PS01.094: PREDICTING FACTOR OF FAILURE OF CONSERVATIVE TREATMENT AND OUTCOME IN PATIENTS WITH ACUTE CAUSTIC FOREGUT INJURY

2018 ◽  
Vol 31 (Supplement_1) ◽  
pp. 76-76
Author(s):  
Jadsada Athigakunagorn ◽  
Panupong Sukpan ◽  
Teerasak Jiravongbunrod
Keyword(s):  
Heart Rate ◽  
Conservative Treatment ◽  
Failure Rate ◽  
Conflicts Of Interest ◽  
Clinical Factor ◽  
Blood Ph ◽  
Band Form ◽  
Wbc Count ◽  
Clinical Records ◽  
Predicting Factor

Abstract Background Most of the patients with caustic injury can be successfully manage with conservative treatment. However, some patients with high severity required surgery. In this study, we assess failure rate, outcome and predictors of failure of conservative treatment in patients with acute caustic foregut injuries. Methods We retrospectively reviewed clinical records of patients with acute caustic foregut injuries who were hospitalized and treated at the Bhumibol Adulyadej Hospital from January2008 – December 2015. Analysis the data included the clinical factor, laboratory result, failure rate and outcome of management. Results Out of the 190 patients with caustic foregut injuries, 7.4%(14 patients) were failed to treat with conservative treatment and underwent to emergency surgery. 2 deaths were found in this study. Factors that associated with failure of conservative treatment were epigastrium tenderness (OR 22.2, 2.8–173.6 95% CI), Heart rate > 100 (OR 7, 2.2- 22.6 95% CI), WBC count > 10,000 (OR 4.9, 1.3–18.3 95% CI), Band form positive (OR 9.2, 2.6–32.7 95% CI), Blood PH < 7.2 (OR 16, 3.6–70.9 95% CI). Conclusion We consider epigastrium tenderness, Heart rate > 100 bpm, WBC count > 10,000 cell/ul, positive band form and blood pH < 7.2 to be the significant factor associating with failure of conservative management in patients with acute caustic foregut injuries. Intensive evaluation and early surgery should be considered in this group of patients. Disclosure All authors have declared no conflicts of interest.

Cardiovascular responses to severe hypercapnia of short duration

1964 ◽  
Vol 207 (3) ◽  
pp. 634-640 ◽  
Author(s):  
Emmett S. Manley ◽  
Clinton B. Nash ◽  
R. A. Woodbury
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Short Duration ◽  
Cardiovascular Responses ◽  
Myocardial Contraction ◽  
Contractile Force ◽  
Sympathetic Activation ◽  
Pentobarbital Anesthesia ◽  
Arterial Blood ◽  
Blood Ph

Dogs under pentobarbital anesthesia were employed in an investigation of the effect of abrupt, severe hypercapnia upon blood pressure, heart rate, and force of myocardial contraction. Electrocardiographic activity and arterial blood pH were also monitored. Hypercapnia was induced for 10-min periods with 15 and 30% CO2 in oxygen. The studies were undertaken in nontreated animals and animals treated with atropine, reserpine, chlorisondamine, P-286, or bilateral adrenalectomy. Severe hypercapnia was shown to be depressant to the cardiovascular parameters evaluated, but blood pressure and contractile force normally demonstrated compensation to this depression. Parasympathetic blockade with atropine did not reduce the depression observed in the nontreated dogs during hypercapnia. Results obtained with other pretreated animals indicate that compensation occurs primarily via sympathetic activation. Adrenal activation may assume importance in compensation to 30% CO2, but intact adrenals were not necessary for survival during hypercapnia. No arrhythmias (excluding bradycardia) were observed during or immediately following exposure to either concentration of CO2.

