Lymphoma-Specific Venous Thromboembolism Score (LyV-Score): Use of Lymphoma Subtype to Refine Risk Prediction

Background: Patients (pts) diagnosed with non-Hodgkin lymphoma (NHL) have increased risk of venous thromboembolic event (VTE). Retrospective studies have observed the risk of VTE is not the same across lymphoma subtypes, with aggressive subtypes having higher risk than indolent lymphomas. Current VTE prediction models such as the Khorana score (K-Score) consider all lymphomas as having equal risk of VTE. We conducted retrospective time - based analyses to develop a VTE prediction model that includes lymphoma subtype as a risk factor. Methods: We accessed the Hematologic Malignancies Database at University Hospitals Seidman Cancer Center and collected records of pts diagnosed with diffuse large B cell lymphoma (DLBCL) or follicular lymphoma (FL) between 2000 and 2016. Pts with CNS involvement or active anticoagulation were excluded. FL grade 3B pts were included in the DLBCL cohort. Information retrieved included demographic characteristics, baseline disease and laboratory parameters, as well as comorbidities and diagnosis of VTE, including radiographic confirmation. Time to VTE was measured from the date of NHL diagnosis to the date of VTE incidence or censored at the date of last follow-up for those without VTE. Cumulative incidence of VTE was estimated using Kaplan-Meier method and its difference among groups was examined by log-rank test. Cumulative incidence of VTE was also calculated considering death as competing risk and comparisons done using the Gray test. Cox proportional hazards model was used to evaluate the effect of continuous and categorical covariates on cumulative incidence of VTE and to identify prognostic factors of VTE. Fifty percent of the study participants were randomly assigned to training cohort or reserved as an independent validation cohort. Performance of multivariate models was evaluated using the Akaike Information Criterion (AIC) and Concordance Index (C-Index). The final models built using the training dataset were further validated using the validation cohort. All tests are two-sided and p-values ≤ 0.05 were considered statistically significant. Results: We identified 627 pts with DLBCL (n=421) or FL (n=206) with available baseline characteristics, (Table 1). After a median follow up of 48 months (range 1-191), 77 pts experienced a VTE after NHL diagnosis. The cumulative incidence of VTE at 4 years for the whole cohort was 10.5% (95% CI 8.3-13.2). DLBCL pts had a significantly higher 4 - year cumulative incidence of VTE: 13.7% (95% CI 10.8-17.5) vs. 4.0% (95% CI 2.0 - 7.9) in FL pts (p <0.0001)(Figure 1). Univariate analysis on the training cohort showed that lymphoma subtype (DLBCL vs. FL) was associated with incidence of VTE (p = 0.02); other baseline variables associated with VTE include ECOG performance status, bulky disease, history of VTE, and serum albumin, calcium, WBC count and WBC subtypes (Table 2). Analysis of overall performance of multivariate models, including the K-Score as well as the variables identified in univariate analysis, demonstrated that the addition of lymphoma subtype and albumin to the K-Score improved the C-Index and the AIC (Table 3). The Lymphoma-specific VTE Score (LyV-Score) including lymphoma subtype, presence of bulky disease, baseline WBC and serum albumin resulted in improved performance, with C-Index of 0.775 and AIC of 234.913. To further evaluate the performance of the LyV-Score model, we performed time - dependent ROC and calibration analyses. When applied to the training cohort, 2 and 4-year AUC for the LyV-Score were 0.7767 and 0.7463, respectively, whereas for the K-Score 2 and 4-year AUC were 0.6215 and 0.6032 (Figure 2). Time - based ROC analyses in the validation cohort confirmed the higher AUC achieved by the LyV-Score. Cumulative incidence analyses show the LyV-Score and the K-Score identified groups with statistically significant differences in VTE risk (Figure 3), these differences were more marked between groups identified by the LyV-Score. Conclusions: VTE risk models have considered all lymphoma subtypes as risk factor for VTE. We show this risk is not equivalent for all lymphoma subjects, with aggressive lymphoma patients presenting higher VTE risk. We have developed the LyV-Score as a VTE prediction model that incorporates NHL histologic subtype. This model shows improved performance over historic VTE risk models and can help identify lymphoma patients that may benefit from interventions to prevent VTE. Disclosures Malek: Celgene: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Medpacto: Research Funding; Janssen: Speakers Bureau; Amgen: Speakers Bureau; Adaptive: Consultancy. Metheny:Takeda: Speakers Bureau; Incyte: Speakers Bureau. Caimi:Genentech: Research Funding; ADC Therapeutics: Research Funding; Celgene: Speakers Bureau.

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Prediction of Acute Graft-Versus-Host Disease Following Allogeneic Hematopoietic Stem Cell Transplantation Using a Machine Learning Algorithm

Blood ◽

10.1182/blood-2018-99-114794 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 68-68

Author(s):

Yasuyuki Arai ◽

Tadakazu Kondo ◽

Kyoko Fuse ◽

Yasuhiko Shibasaki ◽

Masayoshi Masuko ◽

...

Keyword(s):

