Evaluation of Patients with Myelodysplastic Syndromes (MDS) Obtaining Stable Disease with the Use of Decitabine.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2790-2790
Author(s):  
Henry G. Kaplan ◽  
Michael Milder
Keyword(s):  
Stable Disease ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Clinical Importance ◽  
Hematologic Malignancies ◽  
Median Number ◽  
Outpatient Setting ◽  
Entire Cohort ◽  
Increased Risk

Abstract Abstract 2790 Poster Board II-766 BACKGROUND: MDS is a group of hematologic malignancies associated with reduced quality of life related to progressive cytopenias and increased risk of infections and bleeding. Successful treatment in MDS is typically defined in terms of complete remission (CR). Treatment with decitabine, a DNA methyltransferase inhibitor, has led to CR in 9 to 39% of MDS patients. Many patients have responses that do not meet criteria for CR or partial remission, but may be of clinical importance, especially for older MDS patients. Since patients who achieve stable disease may receive benefits from treatment, it was of interest to evaluate patient characteristics and treatment response results of those who achieved stable disease with decitabine. METHODS: 99 patients with de novo (n=88) or secondary (n=11) MDS were treated with decitabine, 20 mg/m2 daily for 5 days every 4 weeks in an outpatient setting (Steensma et al. J Clin Oncol 2009). No dose reductions were allowed but dose delays were permissible. Any FAB, including CMML, were eligible if ECOG 0-2 and normal hepatic and renal function. Supportive care, including blood products, were permitted. G-CSF was permitted for serious infection or sepsis. Twenty-three patients (18 de novo and 5 secondary MDS) achieved stable disease as the best response by IWG 2006 criteria. RESULTS: At baseline, stable disease patients had a median age of 75 years (70% >70 years) and were mainly men (70%). Ten patients had RA, 7 had RAEB, 4 had RAEB-t, and one each had RARS or CMML. The IPSS scores for these patients were Low (n = 1; 4%), INT-1 (n = 8; 35%), INT-2 (n = 5; 22%), and High (n = 9; 39%). Cytogenetics were good 10 (43%), 1 (4%) intermediate, 10 (43%) poor, or unknown 2 (9%). At baseline 19 (83%) were RBC transfusion dependent, 3 (13%) platelet transfusion dependent. 22 patients were ECOG 0-1. Five patients had received prior cytotoxic chemotherapy, none with azacitidine or decitabine. The median number of cycles initiated was 5.0 (range 2 – 19). At the time of the analysis, 12 of the 23 patients had died with a median survival of 19.2 months (95% CI: 9.4, not estimable). This is consistent with the survival response (19.4 months (95% CI: 15, not estimable) for the entire cohort, which included the stable disease patients, 50% who achieved a hematologic improvement or better, and 10% with progressive disease with decitabine (15% not assessable). Median time to AML or death was 16.1 months (95% CI: 7.2, not estimable). Three of 19 RBC-dependent patients at baseline became transfusion independent for at least 8 weeks with treatment. Conversely, 3 of 4 baseline RBC-independent patients became transfusion dependent. One of 3 platelet-dependent patients became transfusion independent. Three of 20 platelet-independent patients at baseline became transfusion dependent. Of ten patients evaluable for cytogenetic responses, 2 patients had partial cytogenetic responses. Eleven out of 23 patients had at least one related SAE. Myelosuppression-related adverse events were common (≥10%) in these 23 patients with grade 3 or higher adverse experiences of anemia (26%), febrile neutropenia (17%), neutropenia (39%), and thrombocytopenia (30%). CONCLUSIONS: In an outpatient setting, approximately one-quarter of MDS patients maintained stable disease with decitabine treatment, with acceptable and manageable toxicity. Overall survival in this subset of patients appeared to be similar to that observed with the entire cohort, which included 50% of patients with an objective clinical benefit. Larger analyses are needed to fully understand the characteristics of and treatment-related benefits for patients who achieve stable disease with decitabine treatment. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Activation of JAK2/STAT5 Pathway Reduces Expression Level of DNMT3a in MPN Cell Line

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5394-5394
Author(s):  
Jie Zhou ◽  
Aibin Liang ◽  
Shaoguang Li ◽  
Wenjun Zhang ◽  
Jianfei FU
Keyword(s):  
Protein Expression ◽  
Cell Line ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Expression Level ◽  
Hematopoietic Stem ◽  
Expression Levels ◽  
Increased Risk

