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Farhad Ravandi MD,
PhD Keyur Patel MD,
Rajyalakshmi Luthra PhD,
Stefan Faderl MD,
PhD Marina Konopleva MD,
Tapan Kadia MD,
Mark Brandt BSc,
Sherry Pierce BSc,
Steven Kornblau MD,
PhD Michael Andreeff MD,
Xuemei Wang PhD, Guillermo Garcia-Manero MD,
Jorge Cortes MD,
Hagop Kantarjian MD
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ABSTRACT: BACKGROUND:IDH1 and IDH2 gene mutations are novel, recurring molecular aberrations among patients with normal karyotype acute myeloid leukemia (AML).METHODS:Among 358 patients with AML treated on 4 protocols using high-dose ara-C plus idarubicin induction, pretreatment samples were available for 170 (median age 53 years, [range, 17-73]; 96% ≤65) and were evaluated for IDH1R132, IDH2R172, and IDH2R140 mutations or the codon 105 single nucleotide polymorphism (SNP) in IDH1.RESULTS:IDH1 and IDH2 mutations were present in 12 (7%) and 24 (14%) of patients, and IDH1 G105 SNP in 24 (14%). Overall, 52 (30%) patients had IDH gene alterations. There was no association with complete response (CR), remission duration, overall survival, and event-free survival and any of the IDH alterations, and no association with a higher CR rate or survival with the 4 regimens for the 52 patients with aberrant IDH. Among the patients with diploid karyotype and NPM1mutFLT3WTgenotype, those with IDH1 or IDH2 mutations had an inferior outcome.CONCLUSIONS:IDH aberrations and IDH1 codon 105 SNP occur in about 30% of younger patients with AML, mostly with diploid karyotype. Using high-dose ara-C-based induction regimens, we did not detect an association with outcome for any of the aberrations. Cancer 2011;. © 2011 American Cancer Society.
Cancer 10/2011; 118(10):2665 - 2673. · 4.77 Impact Factor
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ABSTRACT: BACKGROUND:Despite advances in therapy, the majority of adult patients diagnosed with acute myeloid leukemia (AML) develop disease recurrence and die of their disease. Early intensification of treatment for AML using timed sequential therapy (TST) has been proposed as a means of improving the survival outcome in children. The Children's Cancer Group demonstrated that children with AML who were randomized to receive 2 courses of daunorubicin, cytarabine, thioguanine, etoposide, and dexamethasone (the DCTER regimen) given 10 days apart had an improved event-free survival (EFS) and disease-free survival (DFS) (42% ± 7% and 55% ± 9%, respectively, at 2 years). Reports have suggested an improved outcome in adult patients with AML using TST (at the cost of increased toxicity). The current study was conducted to evaluate the feasibility and effectiveness of the intensively timed DCTER regimen for non-core–binding factor AML in adult patients aged <50 years.METHODS:Between February 2004 and August 2005, 61 patients received this timed sequential induction regimen. Their outcomes were compared with matched historical patients treated with the combination of idarubicin and cytarabine (IA).RESULTS:The median follow-up for surviving patients was 67 months (range, 35-85 months). The timed sequential DCTER regimen had a lower complete remission (CR) rate when compared with the IA combination,, (71% vs 80%, respectively), but this appeared to be counterbalanced by a higher long-term leukemia-free survival rate using the intensified regimen (48% vs 30%, respectively) in patients who achieved a CR (P = .06).CONCLUSIONS:The intensively timed regimen of DCTER was found to induce durable remissions in adult patients with AML, including those patients with high-risk disease. The identification of patients who would potentially benefit from such an intensive regimen may justify the higher early risk of early treatment failure that was found to accompany the intensified DCTER regimen in selected patients. Cancer 2010. © 2010 American Cancer Society.
