scholarly journals The Application of Decitabine in Combination with G-CSF, Low-Dose Cytarabine and Aclarubicin in AML-MRC: A Single Center Case Control Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2320-2320
Author(s):  
Hao Jiang ◽  
Jing Liu ◽  
Xiaohong Liu ◽  
Jinsong Jia ◽  
Lizhong Gong ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Small Dose ◽  
Low Dose ◽  
Conflicts Of Interest ◽  
Hematopoietic Stem ◽  
Significant Difference ◽  
Risk Patients ◽  
Baseline Characteristics ◽  
Control Study ◽  
Low Dose Cytarabine

Abstract Background: It is difficult for AML-MRC patients to achieve complete remission (CR) and these patients develop recurrence and die of either disease progression or associated complications. The CAG regimen (cytarabine, aclarubicin and G-CSF) has been widely used in treating patients with AML-MRC in Asia. Decitabine (DAC) was approved to the treatment of MDS and reported to achieve higher response rate (67%) in AML with unfavorable-risk cytogenetics. Several studies reported low dose DAC in combination with chemotherapy to treat AML. Purpose:To evaluate the clinical efficacy and safety of low-dose decitabine in combination with small-dose CAG regimen (D-CAG regimen) in the treatment of AML-MRC, compared to CAG regimen. Methods:A total of 80 patients with newly diagnosed AML-MRC from September 2015 to January 2020 in our center were included in the study. 43 cases were initially treated with G-CSF for priming, in combination with cytarabine of 10-mg/ m 2q12h for 14 days and aclarubicin of 20 mg/day for 4 days (CAG regimen) and other 37 cases were initially treated with decitabine of 20 mg/m 2 for 5 days and small-dose CAG regimen (cytarabine of 10-mg/ m 2q12h for 7 days, aclarubicin of 10 mg/day for 4 days, and G-CSF for priming (D-CAG regimen). After induction chemotherapy, the patients who achieved CR received consolidation chemotherapy or hematopoietic stem cell transplantation (HSCT). Results:Among a total of 80 patients, the median age was 55 years (18-69 years) and 32 of them were male. Baseline characteristics of patients between D-CAG group and CAG group showed no significant differences (table 1). For the overall AML-MRC patients, the MLFS rate of D-CAG group was higher than the MLFS rate of CAG group after two courses of D-CAG regimen (62.2% v. s. 48.8%, χ2 =8.727, P=0.013, bilateral). Seven patients in CAG group did not response and then received D-CAG regimen as induction therapy, and five of them achieved MLFS (5/7) and one achieved PR (1/7). Among the population with less than 9 months of AML-MRC and/or MDS history, the MLFS rate (74.1%, 20/27) of D-CAG group was statistically higher than the MLFS rate (42.9% 15/35) of CAG group (74.1% v. s. 42.9%, χ 2 =1.909, p=0.008). Compared to the CAG group, the high-risk patients classified according to SWOG criteria in D-CAG group achieved a better MLFS rate (80.0% v. s. 26.1%, χ 2 =11.392, P=0.003, bilateral). Except patients receiving HSCT, the probability of OS and LFS for patients between D-CAG group and CAG group did not show any significant difference, but among the population with less than 9 months of AML-MRC and/or MDS history, the DCAG group showed a better probability of OS than the CAG group (58.3%±18.6% v. s. 11.3%±10.3%, p=0.006). Conclusion: In conclusion, patients with AML-MRC have a poor prognosis, and might benefit from D-CAG regimen as the induction therapy. For patients with less than 9 months of AML-MRC/MDS history or with poor karyotypes, the MLFS rate for patients in D-CAG group was higher than patients in CAG group. Disclosures No relevant conflicts of interest to declare.

Treatment of AML Relapse After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Using Low-Dose Azacitidine (AZA).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3445-3445
Author(s):  
Alexandre Chiattone ◽  
Rima M Saliba ◽  
Borje S. Andersson ◽  
Sergio Giralt ◽  
Manish R Sharma ◽  
...  
Keyword(s):  
Low Dose ◽  
Conflicts Of Interest ◽  
Disease Free Survival ◽  
Control Group ◽  
Hematopoietic Stem ◽  
Dismal Prognosis ◽  
Baseline Characteristics ◽  
And Control

