The Impact of Distance to Treatment Center on the Outcome of AML

Abstract Abstract 4742 Introduction While the distance patients travel to a treatment center (DTC) adversely impacts survival of patients with trauma, cardiac, or neurological disorders, as well as certain solid tumors, less is known of its influence in acute myeloid leukemia (AML). Care for patients with AML involves frequent emergent and urgent management, often complicating primary therapy provided in distant tertiary referral centers. We therefore hypothesized that increased DTC has a negative impact on outcome. We tested this hypothesis by assessing the effect of DTC on survival of patients with AML receiving care at a single institution. Patients and Methods Within the Stanford Leukemia Database, we identified 884 consecutive adult patients between 1993 and 2009 meeting the following criteria: age >=18, newly diagnosed AML (excluding APL), clinical management at Stanford University Medical Center (SUMC), and verified residence location available for DTC determination. Of these, 571 were deemed fit by the admitting physician to receive myelosuppressive induction chemotherapy. DTC was calculated by straight-line journey distance between home address at the time of diagnosis and treatment center. Results The median age for the entire cohort is 55 years and 322 patients (36%) are older than 60 years of age. Median survival for the entire cohort was 14.0 months. DTC was not univariately associated with outcome as a continuous variable. When testing for a critical DTC threshold impacting outcomes across the entire cohort, we found a significant correlation between longer DTC and adverse outcomes, shorter DTC was associated with lower OS. Patients living within 20 miles of SUMC had a worse median overall survival (10.4 months versus 15.0 months, HR 1.23, corrected p-value 0.02). However, when adjusted for administration of induction chemotherapy (p<0.0001), age at presentation (p<0.0001) and karyotype at diagnosis (CBF vs other; p-value- 0.92), the negative impact of DTC was lost (p=0.08). Conclusion After accounting for confounding factors, DTC has no significant impact on the outcome of newly diagnosed AML patients receiving care at our institution. Unlike non-hematologic malignancies, distance to treatment center likely does not adversely influence outcomes for patients with AML. Disclosures: No relevant conflicts of interest to declare.

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Are Gene Expression Signatures Treatment Specific?

Blood ◽

10.1182/blood.v118.21.807.807 ◽

2011 ◽

Vol 118 (21) ◽

pp. 807-807 ◽

Cited By ~ 1

Author(s):

Parantu K Shah ◽

Stephane Minvielle ◽

Hervé Avet-Loiseau ◽

Cheng Li ◽

Nikhil C. Munshi

Keyword(s):

Gene Expression ◽

Clinical Decision Making ◽

Conflicts Of Interest ◽

Clinical Decision ◽

Induction Treatment ◽

P Value ◽

Newly Diagnosed ◽

Gene Expression Signatures ◽

The Difference ◽

The Impact

Abstract Abstract 807FN2 Gene expression profiling (GEP) of newly-diagnosed cancer patients is now a routine task in the oncogenomic research using functional genomics platforms like microarray and next generation sequencing. These profiles are then utilized to derive gene expression signatures (GES) that can stratify patients according to survival groups using various statistical methodologies. This is an active area of research with important implications on clinical decision making and patient care. It is important to note that the treatment itself probably plays a major role in influencing outcome in cancer. Therefore, the GES may be specific to a particular treatment and may not be universally applicable in predicting survival of patients treated with different therapeutic regimen. We evaluated the impact of therapy on GES utilizing two large publicly available gene expression datasets from newly-diagnosed multiple myeloma (MM) patients generated using Affymetrix U133+2 microarrays. The dataset from University of Arkansas Medical Sciences (UAMS; Shaughnessy et al Blood 2007) has gene expression profile (GEP) from 569 patients treated on total therapy (TT)2 and TT3 protocols while the dataset from HOVON-65 trial contains GEO data from 320 patients treated with either the VAD or PAD regimen in equal numbers. The UAMS dataset was partitioned into training and validation sets. Using a combination of a network inspired univariate ranking procedure and ultra refined methods for variable selection we derived a sparse multivariate survival signature consisting of 40 genes that worked extremely well on the training set (p-value < e-16) as well as the validation set (p-value < e-5). Interestingly we saw the difference of performance between TT2 and TT3 induction arms. The p values were 0.002 for the TT2 induction arm while for the TT3 the p value was 0.02. On applying the signature to the whole HOVON-65 test set our signature worked only moderately well (p-value = 0.003). When the HOVON-65 dataset was split according to the induction treatment arms, the GES worked extremely well (p-value < e-5) in predicting the outcome in patients receiving VAD regimen but had no power to distinguish survival in patients receiving PAD regimen. We have evaluated the results on additional data sets that confirmed our observation from the HOVON study. To our knowledge this is the first clear demonstration of treatment specificity of GES. This data suggest that we may need to derive multiple therapy-specific GES to be applied to the patients to treat the new patient with therapy for which he/she is predicted to have best outcome. Disclosures: No relevant conflicts of interest to declare.

