Twice Daily Fludarabine and Cytarabine Combination (BID-FA) Is Effective in Pts with De Novo Acute Myeloid Leukemia (AML), Relapsed/Refractory (R/R) AML, High-Risk Myelodysplastic Syndromes (MDS), and Blast Phase Chronic Myeloid Leukemia (CML-BP)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4939-4939
Author(s):  
Hady Ghanem ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Jorge E. Cortes ◽  
Naveen Pemmaraju ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
High Dose ◽  
Platelet Recovery ◽  
De Novo Aml ◽  
To Receive

Abstract Abstract 4939 Background: High dose cytarabine containing regimens are still considered standard options for pts (pts) with AML relapsing after a first complete remission (CR1) lasting more than 12 months. No standard options exist for pts relapsing after shorter remission duration or with primary refractory disease. We conducted a phase II study assessing the efficacy and safety of twice daily fludarabine and cytarabine (BID FA) in pts with R/R AML, high-risk MDS and CML-BP. Pts and Methods: 147 pts with de Novo AML, R/R AML, intermediate-2 and high-risk MDS, and CML-BP, with a performance status of 3 or less, as well as normal organ functions were eligible. Pts were scheduled to receive fludarabine 15 mg/m2 intravenously (IV) q12 hrs on days 1 to 5 as well as cytarabine at the dose of 0. 5 g/m2IV over 2 hrs q12 hrs on days 1 to 5. GO was administered at the dose of 3 mg/m2 IV on day 1 for the first 70 pts enrolled. Courses were repeated every 4 to 6 weeks for a maximum of 7 courses. Pts with CML-BP were allowed to receive concomitant tyrosine kinase inhibitors. Four pts with AML who had FLT3 mutation were allowed to receive BID FA and sorafenib. Results: A total of 147 pts were treated. The median age was 63 years (range, 20 to 85 years). 131 (89%) had AML, 7 (5%) had high-risk MDS, and 9 (6%) had CML-BP. Of the 131 AML pts, 17 (12%) were de novo AML, 50 (38%) were in first salvage: first CR duration (CRD1) of less than 12 months in 39 pts (29%), and more than 12 months in 11 (9%) pts. Cytogenetic studies showed diploid karyotype in 52 pts (35%) and unfavorable chromosomal abnormalities involving chromosomes 5 and 7 in 30 pts (20%). 128 pts (87%) had a PS ≥1. Sixty-four pts (44%) had failed previous intensive chemotherapy, while 21 (14%) had failed targeted and hypomethylating agents. Forty-three (29%) pts had failed both. Overall, 34 pts (23%) achieved a complete remission (CR) and 8 (6%) achieved a CR without platelet recovery (CRp), for an overall response rate (ORR) of 29%. 6 pts received reinduction therapy, of which 3 achieved a CR. The CR rates for AML pts with frontline therapy, with relapsed AML with CRD1 ≥12 months, relapsed AML with CRD1< 12 months, and R/R AML beyond first salvage were 47%, 64%, 21%, and 14%, respectively. In CML-BP, 2 (22%) of 9 pts had objective responses (1 CR, 1 CRp). 1 of the 7 pts with MDS responded (Table 1). The treatment was well tolerated with only 7 of the pts experiencing grade 3 and 4 toxicities including mainly skin rash and increased liver enzymes. The overall 4-week mortality rate was 13%. With a median follow-up of 24 months (range, 10 to 33), 20 patients (14%) remained alive. The overall 6-month survival rate was 44%. The median overall survival (OS) and event free survival (EFS) were 5 months (range, 0. 1 to 33) and 1 month (range, 0. 1 to 33), respectively. The median CR/CRp duration was 12 months. Median OS for pts with de novo AML, a CRD1≥12 months, pts with CRD1<12 months and pts receiving second salvage and beyond were 8, 12, 5, and 4 months respectively. Median EFS for pts with de novo AML, a CRD1≥12 months, pts with CRD1<12 months and pts receiving second salvage and beyond were 3, 7, 1 and 1 month respectively. Conclusion: BID FA appears to be active with an ORR of 29% in a heavily pre-treated population. This combination is safe with a low rate of 4-week-mortality of 13%. Disclosures: No relevant conflicts of interest to declare.

