Karyotypic Instability Is Common in t(8;21) AML at Relapse.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4452-4452
Author(s):  
Tomoya Maeda ◽  
Fumiharu Yagasaki ◽  
Daisuke Okamura ◽  
Maho Ishikawa ◽  
Nobutaka Kawai ◽  
...  
Keyword(s):  
Induction Therapy ◽  
De Novo ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
High Dose ◽  
Kit Mutation ◽  
Patients Âgés ◽  
Karyotypic Instability ◽  
First Relapse ◽  
Kit D816v

Abstract The t(8;21) is one of the most frequent chromosomal translocation in acute myeloid leukemia (AML). The t(8;21) AML is commonly associated with a favorable prognosis in regard to overall survival (OS) as well as high complete remission (CR) rate. However, approximately 35–45% of patients in first CR will relapse within 5 years. In t(8;21) AML, a worse outcome has been reported in patients with a high presenting white blood cell count, expression of CD56, and activating mutation of c-Kit (D816V). The clinical outcome of t(8;21) AML in first relapse have not been clarified. Further, factors predicting the outcome of patients in first relapse have not been defined. In this study, we evaluated the clinical features, the prognostic significance of c-Kit (D816V) mutation and karyotype instability in 14 relapsed patients among 32 de novo t(8;21) AML patients treated in our institution during the period 1987 to 2006. These 32 patients’ ages ranged from 15 to 73 years (median, 46 years) and they were classified as RAEB-T (n=2), M1 (n=2) and M2 (n=28) according to the FAB classification. Another additional cytogenetic aberrations at diagnosis were loss of Y (n=5), del(9q) (n=3), del(7q) (n=1), and trisomy 4 and 6 (n=1). Of the 32 patients, 14 (44%) were treated with BHAC-DMP (behenoylcytosine arabinoside, daunorubicin, 6-mercaptopurine, and prednisolone) induction therapy and 18 (56%) were treated with induction therapy consisted of an idarubicin or daunorubicin in combination with cytarabine (200mg/m2 for 7 days). For post remission therapy, 26 (82%) were received sequential multiagent chemotherapy and 6 (18%) were received high dose cytarabine alone. All patients achieved first CR (100%), median OS and disease-free survival (DFS) was 5.1 years and 2.4 years, respectively. 14 (44%) had a relapsed and the median duration from initial diagnosis to relapse amounted to 10.5 months (range, 3.8 months to 2.4 years). Among the 14 relapsed patients treated with salvage therapy, 9 (64%) of patients achieved second CR and median OS and DFS after first relapse was 2.0 years and 1.0 year. 4 patients (12%) with c-Kit (D816V) mutation at first diagnosis relapsed within 12 months with the same mutation and died within 2.2 years. Karyotype examination at first relapse were performed in 12 patients and additional karyotypic abnormalities were found in 6 patients. Three or more complex aberrations involving del(5q), del(6q), del(7q) or del(9q) were found in all of 6 patients. Among 6 patients showing karyotypic evolution (KE), 5 achieved second CR and relapsed again shortly. Two patients with KE had c-Kit D816 mutation at diagnosis, however, c-Kit mutations of exon 17 and 8 were not detected in 4 patients with KE at diagnosis and during the course of disease. In conclusion, karyotypic instability is common in t(8;21) AML at relapse and is not associated with c-Kit mutation. Karyotypic instability may contribute to the development of refractoriness of AML to chemotherapy.

scholarly journals Prevalence and prognostic significance of KIT mutations in pediatric patients with core binding factor AML enrolled on serial pediatric cooperative trials for de novo AML

Blood ◽  
2010 ◽  
Vol 115 (12) ◽  
pp. 2372-2379 ◽  
Author(s):  
Jessica A. Pollard ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Phoenix A. Ho ◽  
Rong Zeng ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
De Novo ◽  
Mutational Analysis ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Core Binding Factor ◽  
Kit Mutation ◽  
Free Survival ◽  
Binding Factor ◽  
Pediatric Study