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Response-Adapted Sequential Azacitidine and Induction Chemotherapy in Patients > 60 Years Old with Newly Diagnosed AML Eligible for Chemotherapy (RAS-AZIC): First Data of the Interim Analysis of the DRKS00004519 Study of the East German Study Group (OSHO)

Blood ◽

10.1182/blood.v126.23.1346.1346 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1346-1346

Author(s):

Haifa Kathrin Al-Ali ◽

Nadja Jaekel ◽

Karolin Hubert ◽

Rainer Krahl ◽

Mathias Haenel ◽

...

Keyword(s):

Induction Chemotherapy ◽

Interim Analysis ◽

Research Funding ◽

Data Monitoring Committee ◽

Patient Characteristics ◽

Primary Objective ◽

Epigenetic Therapy ◽

Newly Diagnosed ◽

Entire Cohort ◽

The Impact

Abstract The prognosis of AML in patients (pts) >60 years (y) is poor and there is no universally accepted standard approach. After induction chemotherapy (IC), a complete remission (CR+CRi) rate of 56.4% and a mortality of 21% at day (d) 90 are expected (Niederwieser et al, ASH 2012). Azacitidine (AZA) yields a one-year survival (OS) rate of 46.5% in pts >65 y and >30% marrow (BM) blasts (Dombret et al, Blood 2015). Yet, AZA and IC are not mutually exclusive. First results of the interim analysis of the DRKS00004519 (RAS-AZIC) study which evaluates priming with AZA followed by AZA or IC in pts >60 y with AML are presented. Patients and methods: Major inclusion criteria are newly diagnosed AML with marrow blasts >20% by aspiration or biopsy irrespective of WBC count, age >60 y, and eligibility for IC. Secondary AML from an antecedent hematologic disorder and therapy-related AML are not excluded. In the phase I part of the trial, safety of priming with AZA (75 mg/m2/day s.c) for 7 d followed by IC (Mitoxantrone 10 mg/ m2/day d 1-3 and cytarabine 1 g/m2/BID d 1, 3, 5, 7) on d 17 was established through a 3+3 design. In the multicenter phase II part (figure), priming was sequentially followed by AZA or IC based on d 15 BM blasts and d 56 response which were identified as early predictors for long-term response to AZA in AML (Al-Ali et al., Leuk Lymph 2012). The primary objective is overall response (OR) which includes CR, CRi, and PR at d 90 according to the International Working Group criteria (Cheson et al, J Clin Oncol 2003). Safety, OS, and mortality were secondary end points. According to the optimal two-stage design (Simon, Control Clin Trials 1989), an expected OR of 61% at the end of trial was estimated. Thus in a first stage analysis, < 19 of consecutive 40 (47.5%) pts not achieving the primary objective would be considered an indication for inferiority of the protocol treatment compared to standard IC. Hence, an interim analysis of the first stage was planned per protocol while accrual continues to include the first 40 pts who received the maximal tolerated priming dose of AZA. The trial is supervised by an independent Data Monitoring Committee. Adverse events (AEs) are reported according to the NCI CTCAE 4.03. All pts gave written informed consent. Results: Patient characteristics are shown in table 1. Median age is 69 y and median blast count 39%. All pts received priming with AZA. Median BM blasts at d 15 was 27% (range 2.4-88%). To date, data on subsequent therapies are captured in 33 (82.5%) pts. Except for one (withdrew consent on d 27), all pts received protocol assigned treatment based on BM blasts on d 15 [17/32 (53%) continued with AZA, 15/32 (47%) received IC]. Likewise, 26/32 (81%) pts ([2x data not yet available, 2x death (d 34; d 53), and 2x physician's choice] received response-adapted treatment on d 56 [12/26 (46%) started AZA maintenance and 14/26 (55%) received IC]. OR at d 90 for the 26 as yet evaluable pts is 80.7% [CR (61.5%, n=16); CRi (11.5%, n=3); PR (7.7%, n=2). No additional mortality till d 90 was reported. For the entire cohort, 85% of pts are alive after a median follow-up of 6 months. AEs were consistent with the known safety profile of AZA and IC. AEs > grade 3 were reported 83x in 20 (50%) pts being mainly infectious and respiratory complications (60%). As expected, the majority (57%) were reported under IC, followed by 19% and 17% under priming and the 2. AZA cycle respectively. AEs led to postponement of the planned therapy in 6 pts (3x IC on d 17, 2x 2. AZA, 1x IC on d 56). The final assessment of the interim analysis is set in the near future. Conclusions: These data imply that in a heterogeneous disease like AML, integrating epigenetic therapy with chemotherapy in elderly pts in an individualized response-based approach is feasible, induces responses at least comparable to those seen after IC, and is associated with a remarkable low mortality. The definitive response rate and the impact of such an approach on survival will be answered at the end of the trial. Table 1. Patient characteristics (n=40) Median age, range (years) 69 ( 61 - 82) Male/Female (%) 55 / 45 Baseline ECOG (%)0/1/2 21 / 63 / 16 Type of AMLDo novo/secondary (%) 61 /39 Median WBC (range) x 109/L 6.7 (0.7 - 81.8 ) Median bone marrow blasts (aspiration) (range) (%) 39 (13 - 90) Cytogenetics (n=35)Normal/intermediate/unfavourable (%) 54 /23 / 23 FLT3+ (n=34) (%) 9 NPM1 + (n=34) (%) 9 Figure 1. Figure 1. Disclosures Al-Ali: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Off Label Use: Azacitidine is not approved for the use in patients with AML and blasts > 30% outside clinical trials.

