOMA: THE MANAGEMENT OF ELDERLY PATIENT

2016 ◽  
Vol 9 (1) ◽  
pp. e2017009 ◽  
Author(s):  
Alessia Castellino ◽  
Umberto Vitolo
Keyword(s):  
Elderly Patients ◽  
Follicular Lymphoma ◽  
Randomized Clinical Trials ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Hematological Toxicity ◽  
Mature Adults ◽  
Non Hodgkin Lymphoma ◽  
Incurable Disease ◽  
New Treatment

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma, typically affected mature adults and elderly, with a median age at diagnosis of 65 years. The natural history of FL appears to have been favorably impacted by the introduction of Rituximab. Randomized clinical trials have demonstrated that the addition of rituximab to standard chemotherapy induction has improved the overall survival and new strategies of chemo-immunotherapy, such as Bendamustine combined with Rituximab, showed optimal results on response and lower hematological toxicity, becoming one of the standard treatments, particularly in elderly. Moreover maintenance therapy with Rituximab demonstrated improvement of progression-free survival. Despite these exciting results, FL is still an incurable disease. It remains a critical unmet clinical need finding new prognostic factors to better identify poor outcome patients, to reduce the risk of transformation and to explore new treatment strategies, especially for patients not candidate to intensive chemotherapy regimens, such as elderly patients. Some progresses were already done with novel agents, but larger and more validated studies are needed. Elderly patients are the larger portion of patients with FL and represent a subgroup with higher treatment difficulties, because of comorbidities and smaller spectrum for treatment choice. Further studies, focused on elderly follicular lymphoma patients, with their peculiar characteristics, are needed in order to define the best tailored treatment at diagnosis and at the time of relapse in this setting.

GATA-3 or T-Bet Expression In PTCL-U Identify High-Risk Patients with Poor Outcomes and Distinct Clinical Characteristics Suggesting Their Derivation From Specific Subsets of T Helper Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4125-4125
Author(s):  
Ryan A. Wilcox ◽  
Andrew L Feldman ◽  
Kay Ristow ◽  
Thomas M. Habermann ◽  
Steven Ziesmer ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factors ◽  
High Risk ◽  
Confidence Interval ◽  
Median Overall Survival ◽  
Performance Status ◽  
Univariate Analysis ◽  
Tumor Stage ◽  
Hazard Ratio ◽  
T Helper

Abstract Abstract 4125 Background: With the exception of angioimmunoblastic T-cell lymphomas, which are thought to derive from follicular helper T cells, little is known about the cell of origin for the most common peripheral T-cell lymphoma (PTCL), PTCL-unspecified (PTCL-U). Following appropriate antigenic stimulation, naïve CD4+ T helper (TH) cells differentiate into effector cells that secrete TH cytokines under the transcriptional regulation of subset-specific transcription factors. Methods: PTCL-U patients (n=53) from a single institution were retrospectively identified and immunohistochemical analysis of Foxp3, T-bet and GATA-3 expression performed on diagnostic biopsy specimens. Immunohistochemical staining was reviewed in a blinded fashion by a hematopathologist and all specimens with greater than 10% staining were scored as positive. Transcription factor expression was correlated with patient characteristics and clinical outcomes. Results: GATA-3 expression was observed in 22 (42%) patients, T-bet expression in 17 (32%) patients and Foxp3 expression in 4 (7%) patients. In order to determine the prognostic significance of GATA-3 or T-bet expression, overall survival was compared between patients with GATA-3 (or T-bet) positive or negative tumors. The median overall survival (OS) was 2 years (95% confidence interval 0.7–12.8 years) for patients with GATA-3 negative tumors, compared with a median OS of 0.9 years (95% confidence interval 0.5–1.2 years, p=0.02) for GATA-3 positive cases. The median overall survival was 1.6 years (95% confidence interval 1.0–6.8 years) for patients with T-bet negative tumors, compared with a median overall survival of 0.7 years (95% confidence interval 0.3–0.9 years, p=0.005) for T-bet positive cases. As a subset of tumors coexpressed GATA-3 and T-bet, both of which are adverse prognostic factors, we examined survival outcomes between those patients with tumors expressing either GATA-3 or T-bet (n=29) and those with tumors which do not express either transcription factor (n=24). The median OS and PFS observed for patients with positive tumors was 0.7 years (95% confidence interval 0.6–1.1 years) and 0.7 years (95% confidence interval 0.5–0.9 years), respectively. In contrast, patients with GATA-3/T-bet negative tumors experienced markedly superior survival, with a median OS and PFS of 3.8 years (95% confidence interval 1.6–12.9 years, p<0.0001) and 2.0 years (95% confidence interval 1.5–12.8 years, p<0.0001), respectively. Four-year estimates of overall and progression-free survival were less than 10% for patients with GATA-3/T-bet positive tumors, whereas 4-year OS and PFS were 49% and 32%, respectively, for those with negative tumors. Both GATA-3 and T-bet expression were associated with advanced age and tumor stage. Therefore, we analyzed GATA-3/T-bet expression as a prognostic factor for survival on both univariate and multivariate analyses, adjusting for pertinent risk factors, including patient age and tumor stage. On univariate analysis, GATA-3/T-bet expression was associated with inferior overall survival (hazard ratio 4.4, 95% confidence interval 2.1–10.4, p<0.0001). Patient age (>60 years), poor performance status (ECOG performance status >1), and stage III/IV disease were also associated with inferior overall survival on univariate analysis. However, when adjusting for these latter adverse prognostic factors on multivariate analysis, GATA-3/T-bet expression remained an independent predictor of poor overall survival in PTCL-U (adjusted hazard ratio 3.2, 95% confidence interval 1.4–8.5, p=0.008). Similarly, when adjusting only for high-risk features (>2 adverse prognostic factors), as defined by the Prognostic Index in PTCL-U (PIT), GATA-3/T-bet expression remained an independent predictor of inferior overall survival on multivariate analysis (adjusted hazard ratio 4.9, 95% confidence interval 2.2–11.5, p<0.0001). Conclusions: GATA-3 and T-bet expression identify subsets of high-risk PTCL-U patients who may benefit from alternative treatment strategies. Disclosures: No relevant conflicts of interest to declare.

