NPM-1, but Not FLT3-ITD Mutations Predict Early Blast Cell Clearance and CR Rate in Patients with Normal Karyotype AML or High-Risk Myelodysplastic Syndrome (MDS).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 805-805 ◽  
Author(s):  
Karsten Spiekermann ◽  
Annika Dufour ◽  
Gudrun Mellert ◽  
Evelin Zellmeier ◽  
Jan Braess ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Prognostic Factors ◽  
De Novo ◽  
Blast Cell ◽  
High Dose ◽  
Bone Marrow Blast ◽  
Npm1 Mutation ◽  
Free Survival ◽  
Cell Clearance ◽  
High Dose Cytarabine

Abstract Background: Mutations in the NPM1 gene represent the most frequent alterations in patients with AML and are associated with a favourable clinical outcome. Patients and Methods: We analyzed 803 patients that were treated in the AMLCG2000 study. Patients with de novo or secondary AML or high-risk myelodysplastic syndrome (MDS) were randomly assigned upfront for induction therapy containing one course with standard dose and one course with high-dose cytarabine, or two courses with high-dose cytarabine, and in the same step received postremission prolonged maintenance or busulfan/cyclophosphamide chemotherapy with autologous stem-cell transplantation. At diagnosis mutations in the NPM1 and FLT3 gene were analyzed by routine molecular techniques. Results: The median age of all patients was 60 years and the median observation time 23 months. Results of the mutations status of FLT3 (FLT3-ITD) and NPM1 were available in 761/803 (94,8 %) and 690/803 (85,9 %) patients, respectively. NPM1 and FLT3-ITD mutation were found in 352 (51,1%) and 199 (28,9%), respectively. On the basis of these two molecular markers, patients were grouped in 4 subgroups: 1. NPM1+/FLT3−, N=214 (31%), 2. NPM1+/FLT3+, N=138 (20%); 3. NPM1−/FLT3−, N=276 (40%); NPM1−/FLT3+ (9%). The CR-rates were significantly higher in NPM1+ (74,4%) than in NPM1− (55,9%) patients, but were unaffected by the FLT3-ITD status. Overall survival (OS), event-free survival (EFS) and relapse free survival (RFS) was significantly higher in NPM1 positive and FLT3-ITD negative patients. In a multivariate analysis age, WBC, the presence of the NPM1 mutation and de novo AML were independent prognostic factors for the CR-rate. The NPM1− and FLT3 mutation status, age and LDH were identified as independent prognostic factors for RFS. To further characterize the biological effects of NPM1 and FLT3 mutations, we analyzed the in vivo blast cell clearance measured by the residual bone marrow blast cells one week after the end of the first induction cycle (d+16 blasts). The percentage of patients with adequate blast cell reduction (residual bone marrow blast <10%) was significantly higher in NPM1+ patients (87,3%) compared to NPM1− (65,7%) patients. The presence of a FLT3-ITD mutation had no effect on early blast cell clearance. Conclusions: The presence of a NPM1 mutation represents an independent positive prognostic factor for the CR-rate and RFS/OS. In contrast, FLT3-ITD mutations do not affect the CR-rate, but have a negative prognostic impact on RFS and OS. The higher sensitivity of NPM1-positive blasts towards the induction therapy point to a central role of NPM1 in the regulation of apoptotic cell death in AML.

Bone marrow transplantation versus high-dose cytarabine-based consolidation chemotherapy for acute myelogenous leukemia in first remission.

1992 ◽  
Vol 10 (1) ◽  
pp. 41-46 ◽  
Author(s):  
G J Schiller ◽  
S D Nimer ◽  
M C Territo ◽  
W G Ho ◽  
R E Champlin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Disease Free Survival ◽  
High Dose ◽  
Consolidation Chemotherapy ◽  
Free Survival ◽  
High Dose Cytarabine ◽  
First Remission ◽  
Disease Free

PURPOSE Despite substantial progress in the treatment of acute myeloid leukemia (AML), fewer than 25% of patients survive free of leukemia for more than 5 years without allogeneic bone marrow transplantation (BMT). In this study we analyzed the results of one or more cycles of high-dose cytarabine-based consolidation chemotherapy as compared with allogeneic BMT in first remission. PATIENTS AND METHODS The results in 28 adult patients, aged 16 to 45 years, who underwent a closely HLA-matched BMT for AML in first remission were compared with those in 54 consecutive, age-matched, adult patients treated with one or more cycles of high-dose, cytarabine-based consolidation chemotherapy. RESULTS After a median follow-up of 4 years, the actuarial risk of leukemic relapse was considerably lower in the transplant group than in the group treated with consolidation chemotherapy (32% +/- 26% v 60% +/- 14%; P = .05). Treatment-related mortality, however, was much higher in the group treated with BMT (32% v 6%, P = .002). The actuarial disease-free survival at 5 years was not significantly different for the two groups (45% +/- 24% v 38% +/- 14%). CONCLUSIONS Our results show that BMT in first remission AML did not offer a disease-free survival advantage over intensive postremission consolidation chemotherapy. Larger studies are needed to identify patients who might benefit most from BMT.