Abstract Abstract 3445 Background: Relapsing AML/MDS after HSCT has a dismal prognosis, with few patients achieving long-term control of the malignancy. AZA is a hypomethylating agent that is moderately active against AML/MDS, and may have beneficial immunomodulatory effects after HSCT. We have shown that a significant minority of patients with recurrent disease respond to this drug. Here, we present long-term follow-up after salvage treatment regimens that included AZA, to treat AML/MDS that recurred after HSCT. Patients and Methods: Twenty-three patients received low-dose AZA for recurrence. Decision to use AZA was based on clinical assessment of slow progression of disease and relatively slower disease ‘tempo' and relatively small AML bulk. AZA cohort preparative regimens for 1st HSCT were myeloablative in 12 cases, and of reduced intensity in 11 cases. AZA was used prior to or without a 2nd HSCT (n=17), or after a 2nd HSCT (n=6). Outcomes were compared to controls (n=18) that relapsed ≥ 8 months after HSCT, and did not receive AZA (8 months representing the median disease free survival (DFS) for AZA-treated patients). The control group included all patients that relapsed ≥ 8 months after allogeneic HSCT using myeloablative busulfan 130 mg/m2 and fludarabine 40 mg/m2 for 4 days. AZA was studied as a time dependent variable. AZA and controls had similar baseline characteristics as described in the Table, although median DFS after the first HSCT was 8 (range: 2–51) and 17 (range: 7–59) months, favoring the control group (p=0.08). AZA was administered outpatient, with good tolerance. Fatigue and nausea were commonly observed toxicities. Doses were 8 mg/m2 (n=1), 16 mg/m2 (n=3), 24 mg/m2 (n=10), 32 mg/m2 (n=5), 40 mg/m2 (n=2), and 75 mg/m2 (n=2), administered subcutaneously for 5 days, in 28–32-day cycles. Results: Median number of cycles was 4 (range, 1–44). With a median follow-up of 18 months for AZA and control patients, median survival after relapse was 17 versus 6 months, respectively for AZA and control patients. 11 (48%) AZA patients are alive, while 2 (11%) control patients are alive. Two-year overall survival (OS) for AZA and control groups was 40% and 10%, respectively. AZA and controls had similar baseline characteristics as described in the Table. Conclusion: Low-dose AZA was a well tolerated outpatient treatment that may improve survival after AML/MDS recurrence in selected cases. Major determinants of survival in this setting, however, were remission duration after HSCT, and use of a 2nd HSCT. Disclosures: No relevant conflicts of interest to declare.

Enhanced Expression of PD-1 Modulates CD4+Foxp3+ Regulatory T Cell Homeostasis during Low-Dose IL-2 Therapy in Patients with Chronic Graft-Versus-Host Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 662-662
Author(s):  
Takeru Asano ◽  
Haesook T. Kim ◽  
John Koreth ◽  
Robert J Soiffer ◽  
Yusuke Meguri ◽  
...  
Keyword(s):  
T Cells ◽  
Low Dose ◽  
Conflicts Of Interest ◽  
Self Regulation ◽  
In Vitro Proliferation ◽  
Ki 67 ◽  
Hematopoietic Stem ◽  
Treg Population ◽  
Significant Difference

Abstract CD4+Foxp3+ regulatory T cells (Treg) play a central role in the maintenance of tolerance after allogeneic hematopoietic stem cell transplantation (HSCT). We previously reported that low-dose IL-2 administration preferentially increased Treg in patients with active cGVHD and resulted in clinical improvement with only minor toxicities (NEJM 2011). In the clinical trial, IL-2 induced selective and rapid proliferation of Treg in the first week of therapy but proliferation subsequently returned to baseline levels despite continued daily administration of IL-2 (Matsuoka et al. Sci Trans Med 2013). Mechanisms that limit Treg proliferation may play an important role in Treg homeostasis as continuous high-level proliferation may increase Treg susceptibility to apoptosis resulting in overall reduction of the Treg population (Matsuoka et al. JCI 2010). To examine mechanisms for negative regulation of Treg proliferation we examined expression of Programed Death-1 (PD-1) on Treg during IL-2 therapy. Serial blood samples from 14 patients who received daily subcutaneous IL-2 (3x105-3x106IU/m2/day) for 8 weeks were studied before and at 1, 2, 4, 6, 8, 10 and 12 weeks after starting IL-2. Treg were compared to conventional CD4+Foxp3- T cells (Tcon) within individual patient samples and examined for expression of PD-1. Treg and Tcon were further divided into subpopulations by the expression of CD45RA. Before IL-2 therapy, both CD45RA+ naïve Treg and Tcon showed little expression of PD-1 (%PD-1+ cells; median 2.1%, 1.8%, respectively). However, both CD45RA- activated/memory Treg and Tcon showed significantly higher expression of PD-1 than their naïve counterparts (%PD-1+ cells: median 22%, p<0.0001; median 19%, p<0.0001, respectively) and there was no significant difference in PD-1 expression between CD45RA- Treg and Tcon. After starting IL-2, expression of PD-1 rapidly increased, mainly on the CD45RA- activated/memory Treg subpopulation and this was sustained during 8 weeks of IL-2 therapy (%PD-1+ Treg; median 38.7% at 4 weeks, p<0.002 vs baseline). In contrast, Tcon PD-1 expression did not change during IL-2 therapy. To confirm the inhibitory function of PD-1 on Treg in patients receiving IL-2, we purified Treg and Tcon by cell-sorting, labeled cells with CFSE and cultured each subset separately with or without blocking anti-PD-L1 antibody, in the presence of anti-CD3 and anti-CD28 stimulation for 4 days. Treg obtained during IL-2 therapy showed resistance to in vitro proliferation, but vigorous proliferation was regained in the presence of anti-PD-L1 mAb. In contrast the effect of PD-L1 blockade on Tcon was relatively small. These data suggest that the PD-1 selectively limits Treg proliferation during IL-2 therapy. Based on these findings, we explored the possibility of a novel immune strategy to enhance Treg expansion during low-dose IL-2 by combination with PD-1 blockade using a murine BMT model. Lethally irradiated B6D2F1 mice were transplanted with 1x106 spleen cells from the control B6 mice together with 5x106 TCD-BM from either PD-1 KO B6 or control B6 donors. Recipients were treated with 5x103 IU IL-2 or control vehicle from day 35 to 49. As expected, recipients transplanted with cells from control donors showed significantly higher expression of PD-1 on Treg than Tcon when treated with IL-2 (%PD-1+ cells; median 47.2%, 8.9%, respectively, p<0.0001) and the increase of Treg after IL-2 treatment was more evident in recipients transplanted from PD-1 KO donors (p<0.05). To examine this clinically, we tested whether anti-PD-1 mAb can boost Treg proliferation during IL-2 administration and we confirmed that IL-2 induced Treg proliferation was significantly enhanced with the combined use of anti-PD-1 antibody (%Ki-67 + cells; median 22.9% vs 33.2%, p<0.05). In conclusion, these findings indicate that the self-regulation of Treg homeostasis through the PD-1/PD-L1 pathway can limit the expansion of Treg mediated by exogenously administered IL-2. Blockade of PD-1/PD-L1 pathway may provide an opportunity for in vivo manipulation of Treg homeostasis. Our data provide important information for developing therapeutic strategies to modulate Treg homeostasis in vivo to promote immune tolerance. Disclosures No relevant conflicts of interest to declare.