Maintenance Therapy After Stem-Cell Transplantation for Multiple Myeloma with Bortezomib/Thalidomide Vs. Thalidomide Vs. alfa2b-Interferon: Final Results of a Phase III Pethema/GEM Randomized Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 334-334 ◽  
Author(s):  
Laura Rosiñnol ◽  
Albert Oriol ◽  
Ana Isabel Teruel ◽  
Dolores Hernández ◽  
Javier Lopez-Jimenez ◽  
...  
Keyword(s):  
High Risk ◽  
Maintenance Therapy ◽  
Single Agent ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Hematological Toxicity ◽  
Discontinuation Rate ◽  
End Points ◽  
Contract Research Organization ◽  
The Poor

Abstract Abstract 334 Introduction: The Spanish Myeloma Group (PETHEMA/GEM) conducted a randomized phase III trial comparing induction with thalidomide/dexamethasone (TD) vs. bortezomib/thalidomide/dexamethasone (VTD) vs. VBMCP/VBAD/Bortezomib (VBMCP/VBAD/B) in patients 65 years-old or younger with newly diagnosed symptomatic MM and ASCT with MEL-200 followed by maintenance with thalidomide/bortezomib (TV) vs. thalidomide (T) vs. alfa-2b-interferon (alfa2-IFN). The induction part of the study has been recently published and the maintenance results are reported here. End-points: The primary end-point was progression-free survival (PFS) and the secondary end-points were increase of response rate, overall survival (OS) and safety. Patients and Methods: The maintenance treatment consisted of TV (thalidomide 100 mg daily plus one cycle of bortezomib at 1.3 mg/m2 on days 1, 4, 8 and 11 every 3 months) versus T (single agent thalidomide at a dose of 100 mg daily) versus alfa2-IFN (subcutaneous alfa2b-IFN at a dose of 3 MU three times per week). The planned maintenance duration was three years or until disease progression or toxicity. From February 1, 2007 to January 27, 2011 266 patients were randomized to maintenance therapy (TV: 89; T: 87, alfa2-IFN: 90). Response and survival were evaluated on an intention-to-treat basis. Responses, relapses and progressions (EBMT criteria) were monitored by an external contract research organization and centrally reassessed. Results: Patient's characteristics at diagnosis such as age, M-protein type, ISS stage, cytogenetics and presence of extramedullary plasmacytomas as well as induction regimen (VTD, TD and VBMCP/VBAD/Bortezomib) and diagnosis-randomization interval were similarly distributed among the 3 arms. The response status at the time of randomization for maintenance after ASCT was CR: 51%, nCR: 12%, PR: 34%, MR 2% and SD: 1% and was well balanced in the three groups. The CR rate with maintenance was improved by 19% with TV, 15% with T and 17% with alfa2-IFN (p=NS). After a median follow-up of 34.9 months, the PFS was significantly longer with TV compared with T and alfa2-IFN (figure 1, p=0.0009). However, OS was not significantly different among the 3 arms. Grade 3 and 4 hematological toxicity was similar (22.2% vs. 16% vs. 21.8%). No peripheral neuropathy (PN) was observed with alfa2-IFN being its frequency similar with TV (12.2%) and T (10.1%). No grade IV PN was observed. Dose reductions for TV, T and alfa2-IFN were required in 33.3%, 33.7% and 19.5% of the patients, respectively. The discontinuation rate due to progressions was not significantly diferent among the three arms (35% vs 24% vs 20%, p=NS). The discontinuation rate due to toxicity was higher with thalidomide compared with TV (30.3% vs. 15.6%, p= 0.08) and with alfa2-IFN (30.3% vs. 18.3%, p=0.17). Patients with high-risk cytogenetics [t(4;14), t(14;16) and/or del 17p] had a trend towards a shorter PFS (p=0.1) and a significantly shorter OS (p=0.03). The incorporation of bortezomib was not able to overcome the poor impact of high-risk cytogenetics. Conclusion: The addition of bortezomib to thalidomide maintenance resulted in a significantly longer PFS when compared with thalidomide alone or with single agent alfa2-IFN with no increased toxicity. However, the addition of bortezomib did not overcome the poor impact of high-risk cytogenetics. Disclosures: Rosiñol: Janssen, Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Oriol:Janssen: Honoraria; Celgene: Honoraria. De La Rubia:Celgene, Janssen: Consultancy, Speakers Bureau. Granell:Janssen: Honoraria; Celgene: Honoraria. de Arriba:Jansen: Honoraria; Celgene: Honoraria. Alegre:Janssen: Honoraria; Celgene: Honoraria. Cibeira:Janssen: Honoraria; Celgene: Honoraria. Mateos:Janssen: Honoraria; Celgene: Honoraria. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Janssen: Honoraria; Celgene: Honoraria; Onix: Honoraria; Novartis: Honoraria. Bladé:Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria.