Autologous Transplantation in De Novo Non-Promyelocytic Acute Myeloid Leukemia (AML) Patients in First Complete Remission (CR1) with Peripheral Blood Stem Cell (PBSC) Collection Following Consolidation with High-Dose Cytarabine and Etoposide: A Single Institution Experience

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4461-4461
Author(s):  
Eugene Choi ◽  
Lingyi Chen ◽  
Srikanth Nagalla ◽  
Vamshi Kaveti ◽  
Regina Mullaney ◽  
...  
Keyword(s):  
De Novo ◽  
Disease Free Survival ◽  
High Dose ◽  
Free Survival ◽  
Kaplan Meier ◽  
Cd34 Cells ◽  
High Dose Cytarabine ◽  
Lost To Follow Up ◽  
Disease Free

Abstract INTRODUCTION: Autologous PBSC transplant is an important yet evolving treatment modality for patients with AML. However, the ideal mobilization regimen from which to collect PBSC remains in question. Previous reports have indicated that highdose cytarabine with etoposide is both safe and effective in terms of successful PBSC procurement, subsequent engraftment, and disease outcome. METHODS: At our institution from 1994 to 2007, 38 consecutive patients with de novo non-promyelocytic AML in first complete remission following conventional induction chemotherapy were consolidated with high-dose cytarabine (2000mg/m2 IV q12h × 8 doses, days 1–4) and etoposide (40mg/kg IV over 96h) followed by G-CSF 5 mg/kg subcutaneously starting d14 until completion of PBSC collection. Patients underwent myeloablative therapy with busulfan (1mg/kg po q6h × 16 doses, days –7 to -4) and etoposide (60 mg/kg IV over 10h, day -3) with PBSC infusion occurring on day 0 with daily G-CSF 5 mg/kg. Data regarding stem cell yield, engraftment and patient outcome was collected retrospectively. RESULTS: The average patient age was 44 years (range 19–70). Following consolidation, at least 2×106 CD34 cells/kg were isolated from all 38 patients with a median of 9.4×106 (range 2.2–43) CD34 cells/kg over a mean of 4 collections (range 1–11). Overall, 36 of 38 (95%) remained in CR and went onto PBSC transplant (one died from infectious complications during consolidation, one relapsed before transplant). The median number of stem cells infused was 8.8×106 CD 34 cells/kg (range 2.2–47). All 36 patients engrafted with the mean number of days to neutrophil recovery (ANC>500) being 11 (range 8–17) and the mean number of days to platelet recovery (>20,000) being 12 (range 8–19). Disease-free outcomes in patients undergoing PBSC transplant while in CR1 are presented in Figure 1. The 3y overall survival in all pts was 66%, and 56% at 5y. For good-risk cytogenetic patients, 3y OS was 78% and the 5y OS was 75%. For intermediate-risk cytogenetic patients, OS was 47% and 36% at 3y and 5y respectively. Three patients with poor cytogenetics were autulogously transplanted. One patient relapsed at day 111 and expired at day 450. The second patient remains in CR at day 246. The third patient relapsed at day 104 and expired at day 322. CONCLUSION: In patients with de novo non-promyelocytic AML in CR1, consolidation with high-dose cytarabine plus etoposide is safe and provides excellent yield of PBSCs upon growth factor accelerated hematological recovery. Subsequent engraftment after autologous transplanation is rapid. Our outcomes support the viability of this regimen in patients with good and intermediate-risk cytogenetics. Figure 1: Kaplan-Meier analysis of disease-free survival following autologous PBSC transplant. Cytogenetic analysis was unavailable in 5 patients, and 1 patient was lost to follow-up. Figure 1:. Kaplan-Meier analysis of disease-free survival following autologous PBSC transplant. Cytogenetic analysis was unavailable in 5 patients, and 1 patient was lost to follow-up.

