-
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2012; · 8.30 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Relapse remains the major cause of treatment failure after hematopoietic cell transplantation (HCT) in acute leukemia, even in patients transplanted in morphologic CR. Various techniques now enable the sensitive quantification of 'minimal' amounts of residual disease (MRD) in patients with acute leukemia in remission. Numerous studies convincingly demonstrate that MRD at the time of transplantation is a powerful, independent predictor of subsequent relapse, with current detection levels of one leukemic cell in 10(5)-10(6) normal cells being prognostically relevant. This recognition provides the rationale to assign patients with detectable MRD (that is, 'MRD(+)' patients) to intensified therapies before, during, or after transplantation, although data supporting these strategies are still sparse. Limited evidence from observational studies suggests that outcomes with autologous HCT are so poor that MRD(+) patients should preferentially be assigned to allogeneic HCT, which can cure a subgroup of these patients, particularly if unmanipulated (T-cell replete) grafts and/or minimized immunosuppression are used to optimize the graft-vs-leukemia effect. Emerging data suggest that additional therapy with non-cross-resistant agents to decrease residual tumor burden before transplantation in MRD(+) patients might be beneficial. Further, other studies hint at immunotherapy (for example, rapid withdrawal of immunosuppression and/or donor lymphocyte infusions) as a means to prevent overt relapse if patients remain, or become, MRD(+) after HCT. Ultimately, controlled clinical studies are needed to define the value of MRD-directed therapies, and patients should be encouraged to enter such trials.Bone Marrow Transplantation advance online publication, 23 July 2012; doi:10.1038/bmt.2012.139.
Bone marrow transplantation 07/2012; · 3.00 Impact Factor
-
F Ostronoff,
M Othus,
P A Ho,
M Kutny,
D E Geraghty,
S H Petersdorf,
J E Godwin,
C L Willman,
J P Radich, F R Appelbaum,
D L Stirewalt,
S Meshinchi
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2012; · 8.30 Impact Factor
-
R B Walter,
J M Pagel,
T A Gooley,
E W Petersdorf,
M L Sorror,
A E Woolfrey,
J A Hansen,
A I Salter,
E Lansverk,
F M Stewart,
P V O'Donnell, F R Appelbaum
[show abstract]
[hide abstract]
ABSTRACT: Hematopoietic cell transplantation (HCT) from a matched related donor (MRD) benefits many adults with acute myeloid leukemia (AML) in first complete remission (CR1). The majority of patients does not have such a donor and will require an alternative donor if HCT is to be undertaken. We retrospectively analyzed 226 adult AML CR1 patients undergoing myeloablative unrelated donor (URD) (10/10 match, n=62; 9/10, n=29) or MRD (n=135) HCT from 1996 to 2007. The 5-year estimates of overall survival, relapse and nonrelapse mortality (NRM) were 57.9, 29.7 and 16.0%, respectively. Failure for each of these outcomes was slightly higher for 10/10 URD than MRD HCT, although statistical significance was not reached for any end point. The adjusted hazard ratios (HRs) were 1.43 (0.89-2.30, P=0.14) for overall mortality, 1.17 (0.66-2.08, P=0.60) for relapse and 1.79 (0.86-3.74, P=0.12) for NRM, respectively, and the adjusted odds ratio for grades 2-4 acute graft-versus-host disease was 1.50 (0.70-3.24, P=0.30). Overall mortality among 9/10 and 10/10 URD recipients was similar (adjusted HR 1.16 (0.52-2.61), P=0.71). These data indicate that URD HCT can provide long-term survival for CR1 AML; outcomes for 10/10 URD HCT, and possibly 9/10 URD HCT, suggest that this modality should be considered in the absence of a suitable MRD.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2010; 24(7):1276-82. · 8.30 Impact Factor
-
P A Ho,
T A Alonzo,
K J Kopecky,
K L Miller,
J Kuhn,
R Zeng,
R B Gerbing,
S C Raimondi,
B A Hirsch,
V Oehler, [......],
S H Petersdorf,
J E Anderson,
G H Reaman,
L H Baker,
C L Willman,
I D Bernstein,
J P Radich, F R Appelbaum,
D L Stirewalt,
S Meshinchi
[show abstract]
[hide abstract]
