Association of abnormal cytogenetics at date of morphologic complete remission (CR) with overall (OS), disease-free survival (DFS) and higher relapse rate in acute myeloid leukemia (AML): Results from Cancer and Leukemia Group B (CALGB) 8461

2004 ◽  
Vol 22 (14_suppl) ◽  
pp. 6514-6514
Author(s):  
G. Marcucci ◽  
K. Mrózek ◽  
A. S. Ruppert ◽  
M. J. Pettenati ◽  
N. A. Heerema ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Relapse Rate ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Free Survival ◽  
Group B ◽  
Leukemia Group ◽  
Disease Free ◽  
Acute Myeloid

Abnormal Cytogenetics at Date of Morphologic Complete Remission Predicts Short Overall and Disease-Free Survival, and Higher Relapse Rate in Adult Acute Myeloid Leukemia: Results From Cancer and Leukemia Group B Study 8461

2004 ◽  
Vol 22 (12) ◽  
pp. 2410-2418 ◽  
Author(s):  
Guido Marcucci ◽  
Krzysztof Mrózek ◽  
Amy S. Ruppert ◽  
Kellie J. Archer ◽  
Mark J. Pettenati ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Free Survival ◽  
Group B ◽  
Leukemia Group ◽  
Disease Free ◽  
Acute Myeloid

Purpose As most patients with acute myeloid leukemia (AML) with morphologic complete remission (CR) ultimately relapse, better predictors for outcome are needed. Recently, Cheson et al suggested using cytogenetic remission (CRc) as part of the criteria for CR. To our knowledge, ours is the first relatively large study evaluating the usefulness of CRc attained immediately following induction chemotherapy. Patients and Methods We included AML patients treated on Cancer and Leukemia Group B front-line studies with cytogenetic samples obtained at diagnosis and at the first day of documented CR following induction. Patients with abnormal cytogenetics at diagnosis, and normal cytogenetics at CR (NCR; n = 103) were compared with those with abnormal cytogenetics both at diagnosis and at CR (ACR; n = 15) for overall survival (OS), disease-free survival (DFS), and cumulative incidence of relapse (CIR). Cox proportional hazards models determined the prognostic significance of cytogenetics at CR, adjusting for other covariates. Results Clinical features were similar for both groups, with the exception of favorable cytogenetics [t(8;21), inv(16)/t(16;16), t(15;17)] at diagnosis, which was more frequent (P = .03) in the NCR group. Median follow-up was 3.1 years (range, 1.0 to 11.4 years). ACR patients had significantly shorter OS (P = .006) and DFS (P = .0001), and higher CIR (P = .0001). In multivariable models, the NCR and ACR groups were predictors for OS (P = .03), DFS (P = .02), and CIR (P = .05). The relative risk of relapse or death was 2.1 times higher for ACR patients than for NCR patients (95% CI, 1.1 to 3.9). Conclusion Our data suggest that converting to normal karyotype at the time of first CR is an important prognostic indicator and support the use of CRc as a criterion of CR in AML.

scholarly journals FLT3 internal tandem duplication associates with adverse outcome and gene- and microRNA-expression signatures in patients 60 years of age or older with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study

Blood ◽  
2010 ◽  
Vol 116 (18) ◽  
pp. 3622-3626 ◽  
Author(s):  
Susan P. Whitman ◽  
Kati Maharry ◽  
Michael D. Radmacher ◽  
Heiko Becker ◽  
Krzysztof Mrózek ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Microrna Expression ◽  
Free Survival ◽  
Group B ◽  
Leukemia Group ◽  
Disease Free ◽  
Acute Myeloid

Abstract The clinical impact of FLT3-internal tandem duplications (ITDs), an adverse prognostic marker in adults aged < 60 years with primary cytogenetically normal acute myeloid leukemia (CN-AML), requires further investigation in older patients. In CN-AML patients aged ≥ 60 years treated on Cancer and Leukemia Group B frontline trials, we found that FLT3-ITD remained associ-ated with shorter disease-free survival (P < .001; hazard ratio = 2.10) and overall survival (P < .001; hazard ratio = 1.97) in multivariable analyses. This impact on shorter disease-free survival and overall survival was in patients aged 60-69 (P < .001, each) rather than in those aged ≥ 70 years. An FLT3-ITD–associated gene-expression signature revealed overexpression of FLT3, homeobox genes (MEIS1, PBX3, HOXB3), and immunotherapeutic tar-gets (WT1, CD33) and underexpression of leukemia-associated (MLLT3, TAL1) and erythropoiesis-associated (GATA3, EPOR, ANK1, HEMGN) genes. An FLT3-ITD–associated microRNA-expression signature included overexpressed miR-155 and underexpressed miR-144 and miR-451. FLT3-ITD identifies older CN-AML patients with molecular high risk and is associated with gene- and microRNA-expression signatures that provide biologic insights for novel therapeutic approaches.