Results in Children and Adolescents Treated According to Study AML-BFM 98: Less Toxic Deaths in the Short-Cycle Arm Than in the 6-Week Consolidation Arm.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 274-274
Author(s):  
Ursula Creutzig ◽  
Reinhardt Dirk ◽  
Joerg Ritter ◽  
Norbert Graf ◽  
Johannes Herrmann ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
De Novo ◽  
Disease Free Survival ◽  
Early Death ◽  
Initial Therapy ◽  
High Dose ◽  
Chemotherapeutic Regimen ◽  
Free Survival ◽  
Short Cycle ◽  
High Dose Cytarabine

Abstract Study AML-BFM 98 aimed to improve prognosis by intensification and optimization of the initial therapy elements. Between 7/1998 and 6/2003, 473 children and adolescents < 18 years with de novo AML entered the multicenter AML-BFM 98 trial. Treatment was based on the results of study AML-BFM 93 and was similar in standard risk (SR) and high-risk (HR) patients (definition for SR [n=192]: FABM1/M2 with Auer rods, M4eo with ≤ 5 % blasts in the day-15 bone marrow, all patients with M3; HR: all others [n=281]). Treatment: After induction with AIE (cytarabine, idarubicin and etoposide) all patients (excluding FAB M3) were treated with HAM (high-dose cytarabine 3g/m2/12h x3 days and mitoxantrone 10mg/m2/day x2 days), which, in the previous study 93, was given for HR patients only. Subsequently all patients were randomly assigned to receive either the 6-week consolidation as in the previous studies or two short therapy cycles including higher doses of cytarabine but the same cumulative dose of anthracyclines. The following therapy elements, intensification with high-dose cytarabine/etoposide and maintenance, were similar in studies 93 and 98. Allogeneic stem cell transplantation from a family donor was restricted to HR patients only. Overall results: 418 of 473 (88%) patients achieved remission. Early death rate could be reduced compared to study 93: 3.2% vs.7.4%. Five-year survival, event-free survival (EFS) and disease-free survival (DFS) were 62%±3%, 49%±3% and 57%±3%, respectively. Estimated survival improved (study 93: 58%±2%, plogrank .03), pEFS and pDFS were similar to study 93 (50%±2% and 61%±2%, n.s.). Randomization results of the 6-week consolidation arm (n=191) vs. the 2-short-cycle arm (n=199) were similar (pEFS 51%±4 and 50%±4%, n.s.). However, total treatment duration was shorter (median 15 days) and morbidity was lower in the short-cycle arm (5 vs. 9 deaths in CCR). Five-year pSurvival in HR patients (surviving >.44years, median time to SCT) with or without SCT in 1. CR was similar: 69%±14% vs. 64%±4%; plogrank .35. There was no improvement of prognosis in SR patients (FAB M3 excluded) compared to the previous study 93 despite additional application of HAM (CR rate 93% vs. 89%, p(chi) .24, 5-years pEFS 62%±4% vs. 67%±4%; n.s.). Conclusion: The estimated survival is now in the range of 65%–70% for those patients who achieve remission. Results of study 98 show, that intensification of chemotherapy with HAM does not improve survival in SR patients. There is no difference in survival of HR patients receiving SCT in 1st CR compared to those with chemotherapy alone. Because improvement of prognosis can not be achieved by intensivication of therapy alone, optimizing the chemotherapeutic regimen by introducing less toxic, but similar effective therapy elements together with better supportive care strategies will reduce treatment related mortality and thereby improve survival in small steps.

Clonal Cells Detected by Conventional Cytogenetic Analysis Correlates with Bone Marrow Blast Percentage and Progression Free Survival Into Acute Leukemia In Myelodysplastic Syndromes

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2935-2935
Author(s):  
Miyoung Kim ◽  
Cha Ja She ◽  
Sang Mee Hwang ◽  
Sung-Soo Yoon ◽  
Byoung Kook Kim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Prognostic Factors ◽  
Cytogenetic Analysis ◽  
Chromosomal Abnormalities ◽  
Progression Free Survival ◽  
Bone Marrow Blast ◽  
Free Survival ◽  
Conventional Cytogenetic Analysis ◽  
Cell Percentage ◽  
Clonal Abnormalities