ABSTRACT: Recent whole-genome sequencing efforts led to the identification of IDH1(R132) mutations in acute myeloid leukemia (AML) patients. We studied the prevalence and clinical implications of IDH1 genomic alterations in pediatric and adult AML. Diagnostic DNA from 531 AML patients treated on Children's Oncology Group trial COG-AAML03P1 (N=257), and Southwest Oncology Group trials SWOG-9031, SWOG-9333 and SWOG-9500 (N=274), were tested for IDH1 mutations. Codon R132 mutations were absent in the pediatric cohort, but were found in 12 of 274 adult patients (4.4%, 95% CI 2.3-7.5). IDH1(R132) mutations occurred most commonly in patients with normal karyotype, and those with FLT3/ITD and NPMc mutations. Patients with IDH1(R132) mutations trended toward higher median diagnostic white blood cell counts (59.2 x 10(9) vs 29.1 x 10(9) per liter, P=0.19) than those without mutations, but the two groups did not differ significantly in age, bone marrow blast percentage, overall survival or relapse-free survival. Eleven patients (2.1%) harbored a novel V71I sequence alteration, which was found to be a germ-line polymorphism. IDH1 mutations were not detected in pediatric AML, and are uncommon in adult AML.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2010; 24(5):909-13. · 8.30 Impact Factor
-
Hartmut Döhner,
Elihu H Estey,
Sergio Amadori, Frederick R Appelbaum,
Thomas Büchner,
Alan K Burnett,
Hervé Dombret,
Pierre Fenaux,
David Grimwade,
Richard A Larson,
Francesco Lo-Coco,
Tomoki Naoe,
Dietger Niederwieser,
Gert J Ossenkoppele,
Miguel A Sanz,
Jorge Sierra,
Martin S Tallman,
Bob Löwenberg,
Clara D Bloomfield
[show abstract]
[hide abstract]
ABSTRACT: In 2003, an international working group last reported on recommendations for diagnosis, response assessment, and treatment outcomes in acute myeloid leukemia (AML). Since that time, considerable progress has been made in elucidating the molecular pathogenesis of the disease that has resulted in the identification of new diagnostic and prognostic markers. Furthermore, therapies are now being developed that target disease-associated molecular defects. Recent developments prompted an international expert panel to provide updated evidence- and expert opinion-based recommendations for the diagnosis and management of AML, that contain both minimal requirements for general practice as well as standards for clinical trials. A new standardized reporting system for correlation of cytogenetic and molecular genetic data with clinical data is proposed.
Blood 10/2009; 115(3):453-74. · 9.90 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Survival rates after myeloablative hematopoietic cell transplantation (HCT) in childhood have improved. We conducted a cross-sectional study evaluating the quality of life (QOL) of 214 adult survivors of a childhood HCT compared with controls using standardized self-report measures with strong psychometric properties to evaluate physical function, psychological function and cognitive symptoms. From these results we conducted a multivariate analysis of risk factors. This analysis for physical functioning showed poorer function among myeloid disease survivors compared with patients with all other diagnoses (P=0.02), men functioned better than women (P=0.05) and those >18 years after transplant functioned more poorly than those <18 years after transplant (P=0.05). Psychological functioning showed that those who received more therapy and females were more likely to be depressed (P=0.03) and (P=0.005). Perceived cognitive symptoms showed that female survivors had more symptoms than male survivors (P=0.01), and those receiving more preceding therapy compared with those with less preceding therapy (P=0.001) or cranial irradiation compared with those without cranial irradiation (P=0.002) had more perceived cognitive symptoms. Overall, these data indicate that the majority of adult survivors of a childhood transplant are functioning well, but some have problems that need to be addressed.
Bone marrow transplantation 08/2009; 45(4):746-54. · 3.00 Impact Factor
-
T Furlong,
P Martin,
M E D Flowers,
F Carnevale-Schianca,
R Yatscoff,
T Chauncey, F R Appelbaum,
H J Deeg,
K Doney,
R Witherspoon,
B Storer,
K M Sullivan,
R Storb,
R A Nash
[show abstract]
[hide abstract]
ABSTRACT: We evaluated the pharmacokinetics and efficacy of oral mycophenolate mofetil (MMF) for treatment of refractory GVHD. In a prospective study of acute GVHD, 9 of 19 patients (47%) had a response and 10 (53%) had no improvement. Survival at 6 and 12 months after the start of MMF was 37 and 16%, respectively. In a retrospective study of acute GVHD, 14 of 29 patients (48%) had a response and 15 (52%) had no improvement. Survival at 6 and 12 months was 55 and 52%, respectively. In a prospective study of chronic GVHD, the cumulative incidence of disease resolution and withdrawal of all systemic immunosuppressive treatment was 9, 17 and 26% at 12, 24 and 36 months, respectively, after starting MMF. Thirteen patients (59%) required additional systemic immunosuppressive treatment for chronic GVHD. Nine of the 42 patients (21%) in the prospective studies discontinued MMF treatment because of toxicity. The area under the curve plasma concentrations of mycophenolic acid seemed to be suboptimal among patients with acute GVHD but not among those with chronic GVHD. MMF can be used effectively for treatment of GVHD.