scholarly journals Long-term disease-free survivors with cytogenetically normal acute myeloid leukemia and MLL partial tandem duplication: a Cancer and Leukemia Group B study

Blood ◽  
2007 ◽  
Vol 109 (12) ◽  
pp. 5164-5167 ◽  
Author(s):  
Susan P. Whitman ◽  
Amy S. Ruppert ◽  
Guido Marcucci ◽  
Krzysztof Mrózek ◽  
Peter Paschka ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
Disease Free Survival ◽  
Partial Tandem Duplication ◽  
Group B ◽  
Leukemia Group ◽  
Disease Free ◽  
Acute Myeloid

AbstractThe clinical impact of MLL partial tandem duplication (MLL-PTD) was evaluated in 238 adults aged 18 to 59 years with cytogenetically normal (CN) de novo acute myeloid leukemia (AML) who were treated intensively on similar Cancer and Leukemia Group B protocols 9621 and 19808. Twenty-four (10.1%) patients harbored an MLL-PTD. Of those, 92% achieved complete remission (CR) compared with 83% of patients without MLL-PTD (P = .39). Neither overall survival nor disease-free survival significantly differed between the 2 groups (P = .67 and P = .55, respectively). Thirteen MLL-PTD+ patients relapsed within 1.4 years of achieving CR. MLL-PTD+ patients who relapsed more often had other adverse CN-AML–associated molecular markers. In contrast with previously reported studies, 9 (41%) MLL-PTD+ patients continue in long-term first remission (CR1; range, 2.5-7.7 years). Intensive consolidation therapy that included autologous peripheral stem-cell transplantation during CR1 may have contributed to the better outcome of this historically poor-prognosis group of CN-AML patients with MLL-PTD.

scholarly journals Conventional chemotherapy for acute myeloid leukemia: a Brazilian experience

2000 ◽  
Vol 118 (6) ◽  
pp. 173-178 ◽  
Author(s):  
Kátia Borgia Barbosa Pagnano ◽  
Fabiola Traina ◽  
Tatiana Takahashi ◽  
Gislaine Borba Oliveira ◽  
Marta Soares Rossini ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Disease Free Survival ◽  
Conventional Chemotherapy ◽  
Free Survival ◽  
Disease Free ◽  
Acute Myeloid

CONTEXT: Young patients affected by acute myeloid leukemia (AML) achieve complete remission (CR) using conventional chemotherapy in about 55-85%. However, 30% of patients fail to achieve CR and the remission duration is often only about 12 months. More intensive treatment after CR seems to be necessary in order to maintain CR and obtain a definitive cure. In Brazil, few reports have been published on this important subject. OBJECTIVE: The aim of this study was to describe a Brazilian experience in the treatment of "de novo" acute myeloid leukemia (AML) in younger adult patients (age < 60 years). DESIGN: Retrospective analysis. SETTING: University Hospital, Hematology and Hemotherapy Center, State University of Campinas, Brazil. PARTICIPANTS: Newly diagnosed cases of "de novo" AML in the period from January 1994 to December 1998 were evaluated retrospectively, in relation to response to treatment, overall survival (OS) and disease free survival (DFS). Cases with acute promyelocytic leukemia (APL) were also included in this analysis. RESULTS: On the basis of an intention to treat, 78 cases of AML, including 17 cases of APL, were evaluated. The overall median follow-up was 272 days. The complete remission (CR) rate was 63.6% in the AML group (excluding APL) and 78% in the APL group. The 5-year estimated disease-free survival (DFS) was 80% for the APL group and 34% for the AML group (P = 0.02). The 5-year estimated overall survival (OS) was 52% for the APL group and 20.5% for the AML group, respectively (P = NS). Relapse was observed in 12/39 (30.7%) patients with AML and 1/11 (9%) with APL. CONCLUSIONS: These results are similar to those reported in the literature. However, relapse and mortality rates remain high, and a search for more aggressive strategies in order to prevent relapse is recommended.

scholarly journals Combination of dasatinib with chemotherapy in previously untreated core binding factor acute myeloid leukemia: CALGB 10801