Abstract Abstract 2935 Introduction: Chromosomal abnormalities not only demonstrate the clonality of the disease, but also help to predict the outcome of the patients in MDS. While IPSS suggests conventional cytogenetic analysis as a standard method in detecting clonal abnormalities in MDS, FISH is widely used due to its ability to detect minor clones and to quantitate the clonal abnormalities. In this study, we compared the results of conventional cytogenetic analysis and FISH, and investigated their different prognostic impact in MDS. Materials and Methods: The study included 129 MDS patients composed of 10 RA, 5 RARS, 15 RCMD, 39 RAEB-1, 33 RAEB-2 and 5 MDS, U (WHO classification, 2001). A standard protocol was used to perform conventional cytogenetic analysis (G-banding). Interphase FISH was performed to detect any abnormalities of chromosomes 5, 7, 8, 20 and 1. The result was analyzed as per the manufacturer¡&hibar;s instructions and recorded according to ISCN (2005) criteria. Result: The incidence of −5/5q, −7/7q, +8, −20q and +1q were 13.2%, 14.0%, 19.4%, 7.0% and 7.8%, respectively. Among them, FISH detected occult abnormalities which were not detected in conventional cytogenetic analysis in 1.6%, 3.1%, 5.4%, 1.6% and 5.4%, respectively. Overall, FISH detected occult abnormalities in 18.6% of the patients (24/129), and IPSS grouping was changed in 4.9% (6/129: 1 Low to Int-1; 4 Int-1 to Int-2; 1 Int-2 to High). The abnormalities in −5/5q, −7/7q and +1q were more common with other chromosomal abnormalities, whereas the abnormalities in +8 and −20q were more common as a sole abnormality. The quantity of clonal cells for each chromosome detected in conventional cytogenetic analysis did not correlate with the quantity of clonal cells detected in FISH. The presence of clonal cells either in conventional cytogenetic analysis or in FISH did not correlate with prognostic factors included in IPSS. However, the clonal cell percentage detected in conventional cytogenetic analysis was higher in patients with >5% bone marrow blasts than those with <5% (79.1% vs. 57.9%, p=.013). The clonal cell percentage detected in FISH did not show any relationship with IPSS factors including bone marrow blast percentage. Multivariate analysis showed the presence of clonal cells in conventional cytogenetic analysis were independent prognostic factors in predicting progression free survival into acute leukemia in this patient group (p=.038). Conclusion: FISH is advantageous in identifying cryptic cytogenetic abnormalities which could be overlooked in conventional cytogenetic analysis, and can change the IPSS risk grouping in MDS patients. The quantity of clonal cells detected in conventional cytogenetic analysis correlates with bone marrow blast percentage, whereas the quantity of clonal cells detected in FISH does not. Blasts possess higher proliferating activity than maturing hematopoietic precursors, thus they are more likely to form metaphase required in conventional cytognetic analysis. In contrast, the FISH results performed on non-dividing, interphase cells might reflect the true quantity of clonality both in blasts and maturing hematopoietic precursors. The relationship between the quantity of clonal cells and bone marrow blast percentage, and the prognostic significance of the presence of clonality suggest the novel diagnostic utility of conventional cytogenetic analysis in MDS. Disclosures: No relevant conflicts of interest to declare.

Intensification of Chemotherapy Does Not Improve Prognosis of Standard Risk Patients Undergoing Therapy for Acute Myelogenous Leukemia: Results of the Pediatric Clinical Trial AML-BFM 98.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1793-1793
Author(s):  
Ursula Creutzig ◽  
Dirk Reinhardt ◽  
Joerg Ritter ◽  
Guenter Henze ◽  
Johannes Hermann ◽  
...  
Keyword(s):  
Clinical Trial ◽  
De Novo ◽  
Disease Free Survival ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Free Survival ◽  
High Dose Cytarabine ◽  
Standard Risk ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract In order to further improve survival of children undergoing therapy for acute myeloid leukemia (AML), the multicenter clinical trial AML-BFM 98 intensified chemotherapy for standard risk (SR) patients (pts.). In addition, this randomized trial prospectively evaluated whether 2 short cycles of chemotherapy resulted in better prognosis than a 6-week consolidation. Patients and Methods: Between July 1998 and June 2003, 461 pts. < 18 years with de novo AML were enrolled in the trial AML-BFM 98. The SR group consisted of 170 (37%) pts. (FABM1/M2 with Auer rods or M4eo with ≤ 5 % blasts in the day 15 bone marrow; all pts. with FAB M3). All other pts. (n=291) were considered as high-risk (HR) pts.. In contrast to trial AML-BFM 93, a 2nd induction (HAM) was included in the treatment strategy for SR pts. (excluding FAB M3) which consisted of high-dose cytarabine (3g/m/12h x3 days) and mitoxantrone (10mg/m/d x2 days). Both SR and HR pts. were then randomly assigned to receive a 6-week consolidation or two short cycles of therapy. Compared to the 6-week consolidation, the short cycles contained higher doses of cytarabine, but the same cumulative dose of anthracylines. All other therapy elements [first induction (AIE; cytarabine, idarubicin and etoposide), intensification (HAE; high dose cytarabine, etoposide), and maintenance therapy] were identical in studies 93 and 98. Results: Overall, 407 out of 461 (88%) pts. achieved remission (CR). Five-year survival, event-free survival (EFS) and disease-free survival (DFS) were 59%±3%, 49%±3% and 55%±3%, respectively. Estimated survival and pEFS were similar to those of study 93 (58%±2% and 50%±2%, p logrank .09 and .80). Analysis of SR pts. (FAB M3 excluded) showed that the additional application of HAM did not improve the prognosis of SR pts. compared to AML-BFM 93 [CR rate 92% vs. 91%, p(chi)=.78; 5-year pEFS 58%±5% vs. 66%±4%; p logrank =.24]. However, when comparing HAM in study 98 and the 2nd chemotherapy cycle in study 93, significantly more severe infections (grade 3/4) occurred with HAM. Overall treatment related mortality in CR was 4% in both HR and SR pts., which was similar to trial AML-BFM 93. In addition, the outcome of pts. randomized for the 6-week consolidation was similar to that of the short cycles (p logrank .81). However, morbidity was lower in the short cycle arm (6 vs. 11 deaths in CCR, 2 vs. 4 in SR pts.). Conclusion: Our results indicate that in SR pts. with AML, a more intensive chemotherapy consisting of HAM does not result in improved survival. Therefore, new treatment options should be considered in this patient group. At the same time, optimizing treatment using the less toxic therapy with short cycles and improvement of supportive care strategies might help to reduce treatment related mortality and improve outcome in children with AML.

