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Find video protocols related to scientific articles indexed in Pubmed.
Acute myeloid leukemia in adolescents and young adults: challenging aspects.
Acta Haematol.
PUBLISHED: 09-10-2014
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Treating adolescents and young adults (AYAs) diagnosed with cancer is a challenge. Acute myeloid leukemia (AML) which is usually diagnosed in a previously healthy kid, requiring immediate aggressive chemotherapy, brings difficulties and conflicts associated with severe illness to extremes. The incidence of AML in adolescents aged 15-19 years approaches 8.5 per million. Only in recent years has it become evident that the prognosis of AYAs diagnosed with AML is poorer compared to younger children diagnosed with AML with similar characteristics. No specific genetic aberration or other known poor risk factor was found to explain the inferior prognosis of AYAs. In acute lymphoblastic leukemia the contribution of differences between adult and pediatric protocols to AYA outcome is established. It has been suggested that pediatric protocols should also apply to AYAs with AML; however, data supporting this are vague. Herein, existing evidence regarding special considerations in treating AYAs with AML is discussed. Mental and psychological age-specific aspects important to consider when treating AYAs with AML are overviewed. Awareness for adolescent special needs, adherence to protocols and intensive supportive care are important. Multidisciplinary adolescent-oriented staff should be involved in the therapy of any AYA with AML escorting this special patient population on the road to cure.
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Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia.
Nature
PUBLISHED: 08-17-2014
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T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy with a dismal overall prognosis, including a relapse rate of up to 25%, mainly because of the lack of non-cytotoxic targeted therapy options. Drugs that target the function of key epigenetic factors have been approved in the context of haematopoietic disorders, and mutations that affect chromatin modulators in a variety of leukaemias have recently been identified; however, 'epigenetic' drugs are not currently used for T-ALL treatment. Recently, we described that the polycomb repressive complex 2 (PRC2) has a tumour-suppressor role in T-ALL. Here we delineated the role of the histone 3 lysine 27 (H3K27) demethylases JMJD3 and UTX in T-ALL. We show that JMJD3 is essential for the initiation and maintenance of T-ALL, as it controls important oncogenic gene targets by modulating H3K27 methylation. By contrast, we found that UTX functions as a tumour suppressor and is frequently genetically inactivated in T-ALL. Moreover, we demonstrated that the small molecule inhibitor GSKJ4 (ref. 5) affects T-ALL growth, by targeting JMJD3 activity. These findings show that two proteins with a similar enzymatic function can have opposing roles in the context of the same disease, paving the way for treating haematopoietic malignancies with a new category of epigenetic inhibitors.
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Pathogenesis and prognostication in acute lymphoblastic leukemia.
F1000Prime Rep
PUBLISHED: 07-08-2014
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The process of lymphoid maturation is tightly controlled by the hierarchical activation of transcription factors and selection through functional signal transduction. Acute lymphoblastic leukemia (ALL) represents a group of B/T-precursor-stage lymphoid cell malignancies arising from genetic alterations that block lymphoid differentiation and drive aberrant cell proliferation and survival. With recent advances in next-generation sequencing, we are discovering new mutations affecting normal lymphopoiesis and the significance of cooperating mutations, as well as epigenetic alterations. The data obtained in this way aids in the evaluation of prognosis in the individual patient but, importantly, also in incorporating targeted therapy appropriate for the mutational abnormality.
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Younger adults with acute myeloid leukemia in remission for ? 3 years have a high likelihood of cure: The ECOG experience in over 1200 patients.
Leuk. Res.
PUBLISHED: 04-13-2014
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We examined 1229 younger patients with acute myeloid leukemia who achieved CR1 on Eastern Cooperative Oncology Group trials. We defined late relapse as occurring after ? 3 years of CR1. With median follow-up of 11.3 years, there were 14 late relapses (1.1% of CR1 patients; 3.3% of 3-year CR1 patients). Eight achieved second CR and median overall survival after late relapse was 3.2 years. Most patients tested (9/11) had a normal karyotype at diagnosis; none had new cytogenetic abnormalities at relapse. Late relapse is rare and nearly all 3-year CR1 patients are cured. If late relapse occurs, outcomes are relatively favorable.
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Autologous is superior to allogeneic hematopoietic cell transplantation for acute promyelocytic leukemia in second complete remission.
Biol. Blood Marrow Transplant.