Some physiological changes accompanying tetany induced by exposure to hot, wet conditions

1961 ◽  
Vol 16 (3) ◽  
pp. 409-412 ◽  
Author(s):  
P. F. Iampietro ◽  
M. Mager ◽  
E. B. Green
Keyword(s):  
Heart Rate ◽  
Rectal Temperature ◽  
Inorganic Phosphorus ◽  
Rate Of Change ◽  
Physiological Changes ◽  
Absolute Change ◽  
Blood Constituents ◽  
Blood Ph ◽  
The Absolute

Twenty-seven men were exposed to various hot, wet conditions for a total of 87 experiments. Determinations were made of rectal temperature, heart rate, blood pH, and the concentrations of CO2, calcium, inorganic phosphorus, and protein in plasma. Symptoms ranging from tingling of extremities to carpopedal spasms were observed. The frequency and severity of symptoms were apparently not related to the absolute change in any of the blood constituents but rather to the rate of change. Submitted on October 31, 1960

Comparison of Outcomes After Allogeneic HSCT for Adult Patients with AML in Remission Using in the Conditioning Regimen Either I.V. Busulfex (BU) Plus Cyclophosphamide (Cy) or TBI Plus Cy: An- ALWP-EBMT Survey.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 195-195
Author(s):  
Arnon Nagler ◽  
Myriam Labopin ◽  
Avichai Shimoni ◽  
Liisa Volin ◽  
Donald W. Bunjes ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Post Transplantation ◽  
Allogeneic Hsct ◽  
Reduce Relapse Rate ◽  
Conditioning Regimens ◽  
Wbc Count ◽  
Transplantation Outcomes

Abstract Abstract 195 TBI/CY and oral (p.o) Bu/Cy are the traditional allogeneic HSCT (alloHSCT) myeloablative conditioning regimens for adults with AML with comparable survival and relapse probabilities. Intravenous (i.v.) Bu in contrast to p.o Bu has more predictable pharmacokinetics and a more favorable toxicity profile. Post transplantation outcomes with i.v. Bu/Cy, thus, may be superior to those achieved with TBI/Cy. In order to address these issues, the ALWP of the EBMT performed a survey comparing i.v. Bu/Cy to TBI/Cy as conditioning regimen for adult pts. with AML undergoing alloHSCT. Overall, 603 alloHSCT were analyzed. One hundred pts. underwent alloHSCT with Bu/Cy while 503 with TBI/Cy. Age was 41 (range, 18–57) and 41 (range, 16–61) years and median transplant year was 2004 (2000 – 2005) and 2003 (2000 – 2005) for the Bu/Cy and TBI/Cy groups, respectively. Disease status at alloHSCT were CR1 – 81% vs. 78% and CR2–19% vs. 22% for the Bu/Cy and TBI/Cy groups, respectively. WBC count at diagnosis was 11×109/L and 15×109/L, respectively. Regarding the cytogenetic classification, 10% and 10% were good, 60% and 55% were intermediate and 9% and 6% were poor risk, respectively (data were NA for 21%–26% of pts). Sixty nine percent and 68% of both groups underwent alloHSCT from sibling donors, while 31% and 32% from MUD, respectively. Length of follow up was 37(15–86) and 57 (1–105) months for both groups, respectively. Sixty nine percent and only 41% of the Bu/Cy and TBI/Cy groups received PB, while 31% and 59% received BM grafts, respectively (p<0.0001). Engraftment was similar in the Bu/Cy vs. the TBI/Cy groups, 95% and 96%, respectively. Cumulative incidence of TRM at 2y was 17+4% and 23+2%, respectively (p=0.23). Acute GVHD (II–IV) was also similar between the 2 groups, 28% and 32%, respectively. Two year relapse incidence was 30+5% and 22+2% for Bu/Cy vs. TBI/Cy, respectively (p=0.03) while LFS was comparable 57+5% and 61+2%, respectively (p=0.5). In multivariate analysis Cy/TBI was found to be an independent good prognostic factor for reduce relapse rate (p=0.03, HR-1.67) and there was a trend for higher TRM (p=0.16). Poor prognostic factors for LFS and TRM were age >40y, disease status (CR2 vs. CR1) and MUD vs. Sib. donor. In conclusion, in this retrospective EBMT survey outcomes of alloHSCT in adult pts. with AML in CR using either i.v Bu/Cy or TBI/Cy were comparable. Disclosures: No relevant conflicts of interest to declare.