High-Dose Cyclophosphamide In Combination With G-CSF Versus G-CSF Alone For Mobilization Of Hematopoietic Stem Cells After Induction Therapy Including Velcade, Cyclophosphamide and Dexacort

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5369-5369
Author(s):  
Noam Benyamini ◽  
Irit Avivi ◽  
Eldad J Dann ◽  
Tsila Zuckerman ◽  
Lavi Noa ◽  
...  
Keyword(s):  
Stem Cell ◽  
Induction Therapy ◽  
Conflicts Of Interest ◽  
Young Patients ◽  
High Dose ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Significant Difference ◽  
The Difference

Abstract Introduction Even in the era of novel agents, high-dose chemotherapy followed by autologous stem cell transplant (ASCT) is considered to be an essential part of treatment for young patients with multiple myeloma (MM), providing durable responses. Currently, VCD (velcade, cyclophosphamide and dexacort) is one of the most commonly employed induction regimens. High-dose cyclophosphamide (HDC), often used in stem cell (SC) mobilization in conjunction with G-CSF, is associated with adverse events and only modest efficacy against myeloma. An alternative mobilization regimen, using G-SCF alone, has been recently suggested to provide adequate SC collection with less toxicity. Nevertheless, the efficacy and safety of using G-SCF alone after VCD induction have not been fully explored. The current study compares the safety and efficacy of mobilization using HDC-G-CSF versus G-CSF alone in MM patients treated with VCD as induction therapy. Methods The study was approved by the Institutional Review Board of the Rambam Medical Center (Approval # 0110-13 RMB). Data on all consecutive newly diagnosed transplant-eligible MM patients, treated with VCD between 2009 and 2012, were retrospectively reviewed. Eligibility criteria were: VCD induction followed by SC mobilization, either with G-CSF or HDC-G-CSF, with subsequent high-dose melphalan (200 mg/m2) and ASCT. The mobilization protocol was chosen at the discretion of the treating physician. Evaluated data included patient characteristics, SC collection and engraftment related parameters. For statistical analysis, Mann-Whitney non-parametric test for 2 independent groups was used. Results 79 patients were included: 50 mobilized with HDC-G-CSF, and 29 with G-CSF alone. There were no statistically significant differences in terms of patient demographic and MM-related characteristics (MM type, ISS, number of VCD cycles, and disease status at the end of induction) between the 2 cohorts. The first day of SC collection yielded a median of 14.6x106 (range 1.9 -10.1) vs 5.3x106 CD34 cells/Kg (range 0.6-37.7) in the HDC-G-CSF vs the G-CSF groups (p=<0.001). A significantly higher total CD34 collection was obtained in the HDC-G-CSF treated patients (15.9 x 106 vs 8.1x106 CD34 cells/Kg, respectively, P<0.001). Additionally, a bivariate analysis showed that male gender and platelet count (>150,000/mL) prior to mobilization had a significant impact on the outcome of SC collection. The percentage of patients needing more than one day of leukopheresis following HDC-G-CSF and G-CSF was 42% and 83%, respectively. During treatment and mobilization, 20% of patients in the HDC-G-CSF cohort were hospitalized due to neutropenic fever, while none of the patients from the G-CSF group required hospitalization (P<0.011). In all patients apart from one (G-CSF group), at least the minimum of CD34 cells/Kg required to perform a transplant (2x106 CD34 cells/Kg) was collected. Moreover, most patients succeeded in collecting >5x106 CD34 cells/Kg (96% and 93.1% in HDC-G-CSF and G-CSF groups, respectively). Notably, the difference between the groups achieved statistical significance only in collection of >8x106 CD34 cells/Kg (88% and 55.2% of patients treated with HDC-G-CSF and G-CSF, respectively). The median amount of cells administered at transplantation was 7.9x106 and 4.9x106 for patients mobilized with HDC-G-CSF vs G-CSF, respectively, reflecting the difference in the total amount of collected cells. Despite the variation in the amount of transplanted cells, no significant difference in parameters of the transplant outcome was revealed between the 2 cohorts:  time to neutrophil engraftment (>500 cells/µl) at a median of 12 days in both groups and platelets engraftment (>25,000 cells/µl) at a median of 14.5 vs 13 days in the HDC-G-CSF and G-CSF groups, respectively. The length of hospitalization, approaching 17 days, did not differ between the 2 groups. Conclusions Mobilization using HDC-G-CSF results in a higher total amount of collected CD34 cells and requires less days of leukophersis. Nevertheless, G-CSF alone provides a sufficient number of SC for transplantation in almost all patients, and this approach is much safer than treatment with HDC-G-CSF. Since engraftment results are identical with the 2 mobilization methods, the use of G-CSF alone could be considered as a preferable cell mobilization protocol in patients previously exposed to VCD induction. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Ripk3 Signaling Regulates Hematopoietic Stem Cell Number and Function during Stress