Induction of Complete Remission with 5-Azacytidine in a Patient with Acute Myeloid Leukemia Refractory to Intensive Chemotherapy.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4600-4600
Author(s):  
Andrea Kuendgen ◽  
Thorsten Graef ◽  
Sabine Knipp ◽  
Barbara Hildebrandt ◽  
Akos Czibere ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Complete Remission ◽  
Low Dose ◽  
High Dose ◽  
Intensive Chemotherapy ◽  
Bone Marrow Blast ◽  
Salvage Regimen ◽  
High Dose Cytarabine ◽  
Blast Count ◽  
Acute Myeloid

Abstract Intensive chemotherapy achieves complete remission in about 75% of patients with acute myeloid leukaemia (AML). For patients refractory to intensive chemotherapy, prognosis is very poor and treatment options are limited. We report a case of AML which was refractory to induction chemotherapy as well as two salvage regimens. The patient then achieved CR through monotherapy with low-dose azacitidine. The 57-year-old patient was admitted to our hospital with a diagnosis of AML M1. A bone marrow biopsy revealed a blast count of 88%. The karyotype was 48,XX,+8,+11 [4/20]. The patient received induction chemotherapy with idarubicin, cytarabine, and etoposide (ICE). Because her disease was refractory to treatment, with a bone marrow blast count of 66%, the patient received a salvage regimen with high-dose cytarabine, mitoxantrone, and all-trans retinoic acid (A-HAM). Still, AML blasts persisted, with a blast count of 52%. The patient then received FLAMSA (fludarabine, amsacrine, and high-dose cytarabine) as a second salvage regimen, but again failed to achieve remission (medullary blast count 50%). Pancytopenia persisted over a period of approximately 3 months (WBC <100/μl, Hb and platelets transfusion-dependent). We then decided to treat her with 5-azacitidine. During the first cycle, she received additional G-CSF because of fungal pneumonia. Azacitidine was given at a dose of 100mg/m2 subcutaneously for 5 days. Treatment was tolerated without side effects. The patient responded swiftly. After the first cycle, peripheral cell counts normalized and the peripheral blast count decreased to 1%. The bone marrow blast count was 3% after 3 cycles, and <1% after 5 cycles. Peripheral blood counts dropped only slightly during treatment cycles, and the patient required no further transfusions. Cytogenetic analysis, including FISH with a centromeric probe for chromosome 8, gave normal results. With the exception of the first cycle, azacitidine was administered in an outpatient setting. After completing the fifth cycle, the patient went on to receive allogeneic stem cell transplantation. In the nineteen-seventies and -eighties, conventional (cytotoxic) dosages of 5-azacytidine showed some activity against AML, but did not achieve remission rates comparable to high-dose cytarabine. Treatment-related toxicity was considerable. Recently, low-dose azacitidine, supposedly acting as a demethylating agent, was approved for treatment of myelodysplastic syndromes in the U. S.. According to recent studies, methyltransferase inhibitors seem to achieve good response rates in patients with high-risk MDS. Cytogenetic remissions have been achieved in patients with poor risk karyotypes. Our case report confirms that 5-azacitidine can be effective in AML, even in patients who have a poor prognosis with conventional therapeutic approaches.

Efficacy and Feasibility of High-Dose Cytarabine Plus Idarubicin and Amifostine As Induction Schedule: A Prospective Observational Study of 100 AML Elderly Fit Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3621-3621
Author(s):  
Debora Capelli ◽  
Martina Chiarucci ◽  
Francesco Saraceni ◽  
Antonella Poloni ◽  
Mauro Montanari ◽  
...  
Keyword(s):  
Prospective Observational Study ◽  
Low Dose ◽  
De Novo ◽  
High Dose ◽  
Allogeneic Transplant ◽  
Free Survival ◽  
Induction Regimen ◽  
High Dose Cytarabine ◽  
De Novo Aml ◽  
Grade 3