Machine Learning ◽

Data Mining ◽

Cell Transplantation ◽

Cumulative Incidence ◽

Research Funding ◽

Validation Cohort ◽

Low Risk ◽

Intermediate Risk ◽

Hematopoietic Stem ◽

Training Cohort

Abstract Background Acute graft-versus-host disease (aGVHD) is one of the critical complications following allogeneic hematopoietic stem cell transplantation (HSCT). Thus far, various types of prediction scores have been invented using statistical maneuvers, such as multivariate analyses. Recent progress in the field of machine learning algorithms, which are part of a data mining approach, suggested the application of this technique for the establishment of a novel GVHD risk prediction index using pre-HSCT parameters. The primary objective of this study was to establish and validate such index for aGVHD (grades 2-4 and 3-4). Methods This study was a database dependent retrospective cohort study analyzing the data of adult recipients of HSCT obtained from the registry of Japanese Society for Hematopoietic Cell Transplantation. Pre-HSCT parameters, such as those for patients, donors, conditioning regimens, and other procedures were retrieved from the database and introduced into the data mining approach. The alternating decision tree (ADTree) machine learning algorithm was applied to develop a model. This cohort was randomly divided into the training cohort (70% of the entire dataset) and the validation cohort (the remaining 30%). The algorithm was trained and tested using a 10-fold cross validation on the training cohort. The ADTree was validated in the validation cohort using the competitive risk hazard model. Results In total, 26,695 patients transplanted from allogeneic donors since 1992 to 2016 were included in this study. More than half of the patients were treated for acute myeloid leukemia or myelodysplastic syndrome (50.9%), followed by acute lymphoblastic leukemia (19.2%) and non-Hodgkin lymphoma (8.3%). The cumulative incidence of grades 2-4 and 3-4 aGVHD was 42.8% (95% confident interval [CI], 42.2 - 43.4%) and 17.1% (95%CI, 16.6 - 17.5%), respectively. Predictive ADTree models were established using the training cohort (N = 17,244). Out of >30 variables considered, 15 variables, such as underlying disease, donor source, HLA and sex mismatch, conditioning regimen, GVHD prophylaxis, and donor age, were adapted into each model for aGVHD prediction (Figure 1). Cross validation demonstrated that the models' discrimination for the incidence of aGVHD was appropriate (area under curve: 0.616 and 0.623 for grades 2-4 and 3-4, respectively). These models were tested in the validation cohort (N = 8,050), and the incidence of aGVHD was clearly stratified according to the categorized ADTree scores (Figure 2). The cumulative incidence of grade 2-4 aGVHD was 29.0% for low risk, 35.3% for low-intermediate risk (hazard ratio [HR] compared with the low risk, 1.26; 95%CI, 1.11 - 1.42), 41.8% for intermediate risk (HR, 1.56; 95%CI, 1.39 - 1.76), 48.7% for high-intermediate risk (HR, 2.00; 95%CI, 1.78 - 2.24), and 58.7% for high risk (HR, 2.57; 95%CI, 2.30 - 2.88). Whereas, the cumulative incidence of grade 3-4 aGVHD was 8.6% for low risk, 12.5% for low-intermediate risk (HR, 1.53; 95%CI, 1.20 - 1.93), 14.9% for intermediate risk (HR, 1.85; 95%CI, 1.48 - 2.31), 21.1% for high-intermediate risk (HR, 2.72; 95%CI, 2.19 - 3.38), and 28.6% for high risk (HR, 3.87; 95%CI, 3.13 - 4.78). These two scores for aGVHD also demonstrated the relationship with the inferior overall survival after HSCT. Discussion Variables automatically extracted through machine learning algorithms (i.e., ADTree), in the absence of any bias from researchers, were clinically reasonable, and the obtained systems provided robust risk stratification scores for the incidence of aGVHD following allogeneic HSCT. The high reproducibility and freedom from the interactions among the variables indicate that ADTree, along with the other data mining approaches, may be widely used in the establishment of risk score. The present results should be validated in the other patient cohorts through future studies worldwide. Disclosures Ichinohe: Nippon Shinyaku Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; MSD: Research Funding; Pfizer: Research Funding; JCR Pharmaceuticals: Honoraria; Celgene: Honoraria; Takeda Pharmaceutical Co.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Mundipharma: Honoraria; Novartis.: Honoraria; Kyowa Hakko Kirin Co.: Research Funding; Eisai Co.: Research Funding; CSL Behring: Research Funding; Chugai Pharmaceutical Co.: Research Funding; Astellas Pharma: Research Funding. Kanda:Eisai: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Asahi-Kasei: Research Funding; Pfizer: Research Funding; Taisho-Toyama: Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Tanabe-Mitsubishi: Research Funding; Sanofi: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; MSD: Research Funding; Ono: Consultancy, Honoraria, Research Funding; CSL Behring: Research Funding; Dainippon-Sumitomo: Consultancy, Honoraria, Research Funding; Taiho: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Celgene: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria.

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Risk Factors Associated with Richter's Transformation in Patients with Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2018-99-112442 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1697-1697 ◽

Cited By ~ 1

Author(s):

Yasmin Ben-Dali ◽

Mariam Hussein Hleuhel ◽

Michael Asger Andersen ◽

Christian Brieghel ◽

Erik Clasen-Linde ◽

...

Keyword(s):

Risk Factors ◽

Chronic Lymphocytic Leukemia ◽

Incidence Rate ◽

Cumulative Incidence ◽

Research Funding ◽

Univariate Analysis ◽

Lymphocytic Leukemia ◽

Increased Risk ◽

Binet Stage

Abstract Background Richter's transformation (RT) refers to the development of an aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL). Roughly, 2-10 % of patients with CLL develop RT most often as diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL). Aim This study aimed to assess the incidence rate and risk factors for RT for patients with CLL in a nationwide cohort. Furthermore, we want to assess prognostic risk factors for patients with RT. Methods All patients diagnosed with CLL in Denmark between 2008 and 2016 were included in this study. Clinical data was retrieved from the Danish National CLL Registry (DCLLR), whereas all histologically verified DLBCL, HL and/or transformation diagnoses for patients with CLL were retrieved from the Danish National Pathology Registry. Patients were followed from date of CLL diagnosis until date of RT, death or end of follow-up, whichever came first. The time to RT was estimated as cumulative incidence considering death as a competing risk. Stepwise Cox analysis with backward elimination was applied to identify independent risk factors for RT in patients with CLL. Results A total of 3771 CLL patients were identified, and followed for 14165 person-years. With a median follow-up of 4.3 (IQR (2.4;6.6)) years, 120 (3%) CLL patients had a transformation diagnosis, of which 4 patients were excluded due to misdiagnosis. DLBCL accounted for 78/116 (67%) cases, HL for 15/116 (13%) cases and one patient presented with both DLBCL and HL. In the remaining 22/116 (19%) cases the subtype of the transformation was either unspecified or unclassified RT. The median time to RT was 3.4 (IQR (1.8;5.7)) years from CLL diagnosis and the median overall survival (OS) after development of RT was 4.9 (IQR (0.7;8.4)) years. The cumulative incidence of RT, calculated by Aalen-Johansen estimator, at 5 and 8 years post-CLL diagnosis were 3.3% and 7.9% respectively (Figure 1). The annual crude incidence rate of RT was approximately 0.7% per year for all CLL patients. In all, 918 (24%) patients received CLL-related treatment, of whom 59 (6.4%) patients developed RT, resulting in a cumulative incidence of RT of 7% after 5 years and 11% after 8 years. At the time of CLL diagnosis, patients treated for CLL prior to RT diagnosis had a worse median OS (1.49 years) compared to RT patients who were untreated for CLL (6.16 years). In the univariate analysis, RT was significantly associated with male gender, advanced Binet stage (B or C), unmutated IGHV status (CLL-U), elevated beta-2-microglobulin (>3.5 mg/L) and elevated lactate dehydrogenase (>205 U/L). Of cytogenic aberration, deletion 13q (del(13q)) had a protective effect on the risk of RT, whereas deletion 11q (del(11q)) and deletion 17p (del(17p)) increased the risk. In the multivariable model, advanced Binet stage (HR 2.86 (1.82;4.51), p<0.001), del(17p) ((HR 3.74 (2.12;6.61), p<0.001) and CLL-U ((HR 2.30 (1.46;3.63), p<0.001) showed an independent correlation with development of RT. ZAP70 and CD38 were excluded from statistical analyses due to incomplete data and high inter-laboratory variation. Among RT patients, CLL-U, trisomy 12 and del(17p) at CLL diagnosis as well as ECOG Performance Status (PS) (i.e. PS≥1) at time of RT diagnosis correlated with poor OS in univariate analysis. Both del(17p) and PS≥1 were independently associated with an increased risk of death in a multivariable analysis (HR 2.9, (1.1;7.7), p=0.04 and HR 3.0, (1.0;3.1), p=0.05, respectively). Conclusions To the best of our knowledge, we here report the largest study on RT assessing nationwide data of consecutive patients diagnosed with CLL. The incidence of RT in this unselected population was 3.3% after 5 years while the median OS for patients from time of RT was 4.9 years. Advanced Binet stage, del(17p) and CLL-U were significantly and independently associated with an increased risk of RT. Del(17p) at CLL diagnosis and PS≥1 at RT diagnosis were significant predictors for death for patients with RT. For patients diagnosed with RT prior to any CLL treatment, a less severe disease course with a median OS of 6.16 years was demonstrated. Contrary, the median OS for patients receiving prior CLL treatment was 1.49 years. Thus, assessment of different treatment options for patients developing RT based on whether they have received prior CLL treatment or not is warranted. Figure 1. Figure 1. Disclosures Ben-Dali: Rigshospitalet: Research Funding. Hleuhel:Rigshospitalet: Research Funding. Brieghel:Arvid Nilson's Fund: Research Funding; Rigshospitalet, Denmark: Research Funding. Niemann:Danish Cancer Society: Research Funding; Novo Nordisk Foundation: Research Funding; Janssen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy; CSL Behring: Consultancy.