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3714-3714
Author(s):  
Lei Zhang ◽  
Huacheng Luo ◽  
Jing Li ◽  
Hong-Min Ni ◽  
Mark Sellin ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Low Dose ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Low Doses ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Leukemia Development ◽  
Serial Transplantation

Background: Among all tissues, bone marrow (BM) is the most sensitive tissue to ionizing radiation (IR)-induced acute tissue damage (ATD) and chronic long-term residual damage (LT-RD). BM failure and a significant reduction in blood cells (pancytopenia) often occurs within days after exposure to IR due to the massive death of proliferative hematopoietic progenitor cells (HPCs). However, due to their quiescent cell cycle status and reduced fidelity of DNA repair feature, many hematopoietic stem cells (HSCs) cannot fully eliminate such damage and enter senescence; this results in LT-RD. Abnormal dysplastic hematopoiesis is the most common LT-RD in most victims of IR, followed by an increased risk of leukemia/lymphoma development. Thus IR exposure is an established cause of BM failure and leukemia. A significant increase in the production of inflammatory cytokines is induced by IR which contributes to the pathogenesis of both ATD and LT-RD. Such inflammatory cytokines induce the activation of Ripk3-Mlkl-mediated necroptotic signaling in HSCs. However, the role of Ripk3-Mlkl signaling in IR-induced damage has not studied. Experimental procedures: The self-renewal capacity of HSCs among Ripk3-/-, Mlkl-/- and WT mice were examined and compared by serial transplantation assay. The phenotypes of ATD and LT-RD induced by different dosages of IR were compared among Ripk3-/-, Mlkl-/- and WT mice. The mechanism by which Ripk3 signaling prevents IR-induced leukemia development was studied. Results: Ripk3-Mlkl signaling is not required for hematopoiesis during homeostatic condition. However, during serial transplantation, inactivation of such signaling prevents stress-induced loss of HSCs. Interestingly, Ripk3 signaling also induces an Mlkl-independent ROS-p38-p16-mediated senescence in HSCs. Thus Ripk3-/- HSCs showed better competitive hematopoietic ability compared to Mlkl-/- and WT HSCs during serial transplantation. A sub-lethal dosage of IR (6Gy) induces Ripk3-dependent NF-κB activation and pro-survival gene expression in HSCs, which is necessary for the survival of damaged HSCs. After 6Gy IR, although DNA damage is repaired in most HSCs within 2 days, a proportion of HSCs in WT and Mlkl-/- mice fail to fully repair the damage and undergo p53-p21-dependent senescence. However such cells in Ripk3-/- mice die from apoptosis. Thus the remaining HSCs in Ripk3-/- mice should be functionally normal, while a proportion of the remaining HSCs in Mlkl-/- and WT mice remain damaged but senescent, all as demonstrated by competitive hematopoietic reconstitution assay. Multiple low-doses of IR (1.75Gy once week × 4) induce HSC exhaustion in WT mice but not in Ripk3-/- and Mlkl-/- mice. Interestingly, almost all Ripk3-/- mice develop acute lymphoblastic leukemia within 200 days after such low dose IR, while 45% of WT and 60% of Mlkl-/- mice develop thymomas within 360 days (see Figure). Mechanistically, such low-dose IR stimulates chronic inflammatory cytokine production. Such cytokines induce Ripk3-Mlkl-mediated necroptosis in response to HSC exhaustion observed in WT mice. These cytokines also induce Ripk3-ROS-p38-p16-mediated senescence in response to impaired HSC functioning observed in both WT and Mlkl-/- mice. In Ripk3-/- mice, due to the lack of both necroptotic and senescent signaling, mutant HSCs accumulate and leukemia development is accelerated. Conclusion: Ripk3 signaling plays distinct roles in HSCs in response to different doses of IR. High-dose IR induces Ripk3-dependent NF-κB/survival signaling, which is required for the survival of HSCs which fail to repair the damage. Thus temporal inhibition of Ripk3-NF-κB signaling might help to remove the damaged HSCs thus preventing the occurrence of LT-RD. However multiple low-doses of IR induces Ripk3 activation in HSCs which represses leukemia development by inducing both ROS-p38-p16-mediated senescence and Ripk3-Mlkl-mediated necroptosis. Induced activation of Mlkl-necroptosis might help to repress leukemia development by removing damaged HSCs. Disclosures No relevant conflicts of interest to declare.