Cancer 11/2010; 116(22):5272 - 5278. · 4.77 Impact Factor
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PhD Sergej Konoplev MD,
Xuelin Huang PhD,
Harry A. Drabkin MD,
PhD Hartmut Koeppen MD,
PhD Dan Jones MD,
Hagop M. Kantarjian MD, Guillermo Garcia-Manero MD,
PhD Weina Chen MD,
L. Jeffrey Medeiros MD,
PhD Carlos E. Bueso-Ramos MD,
Sergej Konoplev,
Xuelin Huang,
Harry A. Drabkin,
Hartmut Koeppen,
Dan Jones,
Hagop M. Kantarjian,
Guillermo Garcia‐Manero,
Weina Chen,
L. Jeffrey Medeiros,
Carlos E. Bueso‐Ramos
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ABSTRACT: BACKGROUND:Nucleophosmin (NPM1) gene mutations are reported to predict a favorable prognosis in acute myeloid leukemia (AML) patients. Aberrant cytoplasmic localization of nucleophosmin (NPM) protein is reported be a surrogate for NPM1 gene mutation.METHODS:Using immunohistochemical (IHC) analysis, we assessed for NPM (clone 376) expression in formalin-fixed, formic acid-decalcified bone marrow biopsy specimens. DNA sequencing of exon 12 of NPM1 gene was performed in 104 patients.RESULTS:The study included 252 AML patients: 192 de novo AML, 33 AML preceded by either myelodysplastic syndrome or chronic myelomonocytic leukemia, and 27 therapy-related AML. The median age was 62 years and 115 patients were ≤60 years old. All patients received intensive chemotherapy. Cytoplasmic NPM was detected in 59 of 252 (23%) patients, including 48 of 192 (25%) de novo AML and 33 of 94 (35%) with a normal karyotype. DNA sequencing identified NPM1 mutations in 30 of 38 cases with cytoplasmic NPM and 10 of 66 cases with nuclear NPM. Cytoplasmic NPM was associated with young patient age (P = .024), FLT3/ITD (P = .005), CD34 negative blasts (P < .001), high peripheral blood blast count (P = .041), and high serum albumin level (P = .028). No statistical differences in overall or event-free survival were found on the basis of NPM localization. Similar results were obtained in patients ≤60 years old with normal karyotype and wild-type FLT3 (P = .768).CONCLUSIONS:IHC assessment for NPM localization did not predict prognosis in this patient cohort. The discordance between immunohistochemistry and DNA sequencing results indicates that DNA sequencing cannot be replaced by IHC assessment. Cancer 2009. © 2009 American Cancer Society.
Cancer 10/2009; 115(20):4737 - 4744. · 4.77 Impact Factor
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Deborah A. Thomas MD,
Hagop M. Kantarjian MD,
Wendy Stock MD,
Leonard T. Heffner MD,
Stefan Faderl MD, Guillermo Garcia-Manero MD,
Alessandra Ferrajoli MD,
PhD William Wierda MD,
Sherry Pierce RN,
Biao Lu PhD,
Steven R. Deitcher MD,
Susan O'Brien MD
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ABSTRACT: BACKGROUND:Dose intensification of chemotherapy has improved outcome for younger adults with de novo acute lymphoblastic leukemia (ALL). Novel formulations of standard chemotherapy agents may further reduce the incidence of disease recurrence after frontline chemotherapy. Vincristine (VCR) sulfate liposomes injection (VSLI) is a sphingomyelin/cholesterol nanoparticle encapsulated VCR formulation that improves the pharmacokinetic profile of VCR without augmenting neurotoxicity.METHODS:A phase 1 trial of weekly, intravenous VSLI at 1.5 mg/m2, 1.825 mg/m2, 2.0 mg/m2, 2.25 mg/m2, or 2.4 mg/m2 was conducted to determine the maximum tolerated dose (MTD) using a standard, 3 + 3 dose-escalation design. Dexamethasone (40 mg) was given on Days 1 through 4 and on Days 11 through 14 of each 4-week cycle.RESULTS:Thirty-six adults with relapsed/refractory ALL, all previously treated with conventional VCR, received at least 1 dose of VSLI. The MTD of VSLI was 2.25 mg/m2 based on dose-limiting toxicities of grade 3 motor neuropathy, grade 4 seizure, and grade 4 hepatotoxicity in 1 patient each at the 2.4 mg/m2 dose level. The most common toxicities attributed to VSLI included peripheral neuropathy (55%) and constipation (53%). A complete response (CR) was achieved in 7 of 36 patients (19%) based on an intent-to-treat analysis; the CR rate was 29% for the 14 patients who underwent therapy as their first salvage attempt. Four of 7 patients who achieved a CR underwent subsequent allogeneic stem cell transplantation in remission.CONCLUSIONS:In this study, VSLI plus dexamethasone appeared to be an effective salvage therapy option for relapsed/refractory ALL. A phase 2, international, multicenter clinical trial assessing the efficacy of single-agent VSLI as second salvage therapy for patients with previously treated ALL is underway. Cancer 2009. © 2009 American Cancer Society.