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Analysis Of Transfusion Dependence Development and Disease Evolution In Patients With MDS and Del(5q) and Without Transfusion Needs At Diagnosis

Blood ◽

10.1182/blood.v122.21.1542.1542 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1542-1542

Author(s):

Silvia M Rojas ◽

María Díez-Campelo ◽

Elisa Luño ◽

Teresa Bernal ◽

Monica Cabrero ◽

...

Keyword(s):

Multivariate Analysis ◽

Statistical Analysis ◽

Cumulative Incidence ◽

Research Funding ◽

Statistical Significance ◽

Univariate Analysis ◽

Disease Evolution ◽

Free Survival ◽

Kaplan Meier

Abstract Myelodysplastic syndrome with 5q- (MDS 5q-) is the only cytogenetically defined MDS category recognized by the world Health Organization (WHO) in 2001 and 2008 and is defined as a MDS with isolated deletion on the long arm of chromosome 5 and less than 5% of blast cells in bone marrow (BM). It is well known that for patients with MDS 5q- and transfusion dependence (TD), Lenalidomide is the first choice treatment. However, as far as we know there are no data regarding factors that may impact on the development of TD in these patients or the disease evolution in patients diagnosed without TD. In the present study a retrospective multicenter analysis on patients with low-int 1 MDS 5q- without TD at diagnosis has been performed in order to answer these questions. Patients and methods Data from eighty-four low-Int 1 risk MDS 5q- patients diagnosed between 1980 and 2012 were retrospectively analyzed. Ninety percent of patients had a single 5q deletion and according to IPSS-R 99% were in low and very low risk. Statistical analysis The event of TD was defined as the development of TD according to the IWG criteria (2006) and/or the beginning of a treatment which could modify disease course (Lenalidomide or ESA). Patients follow up was updated on March 30, 2013, and all follow up data were censored at that point. Transfusion free survival (TFS), Overall survival (OS) and AML were analyzed using the Kaplan – Meier method. TFS, OS, and Leukemia free survival (LFS) were measured from diagnosis to TD or to last follow up if transfusion free (TFS), death from any cause or last follow up (OS) and evolution to AML or last follow up (LFS). Multivariate analysis was performed using Cox’s proportional hazards regression model. Incidence of progression to AML was analyzed with cumulative incidence competing risk method. For comparison of Kaplan Meier curves the long rank test was used, with statistical significance with p<0.05 statistical analysis was performed using SPSS 15.0 and NCSS V.8, 2010. Results During the study 61 (73%) became TD at a median of 1.7 years from diagnosis. The unique factor associated with poorer TFS was Hb level <9 g/dl (p=0.007) and this impact retained statistical significance in the multivariate analysis (table.1) Among the 61 TD patients, 49 received treatment: 19 lenalidomide, 24 ESA and 6 other treatments. Fifteen patients were treated (7 with lenalidomide and 8 with ESA) previous to TD development. In order to know the evolution of this very good prognostic subgroup of patients, OS and LFS analysis were performed. Median follow up was 48 months, 46% of patients are alive at the time of the last follow up and 31% developed secondary AML (sAML). Estimated OS at 2 and 5 y was 92% and 50% respectively. Regarding Univariate analysis, platelet <100.000 x109/L, and IPSS-R intermediate risk group were associated with poorer OS (p=0.001 and 0.019 respectively). On the contrary, patients who had received treatment showed better OS. This benefit is more evident among patients receiving Lenalidomide (p=0.015). In the multivariate analysis platelets <100.000 x109/L and Lenalidomide treatment retained the statistical significant impact on OS (table1). When LFS was analyzed the cumulative incidence of progression into AML was 4,4% after 2 y. and 12,7% after 5 y from diagnosis with median time to sAML of 8.16 years (CI 95%: 6.05-10.27). LFS at 2 and 5 y was 86% and 73% respectively. When univariate analysis was performed variables with impact on sAML were platelet <100.000 x109/L (p=<0,001), and to have received treatment (p=0,02). In the multivariate analysis only thrombocytopenia retained statistical significance (table1).In summary, the present analysis shows that Hb is the only parameter that conditions the TD development in MDS-5q- patients. In this very good prognostic subgroup beginning treatment with lenalidomide improves survival. Disclosures: Díez-Campelo: Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen-Cilag: Research Funding. Off Label Use: In the present study we describe Lenalidomide treatment among patients with MDS and del(5q-) receiving this drug, not approval for this use in Europe, patients with anemia and transfusional requirements. Solé:Celgene: Consultancy, Honoraria; Celgene: Consultancy. Consuelo:Celgene Jansen-Cilag Arry Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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Cardiac Morbidity in Adolescents and Young Adult Survivors of Hodgkin Lymphoma

Blood ◽

10.1182/blood-2020-136454 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 18-19

Author(s):

Kristin C. Marr ◽

Jonathan Simkin ◽

Andrea C. Lo ◽

Joseph M. Connors ◽

Alina S. Gerrie ◽

...