Introduction: Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell (HSC) disorders characterized by overproduction of mature blood cells and increased risk of transformation to acute myeloid leukemia (AML), and JAK2V167F is the most frequent MPN driving mutation detected in >95% of PV and 50-60% ET and PMF. DNMT3A is a de novo DNA methyltransferase that catalyzes the addition of methyl groups into active chromatin in CpG-rich regions leading to gene inactivation. Dnmt3a-/- HSC have enhanced self-renewal and a block in differentiation in vivo. Previous study showed that JAK2V617F and Dnmt3a loss cooperate to induce myelofibrosis through activated enhancer-driven inflammation, while whether JAK2V617F regulates DNMT3a still remains unclear. AZ960 is a potent and selective ATP competitive inhibitor of the JAK2 kinase, and previous studies reported that AZ960 possessed the activity selectively against JAK2. LY2784544 has been identified as a selective inhibitor of JAK2V617F and has undergone clinical trials for the treatment of several myeloproliferative disorders. Methods: Empty vector (control) and mutant JAK2V617F were transduced into BaF3 cells using a lentivirus system. JAK2V617F-expressing BaF3 cells grow IL-3 independent and were selected by fluorescence-activated cell sorting (FACS) for GFP expression. The protein expression levels of p-STAT5 and DNMT3a were detected by western blotting. JAK2V617F-expressing and control BaF3 cells were incubated with gradient concentration of LY2784544 or AZ960 to inhibit JAK2/STAT5 pathway. Results: The expression levels of p-STAT5 were obviously up-regulated in the JAK2V617F-expressing BaF3 cells, and DNMT3a was down-regulated. After 1-hour incubation in the serial diluted LY2784544, p-STAT5 were reduced in JAK2V617F-expressing BaF3 cells, with expression of DNMT3a elevated. To further confirm the correlation between JAK2/STAT5 pathway and expression of DNMT3a, another JAK2 inhibitor AZ960 was tested similar to LY2784544. With p-STAT5 expression suppressed, protein level of DNMT3a showed significantly promotion. Conclusion: We observed that JAK2V167F mutation suppresses protein expression levels of DNMT3a in MPN cell lines. JAK2 inhibition by AZ960 and LY2784544 significantly improved expression levels of DNMT3a. The activation of JAK2/STAT5 pathway reduces expression level of DNMT3a in MPN cell line, and the specific mechanism still needs to be explored. Figure Disclosures No relevant conflicts of interest to declare.

Dnmt3a Deletion Predisposes Hematopoietic Stem Cells To Malignant Transformation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4198-4198
Author(s):  
Allison Mayle ◽  
Liubin Yang ◽  
Grant A Challen ◽  
Ting Zhou ◽  
Vivienne I. Rebel ◽  
...  
Keyword(s):  
Malignant Transformation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Hematologic Malignancies ◽  
Myeloproliferative Disease ◽  
Loss Of Function ◽  
Hematopoietic Stem ◽  
Knock Out

Abstract DNA methyltransferase 3A (DNMT3A), a de novo DNA methyltransferase, is mutated in various hematological malignancies affecting both myeloid (20%), mixed (50%), and lymphoid (18%) malignancies and is associated with poor prognosis. The most frequently reported DNMT3A mutation is R882 in acute myeloid leukemia (AML), which results in altered enzyme activity, but various missense and nonsense mutations have also been found throughout the gene, suggesting that loss-of-function mutations in DNMT3A may also contribute to leukemogenesis. Our group recently showed that transplantation of HSCs from Dnmt3a knock-out (KO) mice led to increased hematopoietic stem cell (HSC) self-renewal and inhibition of differentiation, but was insufficient to cause transformation. However, in these experiments, Dnmt3a-KO HSCs were transplanted alongside wild-type whole bone marrow to quantitate HSC function, potentially protecting against malignant transformation. We hypothesized that if Dnmt3a-KO HSCs were transplanted alone, a predisposition to transformation would be uncovered. We established a large non-competitive transplantation cohort receiving 500 control or Dnmt3a-KO HSCs and monitored the mice closely for disease. Strikingly, mice with Dnmt3a-KO HSCs had significantly shorter survival (246d vs 467d, p<0.0001, Figure 1). As mice succumbed to disease, we analyzed histological changes in hematopoietic organs and performed CBCs and immunophenotyping to diagnose the diseases. We identified multiple disease classes within the Dnmt3a-KO recipients, including T-cell acute lymphoblastic leukemia, myeloproliferative disease (MPD), myelofibrosis (MF), and myelodysplastic syndromes (MDS). The relatively long disease latency suggests that acquisition of secondary hits promotes disease; identification of these secondary mutations is ongoing.Figure 1Mice transplanted with Dnmt3a-KO HSCs succumb to hematologic malignanciesFigure 1. Mice transplanted with Dnmt3a-KO HSCs succumb to hematologic malignancies Here, we show that Dnmt3a deletion in noncompetitive transplanted HSCs leads to an array of hematologic disorders that models the spectrum of disorders seen in human malignancies. Since DNMT3A mutations are known early genetic lesions in leukemia development, mutations that cooperate with DNMT3A might influence the type of disease developed. This mouse model serves to validate an important role for Dnmt3a in the development of hematologic malignancies, and is also valuable for the study of future targeted therapies. Mice transplanted with Dnmt3a-KO HSCs died significantly earlier than mice transplanted with control HSCs (median survival 246 days and 467 days, p<0.0001). Fifty and 20 female mice were transplanted with 500 Dnmt3a-KO or control HSCs respectively, all at 6-8 weeks of age. Censored points indicate mice that were euthanized for unrelated reasons. Disclosures: No relevant conflicts of interest to declare.