PUBLISHED: 03-24-2014
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To identify favored choice of transplantation in patients with acute promyelocytic leukemia (APL) in second complete remission, we studied 294 patients with APL in second complete remission (CR2) receiving allogeneic (n = 232) or autologous (n = 62) hematopoietic cell transplantation (HCT) reported to the Center for International Blood and Marrow Transplantation Research (CIBMTR) from 1995 to 2006, including 155 with pre-HCT PML/RAR? status (49% of allogeneic and 66% of autologous). Patient characteristics and transplantation characteristics, including treatment-related mortality, overall survival (OS), and disease-free survival, were collected and analyzed for both univariate and multivariate outcomes. With median follow-up of 115 (allogeneic) and 72 months (autologous), 5-year disease-free survival (DFS) favored autologous with 63% (49% to 75%), compared with allogeneic at 50% (44% to 57%) (P = .10). OS was 75% (63% to 85%) versus 54% (48% to 61%) (P = .002), for autologous and allogeneic transplantation, respectively. Multivariate analysis showed significantly worse DFS after allogeneic HCT (hazard ratio [HR], 1.88; 95% confidence interval [CI], 1.16 to 3.06; P = .011) and age > 40 years (HR, 2.30; 95% CI, 1.44 to 3.67; P = .0005). OS was significantly worse after allogeneic HCT (HR, 2.66; 95% CI, 1.52 to 4.65; P= .0006); age > 40 (HR, 3.29; 95% CI, 1.95 to 5.54; P < .001), and first complete remission < 12 months (HR, 1.56; 95% CI, 1.07 to 2.26; P = .021). Positive pre-HCT PML-RAR? status in 17 of 114 allogeneic and 6 of 41 receiving autologous transplantation did not influence relapse, treatment failure, or survival in either group. The survival advantage for autografting was attributable to increased treatment-related mortality (TRM) in the allogeneic group of 30% compared to 2% in the autologous group, in addition to the added mortality associated with GVHD. We conclude that autologous HCT yields superior OS for APL in CR2. Long-term DFS in autologous recipients, even with minimal residual disease-positive grafts, remains an important subject for further study.
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Platelet factor 4/heparin-particle gel immunoassay (PaGIA) is a weak method for heparin-induced thrombocytopenia (HIT) evaluation of post cardio-pulmonary bypass surgery patients.
J. Thromb. Thrombolysis
PUBLISHED: 02-25-2014
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Diagnosis of heparin induced thrombocytopenia (HIT) is not always easy, especially when a confirmatory functional test is not available. In most cases the diagnosis relies on the combination of pretest probability and an immunologic test. Among patients post cardiopulmonary bypass (CPB) surgery, anti-platelet factor 4/heparin antibodies tend to be high but with low clinical implication. The current retrospective study examined the behavior of patients with positive PF4/heparin-PaGIA results, divided into two groups according to whether or not they have undergone CPB surgery. The main focus of the study was on the reliability of the PF4/heparin-PaGIA test in these two settings. The files of 104 single center patients, who had a positive PF4/heparin-PaGIA test, were reviewed. 62% were post CPB and 38% were not. An association between the intensity of positivity of PF4/heparin-PaGIA test and both the 4Ts pretest probability method (p = 0.003) and the incidence of thrombosis (p = 0.02) was found only in the patients who have not undergone CPB surgery, but not in the CPB patients. This study suggests that PF4/heparin-PaGIA is not a reliable method in patients post CPB surgery who are investigated for a possible diagnosis of HIT.