Abstract Abstract 3621 Acute myeloid leukemia (AML) has a dismal prognosis in elderly population because of intrinsic chemoresistance and frailty of patients. High-dose Cytarabine (HiDAC) in induction therapy did not improve the CR in younger AML patients and recent guidelines discourage this approach in elderly because of high extrahematological toxicity. Amifostine showed to selectively protect normal Hemopoietic progenitors from chemotherapy and we previously successfully tested the feasibility of an induction schedule including HiDAC (3 g/m2 days 1,2,3,4,5), Idarubicin 40mg/m2 on day 3 preceeded by Amifostine (740 mg/m2). We designed a prospective observational study including the same induction schedule, aimed to evaluate the outcome (CR rate, OS and EFS) of a larger population of fit AML elderly patients. Fit patients, selected according the Multidimensional Geriatric Assessment, received 1–2 courses and underwent PBSC mobilization after consolidation. Patients who collected ≥3×10e6CD34+/kg received ASCT, while poor mobilizers were considered for alternative regimen including Allogeneic transplantation from an HLA-matched sibling, chemotherapy (CHT) or Gemtuzumab-Ozogamicin (GO). We registered 156 consecutive patients, aged >59 yrs; 56 were unfit for intensive induction chemotherapy and received only palliative care; 100 (64%) fulfilled the inclusion criteria of our protocol: 91 received the scheduled induction regimen, while 9 received a Fludarabine regimen because of reduced cardiac function. These patients were not included in the response evaluation, but were considered for the outcome (according to the ITT criteria). Patients' characteristics are shown in table 1. CR was achieved in 73.6% of patients; multivariate analysis showed secondary disease as predictive of poor response, with a 65% CR rate (RR = 2.54; 95% CI: 1–6.45; p= 0.05) vs 83% in primary disease. Induction death rate was 5% and not influenced by any prognostic factors. The median time to achieve neutrophil>500× 106/L and platelet>20,000×106/L, were 17 and 19 days (ranges of 9–29 and 3–47 respectively). The main extrahematological toxicity were grade 3–4 mucositis (13%) and hepatic toxicity (9%). We also observed 66 grade III-IV febrile neutropenia/infectious episodes. Overall 65 patients received a first consolidation course and mobilization for PBSC harvest; we observed 6 TRD, a 3% of grade 3–4 hepatic and neurological toxicity and 6% of grade 3–4 cardiac toxicity; in 4 patients we observed rapid early leukemia relapse; overall 55 patients were eligible for post-consolidation therapy. Only 24 patients achieved a succesfull PBSC mobilization and ASCT was performed in 21 (2 relapsed and died before ASCT and 1 received Allogeneic Transplant). Thirty-one patients were poor mobilizers: 3 received Allogeneic Transplant, 3 CHT, 5 stopped treatment because of persistent aplasia and 20 received low-dose GO (3 mg/m2 monthly for 3 times and every 3 months after; median: 3, range 3–6 courses). With a median follow-up of 70 months (range 24–124) 21 patients are alive (19 in continuous CR), 6 after ASCT, 13 after GO, 1 after CHT. The 8 yrs Overall Survival (OS), Disease Free Survival (DFS) and Event Free Survival (EFS) are respectively 20.4% (median: 11.4 months), 24,3% (median 8.8 months) and 17,7% (median: 8.8 months). Secondary AML and hyperleukocytosis are factors predictive of OS at the multivariate analysis. Patients with secondary disease have a 1.59 RR to die with a 9.9% 8 yrs OS vs 27.1% of patients with primary AML. Patients with WBC ≥50,000/mcl had a 2.2 RR to die with a 0% OS at 33 months vs 23.2% 8 yrs OS in patients with WBC<50,000/mcl. In conclusion our novel intensive induction regimen for fit AML patients is safe and effective both in term of CR rate and outcome. The ASCT feasibility was confirmed to be poor in this setting (21%) while GO low-dose seems to be feasible and promising. Finally our prospective study in 156 elderly AML patients describes the real-life outcome of this setting, suggesting that two thirds of AML elderly patients are fit for intensive treatment and that long term OS can be achieved in a relevant proportion of patient with de novo AML. Table 1: Patients' characteristics N (%) Gender: Male 58 Female 42 Karyotype: Favorable 5 (5.7) Intermediate 49 (56.3) Unfavorable 33 (38) De novo AML 61 Secondary AML 39 Age: <70 yrs 55 >69 yrs 45 WBC count: <50,000/mcl 89 ≥50,000/mcl 11 PS: 0–2 96 3 4 FDI 0 60 >0 40 Sorror 0–2 62 (74.7) >2 21 (25.3) Disclosures: No relevant conflicts of interest to declare.