KIT receptor tyrosine kinase mutations are implicated as a prognostic factor in adults with core binding factor (CBF) acute myeloid leukemia (AML). However, their prevalence and prognostic significance in pediatric CBF AML is not well established. We performed KIT mutational analysis (exon 8 and exon 17) on diagnostic specimens from 203 pediatric patients with CBF AML enrolled on 4 pediatric AML protocols. KIT mutations were detected in 38 (19%) of 203 (95% CI, 14%-25%) patient samples of which 20 (52.5%) of 38 (95% CI, 36%-69%) involved exon 8, 17 (45%) of 38 (95% CI, 29%-62%) involved exon 17, and 1 (2.5%; 95% CI, 0%-14%) involved both locations. Patients with KIT mutations had a 5-year event-free survival of 55% (± 17%) compared with 59% (± 9%) for patients with wild-type KIT (P = .86). Rates of complete remission, overall survival, disease-free survival, or relapse were not significantly different for patients with or without KIT mutations. Location of the KIT mutation and analysis by cytogenetic subtype [t(8;21) vs inv(16)] also lacked prognostic significance. Our study shows that KIT mutations lack prognostic significance in a large series of pediatric patients with CBF AML. This finding, which differs from adult series and a previously published pediatric study, may reflect variations in therapeutic approaches and/or biologic heterogeneity within CBF AML. Two of 4 studies included in this analysis are registered at http://clinicaltrials.gov as NCT00002798 (CCG-2961) and NCT00070174 (COG AAML03P1).

Glutathione S-Transferases (GSTT1 and GSTM1) Genes Polymorphisms and Response and Prognosis of Chinese Patients with De Novo Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4293-4293
Author(s):  
Lin Yang ◽  
Zhijian Xiao ◽  
Jianxiang Wang ◽  
Yushu Hao
Keyword(s):  
Overall Survival ◽  
Induction Therapy ◽  
De Novo ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Chinese Patients ◽  
Lower Probability ◽  
Acute Monocytic Leukemia ◽  
Monocytic Leukemia

Abstract The GSTT1 and GSTM1 genes are polymorphic in humans, with the phenotypic absence of enzyme activity caused by a homozygous inherited deletion of the gene. A number of prior studies have reported on GST genotype and outcome of therapy for AML. In this study, we analyzed the prognostic significance of gene polymorphism of GSTT1, GSTM1 in Chinese patients with de novo AML other than M3. A total of 254 cases were entered. There are 157 males and 97 females, ranging in age from 15 to 75 years (median: 32 years). Patients were diagnosed following WHO criteria, 81 were AML with t(8;21) AML1/ETO, 54 were AML with inv(16) or t(16;16) CBF-β/MYH11, 4 were AML with 11q23 abnormalities (MLL), 1 was minimally differentiated, 3 were AML without maturation, 44 were AML with maturation, 17 were acute myelomonocytic leukemia, 42 were acute monocytic leukemia, and 8 were acute erythroid leukemia. All the patients were treated with HAD regimen (Homoharringtonine, HHT, 2.5mg/m2 intravenously on days 1 to7; Ara-c, 150 mg/m2/d continuous infusion on days 1 to 7, and DNR,45 mg/m2 intravenously on days1 to 3.) as induction therapy. Postremission therapy consisted of HA regimen (HHT and Ara-c)(course 1 and 4), DA regimen (DNR and Ara-c)(courses 2 and 5), and MA regimen (MTZ and Ara-c) or HAM (Ara-c 1g/m2,q12h, intravenously on days 1 to 4, combined with MTZ 8mg/m2, intravenously on days 5 to 7(courses 3 and 6). The multiplex PCR method was used to simultaneously amplify and analyze GSTM1,GSTT1, and β-globin from patients. 21 patients died before marrow recovery or adequate assessment of response. 165 (68.5%) achieved a CR after the first course of chemotherapy and 194 (80.5%) achieved a CR after the second course of chemotherapy. Median follow-up was 36 months (11 to 111 months). 104 patients were last known to be alive after entering the study, the other 138 patients are now decease. Twelve patients lost to follow-up are censored at the date they were last known to be alive. Median OS and median RFS was 22 months and 19 months, respectively. OS rates at 3 years and 5 years were 38.9%±3.5% and 25.2%±6.5%, respectively. RFS rates at 3 years and 5 years were 32.8%±3.9% and 22.4%±5.2%, respectively. The rate of early death after the initiation of chemotherapy was similar between the GSTT1+/ GSTM1+ group and GSTT1− / GSTM1- group. The CR rates was higher in GSTM1+ group(71.9%) than GSTM1− group(60.8%) (OR=1.882; P =0.034) after the initiation of chemotherapy, and The CR rates was higher in GSTT1+ group(82.6%) than GSTT1− group (70.75)(OR=2.204; P =0.024) after the second course of chemotherapy. Overall survival and disease-free survival of patients who achieved complete remission (CR) in GSTT1 and GSTM1 double present group(50.1%±9.6% and 43.1%±9.6% at 5 years, respectively) was better than GSTT1- and/or GSTM1- group(27.2%±4.6% and 15.7%±6.3% at 5 years, respectively) (p=0.03 and p=0.022, respectively). For patients with AML with inv(16)(p13q22) or t(16;16)(p13;q22)(CBFβ/MYH11), Overall survival was better in GSTT1+ group than GSTT1− group(69.7%±10.5% v 27.5%±13.0% at 5 years)(p=0.013). Our data showed AML patients with deletions of GSTM1 or GSTT1 or both had a lower probability to achieve CR on induction therapy as compared to patients with intact GST genes and a shorter survival.