Keyword(s):

Cumulative Incidence ◽

Research Funding ◽

Index Date ◽

Population Based ◽

Stage Disease ◽

Increased Risk ◽

Matched Case ◽

Cv Disease ◽

Relapsed Disease

INTRODUCTION Adolescents and young adult (AYA) survivors of Hodgkin lymphoma (HL) are potentially at increased risk of cardiovascular (CV) disease due to anthracycline exposure, in addition to use of mediastinal radiotherapy (RT). Although the risk has been well described in the pediatric age-group, the impact in the AYA population has been less well characterized. Capturing the incidence of these late effects is challenging given that events can occur more than a decade after therapy completion. Using population-based administrative data, we evaluated the incidence of CV disease (combined heart failure (HF) and ischemic heart disease (IHD)) in a cohort of AYA survivors treated for classical HL (cHL) using ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) or equivalent chemotherapy. METHODS Patients with cHL aged 16-39 years (y), diagnosed between 1992-2013 and treated with an ABVD or equivalent therapy, were identified in the BC Cancer Lymphoid Cancer Database. Patients must have survived to an Index Date defined as 2 y from most recent HL event (primary diagnosis or if applicable, most recent relapse) and have had a minimum follow-up of 1 y beyond their Index Date. Patients were excluded if they had history of prior malignancy or HIV positivity. Limited stage disease was defined as stage IA, IB or IIA and absence of bulky disease (≥10cm); all others had advanced stage disease. Cases were linked with population-based databases of BC Cancer Registry; BC Radiation Oncology Database; and BC Ministry of Health (MOH) Chronic Disease Registry (CDR) that captures all BC residents registered with medical service plan coverage during the study period. The outcome variables, including HF and IHD, were defined by the BC MOH CDR using Standardized Case Definitions. To focus on late onset CV complications, only events that occurred after the Index Date were included in the analysis. A 10:1 individually-matched control population was identified from the CDR based on age, sex, and health authority region on the Index Date of the matched case. Controls were excluded if they had a pre-existing malignancy, HF, or IHD prior to the study window. Individual outcomes were collected from the Index Date of the matched case until December 31, 2015 or until an individual was censored due to loss to follow-up or death. Kaplan Meier (K-M) methodology and log-rank test was used to estimate cumulative incidence. A competing risk regression analysis was used to evaluate relative risk (RR) and p-values less than 0.05 were considered significant. RESULTS With a median follow-up time of 11 y (range 3-24 y) from most recent HL event, 764 AYA 2-y survivors were identified, aged 20 to 61 y (median 38 y) at the end of study period. The proportion of limited and advanced stage disease was 34.2% and 65.6%, respectively; and 49.9% were male. Eighty-eight patients (11.5%) had relapsed disease; eighty-six (11.3%) underwent high dose chemotherapy and autologous stem cell transplantation as part of their salvage therapy. In total, 268 patients (36.4%) were treated with mediastinal RT for primary therapy or for relapsed disease. Fifty-three percent received cumulative anthracycline dose ≥300 mg/m2. Survivors had a 3-fold increased risk of CV disease relative to controls (p<0.0001). The onset of CV disease in survivors occurred at median of 11.7 y after most recent treatment (range 2.2-19.2 y), and at a median age of 44.3 y (range 21 - 58 y). At 15 y, the estimated cumulative incidence of CV disease was 6.3% in survivors compared to 2.3% in controls (Figure A). In the 496 survivors that received chemotherapy only, the incidence of CV disease at 15 y was 4.6% vs 2.3% in controls, and those that received anthracyclines and mediastinal RT had significantly higher incidence at 8.6% (Figure B). The increase in risk was greatest for a diagnosis of HF (RR 6.92, p<0.0001): at 15 y, the cumulative incidence of HF was 2.2% vs 0.6% in controls. The RR of IHD was 2.63 (p<0.0001) with incidence of 5.1% in cases compared to 1.8% in controls. CONCLUSION Similar to the pediatric population, AYA cHL survivors are at increased risk of both HF and IHD after completion of treatment. The majority of patients had received ABVD alone and had a lower incidence of CV disease at 15 y when compared to those that received treatment that included mediastinal RT. These results will inform counseling regarding risk factor modification and aid in the development of surveillance guidelines for AYA survivors. Disclosures Gerrie: Sandoz: Consultancy; Roche: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Astrazeneca: Consultancy, Research Funding. Villa:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; AZ: Consultancy, Honoraria, Research Funding; Kite/Gilead: Consultancy, Honoraria; Nano String: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Sandoz Canada: Consultancy, Honoraria; Immunovaccine: Consultancy, Honoraria; Purdue Pharma: Consultancy, Honoraria. Scott:NIH: Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America.; Roche/Genentech: Research Funding; Celgene: Consultancy; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoString, Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy, Research Funding. Sehn:AstraZeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Teva: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Apobiologix: Consultancy, Honoraria; Verastem Oncology: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; Chugai: Consultancy, Honoraria. Savage:BeiGene: Other: Steering Committee; Roche (institutional): Research Funding; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie, Servier: Consultancy; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie: Honoraria.

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Efficacy and Safety of a FLAG-Sequential Regimen Followed By Hematopoietic Stem Cell Transplantation for Myelodysplasia or Acute Leukemia in Fanconi Anemia: A Franco-Brazilian Report

Blood ◽

10.1182/blood-2019-122007 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2498-2498

Author(s):

Pierre-Edouard Debureaux ◽

Flore Sicre de Fontbrune ◽

Carmem M. S. Bonfim ◽

Jean-Hugues Dalle ◽

Nimrod Buchbinder ◽

...

