c-Kit (CD117) Expression Is a Poor Prognostic Factor for Relapse and Overall Survival in Patients with Newly Diagnosed AML.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4510-4510
Author(s):  
Cristina Rodriguez ◽  
Tao Jin ◽  
Rony Abou Jawde ◽  
Wael Saber ◽  
Rachid Baz ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Induction Chemotherapy ◽  
De Novo ◽  
Newly Diagnosed ◽  
Increased Risk ◽  
The Mean ◽  
Wbc Count ◽  
Risk Of Relapse

Abstract Background: C-kit (CD117), a tyrosine kinase receptor, is expressed on most myeloid blasts and is thought to be important in the pathogenesis of AML. Activation of the c-kit receptor leads to phosphorylation and activation of downstream signaling proteins which are important for cell survival and proliferation. Previous studies have demonstrated conflicting results regarding the prognostic impact of c-kit expression. This discordance is likely secondary to limitations in the current method used to measure c-kit. The aim of this study was to evaluate c-kit quantitatively using the mean fluorescent index (MFI), and determine whether this index predicted outcome in patients with newly diagnosed AML. Methods: We conducted a retrospective review of 183 patients with newly diagnosed AML treated with induction chemotherapy at the Cleveland Clinic between January 1998 and December 2005. Flow cytometry was performed on bone marrow or peripheral blood. Blasts were stained with antibodies against CD45 and c-kit (BD Biosciences San Jose, CA). CD45-stained cells without c-kit antibody were used as a negative control. Flow cytometry was performed on FACS Caliber instruments, and data were acquired using Cell Quest software. Using a CD45/orthogonal gate to isolate blasts, the MFI was calculated as the mean channel number (MCN) of the blasts/MCN autofluorescence. Known prognostic factors including: age, WBC count at diagnosis, AML etiology (de novo vs. secondary AML) and cytogenetics (as defined by CALGB criteria) were obtained. Cox proportional hazards analysis was used to identify univariate and multivariate correlates of complete remission (CR), overall survival (OS), relapse after remission, and progression-free survival (PFS). Only variables significant in the univariate setting were included in multivariate analysis. Results were summarized as the hazard ratio (HR) with 95% confidence intervals (CI). Results: All patients underwent anthracycline-based induction chemotherapy. 96 (52.5%) patients were male with a median age of 57 years (17–79). Cytogenetics were favorable in 24 patients (13.1%), intermediate in 98 (53.6%), poor in 47 (25.7%) and unknown in 14 (7.6%). AML was secondary in 52 patients (28.4%) and de novo in 131 patients (71.6%). Median WBC count at diagnosis was 10.3 k/uL [4–259 k/uL]. 139 patients (76%) achieved a CR following induction chemotherapy, and 66 patients (36.1%) relapsed after achieving CR. Median c-kit MFI was 13.1 [0–251.1]. On univariate analysis, c-kit MFI(per 50 unit increase) was associated with an increased risk of AML relapse (HR=1.33 [CI=1.01–1.74 p=.041] ), and a trend towards inferior PFS and OS, HR=1.24 (CI=.97–1.57 p=.08) and HR=1.29 (CI=.99–1.67 p=.06), respectively. On multivariate analysis, c-kit MFI correlated with worse OS (HR=1.37 [CI=1.04–1.82 p=.026]) and an increased risk of relapse (HR=1.32 [CI=1.01–1.73 p=.043]). A trend towards decreased PFS was also seen, but did not reach statistical significance (HR=1.21 [CI=.96–1.53 p=.11]). Conclusion: C-kit MFI, independently of known prognostic factors, predicts OS and risk of relapse in patients with newly diagnosed AML. Whether inhibiting c-kit in patients with AML will alter prognosis is the basis of ongoing clinical trials.