Clonal Markers In Relapsed Acute Promyelocytic Leukemia (APL): Clinicopathological Associations and Relation to All-Trans Retinoic Acid (ATRA) Treatment on Intergroup Phase III Trial C9710.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1038-1038
Author(s):  
Robert E. Gallagher ◽  
Barry K. Moser ◽  
Janis Racevskis ◽  
Xavier Poiré ◽  
Clara D. Bloomfield ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Cell Clone ◽  
Strong Association ◽  
False Negative ◽  
Phase Iii ◽  
Atra Treatment ◽  
Sensitivity Testing ◽  
Clinicopathologic Characteristics ◽  
Phase Iii Trial ◽  
Wbc Count

Abstract Abstract 1038 The relationships of inherent disease-related characteristics and of treatment to the nature of APL cell clones that emerge at disease relapse are poorly understood. We studied these relationships in 45 patients who relapsed after ATRA/chemotherapy treatment on the non-arsenic trixoxide arm of intergroup phase III trial C9710 (Powell, et al. Blood, Epub). Four variably-expressed APL cell clonal markers were assessed: PML-RARA ligand binding domain mutations (LBD-M), FLT3 internal tandem duplication mutations (ITD), FLT3 receptor tyrosine kinase mutations (D835; RTK-M) and additional chromosome abnormalities (ACA), i.e., in addition to the hallmark t(15;17). The methods for mutation analysis of PML-RARA and FLT3 have been reported and were RNA transcript-initiated supplemented by selected quantitative FLT3 mutation analyses initiated from DNA. Karyotype data were derived by standard cytogenetic methods. Four patients were excluded from analysis because the sample level of PML-RARA, as determined by quantitative RT-PCR, was insufficient to exclude possible false-negative mutation results. In 41 evaluable patients, the marker incidences were: LBD-M, 44%; ITD, 37%; RTK-M, 12%; ACA (22 tested), 59%. At presentation, the corresponding incidences were: LBD-M, 0% (by high-sensitivity testing a minor subclone of the relapse mutation was found in 2/7 patients tested); ITD, 43% (37 tested); RTK-M, 22% (37 tested); ACA, 24% (34 tested). The low frequency of RTK-M impeded further analysis. The other markers, using relapse determinations, were assessed for potential associations between the markers and with the following parameters: age, sex, presenting WBC count, PML-RARA type, time to relapse, relapse on or off ATRA treatment (on = taking or within 30 days of discontinuing) and post-relapse survival. The most essential positive findings are summarized below:Association of Marker with Parameter or Other MarkerCases with ParameterCases without Parameterp-valuePretreatment parameters:    LBD-M with WBC count < 5,000/uL12/18 (67%)7/23 (30%)0.030    ITD with WBC count >10,000/uL10/15 (67%)5/26 (19%)0.006    ITD with S-form PML-RARA15/15 (100%)10/26 (38%)<0.0001Relapse parameters:    ITD with lack of ACA1/7 (14%)12/15 (80%)0.007    LBD with relapse On-ATRA11/18 (61%)7/23 (30%)0.064    Off-ATRA only: LBD with lack of ITD0/7 (0%)9/16 (56%)0.019 The results confirm reports, which tested pretreatment samples, of a strong association between FLT3ITD mutations present at relapse and high WBC count and S-form PML-RARA. At relapse, there was, also, divergent selection of ITD-harboring vs ACA-harboring clones. LBD-M occurred more frequently in patients with low presenting WBC counts. They, also, occurred in patients who relapsed while on ATRA, consistent with an ATRA selective role for clones harboring LBD mutations. A significant segregation of patients with LBD-M or ITD was observed after relapse off ATRA treatment (p = 0.019), while no segregation was observed in overall relapse patients (p = 0.346) or after relapse on ATRA (p = 0.316). In 2 patients who relapsed on ATRA, quantitative analysis indicated that LBD-M and ITD mutations must be present in the same APL cell clone. There were no significant survival differences related to any clonal marker (post-relapse survival = 66%). Although the small number of cases is cautionary, the overall data suggest that LBD-M may have an overriding, dominant APL clone selection role in relapse that occurs on ATRA therapy. Other inherent clinicopathologic characteristics of APL may predispose to divergent molecular pathways of disease progression and relapse in patients alternatively harboring clones with LBD-M or ITD after the termination of ATRA selection pressure. Disclosures: No relevant conflicts of interest to declare.