A Phase II Study of Twice Daily Cytarabine and Fludarabine and Gentuzumab Ozogamycin (GO) In Patients (pts) with Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndrome (MDS)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2188-2188
Author(s):  
Elias Jabbour ◽  
Guillermo Garcia-Manero ◽  
Hady Antoine Ghanem ◽  
Farhad Ravandi ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Remission ◽  
Phase Ii ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Phase Ii Study ◽  
Platelet Recovery ◽  
First Relapse ◽  
De Novo Aml ◽  
To Receive

Abstract Abstract 2188 Background: Treatment options for pts with refractory/relapsed (R/R) AML are limited. High dose cytarabine (A) containing regimens are still considered standard options for pts with AML relapsing after a first complete remission (CR) lasting more than 12 months. The combination of A with fludarabine (F) was found to be superior to A alone in this setting, particularly when administered twice daily (BID). In addition, gemtuzumab ozogamicin (GO) has been shown to be active in combination or as single agent in pts with R/R AML. Therefore, we conducted a phase II study assessing the efficacy and safety of BID FA-GO. Patients and Methods: Pts with R/R AML, de novo AML patients unfit for other medical therapies, intermediate-2 and high-risk MDS, and chronic myeloid leukemia in myeloid blast crisis (CML-BC), with a performance status (PS) of 3 or less, as well as normal organ functions were eligible. Pts were scheduled to receive F 15 mg/m2 IV q12 hrs day 1 to 5 as well as A at the dose of 0.5 g/m2 IV over 2 hrs q12 hrs day 1 to 5. GO was administered at the dose of 3 mg/m2 IV on day 1. Treatment course was shortened to 4 days in pts older than 65 years and to 3 days in pts with a PS of 3. Courses were repeated every 4 to 6 weeks for a maximum of 7 courses. Pts with CML were allowed to receive concomitant tyrosine kinase inhibitors. Results: Sixty-five evaluable pts were enrolled: 6 (9%) with de novo AML, 5 (8%) with AML in first relapse with a duration of 1st CR (CRD1) of ≥12 months, 21 (32%) with AML with CRD1 <12 months, 24 (37%) with AML in second relapse and beyond, 3 (5%) with MDS, and 6 (9%) with CML-BC. Median age was 60 years (range, 19 to 80); 58 pts (89%) had a PS ≥1. Cytogenetic analyses were abnormal in 63 % including chromosomes 5 and 7 abnormalities in 17%. The overall response (OR) rate was 31% including CR in 17 pts (26%) and CR without platelet recovery (CRp) in 3 (5%). The overall 4-week mortality rate was 8%. The OR rates for pts with de novo AML, relapsed AML with CRD1 ≥12 months, relapsed AML with CRD1< 12 months, and R/R AML beyond first salvage (S) were 43%, 60%, 35%, and 19%, respectively. The CR rates were 29%, 60%, 27%, and 19%, respectively. The 4-week mortality rates were 19% for pts with R/R AML beyond the first salvage and 0% for the rest (Table1). With a median follow-up of 8 months (range, 1 to 27), the 16-week event-free survival (EFS), overall survival (OS), and complete remission duration (CRD) rates were 25%, 61%, and 89%, respectively. The median EFS and OS for the responding pts were 27 weeks (4-31 weeks). When compared to historical match cohort pts treated at our institution, BID FA-GO was better, with an ORR rate of 60 % in pts with AML in first relapse with CRD1 ≥12 months compared to an expected rate of 50%, 19% in pts with relapsed AML with CRD1< 12 months compared to 11%, and 35% in pts with AML beyond the first salvage compared to 7% (Table 2). The treatment was well tolerated with only 3% of the pts experiencing grade 3 and 4 toxicities including mainly skin rash. The main toxicities were of gastro-intestinal origin and all were of grade 1 and 2. There was no case of veno-occlusive disease reported. Conclusion: BID FA-GO appears to be active with an ORR of 31% in heavily pre- treated population. This combination appears to be safe as well with a low rate of 4-week-mortality of 5%. Ongoing studies are exploring the role of the new generation of nucleoside analogues in this setting. Disclosures: Cortes: Pfizer: Consultancy, Research Funding.