Efficacy and Safety of 5-Azacytidine Based Regimens in Old AML patients: a Retrospective Study of 29 Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4148-4148
Author(s):  
France Roszkiewicz ◽  
Berengere Gruson ◽  
Ioana Vaida ◽  
Gandhi Damaj ◽  
Bruno Royer ◽  
...  
Keyword(s):  
Overall Survival ◽  
Retrospective Study ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Complete Response ◽  
Newly Diagnosed ◽  
Overall Response ◽  
Co Morbidity ◽  
Significant Difference ◽  
Wbc Count

Abstract Abstract 4148 Background 5-azacytidine (AZA) is an hypomethylating drug. The international multicenter AZA-001 trial established that AZA significantly improves overall survival (OS) in patients with high risk myelodysplastic syndromes (MDS) compared with conventional care regimens (Fenaux, Lancet Oncol 2009). Some recent reports have raised the question of a possible efficacy of AZA in selected patients with acute myeloid leukaemia (AML). In this study we retrospectively analysed the safety and efficacy of a 7 days-schedule of AZA alone or in combination with an HDAC inhibitor, Valproic acid (VA) and with All-trans retinoic acid (ATRA) in patients with newly-diagnosed and refractory/relapsed AML not eligible for intensive chemotherapy. Patients and Methods A monocentric retrospective study from October, 2006 until March, 2009 analysed 29 patients with AML. Among these patients. There were 11 males and 18 females, median age 70,8 years (range 51,2-84,1), AML de novo in 15 patients (3 relapse) and secondary in 14 patients (2 post MPD and 12 post MDS). Median WBC count was 2,5 (range 0,7-140).109/L, 4 patients had WBC more than 10.109/L. The median rate of bone marrow blasts is 30%. 12/27 (44%) patients and 15/26 (56%) have respectively an intermediate and poor risk caryotype. Fifteen (54%) were newly-diagnosed patients, 14 (46%) were refractory/relapsed patients. Median co morbidity index (Sorror, J Clin Oncol 2007) of patients is 2 (0-7). Patients received daily AZA 75mg/m2 J1-J7, ± VA 35 to 50 mg/kg J1-J7 and ATRA 45mg/m2 J8-J28 every 4 weeks. Results 5 azacytidine was used alone for 6/29 (21%) patients and in combination with VA and ATRA for 23/29 (79%) patients. Compliance to the planned therapy was good. Average number of AZA administration was 6 days. To date a total 150 treatment-cycles with a median of 5 cycles/patient were applied (1-14). Treatment was well tolerated. Neutropenia grade3III and thrombopenia grade3III occurred respectively in 26/150 cycles (17%) and in 31/150 (20%). Infections grade3III were observed in 14/150 cycles (9,3 %). Overall response was 62% (17/29): 9 complete response (CR=31%), 3 partial response (PR=10%), 5 haematological improvement (HI=21%), There were 2 stable diseases (SD=7%). 28% of responses were obtained after 1 cycle, 56% after 3 and 89% after 4. Median overall survival (OS) was 13,2 months (0.3-26). We did not observe any significant difference on OS regarding: age, cytogenetics, de novo vs secondary AML, newly diagnosed vs refractory/relapsed patients. OS for patients with SD was similar to patients with CR, PR or HI. WBC >10.109/L before treatment was not correlated with a shorter survival (7.73 months vs 13.2 months p=0,6). Correlation was found between OS and clearance of the creatinine (p=0.005). In conclusion, AZA based regimens seems well tolerated and an effective treatment in AML, with an overall response of 62% and an OS of 13,2 months. A minimum of 4 cycles of treatment is necessary to evaluate the efficacy. OS of patients achieving CR, PR or HI is not significantly different of those with SD. Treatment should be continued until progression of the disease. Disclosures: No relevant conflicts of interest to declare.

OCT-2 Expression and OCT-2/BOB.1 Co-Expression Predict Prognosis in Patients with Newly Diagnosed Acute Myelogenous Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1486-1486
Author(s):  
Kathleen Lim ◽  
Sarah Gibson ◽  
Tao Jin ◽  
Eric Hsi ◽  
Matt Kalaycio ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Myelogenous Leukemia ◽  
Age At Diagnosis ◽  
Nuclear Staining ◽  
Newly Diagnosed ◽  
Poor Risk ◽  
Increased Risk ◽  
Acute Myelogenous ◽  
History Of ◽  
Risk Of Relapse