A Phase II Study of Decitabine In Advanced Chronic Myelomonocytic Leukemia (CMML)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1873-1873
Author(s):  
Thorsten Braun ◽  
Nathalie Droin ◽  
Benoit de Renzis ◽  
Francois Dreyfus ◽  
Kamel Laribi ◽  
...  
Keyword(s):  
Phase Ii ◽  
Conflicts Of Interest ◽  
Cytogenetic Response ◽  
Median Number ◽  
Costal Margin ◽  
Monocyte Count ◽  
Blood Monocytes ◽  
Grade 3 ◽  
Wbc Count

Abstract Abstract 1873 Background: CMML, now classified among MDS/MPN, is prognostically heterogeneous. We (JCO 1988 6:1417, Blood 1996 88:2480) and others found prognosis in CMML to depend on both “MDS factors” (% marrow blasts, cytopenias, karyotype) and “MPN” factors, ie splenomegaly (SMG), WBC count, extramedullary disease (EMD). Treatment of advanced CMML is difficult. The hypomethylating agents Azacitidine and Decitabine (DAC) have shown efficacy in CMML, but in prognostically heterogeneous cohorts. We conducted a phase II trial of DAC in a well defined cohort of advanced CMML. Methods: To be included, CMML (according to WHO) should have: if WBC<13G/l an IPSS≥1.5; if WBC≥13G/l, two of the following criteria: marrow blasts≥5%, Hb<10g/dl, plts<100G/l, abnormal cytogenetics, SMG >5cm below costal margin, (SMG>5cm), EMD, based on our previous prognostic factors. Pts received DAC 20mg/m2/d IV for 5 days every 28 days for at least 3 cycles. Response criteria were based on IWG 2006 for pts with WBC <13G/L and for pts with WBC > 13 G/L also included evolution of WBC, SMG and EMD (Blood 1996 88:2480). Results: Between Nov 2008 and June 2009, 41 pts were included in 16 centers, of whom 39 completed at least one cycle and were considered evaluable for response (the 2 other pts died from septic shock before and during the first cycle respectively). Median number of cycles was 9 (range 1–17). Median age was 71 years (range 54–88), M/F:30/9. Seventeen pts had CMML 1 and 22 had CMML 2 (including pts with up to 29% marrow blasts). Median WBC count was 29.5G/l (range 4.1–147.3), median blood monocytes 3G/l (range 1.05–95.7), and median BM blasts 10% (1-29). Nine pts had WBC<13G/l and 30 WBC≥13G/l. Abnormal karyotype was found in 18 (46.2%) pts, including +8 and -7 in 7 and 1 case, respectively. 15 pts (38.6%) had SMG>5cm and 8 (20.5%) EMD involving skin (n=5) and lymph nodes (n=3). Overall Response Rate (ORR,) was 38.6% with 4 (10.3%) CR, 8 (20.5%) marrow CR and 3 (7.7%) Stable Disease (SD) with HI. 1 CR pt received allo SCT. 18 (46%) pts had SD without HI and 6 (15.4%) pts progressed to AML. 8 (36.4%) of the 22 RBC transfused pts became RBC transfusion independent. 3/10 (30%) pts with plt<50G/l reached plt>100G/l. Four pts had cytogenetic response (3 CR and 1 PR) exclusively among pts with +8. Median peripheral monocyte count decreased from 4.8G/l to 0.3G/l after 3 cycles of DAC among responders. SMG disappeared in 6/15 (40%) pts and EMD in 6/8 (75%) pts. 16 pts were receiving Hydroxyurea (HY) at inclusion which could be stopped in 12 of them. With a median follow up of 10 months (1-18), 7 pts had died from progression (n=3), sepsis (n=3) and unrelated cause (n=1). Overall Survival (OS) estimate was 60% at 2 years (median not reached). By comparison, in our previous trial of HY in CMML where inclusion criteria were the same, 2 year survival was 43% (median OS 20 months; Blood 1996 88:2480), for a median follow up of 11 months (range1-43). The only factor associated with response to DAC was WHO subtype, CMML 2 pts showing significantly better ORR (30.8% vs 7.7% in CMML 1; p=0.041).There was no difference in survival between CMML 1 and 2 pts. Treatment with DAC was generally well tolerated with, except for usual grade 3/4 cytopenias, and grade 3 fatigue (n=1). Conclusion: DAC is active in advanced CMML and safe in these elderly pts. A possibly better survival than with HY will have to be confirmed in randomized trials. Correlative genetic studies identifying markers potentially predicting response and survival for DAC are currently underway in our lab. Disclosures: No relevant conflicts of interest to declare.