CSF3R Gene Mutations In Myeloid Malignancy Of Childhood

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1352-1352 ◽  
Author(s):  
Hitoshi Sano ◽  
Kentaro Ohki ◽  
Myoung-ja Park ◽  
Yusuke Hara ◽  
Norio Shiba ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
Rare Event ◽  
Chromosome 8 ◽  
Differential Sensitivity ◽  
Juvenile Myelomonocytic Leukemia ◽  
Missense Mutations ◽  
De Novo Aml

Abstract Background Granulocyte colony-stimulating factor (G-CSF; CSF3) and its receptor (G-CSFR; CSF3R) control neutrophil production under basal circumstances and during episodes of bacterial infections. Mutations in a region of the CSF3R gene coding for the intracytoplasmic domain of the G-CSFR have been discovered in patients with severe congenital neutropenia (CN) and were initially suggested to be the cause of CN. Mutations in CSF3R gene are regarded as an early marker of malignant transformation in CN. Common genetic abnormalities like acquired clonal cytogenetic alterations or activating RAS mutations have also been observed to be associated with CN-related myelodysplastic syndrome(MDS)/leukemia. In adults, a frequency of CSF3R mutation was common (59%) in patients with chronic neutrophilic leukemia (CNL) and atypical (BCR-ABL1–negative) chronic myeloid leukemia (CML), whereas that was low (1%) in patients with de novo acute myeloid leukemia (AML). Sequence variants that were identified included membrane proximal mutations and a number of different frameshift or nonsense mutations that truncate the cytoplasmic tail of CSF3R. These mutations segregate within two distinct regions of CSF3R and lead to preferential downstream kinase signaling through SRC family-TNK2 or JAK kinases and differential sensitivity to kinase inhibitors. However, little is known about the incidence and prognostic values of CSF3R mutations in pediatric myeloid malignancies. Methods CSF3R mutations (exon14 and 17) in a total of 376 samples of pediatric de novo AML, 40 samples of juvenile myelomonocytic leukemia (JMML), and 20 samples of MDS were analyzed from gDNA or cDNA extracted from diagnostic bone marrow samples using direct sequencing. Moreover, we assessed whether CSF3R mutations overlap with known gene abnormalities, such as FLT3, c-KIT, NPM1 and SETBP-1. Mutational analyses of FLT3, c-KIT, NPM1 and SETBP-1 were also performed in AML samples. Results We identified a CSF3R mutation in 5 of 376 patients (1.3%) with AML, 2 frameshift mutations (E788X) and 3 missense mutations (L777F and T618I). The patients with 3 (L777F and E788X) of these 5 mutations had complex chromosomal abnormalities involved in chromosome 8 and 21 (t(8;21) and ins(21;8); AML1/ETO). The other 2 patients with missense mutations (T618I) had normal karyotype. They presented with a relatively high WBC counts of 100.6×10*9/l and 159.5×10*9/l. Although 2 of 5 these patients relapsed, all of them were salvaged successfully. Two of 5 had c-KIT mutations, while none of them had FLT3, NPM1, and SETBP-1 mutations. No mutations of CSF3R in JMML and MDS patients were found. Conclusions To our knowledge, this is the first report to describe the CSF3R mutation in a pediatric de novo AML patient. In our study, CSF3R mutation is detected in 1.3% in childhood de novo AML, which suggests the involvements of CSF3R mutations in the pathogenesis of pediatric de novo AML, JMML and MDS are extremely rare compared with those in SCN and adult CNL and atypical CML cases. Since CSF3R mutation is rare event, the prognostic values of CSF3R mutations in de novo AML are still unclear. Further data accumulation is necessary. Disclosures: No relevant conflicts of interest to declare.