scholarly journals Distinct clinical and biological characteristics of acute myeloid leukemia with higher expression of long noncoding RNA KIAA0125

2020 ◽  
Author(s):  
Yu-Hung Wang ◽  
Chien-Chin Lin ◽  
Chia-Lang Hsu ◽  
Sheng-Yu Hung ◽  
Chi-Yuan Yao ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Noncoding Rna ◽  
De Novo ◽  
Remission Rate ◽  
Prognostic Significance ◽  
Multivariable Analysis ◽  
Disease Free Survival ◽  
Biological Characteristics ◽  
Acute Myeloid

AbstractExpression of long non-coding RNA KIAA0125 has been incorporated in various gene expression signatures for prognostic prediction in acute myeloid leukemia (AML) patients, yet its functions and clinical significance remain unclear. This study aimed to investigate the clinical and biological characteristics of AML bearing different levels of KIAA0125. We profiled KIAA0125 expression levels in bone marrow cells from 347 de novo AML patients and found higher KIAA0125 expression was closely associated with RUNX1 mutation, but inversely correlated with t(8;21) and t(15;17) karyotypes. Among the 227 patients who received standard chemotherapy, those with higher KIAA0125 expression had a lower complete remission rate, shorter overall survival (OS) and disease-free survival (DFS) than those with lower expression. The prognostic significance was validated in both TCGA and GSE12417 cohorts. Subgroup analyses showed that higher KIAA0125 expression also predicted shorter DFS and OS in patients with normal karyotype or non-M3 AML. In multivariable analysis, higher KIAA0125 expression remained an adverse risk factor independent of age, WBC counts, karyotypes, and mutation patterns. Bioinformatics analyses revealed that higher KIAA0125 expression was associated with hematopoietic and leukemic stem cell signatures and ATP-binding cassette transporters, two predisposing factors for chemoresistance.

Outcomes in CCG-2961, a Children’s Cancer Group Phase III Trial for Untreated Acute Myeloid Leukemia (AML).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 169-169 ◽  
Author(s):  
Beverly J. Lange ◽  
Franklin O. Smith ◽  
Patricia A. Dinndorf ◽  
Carola A.S. Arndt ◽  
Dorothy R. Barnard ◽  
...  
Keyword(s):  
De Novo ◽  
Interleukin 2 ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Remission Induction ◽  
High Dose ◽  
Free Survival ◽  
Cancer Group ◽  
De Novo Aml