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Allotransplantation for patients age ?40 years with non-Hodgkin lymphoma: encouraging progression-free survival.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-30-2014
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Non-Hodgkin lymphoma (NHL) disproportionately affects older patients, who do not often undergo allogeneic hematopoietic cell transplantation (HCT). We analyzed Center for International Blood and Marrow Transplant Research data on 1248 patients age ?40 years receiving reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning HCT for aggressive (n = 668) or indolent (n = 580) NHL. Aggressive lymphoma was more frequent in the oldest cohort 49% for age 40 to 54 versus 57% for age 55 to 64 versus 67% for age ?65; P = .0008). Fewer patients aged ?65 had previous autografting (26% versus 24% versus 9%; P = .002). Rates of relapse, acute and chronic GVHD, and nonrelapse mortality (NRM) at 1 year post-HCT were similar in the 3 age cohorts (22% [95% confidence interval (CI), 19% to 26%] for age 40 to 54, 27% [95% CI, 23% to 31%] for age 55 to 64, and 34% [95% CI, 24% to 44%] for age ?65. Progression-free survival (PFS) and overall survival (OS) at 3 years was slightly lower in the older cohorts (OS: 54% [95% CI, 50% to 58%] for age 40 to 54; 40% [95% CI, 36% to 44%] for age 55 to 64, and 39% [95% CI, 28% to 50%] for age ?65; P < .0001). Multivariate analysis revealed no significant effect of age on the incidence of acute or chronic GVHD or relapse. Age ?55 years, Karnofsky Performance Status <80, and HLA mismatch adversely affected NRM, PFS, and OS. Disease status at HCT, but not histological subtype, was associated with worse NRM, relapse, PFS, and OS. Even for patients age ?55 years, OS still approached 40% at 3 years, suggesting that HCT affects long-term remission and remains underused in qualified older patients with NHL.
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Maintenance with rituximab is safe and not associated with severe or uncommon infections in patients with follicular lymphoma: results from the phase IIIb MAXIMA study.
Ann. Hematol.
PUBLISHED: 01-15-2014
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Previous randomized trials have demonstrated that rituximab maintenance (R-maintenance) can prolong time to progressive disease in patients with follicular lymphoma (FL). The phase IIIb MAXIMA study (NCT00430352) was a large prospective evaluation of R-maintenance in a daily care setting. The primary objective was safety. Secondary objectives included progression-free survival, overall survival, time to next lymphoma treatment, and partial response (PR) to complete response/unconfirmed (CR/CRu) conversion rate. Patients (n = 545) with first-line or relapsed FL who responded to 8 cycles of rituximab-based induction received R-maintenance every 2 months for 2 years. At study entry, 380 patients had CR or CRu, and 165 had PR. The median age was 57.0 years. The most common non-hematologic adverse events (AEs, excluding infusion-related reactions) were cough (9.9 % of patients), fatigue (7.5 %), nasopharyngitis (7.1 %), back pain (6.5 %), diarrhea (6.9 %), arthralgia (6.0 %), headache and hypertension (5.2 % each), and pyrexia (5.1 %). The majority of AEs were grade 1 or 2. Grade 3, 4, and 5 infections occurred in 21 (3.9 %), 2 (0.4 %), and 1 (0.2 %) patient, respectively. Fifty-one hematologic AEs occurred in 6.6 % (n = 35) of patients. Grade 3/4 prolonged neutropenia and hypogammaglobulinemia occurred in 13 (2.4 %) and 5 (0.9 %) patients, respectively. All cases of prolonged neutropenia or hypogammaglobulinemia were manageable and resolved. Fast infusion did not alter the safety profile. Efficacy was comparable with results from previous trials. R-maintenance is safe in a daily care setting for patients with first-line or relapsed FL.
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Single cell analysis exposes intratumor heterogeneity and suggests that FLT3-ITD is a late event in leukemogenesis.
Exp. Hematol.
PUBLISHED: 01-05-2014
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FMS-like tyrosine kinase 3 receptor-internal tandem duplication (FLT3-ITD) commonly occurs in acute myeloid leukemia and is considered rare in acute lymphocytic leukemia. Acute leukemia has poor prognosis, mainly due to relapse. Standard FLT3-ITD diagnostic techniques are based on genomic polymerase chain reaction and have recently incorporated GeneScan (Applied Biosystems, Foster City, CA) to identify variations of the FLT3 gene. As this is an average-based assay utilized in a heterogeneous leukemic cell population, we hypothesized that cells of acute leukemia, considered FLT3-ITD-negative by standard methods, could possess a fraction of FLT3-ITD-positive cells. The present study employed single cell mutation analysis to evaluate the FLT3-ITD status in newly diagnosed acute myeloid leukemia (n = 5) and acute lymphocytic leukemia (n = 3) patients. A total of 541 single leukemic cells and 36 mononuclear cells from healthy volunteers were analyzed. Seven patients, considered FLT3-ITD-negative according to bulk DNA analysis, appeared to possess a small fraction of FLT3-ITD-positive cells based on single cell analysis. Moreover, this approach revealed the heterogeneity of the tumor as evident by different FLT3-ITD mutations present in the same patient. The presence of a minor clone carrying FLT3-ITD in almost all patients tested provides evidence that this lesion is a common late event in leukemogenesis. Additionally, 3 relapsed patients demonstrated loss of heterozygosity of the normal allele, affecting 25%-100% of the cells found to be FLT3-ITD-positive. Though further clinical testing is warranted, these findings may have implications on the prognostic significance of FLT3-ITD and the use of targeted therapy.