Co-Existent Hyperdiploidy Does Not Abrogate The Poor Prognosis Associated With Adverse Cytogenetics In Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 529-529 ◽  
Author(s):  
Charlotte Pawlyn ◽  
Lorenzo Melchor ◽  
Eileen M Boyle ◽  
Annamaria Brioli ◽  
Martin F Kaiser ◽  
...  
Keyword(s):  
High Risk ◽  
Single Cell ◽  
Conflicts Of Interest ◽  
Significant Proportion ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
High Risk Population ◽  
Data Set ◽  
Translocation Event ◽  
The Impact

Abstract The development of the cytogenetic abnormalities hyperdiploidy or a translocation involving the immunoglobulin heavy chain are initiating events in the pathogenesis of myeloma. Previous studies have shown that hyperdiploidy is associated with a more favorable outcome whilst the presence of specific translocations (4;14), (14;16) and (14;20) are associated with poor clinical outcomes especially when they occur in association with other high risk features such as del17p and 1q+. While it has been generally accepted that these events are mutually exclusive, review of a number of clinical datasets shows that they occur together in a significant proportion of cases. This raises the mechanistic issue of which cytogenetic abnormality occurs first as well as the more practical issue of what it means for prognosis. In order to address these important questions we have investigated these cases with interphase FISH (iFISH) as well as determining their outcome in the Myeloma IX study. Myeloma IX is a large study (1960 newly diagnosed myeloma patients) that has been extensively described. iFISH results with a complete data set for hyperdiploidy, adverse IgH translocations, 1q+ and del17p were available for 847 patients with a median follow up of 5.9 years. 58% of patients (499/847) had hyperdiploidy and had a significantly improved survival compared with non-hyperdiploid patients (Median OS 49.7 vs 42.8 months, p=0.016 and PFS 18.8 vs 16.3 months, p=0.028). Hyperdiploid patients were divided into those who had one or more of the adverse lesions t(4;14), t(14;16), t(14;20), del17p and 1q+ (61%, 304/499) and their outcome was compared to those with none (39%, 195/499). The overall and progression free survival was significantly worse for those with hyperdiploidy plus an adverse lesion compared to those with hyperdiploidy alone (Median OS 60.9 vs 35.7 months, p<0.001, median PFS 23 vs 15.4 months, p<0.001). These results remained significant on multivariate analysis. When subdivided into those patients with hyperdiploidy plus: del17p alone, 1q+ alone, an adverse translocation alone or >1 adverse lesion, there remained a significant detrimental effect on survival (OS and PFS) for the del17p, 1q+ and >1 lesion groups and a trend towards worse survival for those with an adverse translocation (numbers too small to prove significance) when compared to those with hyperdiploidy and no adverse lesion. (table 1) Table 1 HD = Hyperdiploidy No. of patients PFS (months) OS (months) HD, no adverse lesions 304 23 60.9 HD plus del 17p 20 19.1 (p=0.019) 35.2 (p=0.003) HD plus 1q+ 142 15.4 (p<0.001) 38.1 (p<0.001) HD plus adverse translocation 9 15.4 (p=0.272) 40.1 (p=0.180) HD plus >1 lesion 24 12.1 (p<0.001) 19.9 (p<0.001) The converse situation was also examined by taking each population with an abnormal lesion and dividing them by the presence or absence of hyperdiploidy. 409/847 (48%) of patients had at least one adverse lesion and they had a significantly worse outcome within the whole data set than those without any adverse lesions (OS 60.6 vs 33.7 months, p<0.001, PFS 23.3 vs 15 months, p<0.001). When the impact of hyperdiploidy within the high-risk population (195/409 hyperdiploid, 214/409 non-hyperdiploid) was examined there was no difference in survival, (OS 35.7 vs 33.6 months p=0.64, PFS 15.4 vs 14.5 months, p=0.58). This remained true across each adverse lesion when individually analysed. A group of patients with hyperdiploidy and a (4;14) translocation were analysed at a single-cell level using iFISH. Within each case the percentage of cells with a translocation was consistently high, whereas the frequency of individual chromosomal trisomies varied. This suggests that the translocation event may occur earlier. Single cell genetic analysis using the Fluidigm technology is ongoing in order to confirm this finding. In conclusion, patients with co-existent hyperdiploidy and adverse cytogenetics have worse outcomes than those with hyperdiploidy alone. The progression of their disease is not different to those patients with adverse cytogenetics alone and our data suggests that the presence of hyperdiploidy is not able to abrogate or even ameliorate this adverse prognostic feature. It is important that this is recognised when designing treatment strategies for this group of patients as they should be treated with more aggressive chemotherapy regimens to maximize their response and control disease. Disclosures: No relevant conflicts of interest to declare.