A Complex Karyotype but Not Monosomy 7 Is an Independent Prognostic Factor in Advanced Childhood MDS.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2452-2452
Author(s):  
Gudrun Gohring ◽  
Kyra Michalova ◽  
Berna Beverloo ◽  
David Betts ◽  
Jochen Harbott ◽  
...  
Keyword(s):  
Chromosome Aberrations ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Prognostic Significance ◽  
Complex Karyotype ◽  
Similar Frequency ◽  
Hematopoietic Stem ◽  
Monosomy 7 ◽  
Significant Difference ◽  
Secondary Mds

Abstract Disclosure: No relevant conflicts of interest to declare. To study the clinical significance of recurrent chromosome aberrations in childhood MDS, cytogenetic data of 394 consecutive children with refractory cytopenia (RC) (N=215), RAEB (N=141) and RAEB-T (N=38) analyzed in the regional cytogenetic reference centers and registered in the prospective study EWOG-MDS 98 between 1998 and 2005 were evaluated. At diagnosis, a karyotype could be defined in 279/394 patients (pts) (71%). No karyotype was obtained in 16% of pts with RC compared to 8% pts with RAEB and RAEB-t (p&lt;0.001). Clonal chromosome aberrations were more common in pts with advanced MDS (RAEB and RAEB-T, 61%) compared to RC (29%), and in pts with secondary (69%) compared to primary MDS (36%) (p&lt;0.001). Monosomy 7 was the most frequent aberration occurring with similar frequency in RC (47% of abnormal karyotypes) compared to advanced MDS (49%) and in primary (53%) compared to secondary (41%) MDS. In addition, aberrations typical for de novo AML such as aberrations involving 11q23 or 3q, t(6;9) and del(9q) were noted in morphologically and clinically unequivocal MDS cases. Recurrent aberrations of adult MDS like isolated del(5q), del(20q) and -Y were very uncommon indicating a different pathogenesis of these cases. In pts with advanced MDS, there was no significant difference in overall survival (OS) of pts with normal karyotype (44% ± 18) compared to pts with monosomy 7 (58% ± 19) and patients with other karyotypes (61% ± 22). However, pts with advanced MDS and a complex karyotype (defined by ≥ 3 chromosome aberrations, presence of structural aberrations and excluding clonal evolution of monosomy 7) had a shorter OS (16% ±15, p&lt;0.01). OS and event-free survival after hematopoietic stem cell transplantation (HSCT) in pts with complex karyotypes was inferior compared to that of pts with other cytogenetic aberrations (p=0.012 and 0.039, respectively). Within the group of pts with secondary MDS, complex karyotypes were found in MDS evolving from inherited bone marrow failure disorders or after radio-/ chemotherapy, but absent in familial MDS and cases evolving from acquired aplastic anemia. As shown in a multivariate Cox analysis, advanced MDS, secondary MDS, the presence of a complex karyotype and HSCT were identified as independent prognostic factors for OS. Thus, this study demonstrates the prognostic significance of cytogenetic findings in advanced childhood MDS independent of HSCT.

Clofarabine Plus Low-Dose Cytarabine Induction Followed by Consolidation with Clofarabine Plus Low-Dose Cytarabine Alternating with Decitabine as Frontline Therapy for Patients (pts) with Acute Myeloid Leukemia (AML) ≥ 60 Years (yrs).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2058-2058
Author(s):  
Sameer A Parikh ◽  
Hagop Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Elias Jabbour ◽  
Tapan Kadia ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Research Funding ◽  
Low Dose ◽  
Single Agent ◽  
Disease Free Survival ◽  
Response Rates ◽  
High Response ◽  
Multiple Drugs ◽  
Low Dose Cytarabine