Outcomes of Patients with Myelodysplastic Syndromes/Myeloproliferative Neoplasms with Emphasis On MDS/MPN-Unclassified

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5025-5025
Author(s):  
Charikleia Kelaidi ◽  
Varnavas Constantinou ◽  
George Papaioannou ◽  
Niki Stavroyianni ◽  
Chrysanthi Vadikoliou ◽  
...  
Keyword(s):  
Disease Progression ◽  
Myelodysplastic Syndromes ◽  
Response Rate ◽  
Conflicts Of Interest ◽  
Systemic Mastocytosis ◽  
Myeloproliferative Neoplasms ◽  
Univariate Analysis ◽  
Jak2 V617f ◽  
Female Ratio ◽  
Wbc Count

Abstract Abstract 5025 Background: Data on outcomes of patients (pts) with myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN), especially MDS/MPN-unclassified (MDS/MPN-U), are scarce. Patients/methods: We retrospectively studied pts followed in our center, with MDS/MPN according to WHO 2008 criteria. Because of overlap characteristics of MPN and MDS, pts with systemic mastocytosis associated with MDS (SM/MDS) were also included. Pts with previous MDS or MPN were excluded. Response and disease progression were defined according to IWG 2006 criteria. Results: Twenty-five pts with MDS/MPN were included. Median age was 70 y (range 19–79). Male/female ratio was 1.77/1. Diagnosis was CMML-1 N=7, CMML-2 N=7, JMML N=1, MDS/MPN-U N=8, systemic mastocytosis (SM)/MDS N=2, with one additional pt with CMML subsequently developing SM. At diagnosis, median WBC count was 18.8 G/L (range 3–120), ANC 15.5 G/L (0.6–70), monocytes 1.9 G/L (0.1–16), left shift 16% (0–28), Hb 11.2 g/dL (6–17), platelets 99 G/L (10–680), peripheral and bone marrow (BM) blasts 5% (0–17) and 7% (2–19), respectively (resp.). 25% of pts had platelets count ≥400 G/L. Splenomegaly, B-symptoms and BM fibrosis were present in 23%, 57% and 27% of pts, resp. Karyotype was fav, int and unfav in 55%, 36% and 9% of pts, with −7, +8, del(12)(p11), del(12)(q14;q21), +10, +21, and previously unreported t(9;12)(q13;q13) in 3, 6, and 1 pt each, resp., while +21 and i(17)(q10) appeared during disease progression other than AML transformation. IPSS was low/int-1 and int-2/high in 50% and 50% of pts, resp. JAK2 V617F and CKIT D816V mutations were detected in 2/6 pts and 2/2 SM/MDS pts, resp. 70% and 29% of pts were transfused at diagnosis with PRBC and platelets, resp. Treatment included erythropoiesis stimulating agents (ESAs), low dose chemotherapy, intensive chemotherapy (IC) and azacitidine (AZA) in 40%, 36%, 16% and 48% of pts resp. Response rate to ESAs, IC and AZA was 60%, 14% and 14% resp. Response rate to AZA in CMML-1 pts was 33%. Dasatinib yielded no response in 1 SM/MDS pt with CKIT D816V. 3-year cumulative incidence of AML and median overall survival (OS) in pts with CMML-1, CMML-2 and MDS/MPN-U were 20%, 40% and 0 (P=0.059) and 39, 8, and 20 mo (P=0.50), resp. The pt with JMML died from AML transformation 3 months after diagnosis. 2/3 pts with SM/MDS died from disease progression w/o AML at a median of 10 mo after diagnosis. Median survival after disease progression other than AML transformation was 35, 15 and 14 mo in pts with CMML-1, CMML-2 and MDS/MPN-U, resp. (P=0.88). Cause of death was disease progression other than AML, AML transformation and unrelated to disease in 50%, 50%, and 0 and 80%, 0 and 20% of cases in CMML and MDS/MPN-U, resp. (P=0.10). Percentage of circulating blasts ≥5% was the only independent factor affecting risk of AML transformation in the overall population (P=0.0004). Diagnosis other than CMML-1, WBC ≥30 G/L, % of circulating blasts ≥5% and IPSS high/int-2 were associated with worse survival in univariate analysis (P=0.06, 0.03, 0.04 and 0.08, resp.). No predictive factor of OS was found in multivariate analysis. Conclusion: MDS/MPN are heterogeneous disorders with respect to disease progression and AML transformation. MDS/MPN-U tended to differ from CMML-1 by shorter survival after disease progression other than AML, and from CMML-2 by lower risk of AML transformation. Mortality of pts with MDS/MPN-U was mainly attributed to disease progression without AML transformation. Alternatively to hypomethylating agents, therapeutic options in pts with MDS/MPN-U could include JAK2 inhibitors. Disclosures: No relevant conflicts of interest to declare.