Dose-dense induction with sequential high-dose cytarabine and mitoxantone (S-HAM) and pegfilgrastim results in a high efficacy and a short duration of critical neutropenia in de novo acute myeloid leukemia: a pilot study of the AMLCG

Blood ◽  
2009 ◽  
Vol 113 (17) ◽  
pp. 3903-3910 ◽  
Author(s):  
Jan Braess ◽  
Karsten Spiekermann ◽  
Peter Staib ◽  
Andreas Grüneisen ◽  
Bernhard Wörmann ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Early Death ◽  
High Dose ◽  
Kaplan Meier ◽  
De Novo Aml ◽  
Dose Dense ◽  
Acute Myeloid

AbstractDose density during early induction has been demonstrated to be one of the prime determinants for treatment efficacy in acute myeloid leukemia (AML). The German AML Cooperative Group has therefore piloted a dose-dense induction regimen sequential high-dose AraC and mitoxantrone followed by pegfilgrastim (S-HAM) in which 2 induction cycles are applied over 11 to 12 days instead of 25 to 29 days as used in conventional double induction, thereby increasing dose density 2-fold. Of 172 de novo AML patients (excluding acute promyelocytic leukemia), 61% reached a complete remission, 22% a complete remission with incomplete peripheral recovery, 7% had persistent leukemia, 10% died (early death) resulting in an overall response rate of 83%. Kaplan-Meier estimated survival at 2 years was 61% for the whole group (patients with unfavorable karyotypes, 38%; patients with favorable karyotypes, 69%; patients with intermediate karyotypes, 75%) after S-HAM treatment. Importantly, the compression of the 2 induction cycles into the first 11 to 12 days of treatment was beneficial for normal hematopoiesis as demonstrated by a significantly shortened duration of critical neutropenia of 31 days compared with 46 days after conventionally timed double induction. (European Leukemia Trial Registry LN_AMLINT_2004_230.)

6-Thioguanine, Cytarabine, and Daunorubicin (TAD) and High-Dose Cytarabine and Mitoxantrone (HAM) for Induction, TAD for Consolidation, and Either Prolonged Maintenance by Reduced Monthly TAD or TAD-HAM-TAD and One Course of Intensive Consolidation by Sequential HAM in Adult Patients at All Ages With De Novo Acute Myeloid Leukemia (AML): A Randomized Trial of the German AML Cooperative Group

2003 ◽  
Vol 21 (24) ◽  
pp. 4496-4504 ◽  
Author(s):  
Thomas Büchner ◽  
Wolfgang Hiddemann ◽  
Wolfgang E. Berdel ◽  
Bernhard Wörmann ◽  
Claudia Schoch ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Lactate Dehydrogenase Level ◽  
High Dose ◽  
Free Survival ◽  
Poor Risk ◽  
De Novo Aml ◽  
To Receive ◽  
Acute Myeloid

Purpose: To examine the efficacy of prolonged maintenance chemotherapy versus intensified consolidation therapy for patients with acute myeloid leukemia (AML). Materials and Methods: Eight hundred thirty-two patients (median age, 54 years; range, 16 to 82 years) with de novo AML were randomly assigned to receive 6-thioguanine, cytarabine, and daunorubicin (TAD) plus cytarabine and mitoxantrone (HAM; cytarabine 3 g/m2 [age < 60 years] or 1 g/m2 [age ≥ 60 years] × 6) induction, TAD consolidation, and monthly modified TAD maintenance for 3 years, or TAD-HAM-TAD and one course of intensive consolidation with sequential HAM (S-HAM) with cytarabine 1 g/m2 (age < 60 years) or 0.5 g/m2 (age ≥ 60 years) × 8 instead of maintenance. Results: A total of 69.2% patients went into complete remission (CR). Median relapse-free survival (RFS) was 19 months for patients on the maintenance arm, with 31.4% of patients relapse-free at 5 years, versus 12 months for patients on the S-HAM arm, with 24.7% of patients relapse-free at 5 years (P = .0118). RFS from maintenance was superior in patients with poor risk by unfavorable karyotype, age ≥ 60 years, lactate dehydrogenase level greater than 700 U/L, or day 16 bone marrow blasts greater than 40% (P = .0061) but not in patients with good risk by complete absence of any poor risk factors. Although a survival benefit in the CR patients is not significant (P = .085), more surviving patients in the maintenance than in the S-HAM arm remain in first CR (P = .026). Conclusion: We conclude that TAD-HAM-TAD-maintenance first-line treatment has a higher curative potential than TAD-HAM-TAD-S-HAM and improves prognosis even among patients with poor prognosis.