DNMT3A Mutation Leads to Hematopoietic Dysregulation.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2382-2382
Author(s):  
Jie Xu ◽  
Wei-na Zhang ◽  
Tao Zhen ◽  
Yang Li ◽  
Jing-yi Shi ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Epigenetic Modification ◽  
Hematopoietic Cells ◽  
In Vitro Assays ◽  
Clinical Samples ◽  
Hematopoietic Stem

Abstract Abstract 2382 Epigenetic modification process is required for the development of hematopoietic cells. DNA methyltransferase DNMT3A, responsible for de novo DNA methylation, was newly reported to have a high frequency of mutations in hematopoietic malignancies. Conditional knock-out of DNMT3A promoted self-renewal activity of murine hematopoietic stem cells (HSCs). However, the role of mutated DNMT3A in hematopoiesis and its regulative mechanism of epigenetic network mostly remain unknown. Here we showed that the Arg882His (R882H) hotspot locus on DNMT3A impaired the normal function of this enzyme and resulted in an abnormal increase of primitive hematopoietic cells. In both controlled in vivo and in vitro assays, we found that the cells transfected by R882H mutant promoted cell proliferation, while decreased the differentiation of myeloid lineage compared to those with wild type. Analysis of bone marrow (BM) cells from mice transduced by R882H reveals an expansion of Lin−Sca-1+C-kit+ populations and a reduction of mature myeloid cells. Meanwhile, a cluster of upregulated genes and downregulated lineage-specific differentiation genes associated with hematopoiesis were discovered in mice BM cells with R882H mutation. We further evaluated the association of mutated DNMT3A and HOXB4 which was previously detected to be highly expressed in clinical samples carrying R882 mutation. Compared with wildtype DNMT3A, R882H mutation disrupted the repression of HOXB4 by largely recruiting tri-methylated histone 3 lysine 4 (H3K4). Taken together, our results showed that R882H mutation disturbed HSC activity through H3K4 tri-methylation, and transcriptional activation of HSC-related genes. Disclosures: No relevant conflicts of interest to declare.

Family History Of Hematologic Malignancies and Disorders In a Population Based Study Of Myelodysplastic Syndromes (MDS)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1541-1541
Author(s):  
Angela R. Smith ◽  
Erica D. Warlick ◽  
Rachel K. Fonstad ◽  
Michelle A. Roesler ◽  
Jenny N. Poynter ◽  
...  
Keyword(s):  
Family History ◽  
Conflicts Of Interest ◽  
Positive Family History ◽  
Hematologic Malignancies ◽  
Population Based ◽  
Newly Diagnosed ◽  
Population Based Study ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
History Of

Abstract Background MDS is a clonal hematopoietic stem cell disorder characterized by dysplastic changes in the bone marrow, ineffective hematopoiesis and an increased risk for developing acute myeloid leukemia (AML). The majority of MDS cases are sporadic, but rare familial cases have been described and are often ascertained through clinic-based referrals. To our knowledge, no population based study of MDS has examined the frequency of family history of hematologic malignancies and disorders in patients, nor associations with disease characteristics and outcomes. Methods Newly diagnosed MDS cases are being identified by rapid case ascertainment by the Minnesota Cancer Surveillance System (MCSS), a population-based cancer registry in Minnesota. Eligibility criteria include all newly diagnosed cases of MDS during the period April 1, 2010-October 31, 2014, between 20-85 years, Minnesota resident, and ability to understand English or Spanish. Proxy interviews are not being conducted. Medical records and biologic samples are obtained and questionnaires are filled out by participants. Centralized pathology and cytogenetics review confirm diagnosis and classify by subtype and risk score including the Revised International Prognostic Scoring System (IPSS-R). Since 2010, information on family history has been obtained through questionnaire responses and/or medical record review on 353 MDS patients. Cases were considered to have a positive family history if they reported a first degree relative with MDS, leukemia, lymphoma or other hematologic condition (multiple myeloma [n=4], Waldenstrom’s macroglobulinemia [n=1] and idiopathic thrombocytopenic purpura [n=1]). Treatment related MDS cases were excluded leaving 330 MDS patients for analysis. Unconditional logistic regression was used to calculate crude odds ratios (ORs) and 95% confidence intervals (CI) overall and by sex. Results A total of 61/330 (18.5%) cases reported a family history of a hematologic condition. The mean age at diagnosis was 71.3 years in those with a family history compared to 72.2 years in those without a family history (p=0.53). There was no difference in the sex distribution between the two groups. Though not statistically significant, the odds of having abnormal cytogenetics or an IPSS-R of High/Very High was lower for those having a positive family history (OR 0.57 [CI 0.25-1.33, p=0.19 and 0.67 [CI 0.24-1.84, p=0.29], respectively). The odds of survival at one year after diagnosis was significantly higher in those with a family history (OR 2.79 [CI 1.04-7.51, p=0.04]) compared to those without (Table). Further stratification by sex revealed that this association was strongest for males (OR=4.23, [CI 0.94-19.0, p=0.06] compared to females (OR=1.84 [CI=0.47-7.19, p=0.38]). Discussion In this population based study of adults with MDS, the prevalence of MDS cases having a positive family history was higher than previous reports. Additionally, cases reporting a family history of hematologic malignancies and disorders appear to experience lower risk disease and have significantly improved overall survival, especially males. It is possible that patients with a family history of hematologic conditions are diagnosed earlier in the course of their disease secondary to increased awareness about blood disorders and/or more active screening within the family. Our analysis is limited by relatively small numbers, but enrollment is ongoing so subsequent analyses with larger numbers of subjects may be more revealing. Additionally, a prospective study to examine these families further, including detailed medical histories and collection of biospecimens (saliva, blood, skin) for genetic analyses is underway in order to identify potential mechanisms and mutations involved in the development of MDS and progression to AML. Disclosures: No relevant conflicts of interest to declare.