Abstract OCT-2 and its co-activator, BOB.1, are B-cell associated transcription factors, and are expressed in a subset of pts with acute myelogenous leukemia (AML). Pathways downstream of OCT-2 may serve as therapeutic targets. However, the prognostic significance of OCT-2 and BOB.1 expression in pts with AML is unclear. We evaluated OCT-2 and BOB.1 expression in pts with newly diagnosed AML, and the prognostic impact of expression on achievement of complete remission (CR), risk of relapse, and overall survival (OS). Methods: Between 1998–2005, adult pts with newly diagnosed AML and an available diagnostic BM biopsy performed at the Cleveland Clinic were evaluated. B5-fixed core biopsies were reviewed for areas with the highest concentration of blasts. A tissue microarray was constructed, and the cores were arrayed in duplicate. Immunohistochemistry was performed for OCT-2 (1:200 dilution; polyclonal; Santa Cruz Biotechnology) and BOB.1 (1:500 dilution, polyclonal; Santa Cruz Biotechnology) using automated stainers and heat induced epitope retrieval. Staining was scored as the percent of blasts with nuclear staining. For the purposes of dichotomous classification, nuclear staining in ≥ 10% of the blasts was considered positive. OCT-2 and BOB.1 expression were analyzed both per 10% increase, and as dichotomous variables. Cox proportional hazards analysis was used to identify univariate and multivariate risk factors. Variables included: age at diagnosis, cytogenetic (CG) risk group, gender, OCT-2 expression, BOB.1 expression, history of antecedent hematologic disorder (AHD), CD117 (c-kit) expression, and white blood count (WBC) at diagnosis. Results: One-hundred and seventy-nine pts with newly diagnosed AML were treated with induction chemotherapy, and 99 pts had evaluable BM core biopsies. The median age at diagnosis was 57 yrs (range 17–79), and 52% were male. Fourteen percent of pts had favorable CG, 54% intermediate risk, 25% unfavorable, and 7% unknown CG as defined by CALGB criteria. The median WBC at diagnosis was 10.6 k/uL (range 0.4–259.0), and 28% of pts had an AHD. Nineteen percent of pts co-expressed OCT-2 and BOB.1, 35% expressed neither OCT-2 or BOB.1, and 12% expressed BOB.1 alone. Seventy-seven percent of pts achieved a CR with induction therapy. In first CR, 16% received an allogeneic BMT, 9% received autologous BMT, and 56% received consolidation chemotherapy. The median OS for all pts was 15.5 months after diagnosis, and the median time from diagnosis to relapse was 9.4 months. On univariate analysis, pts with co-expression of OCT-2 and BOB.1 (HR 0.45, 95% CI 0.24–0.84, p=0.013) or poor risk CG had a lower CR rate. OCT-2 expression (per 10% increase) (HR 1.11, 95% CI 1.02–1.21, p=0.013), age at diagnosis (per 10 year increase), and poor risk CG were associated with a decreased PFS. Pts with co-expression of OCT-2 and BOB.1 (HR 2.25, 95% CI 1.00–5.05, p=0.049), poor risk CG, or history of an AHD had an increased risk of relapse. OCT-2 expression (per 10% increase) (HR 1.10, CI 1.01–1.20, p=0.024), age at diagnosis, or poor risk CG, were associated with a decreased OS. On multivariate analysis, age at diagnosis and CG risk group remained statistically significant prognostic factors. The co-expression of OCT-2/BOB.1 also remained prognostic for achievement of CR (HR 0.44, 0.23–0.82, p=0.010) and increased risk of relapse (HR 2.30, 1.01–5.24, p=0.047) (Table 1). In the subgroup of pts without an AHD, the risk of relapse was more striking in pts with co-expression of OCT-2 and BOB.1 (HR 3.24, 1.38–7.64, p=0.007). When OCT-2 and BOB.1 were evaluated separately, and co-expression was not included in the multivariate analysis, OCT-2 (per 10% increase), was associated with a decreased PFS (HR 1.10, 1.01–1.20, p=0.036) and a trend towards a worse OS (HR=1.10, 0.99–1.21, p=0.063) (Table 1). Conclusions: OCT-2 expression and OCT-2/BOB.1 co-expression are associated with a poor prognosis in pts with newly diagnosed AML. OCT-2 may act as a cell survival factor by mediating expression of other factors, such as BCL-2. Therefore, targeting pathways activated downstream of OCT-2, such as the anti-apoptotic gene, BCL-2; the cell surface antigen CD36; and interleukin-2 may potentially improve the prognosis of these particular pts. Table 1 Multivariate Analysis CR Risk of Relapse PFS OS OCT-2/BOB.1 Co-Expression HR.44, p=.01 HR 2.30, p=.047 OCT-2 (per 10% increase) HR 1.10, p=.036 HR=1.10, p=.06