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Generalized Joint Hypermobility and Anxiety in Adolescents and Young Adults, the Impact on Physical and Psychosocial Functioning

Healthcare ◽

10.3390/healthcare9050525 ◽

2021 ◽

Vol 9 (5) ◽

pp. 525

Author(s):

Janneke de Vries ◽

Jeanine Verbunt ◽

Janine Stubbe ◽

Bart Visser ◽

Stephan Ramaekers ◽

...

Keyword(s):

Young Adults ◽

Psychosocial Functioning ◽

Negative Impact ◽

Pain Catastrophizing ◽

Joint Hypermobility ◽

Adolescents And Young Adults ◽

P Value ◽

High Performing ◽

Generalized Joint Hypermobility ◽

The Impact

The purpose of this study was to study the association between the presence of generalized joint hypermobility (GJH) and anxiety within a non-clinical high performing group of adolescents and young adults. Second, to study the impact of GJH and/or anxiety on physical and psychosocial functioning, 168 adolescents and young adults (mean (SD) age 20 (2.9)) were screened. Joint (hyper)mobility, anxiety, and physical and psychosocial functioning were measured. In 48.8% of all high performing adolescents and young adults, GJH was present, whereas 60% had symptoms of anxiety. Linear models controlled for confounders showed that adolescents and young adults with GJH and anxiety had decreased workload (ß (95%CI) −0.43 (−0.8 to −0.08), p-value 0.02), increased fatigue (ß (95%CI) 12.97 (6.3–19.5), p-value < 0.01), and a higher level of pain catastrophizing (ß (95%CI) 4.5 (0.5–8.6), p-value 0.03). Adolescents and young adults with only anxiety had increased fatigue (ß (95%CI) 11 (4.9–19.5). In adolescents and young adults with GJH alone, no impact on physical and psychosocial functioning was found. Adolescents and young adults with the combination of GJH and anxiety were significantly more impaired, showing decreased physical and psychosocial functioning with decreased workload, increased fatigue, and pain catastrophizing. Presence of GJH alone had no negative impact on physical and psychosocial functioning. This study confirms the association between GJH and anxiety, but especially emphasizes the disabling role of anxiety. Screening for anxiety is relevant in adolescents and young adults with GJH and might influence tailored interventions.