Pathway Based Pharmacogenomics of Cytarabine In Pediatric Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 294-294
Author(s):  
Jatinder Lamba ◽  
Amit Mitra ◽  
Kristine Crews ◽  
Pounds Stanley ◽  
Xueyuan Cao ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Continuous Infusion ◽  
Myeloid Leukemia ◽  
Childhood Leukemia ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Leukemic Cells ◽  
High Dose ◽  
To Receive ◽  
Acute Myeloid

Abstract Abstract 294 Acute myeloid leukemia (AML) is the second most common form of childhood leukemia and has the worst prognosis of all major childhood cancers. The mainstay of AML chemotherapy is the nucleoside analog cytarabine (ara-C). Numerous studies suggest that the intracellular concentrations of the ara-C active metabolite, ara-CTP, vary widely among patients, and in turn, are associated with variability in clinical response to AML treatment. In the present study, we have taken a pathway directed approach to identify genetic predictors of ara-C response in pediatric patients treated with ara-C based antileukemic chemotherapy in the AML02 (n=187) and AML97 (n=55) clinical trials. The AML02 trial enrolled AML patients <22 years of age excluding APL or Down's syndrome patients, but those with all other subtypes of de novo or secondary AML, as well as patients with mixed-lineage leukemia, were eligible. Patients were randomized to receive induction I therapy containing high-dose cytarabine or low-dose cytarabine plus daunorubicin and etoposide. We genotyped the genomic DNA from patients enrolled in AML02 study for potentially significant single nucleotide polymorphisms (SNPs) in 10 key ara-C pathway genes and screened for association with 3 endpoints in AML02 study: in vitro ara-C LC50 determined in diagnostic leukemic cells, event free survival (EFS) and overall survival (OS). In samples from St. Jude AML97 study, we screened for association of SNPs with 4 endpoints: intracellular ara-CTP levels after start of induction, DNA synthesis relative to baseline, morphological response after induction I, and EFS. In the St Jude AML 97 study patients were randomly assigned to receive ara-C as either a short daily infusion (500 mg/m2/dose intravenously over 2 hrs daily for 5 days) or a continuous infusion (500 mg/m2/day as a continuous infusion over 5 days). Bone marrow was collected at the end of the ara-C infusion on day 1 for patients receiving the short daily infusion (n=27), and at 10 hrs after the start of the infusion for those receiving the continuous infusion (n=28). Ara-CTP levels in leukemia cells were analyzed by HPLC. Intracellular accumulation of ara-CTP was significantly higher when given as short daily infusion, as compared to continuous infusion (p = 0.01). The inter-patient variability for blast ara-CTP concentrations was 40-fold in the short infusion arm and 101-fold in the continuous infusion arm. We found significant correlations between SNPs in ara-C pathway genes (such as DCK, DCTD, CMPK, CTPS, CDA and NT5C2) and various clinical parameters (after adjusting for arm and/or risk group), some of which are listed below. These results suggest that genetic variation in key candidate genes in ara-C metabolic pathway could in?uence and predict the variability observed in cellular sensitivity and treatment response. The pharmacogenomic factors identi?ed in the present study could be potentially used for tailoring medications to better individualize cytarabine based AML therapy. Disclosures: No relevant conflicts of interest to declare.

Chemotherapy and Venetoclax in Elderly Acute Myeloid Leukemia Trial (CAVEAT): A Phase Ib Dose-Escalation Study of Venetoclax Combined With Modified Intensive Chemotherapy

2020 ◽  
Vol 38 (30) ◽  
pp. 3506-3517 ◽  
Author(s):  
Chong Chyn Chua ◽  
Andrew W. Roberts ◽  
John Reynolds ◽  
Chun Yew Fong ◽  
Stephen B. Ting ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Dose Escalation ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
De Novo ◽  
B Cell Lymphoma ◽  
Intensive Chemotherapy ◽  
Platelet Recovery ◽  
De Novo Aml ◽  
Acute Myeloid