scholarly journals Development of a Medicare Health Outcomes Survey Deficit-Accumulation Frailty Index and Its Application to Older Patients With Newly Diagnosed Multiple Myeloma

2018 ◽  
pp. 1-13 ◽  
Author(s):  
Hira S. Mian ◽  
Tanya M. Wildes ◽  
Mark A. Fiala
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Standard Deviation ◽  
Health Outcomes ◽  
Older Patients ◽  
Frailty Index ◽  
Hazard Ratio ◽  
Newly Diagnosed ◽  
Increased Risk ◽  
The Mean

Purpose To develop a frailty index using the Rockwood Accumulation of Deficits approach for the Medicare Health Outcomes Survey (MHOS) and apply it in a subset of older patients with newly diagnosed multiple myeloma. Methods Data from 2,692,361 patients without cancer, > 66 years of age, in SEER-MHOS linked databases between 1998 and 2009 were analyzed. A frailty index was constructed, resulting in a 25-item scale; cutoff values were created for individuals classified as frail. This frailty index was then applied to 305 patients with newly diagnosed myeloma in the database to predict overall survival. Results In the derivation cohort of patients without cancer, the median age was 74 years and the mean frailty index was 0.23 (standard deviation, 0.17). Among patients without cancer, each 10% increase in frailty index (approximately three to four more deficits) was associated with a 40% increased risk for death (adjusted hazard ratio, 1.397; 95% CI, 1.396 to 1.399; P < .001). In the cohort of patients with newly diagnosed myeloma, the median age was 76 years and the mean frailty index was 0.28 (standard deviation, 0.17). Each 10% increase in frailty index was associated with a 16% increased risk for death (adjusted hazard ratio, 1.159; 95% CI, 1.080 to 1.244; P < .001). Fifty-three percent of patients with multiple myeloma were considered frail. The estimated median overall survival of patients considered frail was 26.8 months, compared with 43.7 months ( P = .015) for those who were not. Conclusion The MHOS-based frailty index was prognostic for patients with multiple myeloma in predicting overall survival.

Importance of Radiotherapy in the Outcome of Patients With Primary CNS Lymphoma: An Analysis of the CHOD/BVAM Regimen Followed by Two Different Radiotherapy Treatments

2002 ◽  
Vol 20 (1) ◽  
pp. 231-236 ◽  
Author(s):  
E. M. Bessell ◽  
A. López-Guillermo ◽  
S. Villá ◽  
E. Verger ◽  
B. Nomdedeu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Performance Status ◽  
Primary Cns Lymphoma ◽  
Complete Response ◽  
Cns Lymphoma ◽  
Reduced Dose ◽  
Increased Risk ◽  
Risk Of Relapse ◽  
All Treatment

PURPOSE: To assess the effect of a reduced dose of radiotherapy (RT) in patients with primary CNS lymphoma (PCNSL) responding to the cyclophosphamide, doxorubicin, vincristine, and dexamethasone (CHOD)/carmustine, vincristine, methotrexate, and cytarabine (BVAM) regimen. PATIENTS AND METHODS: Patients received one cycle of CHOD and two of BVAM. In the first trial, all 31 patients received 45-Gy whole-brain RT (CHOD/BVAM I). In the second, with 26 patients, RT dose was reduced to 30.6 Gy if there was a complete response (CR) after chemotherapy (CHOD/BVAM II). RESULTS: Age, performance status, and chemotherapy received were similar in both protocols. CR rate at the end of all treatment was 68% for CHOD/BVAM I and 77% and for CHOD/BVAM II. Treatment modality was the only predictor of relapse, with 3-year relapse risks of 29% and 70% for CHOD/BVAM I and II, respectively. This was specifically important in the 25 patients less than 60 years old (3-year relapse risk, 25% v 83%; P = .01). The 5-year overall survival (OS) was 36%. Age (< 60 v ≥ 60 years) was the only predictor for OS in the multivariate analysis (relative risk, 2.1; 95% confidence interval, 1.4 to 2.8). RT dose was the only predictor of OS in patients younger than 60 years old who achieved CR at the end of all treatment (3-year OS, 92% v 60% for patients receiving 45 or 30.6 Gy, respectively; P = .04). CONCLUSION: Reduction of the RT dose from 45 Gy to 30.6 Gy in patients younger than 60 years old with PCNSL who achieved CR resulted in an increased risk of relapse and lower OS.