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A Cross-Sectional Survey Exploring the Impact of the COVID-19 Pandemic on the Cancer Care of Adolescents and Young Adults

Current Oncology ◽

10.3390/curroncol28040278 ◽

2021 ◽

Vol 28 (4) ◽

pp. 3201-3213

Author(s):

Kaitlyn Howden ◽

Camille Glidden ◽

Razvan G. Romanescu ◽

Andrew Hatala ◽

Ian Scott ◽

...

Keyword(s):

Young Adults ◽

Cancer Treatment ◽

Cancer Care ◽

Negative Impact ◽

Positive Impact ◽

Care Delivery ◽

Adolescents And Young Adults ◽

P Value ◽

Cross Sectional Survey ◽

The Impact

We aimed to describe the negative and positive impacts of changes in cancer care delivery due to COVID-19 pandemic for adolescents and young adults (AYAs) in Canada, as well as the correlates of negative impact and their perspectives on optimization of cancer care. We conducted an online, self-administered survey of AYAs with cancer living in Canada between January and February 2021. Multiple logistic regression was used to identify factors associated with a negative impact on cancer care. Of the 805 participants, 173 (21.5%) experienced a negative impact on their cancer care including delays in diagnostic tests (11.9%), cancer treatment (11.4%), and appointments (11.1%). A prior diagnosis of mental or chronic physical health condition, an annual income of <20,000 CAD, ongoing cancer treatment, and province of residence were independently associated with a negative cancer care impact (p-value < 0.05). The majority (n = 767, 95.2%) stated a positive impact of the changes to cancer care delivery, including the implementation of virtual healthcare visits (n = 601, 74.6%). Pandemic-related changes in cancer care delivery have unfavorably and favorably influenced AYAs with cancer. Interventions to support AYAs who are more vulnerable to the adverse effects of the pandemic, and the thoughtful integration of virtual care into cancer care delivery models is essential.

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Abstract 3230: Elevated Glucose and Mortality in Patients Hospitalized with Heart Failure

Circulation ◽

10.1161/circ.118.suppl_18.s_1117-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Mikhail Kosiborod ◽

Silvio Inzucchi ◽

John A Spertus ◽

Yongfei Wang ◽

Frederick A Masoudi ◽

...

Keyword(s):

Heart Failure ◽

Cox Regression ◽

Linear Trend ◽

Adverse Outcomes ◽

Entire Cohort ◽

Hazard Ratios ◽

Elevated Glucose ◽

Nationally Representative ◽

Support Resource ◽

The Impact

Background: While some professional societies recommend target-driven blood glucose (BG) control for all hospitalized patients, the association between elevated BG and adverse outcomes has not been well established in patients hospitalized with heart failure (HF). Methods: We evaluated a nationally representative cohort of 50,532 patients hospitalized with HF between 04/1998 – 06/2001. Admission BG was analyzed as a categorical variable (≤110, >110 –140, >140 –170, >170 –200, >200 mg/dL), and in 10 mg/dL increments. The association between BG and all-cause mortality over 30 days and 1 year was analyzed using Cox regression, both in the entire cohort and in patients with and without diabetes (DM). Results: After multivariable adjustment, there was no significant relationship between BG and 30-day mortality (for BG >110 to 140, >140 to 170, >170 to 200, and >200, hazard ratios and 95% confidence intervals were: 1.09 (0.98 –1.22), 1.27 (1.11–1.45), 1.16 (0.98–1.37), 1.00 (0.87–1.15) respectively vs. BG ≤110, P for linear trend 0.53). Results were similar for 1-year mortality, and did not differ between patients with and without DM (P values for DM*BG interaction 0.11 and 0.55 for 30-day and 1-year mortality respectively). A lack of association between BG and mortality over 30-days and 1-year was also observed when BG was analyzed in 10mg/dL increments (Figure ). Conclusions: We found no significant association between BG and mortality in a large cohort of hospitalized HF patients. While the impact of BG lowering on outcomes cannot be determined based on this study, our findings do not support resource-intensive interventions for BG monitoring and management in this patient group.