Cancer 08/2009; 115(23):5490 - 5498. · 4.77 Impact Factor
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Hagop Kantarjian MD,
Susan O'Brien MD,
Farhad Ravandi MD,
Gautam Borthakur MD,
Stefan Faderl MD,
Carlos Bueso-Ramos MD,
Lynne Abruzzo MD,
Sherry Pierce RN,
Jianqin Shan PhD,
Jean-Pierre Issa MD, Guillermo Garcia-Manero MD
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ABSTRACT: BACKGROUND:To define the prognosis in myelodysplastic syndrome (MDS) and deletion 5q with or without other cytogenetic abnormalities.METHODS:Patients with MDS (<20% blasts) and evaluable cytogenetic studies (1966-present) were reviewed. Outcome of patients with deletion 5q or with loss of chromosome 5 (monosomy 5) was analyzed.RESULTS:Of 2743 patients analyzed, 287 (10%) had deletion 5q and 216 (8%) had monosomy 5 abnormalities. The median survival was 9 months with deletion 5q, 6 months with monosomy 5, and 17 months without a chromosome 5 abnormality. Considering patients with deletion 5q, the median survival was 33 months with deletion 5q alone, 17 months with deletion 5q and 1 additional abnormality, but only 6 months to 12 months with deletion 5q and ≥2 abnormalities or chromosome 7 abnormality. Only 93 patients (3.4% of total) had lower risk MDS (international prognostic scoring system low or intermediate 1) and deletion 5q; their median survival was 29 months (2-year survival 60%), and ranged from 13-41 months depending on the presence or absence of additional chromosomal abnormalities. Among 198 patients with MDS with deletion 5q and <10% blasts (a subset now often offered lenalidomide), the median survival was 12 months. Monosomy 5 was significantly more frequently associated with advanced MDS and with other chromosomal abnormalities.CONCLUSIONS:This study provided baseline expectations of outcome in different MDS subsets and deletion 5q. Cancer 2009. © 2009 American Cancer Society.
Cancer 08/2009; 115(22):5202 - 5209. · 4.77 Impact Factor
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Dushyant Verma MD,
Susan O'Brien MD,
Deborah Thomas MD,
Stefan Faderl MD,
Charles Koller MD,
Sherry Pierce RN,
Partow Kebriaei MD, Guillermo Garcia-Manero MD,
Jorge Cortes MD,
Hagop Kantarjian,
Farhad Ravandi MD
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ABSTRACT: BACKGROUND:Secondary malignancies including myeloid neoplasms occur infrequently in acute lymphoblastic leukemia (ALL) and to the authors' knowledge have not been as well documented in adults as in children.METHODS:A total of 641 patients with de novo ALL who were treated with the hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) regimen or its variants were analyzed.RESULTS:Sixteen patients (2.49%) developed secondary acute myelogenous leukemia (AML) (6 patients) or myelodysplastic syndrome (MDS) (10 patients). At the time of ALL diagnosis, the median age was 53 years; cytogenetics were normal in 11 patients, pseudo-diploidy with del(2) in 1 patient, t(9;22) in 1 patient, and unavailable in 3 patients. Frontline therapy included hyper-CVAD in 7 patients, hyper-CVAD with rituximab in 8 patients, and hyper-CVAD with imatinib in 1 patient. Karyotype at time of AML/MDS diagnosis was −5, −7 in 9 patients, normal in 1 patient, complex in 1 patient, inv(11) in 1 patient, t(4;11) in 1 patient, del(20) in 1 patient, and unavailable in 2 patients. Secondary AML/MDS developed at a median of 32 months after ALL diagnosis. Cytarabine plus anthracycline–based treatment was given to 12 patients with AML and high-risk MDS. One patient with MDS received arsenic trioxide, 1 received clofarabine, and 2 received decitabine. Response to treatment was complete remission in 3 patients, partial remission in 6 patients, and no response in 6 patients; 1 patient was untreated. Eight patients (1 with AML and 7 with MDS) underwent allogeneic stem cell transplantation, and all but 2 died at a median of 3 months (range, 0.5–11 months) after transplantation. The median overall survival after a diagnosis of secondary AML and MDS was 9.25 months (range, 1+ to 26+ months).CONCLUSIONS:Secondary AML and MDS occur infrequently in adult patients with de novo ALL treated with the hyper-CVAD regimens, and response to therapy is poor. Cancer 2009. © 2008 American Cancer Society.