Early assessment of minimal residual disease in AML by flow cytometry during aplasia identifies patients at increased risk of relapse

Leukemia ◽  
2014 ◽  
Vol 29 (2) ◽  
pp. 377-386 ◽  
Author(s):  
T Köhnke ◽  
D Sauter ◽  
K Ringel ◽  
E Hoster ◽  
R P Laubender ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Early Assessment ◽  
Increased Risk ◽  
Minimal Residual ◽  
Risk Of Relapse

scholarly journals P14.37 Depression in patients with primary brain tumors: Relation to clinical variables and tumor characteristics

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii75-iii75
Author(s):  
F John ◽  
G R Barger ◽  
S Mittal ◽  
C Juhasz
Keyword(s):  
Overall Survival ◽  
Brain Tumors ◽  
Depressive Disorder ◽  
Malignant Glioma ◽  
Early Recognition ◽  
Antidepressant Treatment ◽  
Newly Diagnosed ◽  
Recurrent Malignant Glioma ◽  
Primary Brain Tumors ◽  
Increased Risk

Abstract BACKGROUND Patients with brain tumor have an increased risk for depressive disorder, however, the association between depression and clinical or tumor-related variables remains mostly unclear. In this study, we analyzed the relation of depression to several clinical and tumor-related characteristics in patients with primary brain tumors. MATERIAL AND METHODS Sixty patients with newly-diagnosed (n=34) or recurrent (n=26) primary brain tumors (50 gliomas, 10 meningiomas) underwent testing with the Beck Depression Inventory-II (BDI-II). Relation of BDI-II scores to clinical and tumor-related characteristics, including age, Karnofsky Performance Status (KPS) scores, presence of antiepileptic, antidepressant, or steroid treatment, as well as tumor grade, lateralization, and lobar localization, were analyzed. In a subset of recurrent malignant glioma patients, the prognostic value of BDI-II scores on overall survival was also analyzed. RESULTS The mean total BDI-II score was 10±8 (range: 0–37); while 27% of patients (n=16) had BDI-II scores indicating at least mild depressive disorder (≥13), only a portion of them (17%) was on antidepressant treatment. No BDI-II difference was found between gliomas vs. meningiomas or newly-diagnosed vs. recurrent tumors; also, no association was found with any tumor-related characteristics. Antiepileptic or steroid therapy had no association with BDI-II scores, while higher BDI-II scores were observed in patients with ongoing antidepressant therapy (15±10 vs. 8±7, p=0.017). Higher BDI-II total and somatic subscale scores correlated with lower KPS scores (r=-0.32, p=0.014 and r=-0.31, p=0.017, respectively). In recurrent malignant glioma patients (n=18), higher depression scores were associated with shorter survival (hazard ratio: 3.7; 95% confidence interval: 1.0–13.6; p=0.048). CONCLUSION Depression affected more than ¼ of patients with primary brain tumors in this single-center cohort and was independent from most clinical and tumor-related characteristics, except KPS scores. Although most of these patients have mild depression that is often overlooked without targeted screening, higher BDI-II scores may predict shorter overall survival in recurrent malignant glioma patients. These data reinforce the importance of early recognition and treatment of depressive symptoms in patients with primary brain tumors.

Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: implications for therapy

Blood ◽  
2002 ◽  
Vol 100 (4) ◽  
pp. 1168-1171 ◽  
Author(s):  
Maurizio Zangari ◽  
Eric Siegel ◽  
Bart Barlogie ◽  
Elias Anaissie ◽  
Fariba Saghafifar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Multivariate Analysis ◽  
High Risk ◽  
Doppler Ultrasonography ◽  
Standard Dose ◽  
Single Agent ◽  
Cytotoxic Chemotherapy ◽  
Newly Diagnosed ◽  
Statistical Association ◽  
Increased Risk

Ten percent of newly diagnosed myeloma patients treated with any type of chemotherapy develop deep venous thrombosis (DVT). Thalidomide has proven activity in refractory multiple myeloma (MM), and although single-agent thalidomide has minimal prothrombogenic activity, its combination with cytotoxic chemotherapy is associated with a significantly increased risk of DVT. We analyzed the incidence of DVT in 232 MM patients who received a combination of chemotherapy and thalidomide on 2 protocols that differed only by the inclusion of doxorubicin in one. DT-PACE (dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophos- phanide/etoposide) was offered to patients with preceding standard dose therapy, but no prior autotransplantation, while DCEP-T (dexamethasone/cyclophosphamide/etoposide/cisplatin/thalidomide) was administered for relapse after transplantation. If there were signs or symptoms suggestive of DVT, patients received additional investigations, including Doppler ultrasonography, followed by venography if indicated. Only patients on DT-PACE but not DCEP-T experienced an increased incidence of DVT. A statistical association between the incidence of DVT and combination chemotherapy including doxorubicin (P = .02) was observed; this association was confirmed on multivariate analysis. MM patients treated with thalidomide and doxorubicin have a high risk of developing DVT.

A Multicentre, Double-Blind, Randomized, Phase 2 Trial Comparing Pegfilgrastim with Filgrastim as an Adjunct to Chemotherapy for Acute Myeloid Leukaemia (AML).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 866-866 ◽  
Author(s):  
Alberto Bosi ◽  
Jeffrey Szer ◽  
Jeannine Kassis ◽  
Jorge Sierra ◽  
Claire Desborough ◽  
...  
Keyword(s):  
Median Time ◽  
Induction Chemotherapy ◽  
De Novo ◽  
Severe Neutropenia ◽  
Single Administration ◽  
Serious Adverse Events ◽  
Treatment Groups ◽  
Risk Of Death ◽  
Increased Risk ◽  
Significant Difference

Abstract BACKGROUND: Heil et al (Blood ‘97) demonstrated that the duration of neutropenia and its clinical consequences following induction chemotherapy for AML were significantly reduced by the addition of filgrastim, with no increased risk of death, second malignancy or relapse (ASH ‘99). A single injection of pegfilgrastim has been shown to be comparable to daily injections of filgrastim in the management of chemotherapy-induced neutropenia. The primary aim of this trial was to estimate the difference in time to recovery from severe neutropenia (SN, ANC < 0.5 x109/L) in the first induction chemotherapy cycle (Induction 1) in AML subjects treated with pegfilgrastim or filgrastim. METHODS: Subjects with de novo AML received 1 or 2 courses of induction chemotherapy (idarubicin 12mg/m2 IV days 1–3, cytarabine 100mg/m2 IV 12 hourly days 1–7 [IA 3+7]) then, if in remission, consolidation chemotherapy (cytarabine 2 [subjects < 55 years] or 3g/m2 [subjects ≥ 55 years] IV 12 hourly days 1, 3, 5). Subjects received either single administration 6μg pegfilgrastim or daily 5μg/kg filgrastim starting 24 hours after completion of chemotherapy until neutrophil recovery. Time to recovery from SN was defined as the number of days from the first day of chemotherapy until the first of two ANC consecutive values after the nadir that were ≥ 0.5 x 109/L whereas duration of SN was defined as the total number of days during the cycle with an ANC < 0.5 x 109/L. RESULTS: Of 84 subjects randomised into the study, 83 received study drug (42 pegfilgrastim, 41 filgrastim). The treatment groups were generally well balanced for demographics and baseline characteristics. The median time to recovery from SN (ANC < 0.5 x109/L) in Induction 1 was 22 days in both treatment groups (95% CI for treatment difference: −1.9, 1.9). There was also no statistically significant difference in the median duration of SN between the 2 groups (21 days pegfilgrastim, 20 days filgrastim). Subjects in the filgrastim group required a median of 16 daily injections compared to a single administration of pegfilgrastim in the second group. Median serum concentration of pegfilgrastim in Induction 1 remained above clinically relevant concentrations until 21 days after the start of chemotherapy, results that are consistent with the neutrophil-mediated clearance of pegfilgrastim. The incidence of serious adverse events was comparable between the 2 groups except for infectious complications, which were higher in the filgrastim group (5 subjects [12%] pegfilgrastim versus 9 subjects [22%] filgrastim). CONCLUSION: In the setting of the first cycle of IA 3+7 induction chemotherapy in AML patients, once per cycle administration of 6 mg pegfilgrastim or daily administration of 5mg/kg filgrastim result in similar median time to recovery to ANC ≥ 0.5 x109/L. Pegfilgrastim is safe and well tolerated in this subject population.