PURPOSE The B-cell lymphoma 2 (BCL-2) inhibitor venetoclax has an emerging role in acute myeloid leukemia (AML), with promising response rates in combination with hypomethylating agents or low-dose cytarabine in older patients. The tolerability and efficacy of venetoclax in combination with intensive chemotherapy in AML is unknown. PATIENTS AND METHODS Patients with AML who were ≥ 65 years (≥ 60 years if monosomal karyotype) and fit for intensive chemotherapy were allocated to venetoclax dose-escalation cohorts (range, 50-600 mg). Venetoclax was administered orally for 14 days each cycle. During induction, a 7-day prephase/dose ramp-up (days −6 to 0) was followed by an additional 7 days of venetoclax combined with infusional cytarabine 100 mg/m2 on days 1-5 and idarubicin 12 mg/m2 intravenously on days 2-3 (ie, 5 + 2). Consolidation (4 cycles) included 14 days of venetoclax (days −6 to 7) combined with cytarabine (days 1-2) and idarubicin (day 1). Maintenance venetoclax was permitted (7 cycles). The primary objective was to assess the optimal dose schedule of venetoclax with 5 + 2. RESULTS Fifty-one patients with a median age of 72 years (range, 63-80 years) were included. The maximum tolerated dose was not reached with venetoclax 600 mg/day. The main grade ≥ 3 nonhematologic toxicities during induction were febrile neutropenia (55%) and sepsis (35%). In contrast to induction, platelet recovery was notably delayed during consolidation cycles. The overall response rate (complete remission [CR]/CR with incomplete count recovery) was 72%; it was 97% in de novo AML and was 43% in secondary AML. During the venetoclax prephase, marrow blast reductions (≥ 50%) were noted in NPM1-, IDH2-, and SRSF2-mutant AML. CONCLUSION Venetoclax combined with 5 + 2 induction chemotherapy was safe and tolerable in fit older patients with AML. Although the optimal postremission therapy remains to be determined, the high remission rate in de novo AML warrants additional investigation (ANZ Clinical Trial Registry No. ACTRN12616000445471).

scholarly journals Adult Patients With De Novo Acute Myeloid Leukemia and t(9; 11)(p22; q23) Have a Superior Outcome to Patients With Other Translocations Involving Band 11q23: A Cancer and Leukemia Group B Study

Blood ◽  
1997 ◽  
Vol 90 (11) ◽  
pp. 4532-4538 ◽  
Author(s):  
Krzysztof Mrózek ◽  
Kristiina Heinonen ◽  
David Lawrence ◽  
Andrew J. Carroll ◽  
Prasad R.K. Koduru ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Extra Chromosome ◽  
Response To Therapy ◽  
High Dose ◽  
Postremission Therapy ◽  
De Novo Aml ◽  
Group B ◽  
Acute Myeloid

Abstract Following reports of childhood acute myeloid leukemia (AML) showing that patients with t(9; 11)(p22; q23) have a better prognosis than those with translocations between 11q23 and other chromosomes, we compared response to therapy and survival of 24 adult de novo AML patients with t(9; 11) with those of 23 patients with other 11q23 translocations [t(11q23)]. Apart from a higher proportion of French-American-British (FAB) M5 subtype in the t(9; 11) group (83% v 43%, P = .006), the patients with t(9; 11) did not differ significantly from patients with t(11q23) in terms of their presenting clinical or hematologic features. Patients with t(9; 11) more frequently had an extra chromosome(s) 8 or 8q as secondary abnormalities (46% v 9%, P = .008). All patients received standard cytarabine and daunorubicin induction therapy, and most of them also received cytarabine-based intensification treatment. Two patients, both with t(9; 11), underwent bone marrow transplantation (BMT) in first complete remission (CR). Nineteen patients (79%) with t(9; 11) and 13 (57%) with t(11q23) achieved a CR (P = .13). The clinical outcome of patients with t(9; 11) was significantly better: the median CR duration was 10.7 versus 8.9 months (P = .02), median event-free survival was 6.2 versus 2.2 months (P = .009), and median survival was 13.2 versus 7.7 months (P = .009). All patients with t(11q23) have died, whereas seven (29%) patients with t(9; 11) remain alive in first CR. Seven of eight patients with t(9; 11) who received postremission regimens with cytarabine at a dose of 100 (four patients) or 400 mg/m2 (2 patients) or who did not receive postremission therapy (2 patients) have relapsed. In contrast, 7 (64%) of 11 patients who received intensive postremission chemotherapy with high-dose cytarabine (at a dose 3 g/m2) (5 patients), or underwent BMT (2 patients) remain in continuous CR. We conclude that the outcome of adults with de novo AML and t(9; 11) is more favorable than that of adults with other 11q23 translocations; this is especially true for t(9; 11) patients who receive intensive postremission therapy.