Cancer 12/2008; 115(1):101 - 106. · 4.77 Impact Factor
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ABSTRACT: BACKGROUND.Acute myelogenous leukemia (AML) associated with core-binding-factor (CBF) abnormalities is the type of leukemia most responsive to cytarabine (ara-C) therapy and is of relative favorable prognosis. In vitro and ex vivo observations suggest that increases in intracellular ara-C levels influenced by administration of fludarabine and granulocyte colony-stimulating factor (GCSF) increase the effect of ara-C, prompting us to clinically evaluate the efficacy of such combinations.METHODS.We analyzed the event-free survival of patients with newly diagnosed CBF AML treated with fludarabine and ara-C (FA) (N = 45) or with FA and GCSF (FLAG) (N = 22) and compared results to patients treated with regimens consisting of idarubicin and ara-C with or without GCSF (IA/IAG) (N = 47).RESULTS.After accounting for prognostic covariates other than treatment (including year in which treatment was administered), FA, and in particular FLAG, were associated with longer event-free survival than IA/IAG.CONCLUSIONS.Thus, our data lends clinical credence to the observed modulation of ara-C by fludarabine and GCSF. Cancer 2008. © 2008 American Cancer Society.
Cancer 10/2008; 113(11):3181 - 3185. · 4.77 Impact Factor
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ABSTRACT: BACKGROUND.Response rates in chronic myeloid leukemia (CML) are now reported based on the cumulative incidence of a single-time best response. The study aim was to examine the significance of different response criteria for CML on imatinib therapy.METHODS.In all, 276 patients with chronic phase CML on imatinib therapy were analyzed. Cytogenetic and molecular responses were coded as to single best response and response at specific intervals of treatment.RESULTS.The cumulative incidence of complete cytogenetic response (CGCR) with imatinib was 91%; however, the incidence of CGCR at 48 months into therapy was only 78%. Similarly, the incidence of major molecular responses (best cumulative vs landmark at 48 months) were 74% versus 62%, and of undetectable BCR-ABL transcripts 38% versus 24%. There was a strong association between achievement of major cytogenetic response (Philadelphia chromosome [Ph]-positivity ≤35%) at 6 months to 12 months and survival as well as progression-free survival (PFS). Achievement of major molecular response (vs lesser molecular response) in patients in complete cytogenetic response was not associated with significant differences in survival, but showed some association with PFS. Durable CGCR and major molecular responses (documented continuously for ≥12 months) were associated with longer PFS duration but not with survival duration differences. Of interest, major molecular responses documented at least twice were noted in 71% of patients on imatinib therapy; undetectable BCR-ABL transcripts documented at least twice were noted in 34%.CONCLUSIONS.Achievement and durability of CGCR and of major and complete molecular responses at landmark times predict outcome in CML, and may help in comparing the efficacy of different treatments. Cancer 2008. © 2007 American Cancer Society.