Abstract CCG-2961 tested an intensively timed induction therapy consisting of cytarabine (AC), etoposide, thioguanine, dexamethasone, idarubicin and daunorubicin. Patients in remission after induction were randomized to a second induction course (Arm A) or a 3-drug combination of fludarabine, AC, and idarubicin (Arm B). Course 3 for patients with related donors was bone marrow transplantation (BMT); for those without donors, high dose AC/l-asparaginase. After Course 3 patients without donors were randomized to 14 infusions of Interleukin 2 (IL2) over 18 days or follow-up. CNS prophylaxis was intrathecal AC. Eligibility included all subtypes of de novo AML except acute promyelocytic leukemia and AML in patients with Down syndrome. CCG-2961 opened in Oct.1996 and closed in Dec. 2002. The DSMC suspended the study between Oct. 1999 and May 2000 while the 2961 Committee developed supportive care policies to reduce treatment-related mortality (TRM). CCG-2961 enrolled 900 de novo patients aged 3 days to 21 years, with 495 and 405 patients accruing pre-and post suspension respectively. Remission induction rate is 88.5%. With median follow-up of 3.6 years (range: 0 – 8.1 years), event-free survival (EFS) at 3 years is 44±3% and survival (OS) 57±3%. Disease-free survival (DFS) following Course 2 Arms A and B are not different, although relapse is significantly higher in Arm A (7.3% .vs. 3.1% P=0.018) and TRM more common in Arm B (7.9% vs.4.2% P=0.059), despite 7 less days of neutropenia in Arm B (P<0.001). DFS is 65±9% for patients with a donor versus 50±5% for patients without a donor (P=0.005); respective OS, 74±8% and 66±5% (P=0.221). However, among 98 patients in CR1 with t(8;21) or inv(16) cytogenetics, outcomes in those without and with a donor were no different: DFS (61±12% vs. 72±18%, P = 0.49) and OS (78±10% vs. 77±17%, l P= 0.85). DFS with and without IL2 is 55±9% and 60±8%(P=0.606). Outcomes improved progressively over time. EFS pre- and post-suspension are 41±4% and 47±5%(P=0.038); OS, 52±5% and 63±5%(P=0.005); TRM is 17±3% pre- and 12±3% post-suspension (P=0.039). Factors predictive of inferior EFS are age >17 years, Afro-American and Hispanic ethnicity, body mass index <10th or >95th percentile for age, absence of related marrow donor, WBC > 50,000/mm3, karyotype with −7/7q, −5/5q- or > cytogenetic 5 abnormalities, FLT3/ITD, >15 % morphologic blasts on day 14 or >0.5% immunologically detectable blasts at the end of induction. CCG-2961 confirms the efficacy and high TRM of intensively timed therapy. Neither fludarabine nor IL2 increases DFS or OS, and availability of a donor does not improve outcomes in those with favorable cytogenetics.

A New Method To Evaluate the Prognostic Value of Response to Prednisone Pre-Treatment in Adult (15–60 Yrs) Patients with Acute Lymphoblastic Leukemia: Results of the GIMEMA LAL 2000 Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1829-1829 ◽  
Author(s):  
Giovanna Meloni ◽  
Simona Iacobelli ◽  
Paola Fazi ◽  
Marco Vignetti ◽  
Francesco Di Raimondo ◽  
...  
Keyword(s):  
Prognostic Value ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Reduction Rate ◽  
Disease Free Survival ◽  
Treatment Phase ◽  
High Dose ◽  
Blast Count ◽  
Pre Treatment ◽  
Wbc Count