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Effects of Board Size, Board Composition and Dividend Policy on Real Earnings Management in the Jordanian Listed Industrial Firms

International Journal of Financial Research ◽

10.5430/ijfr.v11n4p195 ◽

2020 ◽

Vol 11 (4) ◽

pp. 195

Author(s):

Yousef Shahwan ◽

Tareq Hammad Almubaydeen

Keyword(s):

Earnings Management ◽

Dividend Policy ◽

Structural Model ◽

Negative Impact ◽

Industrial Sector ◽

Real Earnings Management ◽

P Value ◽

Board Composition ◽

Board Size ◽

The Impact

Earning manipulation has been a normal transaction among the global businesses, in which business organization sees it as beneficial, thereby turning black eyes to its negative impact on the general economy. This study aimed at examining the impact of board size, Board composition and dividend policy on real earnings management in the listed Jordanian industries. 8 years data (2010 to 2018) was extracted from the audited financial reports of the selected firms. Data was analyzed using Structural Model via AMOS version 26 and SPSS version 21. The findings revealed a positive and significant effect between board size, board composition and real earning management at p-value<0.05 and 0.001 (two-tailed) respectively. While negative of dividend policy on REM was recorded at p-value>0.05 (two-tailed). This study has immensely contributed towards bridging the gap in the existing knowledge as it documented a new finding. The benefits of these findings cross over the managers, shareholders, board of directors, investors, the Jordanian government and all other relevant institute for the buildup of the healthiest industrial sector and better economy.

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TIMP-1 and TIMP-2 Levels Are Directly Correlated with Neoangiogenesis and Are Prognostic Factors in Multiple Myeloma Patients.

Blood ◽

10.1182/blood.v114.22.4866.4866 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4866-4866

Author(s):

Luciana Correa Oliveira de Oliveira ◽

Juliana Alves Uzuelli ◽

Ana Paula Alencar de Lima Lange ◽

Barbara Amelia Aparecida Santana-Lemos ◽

Marcia Sueli Baggio ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Overall Survival ◽