Bone marrow transplantation 05/2009; 44(11):739-48. · 3.00 Impact Factor
-
D L Stirewalt,
Y E Choi,
N E Sharpless,
E L Pogosova-Agadjanyan,
M R Cronk,
M Yukawa,
E B Larson,
B L Wood, F R Appelbaum,
J P Radich,
S Heimfeld
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 03/2009; 23(2):430. · 8.30 Impact Factor
-
E. D. THOMAS,
J. E. SANDERS,
C. D. BUCKNER,
TH. PAPAYANNOPOULOU,
C. BORGNA‐PIGNATTI,
P. STEFANO,
K. M. SULLIVAN,
H. J. DEEG,
R. P. WITHERSPOON, F. R. APPELBAUM,
R. A. CLIFT,
R. STORB
Annals of the New York Academy of Sciences 12/2006; 445(1):417 - 427. · 3.15 Impact Factor
-
M L Slovak,
H Gundacker,
C D Bloomfield,
G Dewald, F R Appelbaum,
R A Larson,
M S Tallman,
J M Bennett,
D L Stirewalt,
S Meshinchi,
C L Willman,
Y Ravindranath,
T A Alonzo,
A J Carroll,
S C Raimondi,
N A Heerema
Leukemia 08/2006; 20(7):1295-7. · 9.56 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: B-cell chronic lymphocytic leukemia (CLL) accounts for 95% of chronic leukemia cases and 25% of all leukemia. Despite the prevalence of CLL, progress in its treatment has been only modest over the past three decades. Based upon the ability of fludarabine to produce high-grade remissions especially among patients with low initial tumor mass, and the ability of alkylators to reduce tumor mass, we hypothesized that sequential administration of a limited number of cycles of intermediate-dose cyclophosphamide followed by fludarabine could result in a larger percentage of patients with complete remissions (CRs). In all, 27 of the 49 eligible patients achieved overall responses of CR, unconfirmed complete remission (UCR), or PR, for a total response rate of 55% (95% confidence interval (CI) 40-69%). Considering the confounding medical issues of this patient population with advanced aggressive disease, the regimen was generally well tolerated. This study demonstrates that high-dose cyclophosphamide followed by fludarabine was relatively well tolerated in this group of advanced CLL patients. The study's criterion for testing whether the regimen is sufficiently effective to warrant further investigation was met: 14 (32%) of the first 44 eligible patients achieved CR or UCR.
Leukemia 12/2005; 19(11):1880-6. · 9.56 Impact Factor
-
F R Appelbaum
Leukemia 03/2005; 19(2):171-5. · 9.56 Impact Factor
-
U Yusuf,
H A Frangoul,
T A Gooley,
A E Woolfrey,
P A Carpenter,
R G Andrews,
H J Deeg, F R Appelbaum,
C Anasetti,
R Storb,
J E Sanders
[show abstract]
[hide abstract]
ABSTRACT: The purpose of this study was to evaluate the role of allogeneic bone marrow transplantation (BMT) in children with myelodysplastic syndrome (MDS). In total, 94 consecutive pediatric patients with MDS received an allogeneic BMT from 1976 to 2001 for refractory anemia (RA) (n=25), RA with ringed sideroblasts (RARS) (n=2), RA with excess blasts (RAEB) (n=20), RAEB in transformation (RAEB-T) (n=14), juvenile myelomonocytic leukemia (JMML) (n=32) or chronic myelomonocytic leukemia (CMML) (n=1). The estimated 3-year probabilities of survival, event-free survival (EFS), nonrelapse mortality and relapse were 50, 41, 28 and 29%, respectively. Patients with RA/RARS had an estimated 3-year survival of 74% compared to 68% in those with RAEB and 33% in patients with JMML/CMML. In multivariable analysis, patients with RAEB-T or JMML were 3.9 and 3.7 times more likely to die compared to those with RA/RARS and RAEB (P=0.005 and 0.004, respectively). Patients with RAEB-T were 5.5 times more likely to relapse (P=0.01). The median follow-up among the 43 surviving patients is 10 years (range 1-25). We conclude that allogeneic BMT for children with MDS is well tolerated and can be curative.
Bone Marrow Transplantation 05/2004; 33(8):805-14. · 3.75 Impact Factor
-
Annals of Hematology 02/2004; 83 Suppl 1:S106-7. · 2.62 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The objective of this prospective study was to determine whether amifostine (Ethyol) reduced conditioning-related toxicity following a regimen of busulfan (7 mg/kg) and fractionated total body irradiation (6 x 200 cGy). In all, 12 patients with advanced myelodysplastic syndrome transplanted from HLA-identical siblings were enrolled. Patients received 340 mg/m(2) amifostine i.v. twice daily during conditioning (days -7 through -1). All patients developed oropharyngeal mucositis. Six patients had evidence of sinusoidal obstruction syndrome of the liver. Six patients experienced pulmonary toxicity of grades II-III. A total of 11 patients died, one with relapse and 10 with infectious complications or regimen-related toxicity. Nonrelapse causes of death included invasive aspergillosis in three, multiorgan failure in three, and idiopathic interstitial pneumonitis in two patients. One patient each died of organizing pneumonia and CMV pneumonia. One patient is alive in complete remission 31 months after transplantation. These results were not superior to those in patients conditioned with busulfan plus fractionated total body irradiation and not given amifostine, and suggest that amifostine, as administered here, has no protective effect against toxicity from this myeloablative regimen.