Abstract The prognostic significance of the response to initial prednisone treatment in adult ALL has been recently emphasized. Prednisone response is usually defined on the basis of the peripheral leukemic blast count. The threshold value for the defintion as good or poor prednisone response is 1000 blasts/mmc on day 8 of prednisone pre-treatment. The drawback of this definition is the difficulty of classifying patients with less than 1000 blasts at diagnosis. In the LAL2000 GIMEMA study we therefore evaluated whether the blast reduction rate, which is not affected by the initial blast level, could be a factor with comparable prognostic value. The protocol design provided a 7-day (−6 to 0) pre-treatment phase with an escalating dose of prednisone up to 60 mg/sqm. On day 1 before starting the induction the response was assessed both according to the absolute blast count (< versus ≥ 1000/mmc) (criterion 1) and according to the blast reduction rate ≥ 75% (criterion 2) in the peripheral blood. The induction included high dose Daunorubicin; for patients in complete remission (CR) this was followed by consolidation with high dose ARA-C, chemo and radio prophylaxis of the central nervous system, and periodical reinduction over a three years maintenance period. Patients with adverse cytogenetic features [i.e. t(9;22), t(4;11), t(1;19)] who achieved a CR were treated according to the HAM protocol that included high dose ARA-C and Mitoxantrone followed by Imatinib for Ph+ ALL and by allogeneic or autologous hemopoietic stem cells transplantation for the others. Between September 2000 and December 2003 a total of 368 patients were evaluable for response to induction. The median age was 35 years (15–60) and median WBC count 15′109/L (0.3–872); 72 (20%) were T ALL and 121 (33%) had cytogenetic high risk features (104 (86%) Ph+, 4 (3%) t(4;11) and 13 (11%) t(1;19)). Eighty-seven percent of the patients were evaluable for response to steroid pre-treatment: ’responders’ were 75% according to criterion 1 (blast <1′109/L on day 0), and 80% according to criterion 2 (blast reduction rate ≤75% on day 0). The overall CR rate was 83%. The probability of response was significantly higher in prednisone responders with respect to non responders according to both criteria: 87% versus 63% (p<0.0001) according to criterion 1, 85% versus 68% (p=0.001) according to criterion 2. Also the post CR outcome was better in steroid responders, regardless of the definition. Using criterion 1, median disease-free survival (DFS) was 24 months in responders and 11 months in non responders; using criterion 2, median DFS was 23 months in responders and 12 months in non responders. Both criteria were significantly related to DFS in a multivariate analysis adjusted for cytogenetic risk and WBC count at diagnosis (>=/<50). In conclusion, our study confirms that the sensitivity to steroids is an independent prognostic factor for the outcome of adult ALL; moreover, we propose an alternative method of its evaluation with respect to the one currently used. This method has the advantage of allowing to classify all patients, regardless of the initial blasts level, and shows a comparable prognostic value.

A Double Blind Placebo-Controlled Randomized Phase III Study of High Dose Continuous Infusion Cytosine Arabinoside (araC) with or without Cloretazine® in Patients with First Relapse of Acute Myeloid Leukemia (AML).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1970-1970
Author(s):  
Francis J. Giles ◽  
Wendy Stock ◽  
Norbert Vey ◽  
Karen Seiter ◽  
Daniel J. DeAngelo ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
De Novo ◽  
Early Death ◽  
Hematologic Malignancies ◽  
Data Safety Monitoring Board ◽  
Phase Iii ◽  
High Dose ◽  
Double Blind ◽  
Phase Iii Study ◽  
First Relapse

Abstract Background: AraC is considered to be the most effective single drug in the treatment of AML. For initial treatment of AML, araC is typically administered by intravenous continuous infusion for 5–7 days at doses of 100–200 mg/m2/day, usually in combination with an anthracycline. In the relapsed setting, araC remains an option for treatment and is generally administered at higher doses either alone or in combination with other agents and in a variety of schedules. Cloretazine (VNP40101M) is a novel alkylating agent that preferentially targets the O6 position of guanine. A Phase I trial of Cloretazine with araC in advanced hematologic malignancies demonstrated significant anti-leukemic activity with minimal extramedullary toxicity (Giles et al, 2005). The purpose of the current double blind randomized Phase III study is to determine if araC with Cloretazine improves outcome in AML patients (pts) in first relapse. Methods: Eligible pts must be ≥18 years old, PS 0–2, and have AML in first relapse following a CR or CRp of 3–24 months duration. Pts are randomized using a 2:1 scheme to receive either araC 1.5 gm/m2 (d 1–3) + Cloretazine 600mg/m2 or placebo on d 2. Pts are stratified by both age and remission duration. Pts achieving CR or CRp are consolidated with araC + Cloretazine 400mg/m2, or araC + placebo according to original treatment assignment. Pts with partial response or bone marrow improvement may receive a second induction cycle. The study will accrue 420 pts, with an interim analysis for safety and efficacy at 210 pts. The primary endpoint is overall response (CR and CRp) rate. Secondary endpoints include time-to-progression, duration of response, and survival. Results: A data safety monitoring board review of the first 32 pts was performed in 12/05. Differential toxicity between the two arms was not observed. From 03/05 to 07/06, 164 pts were enrolled by 47 sites. Median age=59 yrs (range 22–83), and 52%= male. Distribution by stratum: I = 66 (<60, CR<12mos); II= 22 (<60, CR≥12mos); III= 45 (≥60, CR<12mos); IV= 31 (≥60, CR≥12mos). Blinded data are available for 110 monitored pts: 77% were de novo AML, 23% secondary AML. 107/110 pts completed the intended treatment course. The most common reported serious adverse event was infection (50%). Importantly, of 110 pts, early deaths (≤30 days from start of treatment) occurred in only 13 (12%) pts, most of which was due to infection with neutropenia, or progressive disease. Conclusions: A multi-site Phase III double-blind randomized trial for pts with AML in first relapse is feasible and demonstrates a recognized clinical need for new treatments across age and CR duration variables. The ability of pts to tolerate high-dose araC with or without Cloretazine as assessed by rate of SAE and early death is encouraging.