Essential Thrombocythemia Patients with CALR Mutations Have Increased Platelet Activation Markers Compared to JAK2V617F Mutated Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3223-3223
Author(s):  
Maya Koren-Michowitz ◽  
Hagit Hauschner ◽  
Yulia Shuly ◽  
Meital Nagar ◽  
Elena Ribakovsky ◽  
...  
Keyword(s):  
Essential Thrombocythemia ◽  
Conflicts Of Interest ◽  
Thrombus Formation ◽  
Absolute Number ◽  
Median Number ◽  
Healthy Controls ◽  
Activation Markers ◽  
Increased Risk ◽  
Platelet Aggregates ◽  
Calr Mutations

Abstract Essential thrombocythemia (ET) is associated with an increased risk for thrombo-hemorrhagic complications. The presence of the JAK2V617F mutation, found in approximately 50% of ET patients, has been associated with increased indices of platelet (PLT) activation suggesting its casual role in thrombus formation. Mutations in CALR were recently described in the majority of JAK2V617F negative ET patients, and are associated with a decreased rate of thrombotic events. This has led us to hypothesize that CALR mutations have a different influence on PLT activation compared to JAK2V617F. To evaluate the PLT activation state, surface expression of two PLT activation markers - p-selectin (CD62P) and PAC1 was studied using specific antibodies. MFI was analyzed by flow cytometry at baseline, as well as following ADP addition to PLT rich plasma. Monocyte-platelet aggregates were studied in whole blood samples by gating CD45+/CD14+ cells and calculating the percentage of CD41+ cells in the monocytes population. The immature PLT fraction (IPF) was analyzed with the XE-5000 hematology analyzer (Sysmex UK Ltd., Milton Keynes, UK), and the absolute number of immature PLT (nIP) was calculated from the total PLT count. Low risk ET patients (N-13, M/F-5/8) and healthy controls (N-10, M/F-4/6) are included in this analysis. JAK2V617F and CALR mutations were present in 8 and 5 patients, respectively; low dose aspirin (range 75-100mg) was taken by 85% of patients and 90% of controls. Median PLT count in CALR mutated, JAK2V617F mutated and healthy subjects was 913, 579 and 247 K/uL, respectively (p=0.0002), and it was higher in CALR compared to JAK2V617F positive patients (p=0.09). Both patient subgroups had a lower baseline MFI of p-selectin and PAC1 compared to healthy controls (p-selectin: 2.8, 3 and 4.5 for JAK2V617F [p=0.01], CALR [p=0.05] and controls; PAC1: 3, 3.3 and 5.2 for JAK2V617F [p=0.01], CALR [p=0.02] and controls, respectively) with no difference between CALR and JAK2V617F mutated patients. CALR compared to JAK2V617F mutated patients had higher median number of immature PLT (30 and 10.6 K/uL, p=0.04), and a higher fraction of monocyte- platelet aggregates (90 and 58%, p=0.05). nIP and monocyte- platelet aggregates were also significantly higher in CALR mutated but not in JAK2V617F mutated patients compared to healthy controls. Interestingly, there was no difference in post ADP PLT activation (post/baseline ratio) between ET patients and healthy controls. Finally, there were correlations between the PLT counts and nIP (R=0.8, p<0.0001), monocyte- platelet aggregates (R=0.5, p=0.02), baseline p-selectin MFI (R=-0.5, p=0.02) and PAC1 MFI (R=-0.5, p=0.01). Our preliminary results suggest a correlation between PLT activation markers and the PLT numbers, which can explain why CALR mutated patients in our cohort had higher nIP and monocyte- platelet aggregates fractions. The absence of an increased ADP induced PLT activation between patients and controls in this cohort compared with previous reports could be explained by the use of aspirin in the majority of patients and the high ADP concentration used for PLT activation. These results will be further studied in a lager cohort of patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Carfilzomib-Pomalidomide-Dexamethasone (KPD) in Relapsed/Refractory Multiple Myeloma Patients - an Institutional Retrospective Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5572-5572
Author(s):  
Pallavi Mehta ◽  
Neha Yadav ◽  
Mohan Bhaarat ◽  
Sumeet Prakash Mirgh ◽  
Vishvdeep Khushoo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Maintenance Therapy ◽  
Progressive Disease ◽  
Conflicts Of Interest ◽  
Haematological Toxicity ◽  
Response Assessment ◽  
Median Number ◽  
Entire Cohort ◽  
Response Status