scholarly journals A phase 1 study of azacitidine with high-dose cytarabine and mitoxantrone in high-risk acute myeloid leukemia

2020 ◽  
Vol 4 (4) ◽  
pp. 599-606 ◽  
Author(s):  
Kirk E. Cahill ◽  
Yasmin H. Karimi ◽  
Theodore G. Karrison ◽  
Nitin Jain ◽  
Margaret Green ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Phase 1 ◽  
High Dose ◽  
Phase 2 ◽  
Phase 1 Study ◽  
High Dose Cytarabine ◽  
Acute Myeloid

Abstract In this phase 1 study, azacitidine (AZA) was given before high-dose cytarabine (HiDAC) and mitoxantrone (mito) based on the hypothesis that epigenetic priming with a hypomethylating agent before cytotoxic chemotherapy would improve response rates in patients with high-risk acute myeloid leukemia (AML), including relapsed/refractory disease. The primary objective was to establish the recommended phase 2 dose of AZA given before standard HiDAC/mito. In a dose escalation scheme, 46 patients (median age, 66 years) received AZA at 37.5, 50, or 75 mg/m2 subcutaneously or IV once daily on days 1 to 5 followed by HiDAC (3000 mg/m2) and mitoxantrone (30 mg/m2) once each on days 6 and 10 (the HiDAC/mito dose was reduced 33% in elderly subjects). Two dose-limiting toxicities occurred (both in the same patient): acute liver failure and kidney injury at the 50 mg/m2 dose. The 30-day induction death rate was 2.2% (1 of 46). The overall response rate, including complete remission and complete remission with incomplete count recovery, was 61% (28 of 46). Previously untreated patients aged ≥60 years with therapy-related AML and de novo AML were more likely to respond than untreated patients with AML progressing from an antecedent hematologic disorder (myelodysplastic syndrome and chronic myelomonocytic leukemia). Patients with favorable European Leukemia Network risk (P = .008), NPM1 mutations (P = .007), or IDH2 mutations (P = .03) were more likely to respond, and those with TP53 mutations (P = .03) were less likely to respond. The recommended phase 2 dose of AZA is 75 mg/m2 per day on days 1 to 5 followed by HiDAC (3000 mg/m2) and mitoxantrone (30 mg/m2) once each on days 6 and 10. This trial was registered at www.clinicaltrials.gov as #NCT01839240.

The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML

Blood ◽  
2011 ◽  
Vol 117 (7) ◽  
pp. 2137-2145 ◽  
Author(s):  
Sabine Kayser ◽  
Konstanze Döhner ◽  
Jürgen Krauter ◽  
Claus-Henning Köhne ◽  
Heinz A. Horst ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Topoisomerase Ii ◽  
De Novo ◽  
Negative Impact ◽  
Primary Malignancy ◽  
De Novo Aml ◽  
The Impact ◽  
Acute Myeloid