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UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia.
Blood
PUBLISHED: 11-25-2013
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The Philadelphia chromosome positive arm of the UKALLXII/ECOG2993 study for adult acute lymphoblastic leukaemia enrolled 266 patients between 1993 and 2003 (pre-imatinib cohort). In 2003 imatinib was introduced as a single-agent course following induction (N=86, late imatinib). In 2005 imatinib was added to the second phase of induction (N=89, early imatinib). The CR rate was 92% in the imatinib cohort versus 82% in the pre-imatinib cohort (P=0.004). At 4 years, the OS of all patients in the imatinib cohort was 38% versus 22% in the pre-imatinib cohort (P=0.003). The magnitude of the difference between the preimatinib and imatinib cohorts in EFS, OS and RFS seen in univariate analysis was even greater in the multivariate analysis In the pre-imatinib cohort, 31% of those starting treatment achieved alloHSCT as compared to 46% in the imatinib cohort. A Cox multivariate analysis taking alloHSCT into account showed a modest additional benefit to imatinib (hazard ratio for EFS 0.64, 95% CI 0.44-0.93, P=0.02), but no significant benefit for OS and RFS. Adding imatinib to standard therapy improves CR rate and long-term OS for adults with ALL. A proportion of the OS benefit derives from the fact that imatinib facilitates alloHSCT. This study is registered at clinicaltrials.gov; identifier: NCT00002514.
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The high-affinity CXCR4 antagonist BKT140 is safe and induces a robust mobilization of human CD34+ cells in patients with multiple myeloma.
Clin. Cancer Res.
PUBLISHED: 11-18-2013
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CXCR4 plays an important role in the retention of stem cells (SCs) within the bone marrow. BKT140 is a 14-residue bio stable synthetic peptide which binds CXCR4 with a greater affinity compared with plerixafor (4nM vs 84nM). Studies in mice demonstrated the efficient and superior mobilization and transplantation of SCs collected with GCSF-BKT140, compared with those obtained when using SCs obtained with each one of these mobilizing agent alone. These results have served as a platform for the present clinical phase I study.
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Is there a role for allogeneic transplantation in chronic myeloid leukemia?
Expert Rev Hematol
PUBLISHED: 11-14-2013
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Allogeneic hemopoietic cell transplantation has moved away from being the standard of care for patients with chronic myeloid leukemia (CML). Its role is currently limited to an unsatisfactory response to therapy with tyrosine kinase inhibitors as well as advanced stages of the disease. The advent of tyrosine kinase inhibitors has been one of the most remarkable advances in any form of cancer. Never-the-less, as a definitive procedure, allogeneic transplantation remains the only curative modality and its use in carefully selected patients, who have an inadequate response, has been increasingly recognized. It remains a standard of care for patients who present with blast crisis CML and is often used also in accelerated phase. The future for patients with CML has become so much brighter over the past decade but new issues and considerations continually emerge.
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Important milestones in acute leukemia in 2013.
Best Pract Res Clin Haematol
PUBLISHED: 10-16-2013
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This year marked the occurrence of several important milestones in the treatment of acute leukemias. First, the standard 7 + 3 protocol for acute myeloid leukemia (AML) was developed 40 years ago, and with some adaptations, has stood the test of time. Second, the 1 millionth hematopoietic cell transplant was recorded this year. Stem cell transplant, the first reported by Dr E. Donnall Thomas in 1957, had been considered a rare procedure until about a decade ago. Today, it has become a proven and often life-saving therapy for patients with acute leukemia. Advances in the treatment of patients with AML continue to take place, many of which relate to an increased understanding of the clinical heterogeneity of known subtypes. Forty years ago, the regimen that has come to be known as 7+3 for acute myeloid leukemia (AML) was born [1,2]. Cytosine arabinoside, or arabinosylcytosine as it was then called, was given as a continuous intravenous infusion of 100 mg/m(2) for 7 days, and the anthracycline, daunorubicin, was administered at 45 mg/m(2) intravenously for 3 days. Sixteen patients were originally treated on this protocol, and 5 of 8 previously untreated and 2 of 8 previously treated patients achieved a complete response (CR). This regimen has withstood the test of time. Attempts to add or substitute other agents have not yielded superior results. The only major contemporary change is that a higher dose of daunorubicin is safe and has become the standard of care [3].