Keyword(s):

Cumulative Incidence ◽

Research Funding ◽

Bone Marrow Failure ◽

Clonal Evolution ◽

Infectious Complications ◽

Hematopoietic Stem ◽

Free Survival ◽

History Of ◽

Syncytial Virus

Background: Fanconi anemia (FA) is the most frequent genetic cause of bone marrow failure (BMF) due to a DNA repair mechanism defect. The natural history of FA is marked by progressive BMF during early childhood. Throughout life, the hematopoietic situation may change by clonal evolution toward myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for bone marrow failure in FA patients. The role of HSCT for FA patients with AML or advanced MDS is less defined. Currently, HSCT first line result offers 50% Overall Survival (OS) for patients with cytogenetic abnormalities only and 30% OS for patients with advanced MDS or AML in FA (Ayas et al., JCO 2013; Mitchell et al., BJH 2014). We previously reported a FLAG-sequential approach in 6 patients with FA (5 AML and 1 advanced MDS), all alive at a median follow-up of 28 months (Talbot et al., Hematologica 2014). We update here those patients and report 12 more patients treated by FLAG-sequential since then. Materials & Methods: This retrospective study (2006-2019) was conducted in 7 centers in France and Brazil on behalf of the French Reference Center for Aplastic Anemia to evaluate FLAG-sequential in FA patients with morphological clonal evolution (no patients with cytogenetic abnormalities only). The study was conducted in accordance with the Declaration of Helsinki. Anonymous data collection was declared to the appropriate authorities. The FLAG-sequential treatment consisted of FLAG, Fludarabine 30 mg/m²/d for five days and Cytarabine 1 g/m²x2/d with G-CSF for five days, which was followed three weeks later by Cyclophosphamide 10 mg/kg/d for four days, Fludarabine 30 mg/m²/d for four days and TBI 2 Gy (Fig 1A). In a haploidentical setting, Cyclophosphamide at 30 mg/kg/d was performed only in post-transplantation, at Days +4 and +5 (Fig 1B). Results: Eighteen patients were included with 14 AML, 1 acute lymphoblastic leukemia (ALL), and 3 RAEB-2 (Table 1). The median age at the time of HSCT was 22 years (4-37 years). Fifteen patients (83%) were older than 10 years at the time of HSCT. The median follow-up was 31 months (3- 153 months). Eight patients (44%) had complex karyotype. None of the included patients had a history of solid malignancies before HSCT. All patients engrafted. The cumulative incidence of neutrophil engraftment at Day 60 was 94% (95% CI 63-100%) with a median of 18 days (12-343 days). The cumulative incidence of platelet engraftment at Day 60 was 83% (95% CI 50%-96%) with a median of 25 days (17-245 days). The donor chimerism was complete at Day +100 for 15 patients. The three patients without full donor chimerism at Day +100 either had a relapse (n=1) and 2 early deaths before Day+100 from steroid-refractory aGVHD (n=1) or septic shock (n=1). None of the patients received a second HSCT. Non-relapse mortality (NRM) at 3 years was 32% (95% CI 6-58%) (Fig 2). Cumulative incidence of grades II to IV aGVHD was 56% (35% grades III to IV). Cumulative incidence of extensive cGVHD was 16%. Infectious complications during HSCT include the following: CMV (n=8), EBV (n=2), adenovirus (n=4), BK virus (n=7), respiratory syncytial virus (n=1), candidaemias (n=2) and invasive aspergillosis (n=3). Progression free survival (PFS) and OS at 3 years were 53% (95%CI 32-89%) and 53% (95%CI 32-89%), respectively (Fig 2). Cumulative incidence of relapse at 3 years was 13% (95%CI 0-31%) (Fig 2). Seven patients died during the study. Causes of death were relapse (n=2), aGVHD (n=2), cGVHD (n=1), septic shock (n=1), and respiratory syncytial virus associated with invasive aspergillosis (n=1). GVHD-relapse free survival (GRFS) at 3 years was 48% (95%CI 29-78%). One patient had anal epidermoid carcinoma at 4 years after HSCT, which required multiple surgical ablations. Conclusion: With almost 3 years follow-up, which is long enough for our results to be considered robust, we report an OS and PFS of 53%, which compares favorably to historical controls since all of our 18 patients were treated with florid disease at time of HSCT (and not with cytogenetic abnormality only, known to be associated with a better prognosis). Toxicity is still a concern in this particular population of FA patients with notably a high rate of infectious complications. Future well designed prospective clinical trials will refine this sequential strategy, which appears promising in this particular difficult clinical situation. Disclosures Socie: Alexion: Consultancy. Peffault de Latour:Alexion: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding.

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BEACOPP Chemotherapy Is Able to Induce Durable Complete Remission in Poor-Prognosis Hodgkin’s Lymphoma Patients with a Positive Interim PET after 2 ABVD Cycles

Blood ◽

10.1182/blood.v112.11.2594.2594 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2594-2594

Author(s):

Andrea Gallamini ◽

Alessandro Rambaldi ◽

Alberto Biggi ◽

Silvia Tavera ◽

Caterina Patti ◽

...

Keyword(s):

Treatment Failure ◽

Poor Prognosis ◽

Univariate Analysis ◽

Pet Scan ◽

Advanced Stage ◽

Bulky Disease ◽

Interim Pet ◽

Number Of Patients ◽

The Mean

Abstract Background: Early interim-PET (PET-2) is the most powerful factor able to predict treatment outcome in advanced-stage Hodgkin Lymphoma (HL) patients treated with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). The 2-y PFS of PET-2 positive patients is only 12%, but the optimal treatment for this patient subset is still unknown. For this reason in January 2006 a treatment policy was designed by GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) to early intensify chemotherapy with BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) for HL patients with a PET-2 positive after 2 ABVD cycles. Patients and methods: 136 HL patients with advanced-stage or intermediate-stage with adverse prognostic factors (more than 3 nodal sites, ESR > 50 mm, sub diaphragmatic presentation, bulky lesion), consecutively admitted to nine GITIL Italian centers were treated with two ABVD courses and re-evaluated with interim-PET. Twenty-one of these 136 patients proved to be PET-2 positive, and 19/21 are the object of this analysis. The mean age was 31.7 years (16–64), 10 patients were in stage II, 9 in stage III–IV. Bulky disease was present in 11, and B-symptoms in 16. Fourteen patients showed an IPS score 0–2, 5 patients a score 3–7. The median interval between the end of second ABVD course and PET-2 was 11 days (5–14). BEACOPP (4 escalated and 4 standard cycles) was followed by consolidation radiotherapy in 3 patients for bulky mediastinal tumor. PET scan were centrally reviewed by two well-experienced nuclear medicine experts, using the blood pool mediastinal structures (BPMS) as reference for the residual uptake, as elsewhere published (Gallamini, JCO 2007). Results. Upon central review, 2 interim-PET scan were classified as minimally positive in 2 patients, with a single MRU (Minimal Residual Uptake) lesion showing a SUV (Standardized Uptake Value) lower than BPMS, and therefore only 19 cases were suitable for the BEACOPP salvage treatment. After a mean follow-up of 14.3 months (7.0–30.2), 15 patients remain in continuous CR and 4 had a treatment failure because of disease relapse (1) or progression (3). For the responding patients the mean duration of CR was 13.0 months (6.5–30.2). The IPS score for progressing patients was 2, 3, and 4; for the relapsing-one, 0. At time of this analysis, l8 patients are still alive and 1 died during BEACOPP treatment for disease progression. The 1-year second treatment failure-free survival (1-y 2TFFS) was 94.7 % (95% C.I. 84.7–100). The 1 y OS survival was 93.3 (95%C.I. 80.7–100). In univariate analysis the only clinical factor related to treatment failure was the presence of extra-nodal disease. (Log-rank=6.8 p=0.009). Conclusions. BEACOPP-escalated regimen was able to induce durable CR in most (15/19) HL patients with a positive interim-PET. These results, although requiring a longer follow-up and a higher number of patients, seem to suggest that the very-poor prognosis of PET-2 positive, ABVD-treated HL patients can be substantially improved by early chemotherapy intensification; escalated-BEACOPP is likely to represent a good treatment choice for this very poor prognosis patient subset.