Abstract Abstract 2058 Poster Board II-35 Therapy of AML for elderly pts (≥ 60 yrs) remains challenging with low response rates, short durability of responses, and high toxicity rates following conventional therapy with standard-dose ara-C/anthracycline combinations. Clofarabine is a novel deoxyadenosine nucleoside analogue with single agent activity in frontline AML for older pts with ≥ 1 unfavorable prognostic factors. We have recently reported results of a randomized study suggesting higher response rates and comparable safety profile with the combination of clofarabine plus low-dose cytarabine over clofarabine alone. We have designed the current study of clofarabine plus low-dose cytarabine induction followed by consolidation with clofarabine plus low-dose cytarabine alternating with decitabine to maintain high response rates and improve disease-free survival based on the following hypotheses: 1) to extend duration of therapy by administering lower doses of the agents; and 2) to provide multiple drugs with different mechanisms of action to decrease risk of resistance. Pts were eligible if ≥ 60 yrs of age with newly diagnosed AML. Pts were excluded for ECOG PS > 2, creatinine > 1.5 mg/dL, cardiac ejection fraction < 40%, and prior therapy with clofarabine or decitabine. Induction therapy consisted of clofarabine 20mg/m2 i.v daily × 5 days plus cytarabine 20mg s.c. twice daily × 10 days in a laminar air flow room. Responding pts could receive up to 17 courses of consolidation therapy of clofarabine plus cytarabine (over 3 and 7 days, respectively) during consolidation courses 1-2, 6-8, 12-14) alternating with decitabine 20mg/m2 i.v. daily for 5 days during courses 3-5, 9-11, and 15-17. All pts received antibiotic prophylaxis with levofloxacin, valacyclovir and itraconazole (or equivalent). Forty pts have been enrolled with a median age of 70 yrs (range 60-80) of whom 22 (55%) had secondary AML (antecedent hematologic disorder in 11 pts). Two pts had received previous azacitidine for MDS. Fourteen pts (35%) had abnormal cytogenetics of whom 10 (25%) had monosomy 5, 7, or both. Four patients (10%) had a FLT3/ITD mutation. Of the 34 pts evaluable for response, 20 (59%) achieved CR and 2 (6%) CRp for an OR rate of 65%. Only 2 pts required 2 courses to CR. The OR rate for patients with diploid versus abnormal cytogenetics was 80% vs 50%; for pts with prior MDS versus no prior MDS 76% and 50%; and 75% for patients with FLT3 mutation. The median time to CR/CRp was 38 days (range 27-103). With a median follow up of 3.5 months (range 0.7-8.1), 2 pts relapsed (CR duration of 3.3 and 4.2 months, respectively); responses are ongoing in the remainder. Three pts (9%) died during induction therapy (one during re-induction) before a response could be established. The median number of consolidation cycles received by pts in CR was 3 (range 1-5). Most toxicities were ≤ grade 2 and included nausea/vomiting, diarrhea, rash, headache and mucositis. Six pts developed grade 3 elevations in serum transaminases which resolved at the end of induction therapy. Myelosuppression and neutropenic fever were common, but prolonged myelosuppression was rare. In conclusion, clofarabine plus low-dose cytarabine achieves high response rates with a manageable toxicity profile and low induction mortality in elderly pts with previously untreated AML. Time-to-event parameters will be provided with more extensive follow up. Disclosures: Off Label Use: Clofarabine and Decitabine in AML. Kantarjian:Genzyme: Consultancy, Research Funding. Faderl:Genzyme: Consultancy, Research Funding; Eisai: Research Funding, Speakers Bureau.

Long-Term Clinical Outcome of Children with Acquired Aplastic Anemia in Brazil.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4216-4216
Author(s):  
Marlene Pereira Garanito ◽  
Vicente Odone Filho ◽  
Marcela Vieira dos Santos ◽  
Elvira Velloso ◽  
Frederico L. Dulley ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Aplastic Anemia ◽  
Immunosuppressive Therapy ◽  
Cell Transplantation ◽  
Survival Probability ◽  
Conflicts Of Interest ◽  
Time History ◽  
Hematopoietic Stem ◽  
Significant Difference