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Genetic loss of SH2B3 in acute lymphoblastic leukemia.
Blood
PUBLISHED: 08-01-2013
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The SH2B adaptor protein 3 (SH2B3) gene encodes a negative regulator of cytokine signaling with a critical role in the homeostasis of hematopoietic stem cells and lymphoid progenitors. Here, we report the identification of germline homozygous SH2B3 mutations in 2 siblings affected with developmental delay and autoimmunity, one in whom B-precursor acute lymphoblastic leukemia (ALL) developed. Mechanistically, loss of SH2B3 increases Janus kinase-signal transducer and activator of transcription signaling, promotes lymphoid cell proliferation, and accelerates leukemia development in a mouse model of NOTCH1-induced ALL. Moreover, extended mutation analysis showed homozygous somatic mutations in SH2B3 in 2 of 167 ALLs analyzed. Overall, these results demonstrate a Knudson tumor suppressor role for SH2B3 in the pathogenesis of ALL and highlight a possible link between genetic predisposition factors in the pathogenesis of autoimmunity and leukemogenesis.
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Single Infusion of Donor Mononuclear Early Apoptotic Cells as Prophylaxis for Graft-versus-Host Disease in Myeloablative HLA-Matched Allogeneic Bone Marrow Transplantation: A Phase I/IIa Clinical Trial.
Biol. Blood Marrow Transplant.
PUBLISHED: 06-05-2013
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Because of its potent immunomodulatory effect, an infusion of donor mononuclear early apoptotic cells (ApoCell) was tested in addition to cyclosporine and methotrexate as prophylaxis for acute graft-versus-host disease (GVHD) after HLA-matched myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) from a related donor. In a phase I/IIa clinical trial, we treated 13 patients (median age, 37 years; range, 20 to 59 years) with hematologic malignancies: 7 patients with acute lymphoblastic leukemia, 5 patients with acute myeloid leukemia, and 1 patient with chronic myeloid leukemia, who received conventional myeloablative conditioning, with 35, 70, 140, or 210 × 10(6) cell/kg of donor ApoCell, on day -1 of transplantation. Engraftment was successful in all patients with median time to neutrophil recovery of 13 days (range, 11 to 19), and platelet recovery of 15 days (range, 11 to 59). Serious adverse effects were reported on 10 occasions in the trial, all of which were considered unrelated (n = 7) or unlikely to be related (n = 3) to ApoCell infusion. The nonrelapse mortality at day 100 and 180 after transplantation was 7.7% and the overall survival at 100 and 180 days after transplantation was 92% and 85%, respectively. All ApoCell preparations showed an in vitro significant tolerogenic effect upon interaction with dendritic cells. The overall incidence of acute grades II to IV GVHD was 23%, whereas among those receiving the 2 higher doses (n = 6), the rate was 0%. These results suggest that a single infusion of donor ApoCell in HLA-matched allogeneic HSCT is a safe and potentially effective prophylaxis for acute GVHD occurring after myeloablative conditioning. No dose limiting toxicity was observed. (Clinicaltrials.gov no. NCT00524784).
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Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia.
Cancer Cell
PUBLISHED: 05-25-2013
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Glucocorticoid resistance is a major driver of therapeutic failure in T cell acute lymphoblastic leukemia (T-ALL). Here, we identify the AKT1 kinase as a major negative regulator of the NR3C1 glucocorticoid receptor protein activity driving glucocorticoid resistance in T-ALL. Mechanistically, AKT1 impairs glucocorticoid-induced gene expression by direct phosphorylation of NR3C1 at position S134 and blocking glucocorticoid-induced NR3C1 translocation to the nucleus. Moreover, we demonstrate that loss of PTEN and consequent AKT1 activation can effectively block glucocorticoid-induced apoptosis and induce resistance to glucocorticoid therapy. Conversely, pharmacologic inhibition of AKT with MK2206 effectively restores glucocorticoid-induced NR3C1 translocation to the nucleus, increases the response of T-ALL cells to glucocorticoid therapy, and effectively reverses glucocorticoid resistance in vitro and in vivo.