Final results of NCCTG N0489: Epratuzumab and rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (ER-CHOP) in patients with previously untreated diffuse large B-cell lymphoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8508-8508
Author(s):  
I. N. Micallef ◽  
M. J. Maurer ◽  
D. A. Nikcevich ◽  
M. W. Cannon ◽  
E. W. Schaefer ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Phase Iii ◽  
Hematological Toxicity ◽  
Free Survival ◽  
Large B Cell Lymphoma ◽  
Large B Cell

8508 Background: A prior pilot study of epratuzumab (Immunomedics) and rituximab in combination with CHOP chemotherapy (ER-CHOP) in untreated patients with diffuse large B-cell lymphoma demonstrated feasibility and safety. This multicenter NCCTG phase II study was carried out to assess efficacy. Methods: Patients received immunochemotherapy on the following schedule: epratuzumab 360 mg/m2, rituximab 375 mg/m2, and standard dose CHOP every 3 weeks for 6 cycles. Weekly blood counts were obtained to monitor hematological toxicity. Primary endpoint was 12 month event free survival (EFS12). Secondary endpoints were response rate, progression free survival, functional CR (PET negative) and toxicity. Results: 107 patients were accrued from Feb 2006 to Aug 2007. 29 patients were ineligible resulting in 78 eligible patients. Baseline patient characteristics for the eligible patients included median age 61 (range 21–82); 59% were male. 81% had advanced stage; IPI was 0–1 in 17 pts (22%), 2 in 22 pts (28%), 3 in 29 pts (37%) and 4–5 in 10 pts (13%). Based on the revised IPI (R-IPI) 50% were poor/high risk (IPI 3–5). 71% had an elevated LDH. Performance score was 0–1 in 69 pts and 2–3 in 9 pts. The ORR was 95% (CR/CRu: 73%). For the low risk IPI (0–2), ORR was 95% (CR/CRu: 74%) and for the high risk IPI (3–5), ORR was 95% (CR/CRu: 72%). The EFS at 12 months was 80%. The 12 month progression free survival (PFS12) and overall survival (OS12) is 82% and 88% respectively. EFS12, PFS12 and OS12 by IPI risk category is shown ( Table ). Conclusions: ER-CHOP every 21 days is feasible and safe. The ORR, EFS and PFS compare favorably to studies using R-CHOP especially in the high-intermediate and high risk IPI subgroups. A randomized phase III trial of R-CHOP vs ER-CHOP is needed to prove that dual antibody targeting in combination with CHOP is better. [Table: see text] No significant financial relationships to disclose.

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