Abstract Abstract 4216 Introdution/ Backgound Acquired Aplastic Anemia (AAA) is a rare hematologic disorder characterized by pancytopenia and hypocelular bone marrow. The pathophysiology is immune mediated in most cases. Environmental exposures to drugs, viruses and toxins, are thought to trigger the aberrant immune response in some patients. However, 50 to 74 percent of cases are classified as idiopathic. The highest frequency occurs in young population (15 to 25 years) with a second peak at age of 65 to 69 years. Immunosuppressive therapy is the best treatment in children with AAA who do not have a suitable donor for allogeneic stem cell transplantation. Materials and methods We reviewed the medical records of patients diagnosed with severe (SAA) and very severe acquired aplastic anemia (vSAA) at the Department of Pediatrics, Instituto da Criança – Hospital das Clínicas, University of Sào Paulo, Brazil from December, 1992 to December, 2007. We analyzed the clinical characteristics of the patients at diagnosis and the response to immunosuppressive therapy (IST) and hematopoietic stem cell transplantation (HSCT). Results In this study, 47 patients (27 boys and 20 girls), younger than 16 years, were diagnosed with vSAA (n= 21) or SAA (n=26). The median age was 7,71 years, ranging from 0.5 to 16 years and the average time history (beginning of signs and symptoms related to the disease and diagnosis) of the disease was 4,82 months, ranging from 0,25 to 48 months. Of the 47 patients, 45 had idiopathic AAA and 2 had hepatitis-associated. The median follow-up was 6,91 years for the patients treated with IST and 3,10 years for the patients who underwent to HSCT. One patient died before any treatment. For the eight patients who underwent to allogenic HLA-matched HSCT the 5-years-survival probability was 50%. For the 38 patients treated with IST, ten of them received cyclosporine and a short course of corticosteroids (CsA/CE) and 28 received antithymocyte globulin plus cyclosporine (ATG/CSA). The 5 years survival probability was 40% and 55%, respectively (p:0,0054). According to the severity of AAA, we did not show a significant difference in survival (p:0,32). Eight patients received second treatment after 1 year and 6 months (6 ATG from different species and CsA, 1 CsA and 1 thalidomide) and the probably of survival at 5 years was 60%. Among the 18 patients who responded to IST, four relapsed (22%). Two patients developed acute myeloid leukemia at 5 and 12 years after diagnosis. Conclusion Our results both for patients undergoing HSCT, as well as patients undergoing IST are lower in comparison to other hematological centers. Probably, this discrepancy is related to the prolonged time of disease when patients are admitted to our service. Unfortunately, the difficulty of access to specialized centers for diagnosis and early treatment in our country is a reality and this fact contributes to the delay to the beginning of treatment. Disclosures: No relevant conflicts of interest to declare.

The Prohibitin 3′ Untranslated Region Polymorphisms Are Associated with AML Susceptibility.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 5038-5038
Author(s):  
Hye-Ran Kim ◽  
Myung-Geun Shin ◽  
Sun-Seog Kweon ◽  
Hee-Nam Kim ◽  
Hyeoung-Joon Kim ◽  
...  
Keyword(s):  
Untranslated Region ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Inhibitory Effects ◽  
Increased Risk ◽  
Significant Difference ◽  
Hardy Weinberg Equilibrium ◽  
Control Study ◽  
Increased Susceptibility ◽  
Subsequent Risk

Abstract Abstract 5038 The prohibitin gene, which is located on human chromosome 17q21 encodes a certain regulatory RNA molecule responsible for inhibitory effects and the respective tumor suppressor function. Common C/T and A/G polymorphisms occur at nucleotide 10701 and 10730 respectively in the 3' untranslated region (UTR) of the prohibitin gene. Recent findings indicate that presence of at least one mutant allele within the 3' UTR prohibitin gene polymorphism causes inactivation of bioactive RNA, resulting in loss of its pro-apoptotic function and subsequent risk for malignant growth. These observations led to the hypothesis that individual carrying the prohibitin T allele has increased susceptibility to acute myeloid leukemia (AML). To assess this, we carried out a case-control study of the prohibitin genotype in 381 patients with AML and 372 healthy controls. The distribution of genotypes for the prohibitin 3' UTR polymorphism in patients with AML (P=0.79) and controls (P = 0.10) were in Hardy–Weinberg equilibrium. The prohibitin 3'UTR 10701TT genotype was associated with an increased risk for AML (odds ratios (OR)=2.6; 95 percent confidence interval (CI)=1.90 to 6.19, P = 0.031). However, the prohibitin 3'UTR 10730 polymorphism was not related to AML susceptibility. Haplotype (10701T-10730A) increased risk (OR=2.11; CI=1.28-2.94) for AML. There was a significant difference in the frequency of T-allele carriers between the patients and controls (OR=1.34; CI=1.01-1.77; P=0.046). Interestingly, AML patients having 10730GG genotype had shorter overall survival rate than those with AA and AG genotypes. In conclusion, the prohibitin 3'UTR region genotyping is valuable in assessing risk of AML and estimating prognosis. Disclosures No relevant conflicts of interest to declare.

Characteristics and Outcomes of Pulmonary Embolism IN CANCER PATIENTS and IN PATIENTS without CANCER.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 5065-5065
Author(s):  
Asha Karippot ◽  
Michael Maroules ◽  
Vincent A DeBari
Keyword(s):  
Pulmonary Embolism ◽  
Cancer Patients ◽  
Conflicts Of Interest ◽  
Pulmonary Arteries ◽  
Therapeutic Interventions ◽  
Bleeding Complications ◽  
Cancer Group ◽  
Ct Angiogram ◽  
Significant Difference ◽  
Baseline Characteristics