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Prognostic relevance of integrated genetic profiling in adult T-cell acute lymphoblastic leukemia.
Blood
PUBLISHED: 05-17-2013
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Adult T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic tumor associated with poor outcome. In this study, we analyzed the prognostic relevance of genetic alterations, immunophenotypic markers, and microarray gene expression signatures in a panel of 53 adult T-ALL patients treated in the Eastern Cooperative Oncology Group E2993 clinical trial. An early immature gene expression signature, the absence of bi-allelic TCRG deletion, CD13 surface expression, heterozygous deletions of the short arm of chromosome 17, and mutations in IDH1/IDH2 and DNMT3A genes are associated with poor prognosis in this series. In contrast, expression of CD8 or CD62L, homozygous deletion of CDKN2A/CDKN2B, NOTCH1 and/or FBXW7 mutations, and mutations or deletions in the BCL11B tumor suppressor gene were associated with improved overall survival. Importantly, the prognostic relevance of CD13 expression and homozygous CDKN2A/CDKN2B deletions was restricted to cortical and mature T-ALLs. Conversely, mutations in IDH1/IDH2 and DNMT3A were specifically associated with poor outcome in early immature adult T-ALLs. This trial was registered at www.clinicaltrials.gov as #NCT00002514.
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Vaccination with dendritic cell/tumor fusions following autologous stem cell transplant induces immunologic and clinical responses in multiple myeloma patients.
Clin. Cancer Res.
PUBLISHED: 05-17-2013
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A multiple myeloma vaccine has been developed whereby patient-derived tumor cells are fused with autologous dendritic cells, creating a hybridoma that stimulates a broad antitumor response. We report on the results of a phase II trial in which patients underwent vaccination following autologous stem cell transplantation (ASCT) to target minimal residual disease.
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Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia.
Blood
PUBLISHED: 05-02-2013
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Cancer-associated isocitrate dehydrogenase (IDH) mutations produce the metabolite 2-hydroxyglutarate (2HG), but the clinical utility of 2HG has not been established. We studied whether 2HG measurements in acute myeloid leukemia (AML) patients correlate with IDH mutations, and whether diagnostic or remission 2HG measurements predict survival. Sera from 223 de novo AML patients were analyzed for 2HG concentration by reverse-phase liquid chromatography-mass spectrometry. Pretreatment 2HG levels ranged from 10 to 30?000 ng/mL and were elevated in IDH-mutants (median, 3004 ng/mL), compared to wild-type IDH (median, 61 ng/mL) (P < .0005). 2HG levels did not differ among IDH1 or IDH2 allelic variants. In receiver operating characteristic analysis, a discriminatory level of 700 ng/mL optimally segregated patients with and without IDH mutations, and on subsequent mutational analysis of the 13 IDH wild-type samples with 2HG levels >700 ng/mL, 9 were identified to have IDH mutations. IDH-mutant patients with 2HG levels >200 at complete remission had shorter overall survival compared to 2HG ?200 ng/mL (hazard ratio, 3.9; P = .02). We establish a firm association between IDH mutations and serum 2HG concentration in AML, and confirm that serum oncometabolite measurements provide useful diagnostic and prognostic information that can improve patient selection for IDH-targeted therapies.
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Unrelated donor allogeneic transplantation after failure of autologous transplantation for acute myelogenous leukemia: a study from the center for international blood and marrow transplantation research.
Biol. Blood Marrow Transplant.
PUBLISHED: 04-21-2013
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The survival of patients with relapsed acute myelogenous leukemia (AML) after autologous hematopoietic stem cell transplantation (auto-HCT) is very poor. We studied the outcomes of 302 patients who underwent secondary allogeneic hematopoietic cell transplantation (allo-HCT) from an unrelated donor (URD) using either myeloablative (n = 242) or reduced-intensity conditioning (RIC; n = 60) regimens reported to the Center for International Blood and Marrow Transplantation Research. After a median follow-up of 58 months (range, 2 to 160 months), the probability of treatment-related mortality was 44% (95% confidence interval [CI], 38%-50%) at 1-year. The 5-year incidence of relapse was 32% (95% CI, 27%-38%), and that of overall survival was 22% (95% CI, 18%-27%). Multivariate analysis revealed a significantly better overal survival with RIC regimens (hazard ratio [HR], 0.51; 95% CI, 0.35-0.75; P <.001), with Karnofsky Performance Status score ?90% (HR, 0.62; 95% CI, 0.47-0.82: P = .001) and in cytomegalovirus-negative recipients (HR, 0.64; 95% CI, 0.44-0.94; P = .022). A longer interval (>18 months) from auto-HCT to URD allo-HCT was associated with significantly lower riak of relapse (HR, 0.19; 95% CI, 0.09-0.38; P <.001) and improved leukemia-free survival (HR, 0.53; 95% CI, 0.34-0.84; P = .006). URD allo-HCT after auto-HCT relapse resulted in 20% long-term leukemia-free survival, with the best results seen in patients with a longer interval to secondary URD transplantation, with a Karnofsky Performance Status score ?90%, in complete remission, and using an RIC regimen. Further efforts to reduce treatment-related mortaility and relapse are still needed.