Introduction Multiple myeloma has relished the emergence of various novel agents in last few decades. Unfortunately,relapses are still an inevitable part and at each relapse, treatment choice becomes a complex decision making process as these patients usually have exhausted conventional therapeutic regimens.Carfilzomib is a second-in class Proteosome Inhibitor (PI) and has been approved for patientsrefractory to minimum 2 lines of prior therapies. We are, hereby, presenting our initial experience with this novel combination (KPD)in RRMM patients at our centre. Methodology Retrospective study of RRMM patients who received KPD therapy from August 2017 till October 2018. Responses were assessed as per International Myeloma Working Group. Study was approved by Institutional Review Board. Results Total 39 patients were treated with KPD regimen during study period. Median age was 56 (32-74 years) with male ratio of 51.2% (n=20). At baseline presentation, bone disease {n=32 (82%)} was the most common presenting complaint followed by anemia {n=21 (53.8%)} and renal failure {n=16 (41%)}. Most common ISS staging was ISS-3 {n=18(46.1%)} and subtype was Light chain myeloma {n=15 (38.3%)} followed by IgG {n=13 (33.3%)}.Fluorescence In Situ Hybridization (FISH) was available in {n= 10 (25%)} and it was positive for del13q (n=1/10) and del17p (n=1/10) and t(11;14) (n=1/10). (Table-1) Median number of prior lines of chemotherapy was 3(1-15). Thirty-six (91%) patients were relapsed/refractory to both bortezomib and lenalidomide whereas n=3(9%) were relapsed/refractory to bortezomib only. Eleven (30.5%) patients underwent SCT pre KPD therapy including 2/11 patients received double SCT. Pre KPD 25 (64.1%) patients had progressive disease (PD), 10 (25%) had relapse and 4 (11.1%) patients had stable disease (SD). Median number of KPD cycles were 3(1-8). Median number of KPD cycles after which response assessment was donewas 3 (2-8). Median time to treatment response was 3 (2-7) months. ORR was 51.2% {CR-n=5 (12.8%); VGPR-n=5 (12.8%), PR-n=10 (25.6%)} whereas 2 (5.1%) patient had SD and 10 (25.6%) patients had PD at 2-8 cycles. Two (5.1%) patients are yet to be assessed. (Table-1) Common hematological toxicities seen were anemia (n=8), thrombocytopenia (n=13){grade-3/4=30.7%; n=4/13} and neutropenia(n=14){grade3/4=21.4%; n=3/14}.Non haematological toxicity such as cardiac toxicity was not observed in our patients. Pre KPD 2D-ECHO was available for 13 patients and which was normal in all patients. Post 2-4 cycles of KPD, 2D-ECHO was available for 7 patients and all patients had normal ECHO. Carfilzomib induced hypertension was seen in 20 patientsand could be well controlled with antihypertensives. Peripheral neuropathy (grade1/2) was seen in 10 patients. We also observedCarfilzomib induced hyponatremia in one patient.Febrile neutropenia(bacterial =6, viral=4, possible fungal=5) was seen in 14 patients.(Table-2) Twelve (20.5%) patients proceeded to either maintenance therapy or autologous stem cell transplantation (ASCT). Eight patients opted only for maintenance (carfilzomib=5, pomalidomide-dexamethasone=2 and pomalidomide =1). Remaining n=4/12(16%) patients received SCT. Pre SCT response status was VGPR n=2; PR n=1 and SD=1. Post SCT response status was VGPR (n=3) &PR (n=1). Post SCT, 3 patients were started on maintenance therapy as Bortezomib/pomalidomide=1, Pomalidomide/dexamethasone=2. One patient has been continued on KPD as a consolidation therapy. At a median follow-up of 10 months (1-14 months), relapse rate was 12.8% (n=5). Ten (25.6%) patients had PD.Mortality rate was 8.3% (n=3), commonest cause being progressive disease. The estimated mean PFS, OS and EFS of entire cohort was 11.9 months (95% C.I. 10.8- 13 months) (figure-1 a), 13 months (95% C.I. 11.9-14 months) (figure-1 b) and 7.9 months (95% C.I. 6.5-9.3 months) (figure - 1 c) respectively. Conclusion KPD is a well-tolerated regimen for patients with RRMM who have exhausted frontline myeloma regimen, however at the cost of significant side effects like infections and hypertension. It seems to be a convincing regimen as a bridge to ASCT but warrants further studies with longer follow-up to validate our results. Disclosures No relevant conflicts of interest to declare.