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&gt;500) being 11 (range 8–17) and the mean number of days to platelet recovery (&gt;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.

Chemoimmunotherapy with a Modified Hyper-CVAD and Rituximab Regimen Improves Outcome for Patients with De Novo Philadelphia Negative Precursor B-Cell Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 836-836
Author(s):  
Deborah A. Thomas ◽  
Hagop M. Kantarjian ◽  
Stefan Faderl ◽  
William G. Wierda ◽  
Jorge Cortes ◽  
...  
Keyword(s):  
B Cell ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
High Dose ◽  
Induction Phase ◽  
Liposomal Daunorubicin ◽  
Cd20 Expression

Abstract Abstract 836 The hyper-CVAD regimen is an effective frontline program for de novo adult ALL and LL [Kantarjian, JCO 18:547, 2000; Kantarjian, Cancer 101:2788, 2004, Thomas, Blood 104:1624, 2004]. Intensive chemotherapy with hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternates with high dose methotrexate (MTX) and cytarabine every 21 days for 8 courses, followed by maintenance therapy with POMP (6-mercaptopurine, MTX, VCR, prednisone). Historical CR rate was 92% with 3-year disease-free survival (DFS) rate of 38%. The regimen was modified in 1999. Induction chemotherapy was given in a protective environment owing to higher mortality in patients (pts) aged 60 years or older (17% vs 3%). Course 2 of liposomal daunorubicin and cytarabine was incorporated owing to reports suggesting benefit of early anthracycline intensification. Rituximab 375 mg/m2 (days 1 & 11 of hyper-CVAD, days 1 & 8 of methotrexate-cytarabine) was given if CD20 expression was 20% or greater due to its association with disease recurrence [Thomas, Blood 113:6330, 2009]. The maintenance phase was extended to 30 months with additional intensifications owing to late relapses after completion of POMP therapy. Newly diagnosed or primary refractory (1 course only) pts with ALL (n=204) or LL (n=27) were treated on the two sequential studies. Burkitt-type leukemia/lymphoma (BLL) and Philadelphia positive ALL were treated on alternative protocols. From May 2000 to December 2001, 69 pts were treated with modified hyper-CVAD with anthracycline intensification (9 induction-consolidation courses). Course 2 was then eliminated from the regimen (8 courses), with an additional 162 pts treated to date (pts age 30 years or less are now treated with augmented BFM). Median age was 43 yrs (range, 15–83). CD20 expression was noted in 49%. Overall CR rate of the evaluable group (n=225) was 93%; 7 pts achieved PR (LL with residual disease), five failed to respond, and 4 died during the induction phase. Three-yr CRD and OS rates were 70% and 62%, respectively after a median follow-up of 50 months (range, 2–106+). In the younger CD20 positive precursor B-cell ALL subset (n=99), rituximab improved outcome compared to historical experience with hyper-CVAD alone (n=127), with 3-yr CRD rates (75% vs 45%, p<.001) and OS rates (65% vs 38%, p<.001) approaching those of their CD20 negative counterparts. In contrast to the Burkitt experience, rituximab was not beneficial for the elderly subgroup (OS rates 28% vs 34%, p NS). Anthracycline intensification did not improve outcome. The addition of rituximab to the hyper-CVAD regimen appears to benefit the younger pts (age less than 60 yrs) with CD20 positive precursor B-cell ALL. Incorporation of rituximab and other monoclonal antibodies (e.g., ofatumumab, epratuzumab) into frontline chemotherapy regimens for ALL should be investigated systematically. Disclosures: No relevant conflicts of interest to declare.