Expression of CD56 Is an Independent Prognostic Factor to Predict Relapse in Acute Myeloid Leukemia with t(8;21): Results of Japan Adult Leukemia Study Group (JALSG) AML97 Protocol.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2511-2511
Author(s):  
Noriyoshi Iriyama ◽  
Yoshihiro Hatta ◽  
Jin Takeuchi ◽  
Yoshiaki Ogawa ◽  
Shigeki Ohtake ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Performance Status ◽  
Univariate Analysis ◽  
Rank Test ◽  
Hematopoietic Stem ◽  
Wbc Count ◽  
Adverse Factor ◽  
Acute Myeloid

Abstract Abstract 2511 Background: Although prognosis of acute myeloid leukemia (AML) with t(8;21) is better than other types of AML, outcome of the patients has not been satisfied. Previously, aberrant antigen expression has been reported as risk factor for AML with t(8;21). However, in the reported series, number of cases was not large enough and chemotherapy regimens were variable. We investigated the association of prognosis and several biomarkers including immunophenotype, WBC count, age, and performance status for large number of AML patients with t(8;21) uniformly treated in JALSG AML97 regimen. Patients and Methods: Seven hundred eighty-nine eligible AML patients were evaluated for the multicenter JALSG AML97 study. Adult patients with de novo AML except for APL, ages 15–64 years, were registered consecutively from 103 institutions that participated in JALSG from December 1997 to July 2001. One hundred forty-four patients with AML with t(8;21) were analyzed in this study with a median 1205 days of observation term from diagnosis. Complete remission (CR), relapse-free survival (RFS), and overall survival (OS) rates were analyzed by Fisher's exact test and log-rank test. Factors that would affect clinical outcome were analyzed by multivariate Cox proportional hazard regression model. Results: AML with t(8;21) frequently expressed CD19, CD34, and CD56 compared to other subtypes of AML. CD11b was rarely expressed. Expression of CD19 favorably affected on CR rate (96% in CD19 positive and 87% in negative patients, p<0.05). Univariate analysis showed WBC>20×109/L, CD19 negativity, and CD56 positivity were adverse factors for RFS. CD56 expression was the only independent adverse factor for RFS by multivariate analysis (73.7% in CD56 negative and 48.2% in CD56 positive patients at 3 yrs) although its expression did not affect on OS. There was no difference of age, sex, WBC count, presence or absence of Auer rod, performance status, or CD15 expression between CD56 positive and negative cases. Expression of CD19 was more common in CD56 negative patients (50% in CD56 negative and 30.6% in CD56 positive patients, p<0.05). Conclusions: We demonstrated that the expression of CD56 was a distinctive adverse factor in a large number of AML patients with t(8;21) treated with JALSG AML97 regimen. CD56 positive AML patients with t(8;21) are possible candidates for hematopoietic stem cell transplantation. Disclosures: No relevant conflicts of interest to declare.

A Phase I/II Study Of Cytarabine Or Azacitidine In Combination With Tosedostat In Older Patients With AML Or High-Risk MDS

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2698-2698 ◽  
Author(s):  
Courtney D. DiNardo ◽  
Hagop M Kantarjian ◽  
Farhad Ravandi ◽  
Marina Konopleva ◽  
Tapan M. Kadia ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Dose Escalation ◽  
Older Patients ◽  
Progressive Disease ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Study Drug ◽  
Starting Dose ◽  
Wbc Count