2020 ◽  
Vol 4 (4) ◽  
pp. 696-705 ◽  
Author(s):  
Guido Marcucci ◽  
Susan Geyer ◽  
Kristina Laumann ◽  
Weiqiang Zhao ◽  
Donna Bucci ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Core Binding Factor ◽  
Free Survival ◽  
Binding Factor ◽  
Disease Free ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) with either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) is referred to as core binding factor (CBF) AML. Although categorized as favorable risk, long-term survival for these patients is only ∼50% to 60%. Mutated (mut) or overexpressed KIT, a gene encoding a receptor tyrosine kinase, has been found almost exclusively in CBF AML and may increase the risk of disease relapse. We tested the safety and clinical activity of dasatinib, a multi-kinase inhibitor, in combination with chemotherapy. Sixty-one adult patients with AML and CBF fusion transcripts (RUNX1/RUNX1T1 or CBFB/MYH11) were enrolled on Cancer and Leukemia Group B (CALGB) 10801. Patients received cytarabine/daunorubicin induction on days 1 to 7 and oral dasatinib 100 mg/d on days 8 to 21. Upon achieving complete remission, patients received consolidation with high-dose cytarabine followed by dasatinib 100 mg/d on days 6 to 26 for 4 courses, followed by dasatinib 100 mg/d for 12 months. Fifteen (25%) patients were older (aged ≥60 years); 67% were CBFB/MYH11–positive, and 19% harbored KITmut. There were no unexpected or dose-limiting toxicities. Fifty-five (90%) patients achieved complete remission. With a median follow-up of 45 months, only 16% have relapsed. The 3-year disease-free survival and overall survival rates were 75% and 77% (79% and 85% for younger patients [aged &lt;60 years], and 60% and 51% for older patients). Patients with KITmut had comparable outcome to those with wild-type KIT (3-year rates: disease-free survival, 67% vs 75%; overall survival, 73% vs 76%), thereby raising the question of whether dasatinib may overcome the negative impact of these genetic lesions. CALGB 10801 was registered at www.clinicaltrials.gov as #NCT01238211.

scholarly journals Phase 3 study of the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age and older with acute myeloid leukemia: Cancer and Leukemia Group B Study 9720

Blood ◽  
2002 ◽  
Vol 100 (4) ◽  
pp. 1224-1232 ◽  
Author(s):  
Maria R. Baer ◽  
Stephen L. George ◽  
Richard K. Dodge ◽  
Kieran L. O'Loughlin ◽  
Hans Minderman ◽  
...  
Keyword(s):  
Older Patients ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Phase 3 ◽  
Free Survival ◽  
Psc 833 ◽  
Group B ◽  
Leukemia Group ◽  
Disease Free ◽  
Acute Myeloid

The Cancer and Leukemia Group B conducted a phase 3 trial of the P-glycoprotein modulator PSC-833 in untreated acute myeloid leukemia patients aged 60 years and older. Patients were randomized to 1 of 2 regimens, with doses determined in a prior phase 1 study, consisting of cytarabine 100 mg/m2/d by 7-day infusion, with daunorubicin 60 mg/m2 and etoposide 100 mg/m2 daily for 3 days (ADE), or daunorubicin 40 mg/m2 and etoposide 60 mg/m2 for 3 days with PSC-833, 2.8 mg/kg over 2 hours, and then 10 mg/kg/d by 3-day infusion (ADEP). The ADEP arm was closed after randomization of 120 patients (61 to ADE and 59 to ADEP) because of excessive early mortality. Rates of complete remission, nonresponse, and death were 46%, 34%, and 20% for ADE, versus 39%, 17%, and 44% for ADEP (P = .008). Nevertheless, disease-free survival (median 7 vs 8 months; P = .38) and overall survival (approximately 33% alive at 1 year) did not differ and were similar to historical results. Although the number of patients was limited, ADE patients whose pretreatment cells exhibited PSC-833–modulated dye efflux in vitro (n = 22) had worse outcomes than those without efflux (n = 11) (complete remission, nonresponse, and death rates of 41%, 41%, and 18%, compared with 91%, 9%, and 0%; P = .03), but with ADEP outcomes were nearly identical. Moreover, for patients with PSC-833–modulated efflux, median disease-free survival was 5 months with ADE and 14 months with ADEP (P = .07). Further modulation trials in older patients must await the design of less-toxic regimens.

Childhood acute myeloid leukemia: outcome in a single center using chemotherapy and consolidation with busulfan/cyclophosphamide for bone marrow transplantation.