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Gemtuzumab ozogamicin in acute myeloid leukemia: a remarkable saga about an active drug.
Blood
PUBLISHED: 04-16-2013
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Despite living in an era of unprecedented progress in the understanding of the genetic and molecular biology of acute myeloid leukemia (AML), this has not translated into significant advances in therapy. Never before have so many potential targets been studied. Yet most have not advanced beyond the phase 1 and, occasionally, phase 2 studies. The few ongoing phase 3 studies seem unlikely to have more than a marginal benefit, if at all. Thus, it is not surprising that in past few decades almost no new drugs for AML have received regulatory approval. In 2000, gemtuzumab ozogamicin (GO) was granted accelerated approval by the US Food and Drug Administration based on promising phase 2 data in relapsed older adults with AML. GO held promise as a new agent that also could be efficacious in newly diagnosed AML with acceptable toxicity. Several phase 3 studies were designed to test GO in this setting. The results of a randomized study by the Southwest Oncology Group led in 2010 to the voluntary withdrawal of this agent when improved efficacy could not be demonstrated and toxicity appeared excessive. Since then, 4 randomized studies have been completed that, in aggregate, strongly support the efficacy of this agent in newly diagnosed AML with acceptable toxicity. There is a very plausible explanation for this discrepancy, making a compelling case for reapproval of GO in AML.
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Eradication of carbapenem-resistant Enterobacteriaceae gastrointestinal colonization with nonabsorbable oral antibiotic treatment: A prospective controlled trial.
Am J Infect Control
PUBLISHED: 02-16-2013
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Carbapenem-resistant Enterobacteriaceae (CRE) are emerging. In attempt to eradicate CRE colonization, we conducted a semirandomized, prospective, controlled trial using oral nonabsorbable antibiotics.
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Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL.
Nat. Med.
PUBLISHED: 02-03-2013
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Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Despite intensive chemotherapy, 20% of pediatric patients and over 50% of adult patients with ALL do not achieve a complete remission or relapse after intensified chemotherapy, making disease relapse and resistance to therapy the most substantial challenge in the treatment of this disease. Using whole-exome sequencing, we identify mutations in the cytosolic 5-nucleotidase II gene (NT5C2), which encodes a 5-nucleotidase enzyme that is responsible for the inactivation of nucleoside-analog chemotherapy drugs, in 20/103 (19%) relapse T cell ALLs and 1/35 (3%) relapse B-precursor ALLs. NT5C2 mutant proteins show increased nucleotidase activity in vitro and conferred resistance to chemotherapy with 6-mercaptopurine and 6-thioguanine when expressed in ALL lymphoblasts. These results support a prominent role for activating mutations in NT5C2 and increased nucleoside-analog metabolism in disease progression and chemotherapy resistance in ALL.
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The clinical characteristics, therapy and outcome of 85 adults with acute lymphoblastic leukemia and t(4;11)(q21;q23)/MLL-AFF1 prospectively treated in the UKALLXII/ECOG2993 trial.