Three-Month Cumulative Incidence of Thromboembolism and Bleeding After Periprocedural Anticoagulation Management of Patients with Active Cancer.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 491-491 ◽  
Author(s):  
Alfonso J Tafur ◽  
Edyta Wolny ◽  
Robert McBane ◽  
Edyta Sutkowska ◽  
Joshua P Slusser ◽  
...  
Keyword(s):  
Major Bleeding ◽  
Conflicts Of Interest ◽  
Mechanical Heart Valve ◽  
Invasive Procedure ◽  
Anticoagulation Management ◽  
Entire Cohort ◽  
Post Procedure ◽  
Increased Risk ◽  
Anticoagulated Patients ◽  
Active Cancer

Abstract Abstract 491 Introduction: Chronically-anticoagulated patients with active cancer (Ca) often require temporary interruption of warfarin for an invasive diagnostic or therapeutic procedure. While such patients may be at increased risk for periprocedural thromboembolism and bleeding, there are virtually no estimates of these outcomes among Ca patients or the most appropriate periprocedural anticoagulation management. The aims of this study were to estimate rates of these outcomes among Ca patients and to test active cancer and “bridging” low molecular weight heparin (LMWH) as potential predictors of these outcomes. Patients and Methods: In a retrospective cohort study, all chronically-anticoagulated patients referred to the Mayo Clinic Thrombophilia Center for periprocedural anticoagulation management over the 11-year period, 1997-2007, were followed forward in time for the outcomes of venous and arterial thromboembolism (VTE; ATE), major bleeding and vital status within 3 months of consultation. Warfarin was stopped 4-5 days prior to the procedure and patients received bridging LMWH according to the estimated risk of thromboembolism and bleeding. All outcome events were centrally adjudicated using pre specified criteria. Results: The total cohort (n=2517) included 500 patients with Ca. Chronic anticoagulation indications included prior VTE (n=1033), mechanical heart valve (n=669), atrial fibrillation (n=530) and other (mainly vascular bypass; n=285). 65% and 64% of patients with and without Ca received bridging LMWH, respectively. Prior VTE was more common among Ca patients compared to those without CA, both in the bridged (56% vs 37%; p<0.001) and the non-bridged (48% vs 39%; p<0.05) groups. The 3 month rate for the composite of VTE, ATE or bleeding was higher among Ca patients compared to patients without Ca (5% vs 2%; p=0.004) due to higher post procedure rates of VTE (1% vs 0.2%; p<0.001) and major bleeding (4% vs 1.7%; p=0.009); the post procedure ATE rates were low in both groups (0.40% vs 0.45%). For the entire cohort, patients receiving bridging LMWH had a significantly higher rate of post procedure bleeding (5% vs 1%; p<0.05). Finally, there were significantly more deaths in Ca patients compared to non-Ca patients (5% vs. 1%; p<0.001). Conclusions: The three-month rates of VTE, major bleeding and death among patients with Ca in whom anticoagulation is temporarily interrupted for an invasive procedure is significantly higher than in patients without Ca, especially the major bleeding rate. Use of heparin increases this rate even farther, suggesting that bridging should be used with caution in patients with active cancer. Disclosures: No relevant conflicts of interest to declare.

The Prognostic Effects of Anti-ADAMTS13 IgG, IgA and IgM Antibody Subclasses In Acute Idiopathic TTP and the Effect of Rituximab,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3305-3305
Author(s):  
Vickie McDonald ◽  
Samuel J Machin ◽  
Ian J Mackie ◽  
Marie A Scully
Keyword(s):  
De Novo ◽  
Limit Of Detection ◽  
Median Number ◽  
Igg Subclasses ◽  
Sustained Remission ◽  
Adamts13 Activity ◽  
Normal Range ◽  
Increased Risk ◽  
The Difference ◽  
Antibody Levels