Cytogenetic, Molecular and Clinical Features Associated with Rare CBFB-MYH11 Fusion Transcripts in Patients (Pts) with Acute Myeloid Leukemia (AML) and inv(16)/t(16;16)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2514-2514
Author(s):  
Colin G Edwards ◽  
Kati Maharry ◽  
Krzysztof Mrózek ◽  
Sebastian Schwind ◽  
Peter Paschka ◽  
...  
Keyword(s):  
De Novo ◽  
Fusion Transcript ◽  
Type A ◽  
High Dose ◽  
Type I ◽  
Consolidation Therapy ◽  
Kit Mutation ◽  
Fusion Transcripts ◽  
Cell Counts ◽  
The Impact

Abstract Abstract 2514 Approximately 8% of de novo AML pts have inv(16)(p13q22) or t(16;16)(p13;q22) [inv(16)] and this cytogenetic group is associated with high complete remission (CR) rates and a relatively favorable outcome after cytarabine/daunorubicin (ara-c/dnr)-based induction and high-dose ara-c (HiDAC) consolidation therapy. However, ∼40% of these pts still relapse. The molecular mechanisms that impact on the prognosis of inv(16) pts remain to be fully elucidated. We and others reported that presence of the mutated KIT (mutKIT) gene is associated with worse outcome, but other contributing factors may play a role. Molecularly, inv(16) results in disruption of the MYH11 gene at 16p13 and CBFB gene at 16q22, creating a CBFB-MYH11 fusion gene. Since the genomic breakpoints within CBFB and MYH11 are variable and the fusion transcripts depend on the exons fused, at least 11 different sized CBFB-MYH11 fusion transcript variants have been found. The frequency of each fusion varies, with ∼85% being type A and ∼5% each types D and E; types B, C, and F-K were reported in single cases (hereafter we refer to non-type A fusions as “rare”). To our knowledge, only one study (Schnittger et al. Leukemia 2007;21:725) has examined the biological and clinical significance of rare CBFB-MYH11 fusions in AML. Fusion type was not found to be prognostic, but the cohort included pts with therapy-related and secondary AML. Thus, further studies are warranted. Accordingly, we analyzed 149 de novo CBFB-MYH11 positive AML pts aged <60 years (y; median, 40 y; range 18–59) receiving ara-c/dnr-based induction and HiDAC consolidation therapy (Cancer and Leukemia Group B protocols 9621, 19808, 10503). Among 149 pts, 129 (87%) had type A fusion, 17 (11%) type E, 2 (1%) type D, and 1 (<1%) type I. Pts with rare fusions had lower white blood cell counts (P=.02; median, 18.9 v 27.5 ×109/L), less often skin infiltration (P=.04; 0% v 18%) and tended to have FAB subtype M4Eo less often than the type A fusion pts (P=.13; 67% v 85%). Eighteen rare and 100 type A fusion pts had at least 1.7 y follow-up and thus could be analyzed for outcome. No significant differences in CR rates (P=1.00; 94% v 92%), cumulative incidence of relapse (CIR; P=.16; 5 y rates, 30% v 47%) or overall survival (OS; P=.30; 5 y rates, 78% v 60%) were found between rare and type A fusion pts. However, a trend toward longer event-free survival (EFS) was observed for rare fusion pts compared with type A pts (P=.07; 5 y rates, 66% v 42%; Figure). In an analysis of secondary cytogenetic abnormalities (abns) we found trisomies 8, 13 and 21 were more frequent in rare fusion pts than in type A pts (P=.03; P=.07; P<.001, respectively). Of the rare fusion pts, 44% had at least one of +8, +13 or +21 compared to only 11% of the type A pts. No rare fusion transcript pt harbored +22, which was present in 24 (19%) pts with type A fusion (P=.05; Table]. Strikingly, no rare fusion pt had mutKIT compared with 29% of type A fusion pts (P=.01). Given that +22 has been associated with improved and mutKIT with worse outcome, we also assessed the impact of fusion transcript type by restricting our analysis first to pts with no +22, then to pts without mutKIT, and finally excluding both +22 and mutKIT. No significant differences in CR rates, CIR, OS or EFS were observed between the two groups. We conclude that the type of fusion transcript does not appear to affect significantly the prognosis of inv(16) pts, although a favorable trend for pts with the rare transcript exists. Type A and rare fusion pts differ with regard to distribution of accompanying genetic or cytogenetic alterations, such as KIT mutation or +22, which did not occur in any of the rare fusion pts. Further studies are required to elucidate if the rare fusion transcripts themselves created the necessary biologic conditions that exclude the concurrent presence of the genome aberrations.Table.Secondary abns in pts with rare v type A fusionsAbn type*Rare fusion (n=20†) No. pts (%)Type A fusion (n=129) No. pts (%)P‡None [sole inv(16)]8 (44)81 (63).20+220 (0)24 (19).05+85 (28)11 (9).03+215 (28)2 (2)<.001+132 (11)2 (2).07At least one +8 or +13 or +218 (44)14 (11).001del(7q)/add(7q)0 (0)7 (5).60Other2 (11)11 (9).66*Pts may have multiple secondary abns.†2 unknown.‡Fisher's exact test. Disclosures: No relevant conflicts of interest to declare.