Prognostic Factors ◽

Bone Disease ◽

Cox Regression ◽

Conflicts Of Interest ◽

Newly Diagnosed ◽

Significant Difference ◽

The Impact

Abstract Abstract 4866 Background Multiple myeloma (MM) is an incurable malignant disease, characterized by increased angiogenesis in the bone marrow (BM) microenvironment and aberrant BM metabolism. Matrix metalloproteinases (MMP) are a family of zinc-dependent endopeptidases implicated in tumour progression, invasion, metastasis and angiogenesis, via proteolytic degradation of extracellular matrix. MMPs are inhibited by tissue inhibitors of metalloproteinase (TIMP). Although recent studies have implicated MMP 9 in MM bone disease, little is known about the role of the TIMPs. Objectives a) to compare levels of sRANKL, OPG, MMP-2, MMP-9, TIMP-1, TIMP-2, VEGF, bFGF, microvessel density (MVD) between newly diagnosed MM patients and healthy controls; b) to determine the association of these molecules with disease progression, bone disease and neoangiogenesis and c) to evaluate the impact of these variables on survival. Patients and Methods As of July 2009 38 newly diagnosed and untreated multiple myeloma patients were enrolled in the study. The median age was 61years-old (range 39-91) with 24 (63%) males. Patients were diagnosed and categorized according The International Myeloma Working Group criteria and ISS, respectively. Bone involvement was graded according to standard X-ray: patients with no lesions, or with one/ two bones involved or diffuse osteoporosis were classified as low score, whereas patients with lesions in more than two bones or presence of bone fracture were classified as high score. MMP-2 and MMP-9 were determined by PAGE gelatin zymography from plasma as previously described. MMP-9, TIMP-1 and TIMP-2, OPG and sRANKL concentrations were measured by ELISA. The levels of VEGF, bFGF were obtained using cytometric bead array. Ten healthy volunteers were used as controls. Bone marrow MVD measured in hotspots was evaluated in 26 out of 38 patients at diagnosis and 15 patients with Hodgkin Lymphoma stage IA and IIA (used as controls) by staining immunohistochemically for CD34. Comparisons among groups were analyzed by ANOVA and the correlation by the Spearman's correlation coefficient. Cox regression were performed for overall survival (OS) analysis. Results Patients with MM had elevated TIMP-1, TIMP-2 and OPG values compared with controls. No significant difference was found between plasma sRANKL, pro-MMP2, pro-MMP9 and MMP-9 levels. We found that plasma TIMP-1 levels correlated positively with bFGF, VEGF, MVD, beta-2 microglobulin (B2M) and OPG (r: 0.514, p=0,001, r: 0.350, p=0,031; r: 0.610, p<0.0001; r: 0.760, p<0.0001 and r: 0.701, p<0.0001, respectively) and TIMP-2 levels with bFGF, DMV, B2M and OPG (r: 0.512, p=0.002; r: 0.595, p<0.0001; r: 0.587, p<0.0001 and r: 0.552, p<0.0001, respectively). TIMP-1 and TIMP-2 levels correlated with the ISS stage (p<0.0001, p=0.006, respectively). The only variables that correlated with clinical bone disease staging were hemoglobin, B2M and albumin levels, whereas TIMP-1, TIMP-2, bFGF, VEGF and OPG correlated with DMV. On the univariate analyses, age, gender, proMMP2, TIMP-1, TIMP-2, creatinine, B2M and MVD were significantly associated with overall survival. In Cox regression model, TIMP-1, TIMP-2 and B2M levels remained to be significantly associated with OS. In conclusion, our results suggest that TIMP-1 and TIMP-2 levels are strongly associated with neoangiogenesis and are independent prognostic factors in MM. Disclosures No relevant conflicts of interest to declare.

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Improved Overall Survival in Myeloma Patients Treated with Regimens Including Thalidomide/Revlimid/Velcade Vs Melphalan/Prednisone; a Retrospective Analysis.

Blood ◽

10.1182/blood.v114.22.4961.4961 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4961-4961

Author(s):

Pandora Ashley ◽

Mark Holguin ◽

Juhee Song

Keyword(s):

Retrospective Analysis ◽

Conflicts Of Interest ◽

High Dose Chemotherapy ◽

Rank Test ◽

P Value ◽

High Dose ◽

Survival Times ◽

Entire Cohort ◽

Stem Cell Rescue ◽

Kaplan Meier

Abstract Abstract 4961 A retrospective study was conducted to ascertain if the use of thalidomide, revlimid and or velcade was associated with improved survival compared to melphalan and prednisone or vincristine, adriamycin and dexamethasone (VAD). To avoid possible confounding issues of treatment with high dose chemotherapy and stem cell rescue, those patients were excluded from this analysis. From 1997 to 2003, 98 patients diagnosed with myeloma and treated at Scott & White Memorial Hospital using non-transplant containing regimens were identified through the Scott & White Tumor Registry. Patients were divided into two groups based on treatment received. One group was treated with melphalan and prednisone or VAD chemotherapy (59 patients) and the second group was treated with regimens that included thalidomide, revlimid, or velcade (39 patients). Median survival times were estimated for the entire cohort and each treatment group. Kaplan-Meier estimates of the survival by treatment received were estimated and log-rank test was performed to compare the survival distributions of the two treatment groups. Five year survivals of the 2 groups were compared using the Z test. Median follow-up time for the entire cohort is 32.6 months (95% CI: 24.4-37.6) Median survivals are 38.7 months (95% CI 32.7-58.5) for the thalidomide/revlimid/velcade group and 24.4 months (95% CI: 14.4-35.7) for the melphalan and prednisone or VAD group. Five year Kaplan-Meier survival estimates are 0.3452 (95% CI: 0.2007-0.4945) for the thalidomide/revlimid/velcade group and 0.1325 (95% CI: 0.0593-0.2354) for the melphalan and prednisone or VAD group. The difference in survival between the two groups is statistically significant with p value of 0.0179. In this retrospective analysis, treatment with newer agents such as thalidomide, revlimid or velcade is associated with a significant improvement in survival compared to melphalan and prednisone or VAD. Disclosures No relevant conflicts of interest to declare.