Abstract Abstract 3305 Acquired idiopathic TTP is associated with severe ADAMTS13 (A13) deficiency/anti-A13 IgG antibodies. Management is with plasma exchange (PEX) and immunosuppression. Rituximab is known to induce a sustained remission by eradicating the A13 inhibitor. We studied the prognostic value of anti-A13 IgG subclasses and the effect of rituximab on these antibodies. Anti-A13 IgG subclasses were detected using ELISA: microtitre plates coated with rADAMTS13 and antibody detected using biotinylated monoclonal anti-IgG1-4. Results: 70 acute episodes from a 4 year period were analysed. In addition, 23 deaths and 25 relapsed TTP episodes were selected to ensure adequate numbers in these groups for comparison. The median ADAMTS13 activity was <5% and the median IgG anti-ADAMTS13 was 48.5% (7–164.3%, normal <4%). The total IgG positively and significantly correlated with the number of IgG subclasses present. Increasing levels of IgG1-3 were associated with increasing total IgG however the levels of IgG4 did not correlate with total IgG levels. IgG4 and IgG1 inversely correlated with each other. IgG4 was the predominant subclass (74%), followed by IgG1 (73%), IgG2 (69%) and IgG3 (50%). This pattern was similar for de novo and relapsed cases and for men and women. The percentage of patients with 1,2,3 and 4 subclasses concurrently was 14, 29, 32 and 25% respectively showing that this is a polyclonal disease. De novo presentations were more likely to present with a greater number of subclasses than relapses. The mortality increased with increasing numbers of subclasses: 1 subclass 0%, 2 subclasses 15%, 3 subclasses 24% and 4 subclasses 31% mortality. The presence of IgG2 but not the other subclasses was associated with mortality (OR 12.4, p 0.018). IgG2 also correlated with cardiac disease. Higher IgG1 and 2 levels were seen in those with neurological and cardiac involvement. IgG2 and IgG4 significantly correlated with the number of PEX to remission (p<0.0001 and p 0.027 respectively). The median number of PEX increased with increasing numbers of IgG subclasses at presentation: one subclass 8.85, two subclasses 11.25, three subclasses 16 and four subclasses 24. 28% patients had IgA anti-ADAMTS13 at presentation and 7.9% had IgM. The total anti-ADAMTS13 IgG was higher in those with IgA (80%) compared to those without (39.6%, p 0.0004). The median PEX was not influenced by the presence of IgA (22 vs 15, p0.49). There was no influence of IgA on mortality however all of the relapses occurred in the IgA negative group. A subset of 64 (48F/16M; 47de novo/17relapses; 3 deaths; median PEX 16) episodes had received weekly rituximab, median 4 doses, range 2–8. Of these patients, 60.9, 62.5, 42.2 and 81.3% patients had IgG 1, 2, 3 &4 respectively at presentation. On completing rituximab the %patients with IgG1, 2, 3 &4 was 48.1, 23.1, 3.8 and 51.9. By 6 months the percentages were 30.8, 12.8, 0 and 15 and at 12 months were 26.5, 6.1, 4.1 and 12.2. 25% patients had all 4 subclasses at presentation compared to 2% at 12months. The median A13 activity at 12 months was lower in those with persistent subclasses (63%) compared to those with none (77%) but the difference did not reach significance (p=0.06). Not all patients with antibody levels above the limit of detection had low A13 activity so clearly some antibodies are non-inhibitory. The median anti-A13 IgG subclass levels all fell with therapy (by >50% after 2 rituximab doses). 5.8% patients with no subclasses at 12months relapsed compared to 17.6% of those with detectable subclasses. In conclusion, TTP is a polyclonal disease. The presence of increased numbers of IgG anti-ADAMTS13 subclasses is associated with increased mortality and increased PEX requirement. Rituximab leads to the eradication of most anti-A13 subclasses but IgG1&4 are more likely to remain above the normal range despite clinical remission and in some cases normalisation of ADAMTS13 activity. Persistence of antibodies in remission leads to an increased risk of relapse. IgA at presentation is associated with may protect from relapse. Disclosures: Off Label Use: This talk contains discussion of the off license use of rituximab in TTP.

Overall Survival by Prognosis Score in High-Risk Myelodysplastic Syndromes (MDS) Patients Receiving Decitabine Treatment: Results From Clinical Experience

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5024-5024
Author(s):  
Marcelo Iastrebner ◽  
Jun Ho Jang ◽  
Kihyun Kim ◽  
Chul W. Jung ◽  
Elsa Nucifora ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Life Expectancy ◽  
Stable Disease ◽  
Myelodysplastic Syndromes ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Prognosis Score