Myeloid Dyspoiesis as Determined by Flow Cytometry Is a More Powerful Predictor of Post-Transplant Relapse with MDS Than the Marrow Myeloblast Count.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1656-1656
Author(s):  
Denise A. Wells ◽  
Bart L. Scott ◽  
Wendy M. Leisenring ◽  
Michael R. Loken ◽  
H. Joachim Deeg
Keyword(s):  
Flow Cytometry ◽  
Hematopoietic Cell Transplantation ◽  
International Prognostic Scoring System ◽  
Initial Report ◽  
Post Transplant ◽  
Transplant Outcomes ◽  
Myeloid Antigens ◽  
Increased Risk ◽  
Good Risk ◽  
Risk Of Relapse

Abstract We showed previously that the presence of aberrant marrow myeloblasts, as determined by flow cytometry immediately pre-transplant had predictive value for post-transplant outcomes in patients undergoing hematopoietic cell transplantation (HCT) for Myelodysplastic Syndrome (MDS). The characteristics of phenotypically abnormal myeloblasts in MDS include decreased expression of CD45, presence of non-lineage lymphoid antigens including CD56, and differences in the intensity of various myeloid antigens in comparison to healthy controls. In the present study, the bone marrow aspirates of 156 patients with MDS were analyzed before HCT for the presence of abnormal myeloblasts with the aim of determining whether myeloid dyspoiesis by flow cytometry was predictive of post-transplant outcomes, specifically in patients who were considered good risk by currently accepted criteria. All patients received ”myeloablative” conditioning, which in most patients (78%) consisted of busulfan (targeted) and cyclophosphamide followed by HLA-identical related (52%), HLA-matched unrelated (39%), or alternative donor (9%) stem cell infusions. In agreement with our initial report, patients with severe flow scores (≥4) had an increased hazard of relapse (HR=2.7, 95% CI_1.1–6.3, p=0.017) in comparison to patients with normal flow scores. In addition, even among patients with less than 5% marrow myeloblasts, dyspoietic characteristics of the blasts, as assessed by flow cytometry criteria were associated with an increased hazard of relapse (HR=4.0, 95% CI 1.4–12.1, p=0.013) as compared to patients without dyspoiesis by flow. The cumulative incidence of relapse in MDS patients with flow cytometrically normal marrow myeloblasts was 11.7%, compared to 28.1% in patients with less than 5% but phenotypically aberrant myeloblasts; the latter was not different from a relapse incidence of 31.4% in patients with 5% or more abnormal marrow myeloblasts. Furthermore, patients with intermediate-1 risk disease by the International Prognostic Scoring System, who showed flow cytometric aberrancies were at significantly increased risk of relapse (HR=4.2, p=0.01) in comparison to patients with intermediate-1 risk disease and no or mild dyspoiesis by flow cytometry. Thus, the presence of dyspoietic changes was more relevant than the proportion of marrow myeloblasts in predicting the risk of relapse, suggesting that flow cytometry is a powerful tool to select high risk patients from cohorts of patients who by established criteria would be considered to have good risk MDS.