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A Better Mobilization Regimen for Newly Diagnosed Multiple Myeloma Patients,

Blood ◽

10.1182/blood.v118.21.4051.4051 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4051-4051

Author(s):

Ahmed Y Abuabdou ◽

Eric R Rosenbaum ◽

Saad Usmani ◽

Bart Barlogie ◽

Michele Cottler-Fox

Keyword(s):

Multiple Myeloma ◽

Conflicts Of Interest ◽

Optimal Number ◽

P Value ◽

Newly Diagnosed ◽

The Poor ◽

Cd34 Cells ◽

Significant Difference ◽

Minimum Number ◽

Poor Mobilizer

Abstract Abstract 4051 Introduction: What constitutes an acceptable mobilization regimen for collecting CD34+ cells depends on whether the goal of collection is to obtain a minimum number versus optimal number of cells. When treating patients with high-risk myeloma it may be important to obtain an optimal number. Here we compare retrospectively our earlier mobilization regimen, VTD-PACE, with MVTD-PACE in newly diagnosed, previously untreated multiple myeloma patients. Materials and Methods : We reviewed data for all patients who collected hematopoietic progenitor cells on Total Therapy protocols TT3a/TT3b with VTD-PACE (n=394) from February 2004 to September 2008 (138 females and 256 males, median age 59y; range 31–75), and on TT4/TT5 with MVTD-PACE (n=188) from August 2008 to May 2011 (78 females and 110 males, median age 61y, range 30–76). Based on their predicted first day collection with a large volume leukapheresis (30L processed), using our center's predictive formula (Blood 2010; 116(21):1182a), patients were stratified into 4 mobilizer types: poor (<2×106 CD34+ cells/kg), intermediate (≥2 to 10×106), good (>10 to 20×106) and excellent (>20×106). Variables examined included number of CD34+ cells/μl blood on day 1 and day 2 of collection (we have a minimum 2 day collection requirement), number of collection days to reach our minimum goal of 20×106 CD34+ cells/kg, and total CD34+ cells/kg collected for both chemotherapy groups. Variables for both groups stratified by mobilizer type were compared using two-tailed student's t-tests, except for the poor mobilizer group, where population size was too small for formal statistical analyses (VTD-PACE n=7, MVTD-PACE n=4), although averages were calculated. Results : There was no significant difference between VTD-PACE and MVTD-PACE for CD34+ cells/μl blood on day 1 of collection among the excellent [mean 368.9 (n=184) vs. 434.6 x106 (n=92); p-value 0.07], good [mean 138.6 (n=102) vs. 128.6 x106 (n=40); p-value 0.19], and intermediate [mean 60.1 (n=100) vs. 55.9 x106 (n=52); p-value 0.39] groups. A statistically significant difference between VTD-PACE and MVTD-PACE was found for CD34+ cells/μl blood on day 2 of collection for excellent mobilizers [mean 333.8 (n=184) vs. 460 ×106 (n=92); p-value <0.001], but not for the good [mean 165.7 (n=102) vs. 189.5×106 (n=40); p-value 0.21] and intermediate [mean 80.1 (n=101) vs. 102.3 ×106 (n=52); p-value 0.07] groups. When CD34+ cell/kg collection totals with VTD-PACE and MVTD-PACE were compared, a significant difference was seen for the intermediate mobilizer group only [mean 23.6 (n=101) vs. 26.3 ×106 (n=52); p-value 0.03]. For the poor mobilizer group, VTD-PACE had an average CD34+ cells/μl blood of 13.5×106 for day 1 of collection and 17.0 ×106 for day 2, with a total of 14.5×106 CD34+cells/kg collected; while MVTD-PACE had an average of 13.2×106 CD34+ cells/μl blood for day 1 of collection, 24.9×106 for day 2, with a total of 24.2×106CD34+ cells/kg collected. The number of collection days was similar between VTD-PACE and MVTD-PACE in the excellent mobilization group (2 days), but was slightly more for VTD-PACE compared to MVTD-PACE for the good (2.1 vs. 2 days), intermediate (3.2 vs. 2.9 days), and poor (6.1 vs. 5.8 days) groups. Conclusion : Both regimens allow more than minimum collections, but MVTD-PACE provides a higher peak number of CD34+ cells/μl blood, resulting in a slightly lower mean number of days of collection than VTD-PACE to reach an optimal collection. Disclosures: No relevant conflicts of interest to declare.