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Rituximab In Allogeneic Hematopoietic Stem Cell Transplantation for Advanced Chronic Lymphocytic Leukemia with Fludarabine + Total Body Irradiation Conditioning: Results of a Phase II Prospective Multicenter Study (ITAC 02-02)

Blood ◽

10.1182/blood.v116.21.3520.3520 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3520-3520

Author(s):

Mauricette Michallet ◽

Mohamad Sobh ◽

Stephane Morisset ◽

Mohamad Mohty ◽

Gerard Socie ◽

...

Keyword(s):

Median Time ◽

Total Body Irradiation ◽

Cumulative Incidence ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Lymphocytic Leukemia ◽

Positive Trend ◽

Hematopoietic Stem ◽

Total Body

Abstract Abstract 3520 Background: CLL remains incurable with standard therapies. Myeloablative allogeneic SCT (allo-HSCT) is still associated with high TRM and few late relapses. Recently, the major focus of transplantation in CLL has been with reduced-intensity conditioning (RIC) allo-HSCT, which is applicable to the more elderly patient population and which attempts to exploit the graft-versus-leukemia (GVL) effect that was proved in CLL Objective: To evaluate the efficacy and toxicity a RIC regimen including fludarabine and total body irradiation (TBI) with the introduction of rituximab for allo-HSCT in patients with a CLL stage B or C diagnosis. Materials and methods: This prospective study included adult CLL patients with age < 65 years in stage B or C in response after a salvage treatment either following at least 2 treatment lines (1 including fludarabine) or after a progressive disease after auto-HSCT, having a HLA identical sibling donor and a good performance status (Karnfosky >70%). Donors were mobilized by G-CSF and in case of collection failure, bone marrow aspiration was authorized. The conditioning included: rituximab 375mg/m2 on day -5, fludarabine 30 mg/m2 from day-4 to day-2, TBI 2grays (6-7 cGrays/minute) on day 0 and rituximab 500mg/m2 on day1 and day8. GVHD prophylaxis used cyclosporine A (IV 3mg/kg/day) from day-2 and mycomofetil fenolate oral (2g/day) from day 1. Results: Between April 2003 and December 2008, 40 patients were included, 34 (85%) males and 6 females with a median age of 54 years (35-65), 38 (95%) were in B stage at diagnosis and 2 in stage C. Among 23 explored for cytogenetics, 8 were abnormal (3 del17, 1 trisomy12, 1 t(8-11) & 1 del13). Before transplantation, 17 patients received 2 lines treatment, 10 three lines, 5 four lines, and 8>4. Only 1 patient received a previous auto-HSCT. Among 18 explored for Matutes status, 1 was in score 1, 1 in score 2, 3 in score 3, 5 in score 4 & 9 in score 5. At time of allograft, 7 (17%) patients were in complete response (CR), 29 (73%) in partial response (PR) and 4 (10%) < PR. For sex-matching, 59% were mismatched (27%of them were F>M). For ABO matching, 68% were compatible, 19% major incomp. & 13% minor incopm. The median interval diagnosis-allo-HSCT was 58 months (6-177). Median CD34+ number was 7.64 (3.1-18.7). Seven (17%) patients did not receive rituximab during conditioning because the protocol did not include it at the beginning and has been amended later. Thirty-nine (98%) patients engrafted with a median time to neutrophils recovery of 20 days (11-70), 79% of patients reached a total donor chimerism at day 90. Seventeen patients developed aGVHD grade ≥II (8 grII, 8 grIII & 1 grIV) with a cumulative incidence at 3 months of 44% (36-52). The cumulative incidence of cGVHD was, at 12 months: 29% (21-36) for limited and extensive; at 18 months: 32% (24-40) limited and 42% (34-50) extensive. After a median follow-up of 28 months (3-71), the median OS was not reached with 3 and 5-years probability of 55%(41-74). The median time of EFS was 30 months (15 - 70) with a 5-years probability of 46%(33-66). The cumulative incidence of relapse at 1 and 3 years was 17% (11-23) and 22% (15-29) respectively. The cumulative incidence TRM at 1 and 3 years was 10% (5-15) and 27% (20-35) respectively. At the last follow-up, 17 patients died, 6 due to relapse and 11 due to TRM. We noticed a high severe infection rate (56%) and 4% of deaths related only to infection. The univariate analysis showed a positive trend of rituximab on OS and relapse, and a significant protective effect on aGVHD>=2 (p=0.02). The multivariate analysis studying age, interval diagnosis-allo-HSCT, ABO and sex matching, disease status at allo-HSCT, CD34+ number, and rituximab, showed a positive significant impact of this last factor (rituximab) on OS and EFS [HR=0.1 [0-0.6] p=0.02 & HR=0.1[0-0.4] p=0.035 respectively]. Conclusion: We showed interesting results in terms of OS, relapse and TRM in patients with advanced CLL after Fludarabine/TBI allo-HSCT. The introduction of rituximab allowed a better outcome especially a significant reduction of incidence and severity of acute GVHD. Nevertheless there was still a high incidence of cGVHD, already known following the Fludarabine/TBI conditioning, leading us to propose either to increase the number of rituximab injections after allo-HSCT, or to test Fludarabine/busilvex/ATG associated to rituximab. Disclosures: No relevant conflicts of interest to declare.

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A Multicenter Randomized Placebo Controlled Trial of Compression Stockings to Prevent the Post-Thrombotic Syndrome After Proximal Deep Venous Thrombosis: The S.O.X. Trial

Blood ◽

10.1182/blood.v120.21.393.393 ◽

2012 ◽

Vol 120 (21) ◽

pp. 393-393 ◽

Cited By ~ 3

Author(s):

Susan R. Kahn ◽

Stan Shapiro ◽

Phil S Wells ◽

Marc A. Rodger ◽

Michael J. Kovacs ◽

...