Cancer 12/2007; 112(4):837 - 845. · 4.77 Impact Factor
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ABSTRACT: BACKGROUND
Decitabine, a hypomethylating agent, is active and has been approved for the treatment of myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia. Intensive chemotherapy is an accepted form of therapy for patients with higher risk MDS. The comparative efficacy of these 2 forms of treatment in MDS is unknown. The objective of the current study was to compare the efficacy and toxicity profiles of decitabine and intensive chemotherapy in MDS.METHODS
The authors compared lower intensity decitabine therapy (n = 115 patients) with intensive chemotherapy (as it is used in acute myeloid leukemia [AML]) in patients with higher risk MDS. Two comparisons were made with a cohort of 376 historic patients (from 1995 to 2005): The first comparison included a subcohort of 115 patients (Group A) who matched the 115 decitabine study patients according to age, International Prognostic Scoring System, and cytogenetics; and the second comparison included the whole cohort of 376 patients without matching (Group B). A multivariate analysis was performed for outcome.RESULTSThe complete remission (CR) rate according to AML criteria was 43% with decitabine, 46% with intensive chemotherapy in Group A, and 52% with intensive chemotherapy in Group B. Compared with Group A, mortality at 6 weeks was 3% with decitabine versus 13% with intensive chemotherapy (P = .006) and, at 3 months, 7% with decitabine versus 23% with intensive chemotherapy (P = .001). Survival was better with decitabine versus intensive chemotherapy in Group A (median survival: 22 months vs 12 months; P < .001). A multivariate analysis of survival in all 491 patients who received decitabine or intensive chemotherapy (Group B) selected decitabine as an independent, favorable prognostic factor for survival (P = .006; hazard ratio, 0.74) after accounting for the independent prognostic effect of pretreatment factors.CONCLUSIONS
In this analysis, decitabine was associated with a survival advantage compared with intensive chemotherapy in patients with higher risk MDS. Future studies should evaluate prospectively the results of decitabine versus intensive chemotherapy in this setting. Cancer 2007 © 2007 American Cancer Society.
Cancer 03/2007; 109(6):1133 - 1137. · 4.77 Impact Factor
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Susan O'Brien MD,
Francis Giles MD,
Moshe Talpaz MD,
Jorge Cortes MD,
Mary Beth Rios RN,
Jianqin Shan PhD,
Deborah Thomas MD,
Michael Andreeff MD,
Steven Kornblau MD,
Stefan Faderl MD, Guillermo Garcia-Manero MD,
Kevin White C-PA,
Susie Mallard RPh,
Emil Freireich MD,
Hagop M. Kantarjian M.D
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ABSTRACT: BACKGROUND
Before the discovery of imatinib mesylate, a Bcr-Abl selective tyrosine kinase inhibitor, three agents, interferon-alpha (IFN-α), cytarabine (ara-C), and homoharringtonine (HHT), had demonstrated activity against Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) as single agents and in couplet combinations. The goals of the current study were to evaluate the efficacy of the triple combination regimen with IFN-α, ara-C, and HHT in newly diagnosed Ph-positive CML and to assess the impact of the added sequential therapy with imatinib on overall prognosis.METHODS
Ninety patients with Ph-positive CML in early chronic phase received the triple regimen. Therapy consisted of 5 million units (MU)/m2 IFN-α subcutaneously (s.c. daily, ara-C 10 mg s.c. daily, and HHT 2.5 mg/m2 by continuous infusion over 24 hours daily × 5 every month. After a median duration of 16.5 months of therapy, 78 patients had their therapy changed to 400 mg orally administered imatinib daily.RESULTSWith the triple regimen, 85 patients (94%) achieved complete hematologic response and 67 patients (74%) had a cytogenetic response (Ph suppression to ≤ 90%) which was complete (Ph 0%) in 20 patients (22%) and major in 42 patients (46%). Myelosuppression was significant, resulting in considerable reductions in the dose schedules. After 12 months of therapy, the median IFN-α dose was 1.6 MU/m2 daily, the median ara-C dose was 1.85 mg daily, and the median number of HHT days was 2 every month. Only three patients developed blastic phase while receiving the triple regimen. With the change to imatinib therapy, currently 57 patients (63%) are in complete cytogenetic response and 69 patients (76%) in major cytogenetic response. With a median follow-up time of 46 months for the total study group, the estimated 5-year survival rate was 88%, and only 8 patients (9%) to date have developed blastic phase.CONCLUSIONS
The sequence of IFN-α, ara-C, and HHT followed by imatinib (imposed by the discovery of the latter drug) resulted in an estimated 5-year survival rate of 88%. This finding suggests that imatinib combination regimens may improve the prognosis in CML. Cancer 2003;98:888–93. © 2003 American Cancer Society.DOI 10.1002/cncr.11620
Cancer 08/2003; 98(5):888 - 893. · 4.77 Impact Factor