Maintenance Treatment with 5-Azacitidine for Patients with High Risk Myelodysplastic Syndr–ome (MDS) or Acute Myeloid Leukemia Following MDS (MDS-AML) in Complete Remission (CR) after Induction Chemotherapy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 223-223 ◽  
Author(s):  
Michael Grövdal ◽  
Rasheed Khan ◽  
Anni Aggerholm ◽  
Petar Antunovic ◽  
Jan Astermark ◽  
...  
Keyword(s):  
Overall Survival ◽  
Side Effects ◽  
High Risk ◽  
Induction Chemotherapy ◽  
Maintenance Treatment ◽  
Methylation Status ◽  
Induction Treatment ◽  
The Mean ◽  
Pre Treatment

Abstract Around 50% of patients with high-risk MDS or MDS-AML may enter CR after induction chemotherapy, but CR duration, as well as overall survival is usually short. To address this clinical problem the Nordic MDS Group designed a prospective multicenter phase II study, which assessed the clinical feasibility and utility of long-term maintenance treatment with azaciditine. Sixty patients with high-risk MDS (IPSS intermediate-2 or high) (n=23) or AML following a previous known MDS (n=37) were enrolled between 2004 and 2006. The mean age was 68 (54–83) and patients should not be eligible for stem cell transplantation. Induction treatment consisted of standard doses of daunorubicin and ara-C. Patients in CR received low dose azacitidine subcutaneously 5/28 days until relapse, unless unacceptable toxicity developed. Methylation status of the P15ink4b (P15), E-cadherine (CDH) and Hypermethylated in Cancer 1 (HIC) gene was analysed at study start, in CR and in some patients during follow up. Last follow up was on August 1 2008, 24 months after the last CR was reported. Twenty-four patients (40%) reached CR and 23 of these started maintenance treatment with azacitidine. The initial dose of azacitidine was 75 mg/m2 but as four of the first five enrolled patients developed grade 4 cytopenia, the starting dose was lowered to 60 mg/m2, and was allowed to be reduced to 45 or 30 mg/m2 to avoid severe cytopenias. The mean dose of azacitidine was 54.3 mg/m2. Azacitidine was well tolerated. In 52% of the cases no side effects at all were reported. The most commonly reported side effect was mild rashes at the injection site (35%). Twenty-two percent developed fever or some kind of infection, mostly mild. Myelosuppression (grade 1–3) was seen in 22% of the cases. As previously reported, the probability of reaching CR was negatively correlated to promoter hypermethylation of CDH (p=0.008) and none of the 6 patients hypermethylated on all 3 genes reached CR (p=0.03) and hence only four patients hypermethylated on other genes than P15 received demethylating therapy. The median CR duration for the azacididine treated group was 13.5 months (2–49+) and median survival time from time of inclusion in the study for the same group was 20 months (4–52+). Four of 23 patients (17%) had a CR exceeding 24 months (32–52+). The two patients hypermethylated on CDH pre-induction had CR durations of only 2 and 5 months respectively. By last follow up 3 patients were still in CR. Of 10 patients without any methylation pre-treatment, all but one maintained this pattern in CR. Of the nine patients with pre treatment methylation of at least one gene, only one remained hypermethylated in CR. This patient had a CR duration of only 5 months. One patient showed development of P15 hypermethylation in the bone marrow sampled at 12 months and relapsed at 15 months. These findings support previous reports on P15 hypermethylation as a marker for minimal residual disease (MRD) and threatening relapse. In the whole group, survival was significantly shorter in patients with CDH methylation (3 vs 9 months, p=0.005), while pre-treatment p15 methylation status did not affect CR duration or overall survival. In conclusion, we show for the first time that maintenance treatment with azacytidine is feasible and associated with a median CR duration of 13.5 months, and very mild side effects. However azacytidine does not seem to prevent relapse in the majority of patients, including those with hypermethylation pre-treatment and/or in CR. Hypermethylation of multiple genes is a strong negative factor for survival, probability of CR, and CR duration. We observe a subset of patients, 17%, with a CR duration of &gt;24 months; but no persistent pattern regarding cytogenetics, methylation or morphology could be identified in this group. The strong negative impact of E-Cadherin methylation, a gene involved in adhesion, warrants further investigation.

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