1994 ◽  
Vol 12 (10) ◽  
pp. 2138-2145 ◽  
Author(s):  
P J Shaw ◽  
M E Bergin ◽  
M A Burgess ◽  
L Dalla Pozza ◽  
S J Kellie ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Bone Marrow Transplantation ◽  
Survival Rate ◽  
Complete Remission ◽  
Relapse Rate ◽  
Marrow Transplantation ◽  
Myeloid Leukemia ◽  
Free Survival ◽  
Acute Myeloid

PURPOSE To report the impact of bone marrow transplantation (BMT) with busulfan/cyclophosphamide (BuCy) as end consolidation in a cohort of consecutively diagnosed children with acute myeloid leukemia (AML). PATIENTS AND METHODS Between May 1987 and November 1992, 43 patients were diagnosed with AML. Tissue typing at diagnosis determined whether patients would proceed to autologous or allogeneic BMT as end consolidation after six cycles of chemotherapy. Conditioning for BMT was with BuCy, followed by allogeneic or unpurged autologous marrow infusion. RESULTS Of 37 patients who received chemotherapy, 35 achieved remission (95%) after one to six courses of treatment and 34 (92%) were transplanted. Five relapsed before BMT, four were subsequently transplanted in second complete remission (CR2) (n = 3) or untreated first relapse (n = 1), and one failed to respond to further therapy. All other patients proceeded to BMT in first complete remission (CR1). Eleven patients received allografts: one relapsed and one died of graft-versus-host disease (GvHD), for a leukemia-free survival rate of 90% at a median of 41 months after BMT (range, 3 to 60). For 23 autografts, there were two toxic deaths and eight relapses, with a leukemia-free survival rate of 61% at a median of 11 months after BMT (range, 0 to 66). The high relapse rate following autologous BMT led us to escalate the dose of Bu from 16 mg/kg to 600 mg/m2 using a single daily dose of Bu. CONCLUSION With modern supportive therapy, most newly diagnosed children with AML will enter remission and are eligible for intensification therapy. BuCy is well tolerated in children, which allowed us to escalate the dose of Bu in recent patients. Further follow-up is needed to determine whether this has an impact on the relapse rate following autologous BMT.

Autologous Bone Marrow Transplantation as an Intensive Consolidation Therapy for Adult Patients in Remission from Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5121-5121
Author(s):  
Andre S. Jung ◽  
Asad Bashey ◽  
Peter R. Holman ◽  
Eva Carrier ◽  
Januario Castro ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Consolidation Therapy ◽  
Free Survival ◽  
Risk Patients ◽  
Disease Free ◽  
Acute Myeloid

Abstract Introduction: Autologous peripheral blood stem/progenitor cell transplantation (APBSCT) has been investigated as a potential therapeutic option to improve outcome in patients with acute myeloid leukemia. The optimal consolidation therapy for adults in remission without a histo-compatible donor has yet to be clearly established. Patients and Methods: This was a retrospective analysis of forty patients (23 females and 17 males) diagnosed with de novo acute myeloid leukemia, who were without a histo-compatible donor, that underwent APBSCT between the year 2000 and 2006 at a single institution. The patients’ age ranged from 18 to 73 with a median age of 50. Cytogenetic analysis was available on 37 of the patients. Complete remission (CR) was confirmed by bone marrow morphology and immunophenotype analysis by flow cytometry. Patients in remission were further consolidated with variable cycles of chemotherapy prior to stem cell transplantation. For stem cell mobilization, patients received high-dose cytarabine (2000mg/m2) and etoposide (5mg/kg) for three days followed by G-CSF at 10μg/kg, starting 10 days after the chemotherapy, before the peripheral stem cell collection. The preparative regimen prior to transplantation with unpurged stem/progenitor cells consisted of a combination of intravenous busulfan (0.8 mg/kg for 16 doses) and cyclophosphamide (60 mg/kg for two doses) (37 patients) or busulfan and melphalan (3 patients). Patients were then followed for treatment-related mortality, disease free survival, and overall survival. The analysis was stratified according to age, cytogenetic risk, and remission state. Results: There was no treatment-related mortality. Nineteen out of forty patients had relapse of their disease. The relapse rate was lowest in the low risk cytogenetic group who were under the age of 60 and highest in the high risk cytogenetic group who were over the age of 60. The overall 5 year survival for all patients was 47%. When stratified for cytogenetic risk and age, the overall survival for low, intermediate, and high cytogenetic risk patients under the age of 60 were 67%, 59%, and 75% respectively. The overall survival for intermediate and high cytogenetic risk patients over the age of 60 were 33% and 0% respectively. The projected rate of disease free survival at 5 years was 40%. When stratified for cytogenetic risk and age, the disease free survival for low, intermediate, and high cytogenetic risk patients under the age of 60 were 33%, 52%, and 50% respectively. Disease free survival for intermediate and high cytogenetic risk patients over the age of 60 were 33% and 0%. Comparing patients in CR1 versus patients in CR2, the overall survival was 47% in CR1 and 50% in CR2. The disease free survival, when grouped as above, were 41% for those in CR1 and 33% for those in CR2. Conclusion: APBSCT is a reasonable and safe intensive consolidation therapy for those patients without a compatible HLA matched donor in first or second complete remissions, notably for those under the age of 60 regardless of their cytogenetic risk. The number of standard consolidations prior to APBSCT may be an important variable predicting outcome.

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