Abstract Background The aminopeptidase inhibitor tosedostat is an orally bioavailable novel chemotherapeutic, functioning through enzymatic blockade of intracellular protein degradation and re-synthesis. Encouraging results have been observed with tosedostat monotherapy in Phase I and II trials of relapsed and refractory elderly AML patients. Aims This Phase I/II trial explores the safety, tolerability and activity of tosedostat in combination with cytarabine or azacitidine in older patients with AML or high-risk MDS. Methods Eligibility includes age >60 years, performance status of 0-2, with relapsed/refractory AML or high-risk MDS having failed prior hypomethylating agent (HMA) and/or lenalidomide therapy. All subjects received tosedostat 120mg orally once daily for 28 day cycles, with either subcutaneous (SQ) cytarabine at starting dose of 7.5mg twice daily for 10 days, or azacitidine (AZA) IV/SQ at starting dose of 50mg/m2 daily for 7 days, per investigator’s choice. A modified 3+3 dose escalation design was used in the Phase I portion to identify the maximum tolerated dose independently for both arms. Escalation to the predefined target dose levels of 10mg SQ cytarabine twice daily for 10 days, or azacitidine 75mg/m² IV/SQ daily for 7 days per 28 day cycle was achieved. Dose escalation to 180mg daily tosedostat was allowable for patients not achieving a CR after 4 weeks on therapy. Results From November 2012 to April 2013, the Phase I portion completed enrollment with a total of 18 patients (10 with AZA, 8 cytarabine). Six patients discontinued prior to completion of cycle 1 for reasons other than study-drug related toxicity or progressive disease and were replaced; they are considered as non-responders in the primary efficacy analysis. Median age was 73 (range 60-81), and 56% were male. 13 patients (72%) had secondary or therapy-related AML, of which 11 (61%) had prior MDS. The median number of prior treatments for MDS and/or AML was 2 (range 1-6), and 11 (61%) had received prior HMA therapy. Median white blood cell (WBC) count at study start was 5x10⁹/L (range 0.3 – 44.2), with median peripheral blood blasts of 27% (range 0-95%), and bone marrow blasts 57% (range 6-90%). The majority (61%) of patients had complex cytogenetics or abnormal cytogenetics involving chromosome 5 and/or 7; six patients (33%) had diploid cytogenetics. Molecular analysis identified 1 FLT3-ITD, 3 DNMT3A, 2 JAK2 V617F, 2 NRAS, 2 KRAS, and 1 IDH1 mutation. Median duration on study was 49 days (range 13 – 254), with median overall survival (OS) of 3.1 months (range 0.4-8.5) and an overall response rate (ORR) of 33% (CR/CRp/MLFS 17%, PR 17%). ORR was 50% (CR/CRp/MLFS 25%, PR 25%) in fully evaluable patients remaining on study for >28 days. Median OS for patients with CR/CRp/MLFS and PR was 7.3 and 3.5 months, respectively, while OS for unevaluable patients or those with progressive disease was 29 days. On univariate analysis, the presence of a diploid karyotype (p=0.001) or WBC count <4x10⁹/L (p=0.036) associated with an improved ORR. The most common non-hematologic toxicities regardless of attribution (all %; grade >3) included pleural and pericardial effusions (72%; 0%), dyspnea (67%; 0%), peripheral edema (61%; 6%), pneumonia (56%; 50%), fatigue (50%; 0%), diarrhea (50%; 0%), and cough (39%; 0%). Additional cardiac toxicities included systolic dysfunction (17%; 6%), QTc prolongation (50%; 6%) and myocardial infarction (MI) (11%; 11%). One fatal acute coronary event on cycle 2, day 2 of tosedostat 180mg and AZA 75mg/m² was considered possibly related to study drug. Conclusions The combination of tosedostat with low-dose cytarabine or azacitidine appears effective in a population with an overall very poor prognosis. Additional safety and efficacy evaluations are ongoing. Updated results and follow-up will be presented at the annual meeting. Disclosures: No relevant conflicts of interest to declare.

Genetic Markers Add Significant Prognostic Information to Age and WBC Count in High-Risk, Ph-Negative, B-Precursor Adult Acute Lymphoblastic Leukemia (ALL): Study of 96 Patients Treated According to Risk-Adapted Protocols from the Pethema Group

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3798-3798
Author(s):  
Jordi Ribera ◽  
Lurdes Zamora ◽  
Eulàlia Genescà ◽  
Mireia Morgades ◽  
Pau Montesinos ◽  
...  
Keyword(s):  
High Risk ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Homozygous Deletion ◽  
Advanced Age ◽  
Prognostic Information ◽  
Independent Prognostic Significance ◽  
Multivariable Analyses ◽  
Wbc Count