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Aberrant Expression of DOCK4 Leads to Disruption of the F-Actin Skeleton and Altered Membrane Stability in MDS Erythroblasts and Mature Erythrocytes

Blood ◽

10.1182/blood.v120.21.924.924 ◽

2012 ◽

Vol 120 (21) ◽

pp. 924-924 ◽

Cited By ~ 1

Author(s):

Sriram Sundaravel ◽

Tushar D. Bhagat ◽

Carolina Schinke ◽

David Ebenezer ◽

Hui Liu ◽

...

Keyword(s):

Actin Polymerization ◽

Conflicts Of Interest ◽

Osmotic Fragility ◽

Membrane Stability ◽

Refractory Anemia ◽

P Value ◽

Down Regulation ◽

Acute Leukemias ◽

Aberrant Expression ◽

The Impact

Abstract Abstract 924 Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic disorders that are commonly characterized by anemia due to ineffective hematopoiesis. Even though a third of patients with MDS may transform to acute leukemias, cytopenias drive morbidity for most patients. Anemia remains a major cause of morbidity from fatigue. Most of the morbidity experienced by such patients is due to low red blood counts and therefore studies on the molecular pathogenesis of dysplastic erythropoiesis leading to anemia are critically needed. We have identified DOCK4, an important cofactor for various GTPases located on the chromosome 7q segment as a novel silenced gene in MDS and show that it's down regulation leads to disruption of normal erythropoiesis. In an attempt to uncover genes aberrantly expressed in MDS, we initially performed an integrative genomic analysis of primary hematopoietic cells from MDS patients. These studies revealed that DOCK4 is significantly under-expressed and hypermethylated in MDS stem and progenitor cells. Immunohistochemcial analysis revealed significantly reduced levels of DOCK4 in MDS erythroblasts. We then evaluated DOCK4 expression in a large published cohort of MDS gene expression datasets (N=183) and found that DOCK4 expression was strikingly reduced in the subset of 55 MDS patients with refractory anemia (RA; P value = 0.006). The RA subset of patients only has isolated anemia as the clinical presentation and has no apparent abnormalities in white cells or platelets. This association strongly alludes to a role of DOCK4 down-regulation in the erythroid dysplasia and anemia seen in this disease. Inorder to elucidate the functional implications of aberrant DOCK4 expression during erythropoiesis we used a dynamic model of human erythropoiesis to determine normal expression pattern during terminal differentiation and the impact of silencing DOCK4 expression on healthy primary erythroblasts. These studies revealed that DOCK4 is highly expressed during late stages of normal erythropoiesis and knockdown of DOCK4 in primary erythroblasts disrupted the F-actin skeleton. We then examined F-actin skeletal disruption in CD34+ derived erythroblasts from MDS patients. In order to quantify the extent of actin filament disruption directly in patient derived erythroblasts we first developed an assay based on multispectral flow cytometry (ImageStream™). This assay not only allowed us to visualize individually F-actin-stained cells but also allowed us to determine the percentages of cells in a given sample that contained shorter fragmented F-actin. These experiments revealed that approximately 85% of the cells in MDS patients with -7q deletion and/or hypermethylated promoter region in the DOCK4 gene contained shorter disrupted actin compared to the healthy controls that showed only 10% of the cells with disrupted F-actin. The level of F-actin disruption in healthy samples treated with cytochalasin D, an inhibitor of actin polymerization was 90%. We then examined the membrane stability of -7q MDS erythrocytes by performing osmotic fragility assays and found that these patients possessed erythrocytes that were more fragile compared to healthy erythrocytes. Based on these results we conclude that DOCK4 is an important signaling intermediate that is instrumental in maintaining erythroblast membrane homeostasis and silencing of DOCK4 in MDS contributes to anemia. Disclosures: No relevant conflicts of interest to declare.

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