Abstract To study the characteristics and clinical impact of therapy-related acute myeloid leukemia (t-AML). 200 patients (7.0%) had t-AML and 2653 de novo AML (93%). Patients with t-AML were older (P < .0001) and they had lower white blood counts (P = .003) compared with de novo AML patients; t-AML patients had abnormal cytogenetics more frequently, with overrepresentation of 11q23 translocations as well as adverse cytogenetics, including complex and monosomal karyotypes, and with underrepresentation of intermediate-risk karyotypes (P < .0001); t-AML patients had NPM1 mutations (P < .0001) and FLT3 internal tandem duplications (P = .0005) less frequently. Younger age at diagnosis of primary malignancy and treatment with intercalating agents as well as topoisomerase II inhibitors were associated with shorter latency periods to the occurrence of t-AML. In multivariable analyses, t-AML was an adverse prognostic factor for death in complete remission but not relapse in younger intensively treated patients (P < .0001 and P = .39, respectively), relapse but not death in complete remission in older, less intensively treated patients (P = .02 and P = .22, respectively) and overall survival in younger intensively treated patients (P = .01). In more intensively treated younger adults, treatment-related toxicity had a major negative impact on outcome, possibly reflecting cumulative toxicity of cancer treatment.

Phase I/II Study of Clofarabine Combined with Standard Dose Cytarabine as Remission Induction Therapy of De Novo AML in Elderly Patients ≥60 Years.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4635-4635
Author(s):  
James M. Foran ◽  
Angeline S. The ◽  
Marcel Devetten ◽  
Sreelatha Meleth ◽  
Jeff Worrell ◽  
...  
Keyword(s):  
Complete Remission ◽  
Phase I ◽  
Dose Level ◽  
Induction Therapy ◽  
De Novo ◽  
Standard Dose ◽  
Level I ◽  
De Novo Aml ◽  
To Receive ◽  
Dose Limiting Toxicity

Abstract Despite significant advances in the treatment of acute myeloid leukemia (AML) in younger adults, there has been little progress in the treatment of older patients (age≥60 years), who comprise the majority of those with the disease. Clofarabine is a purine nucleoside analog with single agent activity in patients with relapsed AML. In addition, clofarabine potentiates Ara-C cytotoxicity in vitro through increased intracellular Ara-CTP accumulation, making this an attractive combination. A phase I/II study has therefore been initiated combining clofarabine with standard dose cytarabine (100mg/m2/day x 7) in pts age ≥60 years with de novo AML. The starting dose of clofarabine was 30mg/m2/day x 5 beginning on day 2 (Dose level I). Patients were accrued in cohorts of 3–6 to establish dose limiting toxicity (DLT); cohort expansion at the maximum tolerated dose (MTD) is planned in phase II using a Simon 2-stage design. Detailed plasma and intracellular pharmacokinetics were performed during induction therapy with Ara-C alone (day 1), and following the addition of clofarabine (day 2) to determine the effect of clofarabine on intracellular Ara-CTP accumulation. Pts with residual AML on d14–21 restaging bone marrow (BM) biopsy were eligible to receive Re-Induction with 5 days of clofarabine & Ara-C. Those achieving complete remission were also eligible to receive 1–2 cycles of consolidation with Ara-C (d1–5) & clofarabine (total 3 cycles of planned therapy). Dose limiting toxicity was encountered at dose level I (see Table 1). 2/4 pts achieved CR, in 1 case with residual cytogenetic abnormality, and there were 2 treatment-related deaths from infxn (culture neg sepsis, n=1; Candida tropicalis, n=1). In the latter case (pt 4), BM aplasia was achieved, but the pt died on d25 prior to hematologic recovery. In view of the DLT, the protocol has therefore been amended to allow 25% dose de-escalation of clofarabine to Dose Level -I (22.5mg/m2/day x 5), and to limit eligibilty to pts age 60–75 yrs inclusive. Routine use of aggressive pre-hydration and antibiotic and antifungal prophylaxis is now mandated. Clofarabine & cytarabine is a highly active induction regimen in older adults age ≥60 yrs with de novo AML, but has significant myelosuppressive and infectious toxicity. The study is proceeding in phase I at Dose Level -I to establish the MTD. Phase I, Dose Level I PT AGE, GENDER FAB CYTOGENETICS F/U BM TOXICITY (Gr.III/IV) OUTCOME MLD - multilineage dysplasia; F&N - fever & neutropenia; CR - complete remission 1 66M M2 Diploid D21: residual AML renal, infxn Death 2 61M M2 Complex D14: aplastic F&N CR 3 69M M2 with MLD Intermediate Risk D21: recovering F&N CR 4 77F M2 Diploid D14: aplastic renal, infxn, capillary leak Death

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