Assessment Of The Value Of a Day 14 Bone Marrow In Newly Diagnosed AML

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5002-5002
Author(s):  
Todd Allen Yezefski ◽  
Hu Xie ◽  
Pamela S. Becker ◽  
John M. Pagel ◽  
Roland B. Walter ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Induction Therapy ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Standard Dose ◽  
Similar Proportion ◽  
High Dose ◽  
Newly Diagnosed ◽  
Resistant Disease ◽  
High Dose Cytarabine

Abstract Introduction Mangement of AML typically calls for a bone marrow aspirate 7-10 days after completion of induction therapy with standard or high-dose cytarabine (HiDAC)-containing regimens (day 14 marrow). If this marrow contains >5-10% blasts, National Comprehensive Cancer Network guidelines recommend a second course of induction therapy. However, nearly 70% of patients who have persistent blasts in a day 14 marrow do not begin reinduction within 1 week. Additionally, at least in patients given higher doses of cytarabine as part of induction therapy, blast counts often continue to decrease between days 14 and 21, and many such patients will achieve complete remission (CR) without a second induction. These findings call into question the value of a day 14 marrow. Methods Our database contained 154 patients with newly diagnosed AML or MDS with 10-19% blasts seen in our hospital from 2008-2013. Patients lived at least 21 days after receiving induction therapy with regimens containing standard-dose cytarabine (114 patients, typically given “3+7” ) or high-dose cytarabine (40 patients). The treatments were not given on protocol, thus granting physicians discretion to determine when to examine the marrow. Marrow exams performed between days 10 and 17 after starting induction were considered a “day 14 marrow.” Response was assessed at least 21 days from the start of the initial induction course. Our goals were (1) to identify pretreatment factors (described below) associated with the decision to obtain a day 14 marrow and (2) to determine the influence obtaining a day 14 marrow had on the likelihood of CR on course 1, after accounting, by multivariable logistic regression, for age, cytogenetic risk (SWOG criteria), pretreatment blast % (morphologic count in marrow; peripheral blood if no marrow available), and type of AML (de novo vs. secondary). Results 116 of 154 patients (75%) had a day 14 marrow. Patients who had and did not have a day 14 marrow were similarly-aged (average 53 in both groups), had similar pretreatment blast percentages (52% vs 47%, respectively), and had a similar proportion with de novo AML (66% vs 68%). Patients who had a day 14 marrow more often received 3+7 (79% of standard-dose cytarabine patients had a day 14 marrow vs 65% of HiDAC, p=0.06). Only 60% of patients with favorable risk cytogenetics had a day 14 marrow vs 79% of patients with intermediate or unfavorable risk (p=0.03). Considering the 3+7 group separately, only a higher pretreatment blast count predicted the likelihood of a day 14 marrow (53% with a day 14 marrow vs 38% without, p=0.02). No factors were predictive in the HiDAC group. As expected, favorable cytogenetics were associated with a higher CR rate while age, pretreatment blast %, and de novo vs secondary AML did not influence CR. After accounting for these covariates, there was no difference in the rate of CR between patients who did and did not have a day 14 marrow (66% vs 74%, p=0.61). The same was true when standard and high-dose cytarabine were analyzed separately (p=0.80 and 0.26, respectively). 18 patients with a day 14 marrow had resistant disease and received a second induction course; of these, two achieved CR. Likewise, two patients without a day 14 marrow were reinduced for resistant disease, and one entered CR. While the response to the second induction was not included in the analysis, results would not be expected to vary significantly given the CR rates with the second course. Conclusions These results suggest that while patients are more likely to have a day 14 marrow if they have intermediate- or poor-risk cytogenetics and receive 3+7, the decision to obtain a day 14 marrow does not lead to a higher CR rate. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Astarabine, a Novel Leukemia-Targeted Cytarabine Composition Allows, for the First Time, the Delivery of High Cytarabine Doses for Older or Unfit Patients with Acute Leukemia. Results of an Ongoing Phase I/IIa Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1650-1650
Author(s):  
Tsila Zuckerman ◽  
Stela Gengrinovitch ◽  
Ruth Ben-Yakar ◽  
Ron Hoffman ◽  
Israel Henig ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
De Novo ◽  
Intensive Therapy ◽  
High Dose ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Unfit Patients ◽  
Equity Ownership ◽  
High Doses