Bone Marrow Transplantation 01/2004; 32(11):1071-5. · 3.75 Impact Factor
-
Chien-Shing Chen,
M Boeckh,
K Seidel,
J G Clark,
E Kansu,
D K Madtes,
J L Wagner,
R P Witherspoon,
C Anasetti, F R Appelbaum,
W I Bensinger,
H J Deeg,
P J Martin,
J E Sanders,
R Storb,
J Storek,
J Wade,
M Siadak,
M E D Flowers,
K M Sullivan
[show abstract]
[hide abstract]
ABSTRACT: The incidence, etiology, outcome, and risk factors for developing pneumonia late after hematopoietic stem cell transplantation (SCT) were investigated in 1359 patients transplanted in Seattle. A total of 341 patients (25% of the cohort) developed at least one pneumonic episode. No microbial or tissue diagnosis (ie clinical pneumonia) was established in 197 patients (58% of first pneumonia cases). Among the remaining 144 patients, established etiologies included 33 viral (10%), 31 bacterial (9%), 25 idiopathic pneumonia syndrome (IPS, 7%), 20 multiple organisms (6%), 19 fungal (6%), and 16 Pneumocystis carinii pneumonia (PCP) (5%). The overall cumulative incidence of first pneumonia at 4 years after discharge home was 31%. The cumulative incidences of pneumonia according to donor type at 1 and 4 years after discharge home were 13 and 18% (autologous/syngeneic), 22 and 34% (HLA-matched related), and 26 and 39% (mismatched related/unrelated), respectively. Multivariate analysis of factors associated with development of late pneumonia after allografting were increasing patient age (RR 0.5 for <20 years, 1.2 for >40 years, P=0.009), donor HLA-mismatch (RR 1.6 for unrelated/mismatched related, P=0.01), and chronic graft-versus-host disease (GVHD; RR 1.5, P=0.007). Our data suggest that extension of PCP prophylaxis may be beneficial in high-risk autograft recipients. Further study of long-term anti-infective prophylaxis based on patient risk factors after SCT appear warranted.
Bone Marrow Transplantation 09/2003; 32(5):515-22. · 3.75 Impact Factor
-
F R Appelbaum
Leukemia 04/2003; 17(3):492-5. · 9.56 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is a rate-limiting enzyme in the mevalonate biochemical pathway and HMG-CoA reductase inhibitors (statins) show toxicity for certain tumors, including acute myeloid leukemia (AML). This toxicity has been attributed to statin inhibition of Ras isoprenylation in tumors like AML where oncogenic ras mutations and/or overexpression are common. We show that mevastatin kills certain AML cell lines and is more toxic to a majority of primary AML cell samples than to myeloid cells in bone marrow (BM) samples from normal donors, and that mevastatin can produce more than additive kill with standard chemotherapeutics. Mevastatin reduces Ras membrane localization, but statin sensitivity in primary AML cells is not consistently associated with ras mutations nor with Ras overexpression, suggesting that another mevalonate pathway by-product(s) is the statin target in at least some AMLs.
Leukemia Research 03/2003; 27(2):133-45. · 2.92 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We retrospectively analyzed the relationship between busulfan average steady-state plasma concentration (C(SS)) and graft rejection in 53 children receiving busulfan/cyclophosphamide (BU/CY) preparative regimens prior to hematopoietic stem cell transplantation (HSCT). Patients received a total oral busulfan dose of 11 to 28 mg/kg followed by a total cyclophosphamide dose of 120 to 335 mg/kg in preparation for allogeneic grafts (HLA-matched or HLA partially matched sibling, parent or unrelated donor). Graft rejection occurred in eight (15%) patients. Busulfan C(SS) (P = 0.0024) was the only statistically significant predictor of rejection on univariate logistic regression analysis, with the risk of rejection decreasing with an increase in busulfan C(SS). Severe (grade 3 or 4) regimen-related toxicity (RRT) occurred in four patients. Ten patients (19%) had a busulfan C(SS) higher than 900 ng/ml, one of whom had severe RRT. Higher and variable doses of cyclophosphamide may explain the lack of a relationship between busulfan C(SS) and RRT in children. It may be possible to improve the outcome of HSCT in pediatric patients receiving the BU/CY regimen through optimization of busulfan C(SS) and better definition of the contribution of activated cyclophosphamide metabolites to toxicity.
Bone Marrow Transplantation 09/2002; 30(3):167-73. · 3.75 Impact Factor