Abstract Abstract 5065 Background Venous thromboembolism (VTE), a frequent complication in cancer and, occasionally, a harbinger of occult cancer, is one of the leading causes of death in cancer patients. VTE recurs with a three-fold greater frequency in cancer patients than in patients who do not have cancer, and requires long-term anticoagulation. There is a two-fold greater risk of bleeding complications in these patients compared to patients who do not have cancer. Because pulmonary embolism (PE) is a life-threatening sequel of VTE, we sought to evaluate the hypothesis that cancer patients suffer from extensive pulmonary embolism (involving central pulmonary artery or bilateral pulmonary arteries) and to determine if we could detect differences in two clinical outcomes, length of stay (LOS) and mortality. Patients and Methods This retrospective cohort of subjects with pulmonary embolism (PE) was developed using data beginning in January 2003 to December 2007 at a 680 bed, urban teaching hospital. The cohort of 118 patients with PE diagnosed with CT angiogram yielded 41 patients in cancer group (20 males and 21 females) and 47 (23 males and 24 females) patients in non cancer group. Other baseline characteristics gathered for the two groups included age, gender, race, co-morbidities, ambulatory status and therapeutic interventions. Criteria for being assigned to the “central PE” were a filling defect in the pulmonary arteries or the main stem. Patients who showed filling defects in both central and peripheral vessels were also assigned to the “central PE”. All other patients with filling defects in one or more peripheral vessels were assigned to the “peripheral PE” group. Results The baseline characteristics did not show significant differences between the groups. Our data demonstrated that central PE was strongly associated with the cancer group (26/41; 63.4%) compared with 15 of 47 (31.9%) in the non-cancer group (OR = 3.70; 95% CI: 1.53 to 8.95; p = 0.0051). The common cancers associated with VTE were genito–urinary (13) followed by gastro-intestinal (10), then lung and breast (6 in each group). LOS was significantly greater in the cancer group (median: 9d; IQR: 7-19d) compared to non-cancer group (median: 7d; IQR: 5-11d; p = 0.032. We detected no significant difference in overall mortality between the two groups (p = 0.11). Kaplan-Meier analysis of survival, similarly, demonstrated no significant difference (95% CI of HR: 0.62 to 3.18; p = 0.42) Conclusion Cancer patients appear to be at a higher risk for central PE and have longer stay in the hospital after diagnosis than patients without cancer. However, in this study we did not detect increased mortality over a twelve-month observation period. Disclosures No relevant conflicts of interest to declare.

Cytogenetic Evolution (CE) In Patients (pts) with Low and Intermediate Risk Myelodysplastic Syndromes (MDS) Is Associated with Poor Prognosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2941-2941
Author(s):  
Liunan Li ◽  
Elias Jabbour ◽  
Gautam Borthakur ◽  
Stefan Faderl ◽  
Tapan Kadia ◽  
...  
Keyword(s):  
Disease Progression ◽  
Cytogenetic Analysis ◽  
Conflicts Of Interest ◽  
Myelogenous Leukemia ◽  
Intermediate Risk ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Significant Difference ◽  
The Impact ◽  
Cytogenetic Evolution

Abstract Abstract 2941 Introduction: MDS is a spectrum of abnormalities in the proliferation and differentiation of hematopoietic stem cells that result in peripheral cytopenias, bone marrow dysplasia and increased risk of transformation to acute myelogenous leukemia (AML). Cytogenetic abnormalities occur in more than 50% of patients (pts) and have an impact on survival and risk of transformation to AML. CE, or acquisition of additional clonal chromosomal abnormalities, has been reported to occur in 30 to 50% of primary MDS pts. Their impact on prognosis and transformation into AML among pts with low and intermediate risk MDS is not known. In this study, we analyzed the impact of CE on prognosis in lower risk MDS. Methods: we reviewed 722 pts clinic records of low and intermediate risk MDS pts at MD Anderson Cancer Center (MDACC) from 2000–2010 and conducted a retrospective analysis of all MDS pts with at least two consecutive cytogenetic analysis (365 patients, 50.6%) and compared the cytogenetic evolution group (CE group) with the group without cytogenetic changes (no CE group). Cytogenetic analysis was performed in the Cytogenetics Laboratory at MDACC. Results: CE was detected in 200 pts (55%). Characteristics of patients with CE are: median age 65 years (23-91), IPSS int-1 79%, diploid CG 42%, excess blasts 25%. Pts with CE were more frequently female (p=0.005), and had more frequently abnormalities of chromosome 5 and 7 (p<0.001) at baseline. There were no statistically significant difference between these two groups (p>0.05) regarding age, WBC, platelet, hgb, ANC, BM blasts percent, diagnosis (RA or RAEB), and IPSS score. There were more chr.-5/-7, insufficient metaphases, and other abnormalities, but less diploid cases in CE group compared with no CE group (p<0.001). History of malignancy (p=0.001) and prior chemotherapy exposure were also associated with CE (p=0.001), but this was not as strong for radiation exposure (p=0.066). Also, more CE patients required therapy for MDS compared to no CE patients (p=0.039). Progression free survival was significantly extended in no CE patients (p=0.02). Overall survival was a longer in no CE (34.1months), compared with CE group (26.2 months), although this was not statistically significant. Conclusion: CE is more commonly observed among pts with high-risk features, and is usually associated with disease progression and resistance. Also, prior malignancy and chemotherapy exposure were associated with CE in this study. This data indicates that genomic instability has a role in disease progression in MDS. Further analysis of CE in MDS is needed. Disclosures: No relevant conflicts of interest to declare.

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