Abstract Introduction Recurrent Copy Number Alterations (CNA) in genes potentially involved in the pathogenesis of ALL have been identified in genes involved in B-cell development, cell cycle regulation, proliferation, apoptosis and drug resistance. Their independent prognostic significance in adult ALL patients is controversial. The aim of this study was to analyze the prognostic significance of CNA in a series of 96 high-risk, Ph-negative, B-precursor adult ALL patients treated according to risk-adapted protocols from the Spanish PETHEMA Group. Methods MLPA assays (MRC-Holland) were performed for the following genes: IKZF1, IKZF2, IKZF3, EBF1, CDKN2A/B, PAX5, ETV6, BTG1, RB1, hsa-miR-31, X/Y PAR1 region genes (CRLF2, CSF2RA, IL3RA) and 14q32.33 region genes (IGH D, MTA1, KIAA0284). Fragment analysis was made by Genescan in an ABI-3130 sequencer (Applied Biosystems). Data normalization provided a value indicative of the presence or absence of CNA: 0-0.20 homozygous deletion, 0.21-0.70 heterozygous deletion, 0.71-1.30 normal, 1.31-1.70 heterozygous duplication and 1.71-2.20 homozygous duplication. Univariable and multivariable analyses including the most relevant clinical parameters (age, WBC count, phenotype, cytogenetics, CNS involvement) were performed for CR attainment, CR duration and OS. Results The median age [range] of the 96 patients was 39 [15-72] years, 50 (52%) patients were males, with a median WBC count 14.3 x109/L [0.4-388]. Phenotype: early pre-B 19 (20%), common 51 (54%), pre-B 22 (24%), unknown 2 (2%). Cytogenetics: normal 18 (19%), hyperdiploid 5 (5%), hypodiploid 2 (2%), near haploid 6 (6%), t(1;19) 7 (8%), 11q23/MLL 11 (12%), complex 1 (1%), other 27 (29%), no growth 17 (18%). The most frequent CNA deletions involved CDKN2A/B (43/96, 45%), PAX5 (34/94, 36%), IKZF1 (32/95, 34%), hsa-miR-31 (25/96, 26%), 14q32.33 region (18/96, 19%), RB1 (17/96, 18%), EBF1(12/91, 13%) and X/Y PAR (10/96, 10%). The most frequent duplications involved X/Y PAR (11/96, 12%) and 14q32.33 region (7/96, 7%). The CR rate was 83% (80/96), the median (95%CI) of CR duration was 2.7 years (0-5.9) and the median (95%CI) of OS was 2.1 (1.0-3.2), being the median (range) follow-up of the series of 3.8 (0.6-8.0) years. Table 1 shows the results of univariable and multivariable analyses. By multivariable analyses advanced age and EBF1 deletions were significantly associated with less CR rate, WBC count and X/Y PAR duplication were associated with shorter CR duration, and advanced age and CDKN2A/Bdeletion were associated with shorter OS. Conclusions The CNA of EBF1, X/Y PAR1 genes and CDKN2A/Bhave independent prognostic significance in adult patients with high-risk, Ph-negative, B-precursor ALL. This study suggests that these genetic studies should be added to the initial work-up of these patients for more accurate prognostic assessment Supported by grants PI10/01417, RD12-0036-0029 from Instituto Carlos III, 2014 SGR225 (GRE) from Generalitat de Catalunya and a grant from the Spanish Society of Hematology and Hemotherapy (2012). Abstract 3798. Table 1. Results of the univariable and multivariable studies. Variable CR rate CR duration OS P (univ) OR (95%CI) P (univ) HR (95%CI) P (univ) HR (95%CI) Age 0.011 0.93 (0.89 - 0.98) NS - 0.005 1.03 (1.01 - 1.05) WBC NS - <0.001 1.01 (1.00 - 1.01) NS - IKZF1 * NS - 0.048 - NS - EBF1 * 0.025 0.11 (0.02 - 0.54) NS - NS - CDKN2A/B * NS - NS - 0.014 2.32 (1.35 - 4.00) X/Y PAR** NS - 0.013 4.26 (1.64 - 11.09) NS - *Normal versus deleted; ** Normal versus duplicated; NS: not significant Disclosures No relevant conflicts of interest to declare.

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