Mantle cell lymphoma (MCL): Induction therapy with HyperCVAD/High-dose methotrexate and cytarabine (M-C) (±rituximab) improves results of autologous stem cell transplant in first remission

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7511-7511 ◽  
Author(s):  
J. Vose ◽  
F. Loberiza ◽  
P. Bierman ◽  
G. Bociek ◽  
J. Armitage
Keyword(s):  
Stem Cell ◽  
Induction Therapy ◽  
Stem Cell Transplant ◽  
Disease Free Survival ◽  
Autologous Stem Cell Transplant ◽  
High Dose ◽  
Cell Transplant ◽  
Free Survival ◽  
Disease Free

7511 Background: Although patients (pts) with MCL have a high response rate to standard chemotherapy, they continue to relapse with no plateau in long term disease-free survival. The use of dose intense induction therapy such as HyperCVAD (M-C) ±Rituximab(R) and high-dose therapy and stem cell may improve these results. In this analysis the outcomes of pts receiving a standard anthracycline induction therapy or HyperCVAD(M-C)(±R) then followed by a stem cell transplant in first complete (CR1) or partial remission (PR1) were compared. Methods: Between 6/91 and 11/05, 124 pts with MCL received high-dose chemotherapy and a stem cell transplant. Of these pts, 80 received an autologous stem cell transplant in CR1 (N = 47) or PR1 (N = 33). A standard anthracycline based CHOP-like (±R) induction therapy was given to 48 pts compared with 32 pts who received HyperCVAD(M-C)(±R) prior to transplant. Results: The median age of pts was 56 years (range 33–70). The male:female ratio was 33:57. Bone marrow involvement prior to conditioning was present in 52% of pts. An elevated lactic dehydrogenase (LDH) was present in 58% of pts. 65% of patients received one prior chemotherapy before coming to stem cell transplant. The median follow up of pts is 38 months (range 3–143). Progression-free survival (PFS) and overall survival (OS) are outlined in table 1 . Characteristics associated with an improved OS by multivariate analysis included receiving HyperCVAD induction (p = 0.04), transplant in CR1 (p = 0.009), ≤ 3 prior chemotherapy regimens (p = 0.02) and no B symptoms at transplant (p = 0.05). Conclusions: To improve the long term disease free survival for pts with MCL, Hyper-CVAD(M-C)(±R) induction should be given to eligible patients with autolgous stem cell transplantation in CR1. [Table: see text] No significant financial relationships to disclose.

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