Abstract Introduction: Therapy of acute myeloid leukemia (AML) has not changed significantly during several decades. High-dose cytarabine, although used as the first-line treatment for AML since 1970s and as a second-line treatment for acute lymphoblastic leukemia (ALL), is associated with severe side effects, such as cerebellar toxicity and bone marrow suppression. Hence, while the incidence of AML increases with age, doses of cytarabine are significantly attenuated or the drug is entirely excluded from the regimen used in older adults due to its potential toxicities, particularly in individuals with hepatic or renal dysfunction. Astarabine is a new composition of cytarabine covalently bound to asparagine. It is designed to target cytarabine to leukemic blasts, thus avoiding extramedullary toxicity. Leukemic cells, which are dependent on an external source of amino acids in general and asparagine in particular, due to their high metabolic rate, have a relatively increased uptake of Astarabine. Inside the blasts, Astarabine is cleaved to cytarabine, enabling targeted killing and relative sparing of normal hematopoiesis. As such, Astarabine may serve as an ideal therapy for leukemia, particularly for delivering high doses of cytarabine to medically unfit or older adults who otherwise can be given supportive therapy only. The aim of this study was to evaluate the safety and optimal dose of Astarabine in refractory/relapsed or medically unfit patients with acute leukemia. Methods: This Phase I/IIa prospective open label study enrolled patients aged ≥18 years with relapsed/refractory or newly-diagnosed acute leukemia unfit for intensive therapy, as judged by the treating physician. The study was approved by the Rambam IRB (approval #0384-11). Patients were enrolled into 6 Astarabine escalating-dose cohorts, each composed of 3-6 patients. Treatment was administered as a 1-hour single daily infusion for 6 days. For cohorts 1-4, Astarabine doses for each infusion were 0.5g/m2, 1.5g/m2, 3g/m2 and 4.5g/m2. The doses were reduced by 50% for patients >50 years. Since dose limiting toxicity (DLT) was not reached in cohorts 1-4, the study was extended to include cohorts 5 and 6 with daily Astarabine doses of 4.5g/m2 and 6g/m2, respectively, with no dose reduction for patients >50 years old. Results: The outcome of 15 patients is reported herein. Six patients with a median age of 64 years (range 27-81) had refractory/relapsed AML, 9 patients with a median age of 80 years (range 70-90) were newly diagnosed (secondary AML - 6, de-novo AML - 2, de-novo ALL - 1) and unfit for intensive therapy. Astarabine treatment was well-tolerated. Two patients died (one from pneumonia and one from sudden death 2 weeks from end of treatment) before completing 30 days post-treatment and hence were excluded from the outcome analysis. Response to the treatment was observed in the bone marrow of 6 of the 7 newly-diagnosed patients for whom bone marrow analysis was available, 3 of whom had a continuous complete remission (CR) for 4 (ongoing), 8, and 10 months post-treatment, and 3 had a continuous partial remission (PR) for 3,7, and 7 (ongoing) months. The median overall survival (OS) of the patients with CR/PR is 7 months to date (table 1). No significant response was observed in the relapsed/refractory patients, with a median OS of 2.5 months. Twelve patients died from disease progression. Conclusions: Astarabine, a new composition of leukemia-targeted cytarabine, is safe and very well tolerated, even in patients over 80 years of age, resulting in response in 6 of 7 newly diagnosed patients with acute leukemia. To the best of our knowledge, this is the first report permitting high-dose of cytarabine, considered a cornerstone of leukemia therapy, to be given to a population of patients that heretofore did not have this option. Further dose escalation studies are currently ongoing at a cytarabine-equivalent dose of 4.5 and 6 g/m2/day. A phase II study is planned to confirm these encouraging results and define the use of Astarabine for patients otherwise unable to receive high doses of cytarabine. Disclosures Zuckerman: BioSight Ltd: Consultancy, Research Funding. Gengrinovitch:BioSight Ltd: Employment, Equity Ownership, Patents & Royalties: Inventor all of the patents. Ben-Yakar:BioSight Ltd: Consultancy, Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor of all patents.

Cell of origin, germinal center versus nongerminal center, determined by immunohistochemistry on tissue microarray, does not correlate with outcome in patients with relapsed and refractory DLBCL

Blood ◽  
2005 ◽  
Vol 106 (10) ◽  
pp. 3383-3385 ◽  
Author(s):  
Craig H. Moskowitz ◽  
Andrew D. Zelenetz ◽  
Tarun Kewalramani ◽  
Paul Hamlin ◽  
Simone Lessac-Chenen ◽  
...  
Keyword(s):  
De Novo ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Second Line ◽  
Cell Of Origin ◽  
Free Survival ◽  
Significant Difference ◽  
The Common

AbstractA number of prognostic factors affect outcome in patients with relapsed or primary refractory diffuse large B-cell lymphoma (DLBCL), including refractory disease and the second-line age-adjusted international prognostic index. In de novo DLBCL, the cell of orgin, as determined by expression microarray analysis or immunohistochemistry (IHC), predicts event-free survival (EFS). We evaluated the cell of origin, as well as other pathologic markers of outcome, on the repeat biopsy specimen of 88 transplantation-eligible patients undergoing ifosfamide, carboplatin, etoposide (ICE) second-line chemotherapy (SLT) followed by high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) to see if were they prognostic in the salvage setting. Pretreatment clinical factors were well balanced between the cohorts. There was no significant difference in response to SLT, HDT, event-free or overall survival based on the cell of origin or any of the common pathologic markers examined. The cell of origin as determined by IHC does not predict outcome in transplantation-eligible patients with relapsed or primary refractory DLBCL.

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