Abstract Abstract 5024 Background The DNA-targeted hypomethylating agent, decitabine, has made a real impact on response rate in Myelodysplastic Syndromes (MDS) patients, and may improve overall survival in high-risk patients. Aim: To describe overall survival by prognosis score in decitabine-treated MDS patients. Methods: From May 2007 to January 2011, MDS patients who received decitabine were followed at centers in Argentina and South Korea. Patients ≥18 years of age with de novo MDS (all WHO Subtypes and CMML type-1 and type-2) were included, provided they had received ≥4 cycles of decitabine (recommended dose, 20 mg/m2 IV over 1 hour × 5 days every 4 weeks) and had stable disease or better by IWG 2006 criteria. Median life expectancy was determined according different categories of the MD Anderson and International Prognostic Scoring Systems (MDAPSS and IPSS). Decitabine treatment was effective when the patient outlived the median life expectancy. Results: Sixty-one patients received ≥4 cycles of decitabine and had stable disease or better. Median age was 61 years and 69% were male. All patients had de novo MDS with ECOG ≤2. Median time from MDS diagnosis was 24 months. Baseline WHO classification was: RA (0%); RARS (2%); RCMD (18%); RCMDRS (3%); RAEB-1 (13%); RAEB-2 (30%); MDS/MPD (2%); AML/MDS (5%); CMML type-1 (21%); and CMML type-2 (6%). Forty one percent had comorbidities. Patients received a median of 8 cycles of decitabine (range, 4–18). Forty four percent died during the study and 31% progressed to AML. Median overall survival was higher than life expectancy among patients with high-risk MDS by MDAPSS (Kantarjian H. et al. Cancer 2008; 113: 1351) and by IPSS (Greenberg P. et al. Blood 1997; 89: 2079). Survival exceeded life expectancy for 90%, 100%, and 86% of patients with MDAPSS 7–8, MDAPSS ≥9, and IPSS Int-2 + High, respectively. Conclusion: High-risk MDS patients who received ≥4 cycles of decitabine and had stable disease or better showed improvement in survival compared with predicted life expectancy published in literature.Median OS, MonthsPredictedActual*p-ValueMDAPSS (N=61)0–454395–625697–81431> 96230.014IPSS (N=58)Int-14237Int-2 + High14 to 5290.001*Kaplan-Meier and log-rank Test (Mantel-Cox). Disclosures: No relevant conflicts of interest to declare.

Unrelated Umbilical Cord Blood Transplantation for Hematological Malignancies Using Fludarabine/BUCY2 Conditioning Regimen

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4572-4572
Author(s):  
Zimin Sun ◽  
Huilan Liu ◽  
Liangquan Geng ◽  
Xingbing Wang ◽  
Kaiyang Ding ◽  
...  
Keyword(s):  
Cord Blood ◽  
Graft Failure ◽  
Conflicts Of Interest ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Median Number ◽  
Myelogenous Leukemia ◽  
Blood Transplantation

Abstract Abstract 4572 Cord blood transplantation (CBT) is largely used to treat patients affected by hematological malignant disorders. Myeloablative TBI-based conditioning appears to provide reliable engraftment after CBT for malignancies. However, the toxicity of TBI limits their widespread use. So far, a standard non-TBI based regimen has not been firmly established. In order to overcome graft failure, we investigated a strategy using Fludarabine (FLU)/BUCY2 regimen in CBT for patients with hematologic malignancies. Seventeen patients(children 16, adult 1) with hematologic malignancies who underwent single-unit CBT used a conditioning regimen comprising FLU 120 ‡r/‡u, intravenous busulfan (BU) 12.8‡r/kg and cyclophosphamide (CY)120 mg/kg (FLU/BUCY2). All patients were given a combination of cyclosporine A and mycophenolate mofetil for graft-versus-host disease (GVHD) prophylaxis. Seventeen patients with acute leukemia (n=13), chronic myelogenous leukemia (n=4) were treated, thirteen of whom were high risk diseases and two were advanced-stage at CBT. Seventeen patients with a median age of 8 years (range,2.5–46 years) and a median weight of 32 kg (range, 12–55 kg)received the median number of nucleated cells and CD34+cells infused were 5.70× 107/kg (range: 3.15–9.60×107/kg) and 3.84× 105/kg (range:1.27–5.24 ×105/kg), respectively. The cumulative incidence of primary donor engraftment was 94% (16 patients); one patient had secondary graft failure. Median time to neutrophil≥0.5×109/L was 17 days (range 12–30) and platelet engraftment (≥20×109/L) was 35 days (range 14–56). Preengraftment syndrome (PES) developed in 71% of the patients at a median of 7days (range: 5–13).9 cases developed acute GVHD (56%), more than grade II in three cases. Two of fourteen patients who survived more than 100 days developed chronic GVHD. 12 cases are alive at a median follow-up of 7 months (range 3~ 11).The probability of overall survival at 100 days and 1 year are 88.2% and 67.9%, respectively. Two cases had extramedullary relapsed. Five cases died of severe GVHD (n=3), pulmonary toxicity (n=1) and secondary graft failure (n=1). Preliminary evidence of the small study suggests successful engraftment and decreasing relapse rate following FLU/BUCY2 regimen for CBT in patients with hematologic malignancies. But it had a tendency towards increasing the incidence of GVHD-related morbidity and mortality. Whether this regimen offers a survival benefit for patients with poor-risk leukemia has to be tested in larger prospective trials. Disclosures: No relevant conflicts of interest to declare.

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