Keyword(s):

Venous Thrombosis ◽

Deep Venous Thrombosis ◽

Cumulative Incidence ◽

Research Funding ◽

Primary Outcome ◽

Controlled Trial ◽

Event Analysis ◽

Time To Event ◽

Compression Stockings

Abstract Abstract 393 Background: The post-thrombotic syndrome (PTS) is a burdensome, costly complication of deep venous thrombosis (DVT). Investigating strategies to prevent PTS is important, as treatments for PTS are limited. To date, randomized trials of elastic compression stockings (ECS) to prevent PTS were small, single-center, none used a placebo control and results are conflicting. Objective: To determine whether ECS, compared with inactive (placebo) stockings, are effective to prevent PTS in patients with proximal DVT. Methods: We conducted a multicenter (24 centres, Canada and U.S.) randomized placebo controlled trial of active ECS (A-ECS) vs. placebo ECS (P-ECS) to prevent PTS after a first, symptomatic proximal DVT. A-ECS were knee length 30–40 mm Hg (Class II) graduated ECS. P-ECS were manufactured to look identical to A-ECS but lacked therapeutic compression. Stockings were mailed directly to patients and worn on the DVT-affected leg daily for up to 2 years. Patients did not wear their stockings at study follow-up visits (1, 6, 12, 18 and 24 months) to maintain study personnel blinding. The primary study outcome, PTS, was diagnosed at or after the 6 month visit using the Ginsberg measure (leg pain and swelling of 3 1 month duration and typical in character: worse end of day or after prolonged sitting/standing and improved after rest/leg elevation). All PTS diagnoses were confirmed by the local study physicians. Secondary outcomes were incidence and severity of PTS using the Villalta scale, venous ulcers, VTE recurrence and death from VTE. A sample size of 800 patients was targeted based on a hypothesized cumulative incidence of the primary outcome of 30% in P-ECS vs. 20% in A-ECS, 2-tailed a of 0.05 and 80% power, and anticipated 25% rate of death/withdrawal/lost-to-follow-up. Using a modified intent to treat approach, we performed a time-to-event analysis using a Cox proportional hazards model adjusted for center to calculate hazard ratios (HR) and 95% confidence intervals (CI) to compare rates of the primary outcome in A-ECS vs. P-ECS. A similar time-to-event analysis was performed for Villalta PTS (Villalta score ≥ 5 at or after the 6 month visit). Results: From 2004–2010, 398 patients were randomized to A-ECS and 408 to P-ECS. 3 patients found to be ineligible soon after randomization were excluded from the analysis. Median time from DVT diagnosis to randomization was 4 days. Baseline features were similar in the 2 groups; overall, 60% were male, mean age was 55 years, and most proximal extent of DVT was iliac or femoral vein in 70% and popliteal vein in 30% of patients. The cumulative incidence of PTS (primary outcome) by 750 days was 14.8% in A-ECS vs. 12.3% in P-ECS (Figure) (HRadj 1.17; 95% CI 0.75–1.81; p=0.49). The cumulative incidence of Villalta PTS (secondary outcome) was 52.1% in A-ECS vs. 52.2% in P-ECS (HRadj 0.96; 95% CI 0.78–1.19; p=0.69). Additional outcomes were also similar in the two intervention groups (Table). Rates of loss to follow-up (5.5% vs. 5.4%) and withdrawal (8.3% vs. 9.1%) were similar in A-ECS and P-ECS. Overall, ∼70% of patients in both groups continued the intervention throughout study follow-up, and of these, >80% of patients in both groups reported use for ≥ 3 days per week. Conclusions: In a large randomized placebo-controlled trial, ECS did not prevent the occurrence of PTS after a first proximal DVT and did not influence the severity of PTS or rate of recurrent VTE. The reported benefits of ECS to prevent PTS in some prior studies could be due, at least in part, to bias from open-label design. Whether ECS may be of benefit to manage symptoms of established PTS should be evaluated in future studies. Disclosures: Kahn: NIH: Research Funding; Canadian Institutes for Health Research: Research Funding; Sigvaris: Research Funding.

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Long-Term Outcomes of Patients with Systemic Light Chain Amyloidosis (AL) Treated At Diagnosis with Risk-Adapted Stem Cell Transplant and Consolidation with Novel Agents.

Blood ◽

10.1182/blood.v120.21.3150.3150 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3150-3150 ◽

Cited By ~ 4

Author(s):

Raymond L. Comenzo ◽

Daniel E Fein ◽

Hani Hassoun ◽

Christina Bello ◽

Joanne F Chou ◽

...

Keyword(s):

Board Of Directors ◽

Light Chain ◽

Cumulative Incidence ◽

Research Funding ◽

Initial Therapy ◽

Novel Agents ◽

Cell Transplant ◽

Advisory Committees ◽

Hematologic Response

Abstract Abstract 3150 Background: AL is a plasma cell dyscrasia characterized by the pathologic production of monoclonal light chains which misfold, deposit in various organs, including the heart, and can cause early death. High dose melphalan with stem cell transplant (SCT) results in high hematologic response rates and is a standard treatment for eligible patients. Achieving a complete hematologic response (CR) to SCT results in extended event-free and overall survival (OS), up to 8 and 13 years respectively in one large series. (Blood 2011; 118:4346) We have studied the addition of novel agents as consolidation following risk-adapted SCT (RA-SCT) in order to improve hematologic response (HR) rates and therefore outcomes. (Br J Haem 2007;139:224; Amyloid 2010;17:80a) In this report we examine the long-term outcomes of patients who received initial therapy with RA-SCT followed by consolidation for hematologic response less than CR (HR < CR). Methods: We performed a retrospective study to assess the HR rates, incidence of hematologic progression and overall survival (OS) of AL patients enrolled at diagnosis on two consecutive phase II trials using RA-SCT with consolidation for HR < CR (NCT01527032 and NCT00458822). OS was calculated from date of transplant to date of death or last follow up. Median event free survival (EFS) and OS were estimated by the method of Kaplan Meier. Cumulative incidence function was used to estimate the incidence of progression and death. Results: Between 2002 and 2011, 83 patients were enrolled and underwent RA-SCT on these trials and, following RA-SCT, those with HR < CR received consolidation with thalidomide and dexamethasone (TD) in the first and bortezomib and dexamethasone (BD) in the second trial. Thirty-six patients had cardiac involvement (43%) and all patients had free light chain measurements employed to score hematologic response and progression using consensus criteria (Am J Hematol 2005;79:319; Blood 2010;116:1364a). The frequency of CR following SCT was 24% and increased to 48% with post-SCT consolidation. The CR rates increased at 1 year compared to 3 months post-SCT from 21% to 36% with TD and from 28% to 62% with BD. With a median follow up of 5.1 years, the EFS is 4.5 years (95% CI: 2.6 to not reached) and the OS of all patients has not been reached (Figure 1). Sixteen patients died prior to hematologic progression and 26 patients have progressed with a cumulative incidence of hematologic progression of 8%, 18%, and 29% at 1, 2 and 3 years, respectively (Figure 2). Thirty-one percent (8/26) of relapsed patients have not required second-line therapy while among those who have, 78% (14/18) have responded including 44% (8/18) with CR. The median OS following hematologic progression was 5 years (95% CI: 2.6–5.8). Conclusions: Half of the AL patients on initial therapy trials employing RA-SCT and consolidation for HR < CR achieved CR with 36% of pts on the TD and 62% on the BD consolidation trial in CR at 1 year post-SCT respectively. At 3 years post-SCT the cumulative incidence of relapse was 29% and a third of relapsed patients did not require therapy, likely due to the very sensitive serum free light chain assay that detects low level hematologic progression in the absence of organ progression. Almost 80% of patients requiring second-line therapy responded, over half with CR, and median OS after relapse was 5 years. These results indicate that initial therapy with RA-SCT and consolidation is an effective initial treatment strategy for patients with AL in the era of novel agents. With over 5 years of follow up the median OS has not been reached. Disclosures: Comenzo: Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Use of the investigational agent MLN9708, an oral proteasome inhibitor, in the treatment of relapsed or refractory light-chain amyloidosis. Hassoun:Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Giralt:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding. Landau:Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Research Funding.

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Renal Disease In Patients With Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v122.21.5302.5302 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5302-5302 ◽

Cited By ~ 4

Author(s):

Tait D Shanafelt ◽

Kari G. Rabe ◽

Curtis A Hanson ◽

Timothy G. Call ◽

Susan Schwager ◽

...

Keyword(s):

Renal Function ◽

Chronic Lymphocytic Leukemia ◽

Renal Insufficiency ◽

Serum Creatinine ◽

Research Funding ◽

Univariate Analysis ◽

Lymphocytic Leukemia ◽

Disease Course ◽

To Receive

Abstract Background Chronic lymphocytic leukemia (CLL) can effect renal function in a variety of ways including direct infiltration of the kidney, ureteral obstruction by lymphadenopathy, and treatment related tumor lysis syndrome (uric acid nephropathy). Rarely, CLL has also been reported to be associated with light chain nephropathy, renal amyloidosis, membranoproliferative glomerulonephritis (MPGN), granulomatous interstitial nephritis (GIN), and minimal change disease (MCD). Nearly all the data on the effects of CLL on renal function is at the case report level. We systematically evaluated the prevalence of renal insufficiency at diagnosis as well the incidence of acquired renal insufficiency during follow-up in a large cohort of patients with newly diagnosed CLL to more accurately define the effects of CLL on the kidney and its impact on clinical outcomes. Methods Between January 1995 -February 2013, previously untreated CLL patients seen in the Division of Hematology at Mayo Clinic at diagnosis (<12 months) and who had baseline assessment of serum creatinine were included in this analysis. Patients with serum creatinine (Cr) ≥1.5 mg/dL at baseline were classified as having renal insufficiency at diagnosis. Patients who initially had baseline creatinine <1.5 mg/dL but who developed a Cr≥1.5 mg/dL during the course of their disease were considered to have acquired renal insufficiency. Results Existing renal insufficiency at the time of CLL diagnosis: Of 2047 patients who met the eligibility criteria, 153 (7.5%) patients had renal insufficiency (Cr≥1.5 mg/dL) at the time of CLL diagnosis including 15 (0.7%) with a Cr≥3 mg/dL. Renal insufficiency was also more common among men (9.3% vs. 3.9%; p<0.00001), those with advanced stage disease (Rai 0=7.0%; Rai I-II=6.4%, Rai III-IV=20.2%; p<0.0001), and CD49d positive patients (6.8% vs. 3.8%; p<0.038). Patients with renal insufficiency at diagnosis were also older (median age 72.2 vs. 63.9; p<0.0001). No difference in the prevalence of renal insufficiency at diagnosis was observed based on cytogenetic abnormalities detected by FISH or CD38, ZAP-70 or IGHV gene mutation status. Although renal insufficiency at diagnosis was strongly associated with OS on univariate analysis (p<0.001), no association was observed between renal insufficiency and TTT or OS on multi-variate analysis adjusting for age, sex, and Rai stage. Acquired renal insufficiency during CLL disease course: Among the 1894 patients with normal renal function at diagnosis, 304 (16.1%) acquired renal insufficiency (Cr≥1.5 mg/dL) during the course of their CLL disease course including 43 (2.3%) with peak Cr≥3 mg/dL. In addition to age (older) and male sex, a number of CLL disease characteristics were associated with a higher likelihood of acquired renal insufficiency including: IGHV UM (OR=2.0; p=0.0001), unfavorable FISH (del17p- or 11q-; OR=2.0; p=0.001), and being CD49d+ (OR=1.8; p=0.002), ZAP-70+ (OR=1.6; p=0.004), or CD38+ (OR=1.4; p=0.0.032),. Shorter TTT (p<0.001) and OS (P<0.001) was observed among patients with initially normal creatinine who acquired renal insufficiency (Figure 1A and 1B). On MV analysis adjusting for age, sex, and stage at diagnosis, acquired renal insufficiency remained an independent predictor of TTT (OR=1.77; p=0.001) and OS (OR=2.67; p<0.001). Renal insufficiency and therapy selection After median follow-up of 4.5 years (range 0-18.0), 620 of 2047 (30.3%) patients have progressed to require treatment. Patients with renal insufficiency prior to treatment were less likely to receive purine nucleoside analogue based therapy and more likely to receive single agent alkylator based treatment. Conclusions Approximately 1 in every 13 patients (7.5%) with CLL has renal insufficiency at the time of diagnosis and an additional 16.1% acquire renal insufficiency during the course of the disease. The risk of developing renal insufficiency is associated with a variety of CLL B-cell characteristics and is associated with TTT and OS. Data on causes of acquired renal insufficiency is being abstracted and will be presented at the meeting. Disclosures: Shanafelt: Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding. Off Label Use: MK2206 in a phase 1 trial of CLL.

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