Haematologica
PUBLISHED: 01-24-2013
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The biology and outcome of adult t(4;11)(q21;q23)/MLL-AFF1 acute lymphoblastic leukemia are poorly understood. We describe the outcome and delineate prognostic factors and optimal post-remission therapy in 85 consecutive patients (median age 38 years) treated uniformly in the prospective trial UKALLXII/ECOG2993. The immunophenotype of this leukemia was pro-B (CD10(NEG)). Immaturity was further suggested by high expression of the stem-cell antigens, CD133 and CD135, although CD34 expression was significantly lower than in t(4;11)-negative patients. Complete remission was achieved in 77 (93%) patients but only 35% survived 5 years (95% CI: 25-45%); the relapse rate was 45% (95% CI: 33-58%). Thirty-one patients underwent allogeneic transplantation in first remission (15 sibling donors and 16 unrelated donors): with 5-year survival rates of 56% and 67% respectively, only 2/31 patients relapsed. This compares with a 24% survival rate and 59% relapse rate in 46 patients who received post-remission chemotherapy. A major determinant of outcome was age with 71% of patients aged <25 years surviving. Younger patients had lower relapse rates (19%) but most received allografts in first complete remission. In conclusion, multivariate analysis did not demonstrate an advantage of allografting over chemotherapy but only five younger patients received chemotherapy. Prospective trials are required to determine whether poor outcomes in older patients can be improved by reduced-intensity conditioning allografts. NCT00002514 www.clinicaltrials.gov.
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Strikingly high false positivity of surveillance FDG-PET/CT scanning among patients with diffuse large cell lymphoma in the rituximab era.
Am. J. Hematol.
PUBLISHED: 01-13-2013
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Predictive value (PV) of surveillance fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with diffuse large B-cell lymphoma (DLBCL) treated with chemotherapy-rituximab (R) versus chemotherapy only, remains unclear. The aim of the current study was to compare the performance of surveillance PET in DLBCL patients receiving CHOP (cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, and prednisone) alone versus CHOP-R. Institutional database was retrospectively searched for adults with newly diagnosed DLBCL, receiving CHOP or CHOP-R, who achieved complete remission and underwent surveillance PETs. Follow-up (FU) PET was considered positive for recurrence in case of an uptake unrelated to physiological or known benign process. Results were confirmed by biopsy, imaging and clinical FU. One hundred nineteen patients, 35 receiving CHOP and 84 CHOP-R, who underwent 422 FU-PETs, were analyzed. At a median PET-FU of 3.4 years, 31 patients relapsed (17 vs. 14, respectively; P = 0.02). PET detected all relapses, with no false-negative studies. Specificity and positive PV (PPV) were significantly lower for patients receiving CHOP-R vs. CHOP (84% vs. 87%, P = 0.023; 23% vs. 74%, P < 0.0001), reflecting a higher false-positive (FP) rate in subjects receiving CHOP-R (77% vs. 26%, P < 0.001). In the latter group, FP-rate remained persistently high up to 3 years post-therapy. Multivariate analysis confirmed rituximab to be the most significant predictor for FP-PET. In conclusion, routine surveillance FDG-PET is not recommended in DLBCL treated with rituximab; strict criteria identifying patients in whom FU-PET is beneficial are required.
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Administration of ATRA to newly diagnosed patients with acute promyelocytic leukemia is delayed contributing to early hemorrhagic death.
Leuk. Res.
PUBLISHED: 01-10-2013
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We hypothesized that the high early death rate (EDR) due to bleeding in acute promyelocytic leukemia (APL) is in part attributable to delays in all- trans retinoic acid (ATRA). We conducted a retrospective analysis of the timing of ATRA administration. 204 consecutive patients with newly diagnosed APL between 1992 and 2009 were identified. The EDR was 11%. 44% of early deaths occurred in the first week. Hemorrhage accounted for 61% of early deaths. ATRA was ordered the day APL was suspected in 31% of patients. Delays in ATRA administration led to increases in the percentage of early deaths from hemorrhage.
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All-trans retinoic acid and late relapses in acute promyelocytic leukemia: very long-term follow-up of the North American Intergroup Study I0129.
Leuk. Res.
PUBLISHED: 01-05-2013
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We report a long-term follow-up (median 11.8 years) of the First North American Intergroup Study. 379 patients were randomized to induction with ATRA or to chemotherapy. All complete responders (CR) received consolidation chemotherapy, then randomized to 1 year ATRA or observation. 245 patients received ATRA sometime during the study: 195 (80%) achieved a CR. Nine (4.6%) relapsed late (>3 years from CR), the last occurred after 4.6 years; 7 of them were still alive after 5.5-15 years. In APL patients, late relapses are uncommon, and those who sustain CR >5 years can be considered cured.
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Interpreting outcome data in hematological malignancies: a paradigm for clinical studies.
Rambam Maimonides Med J
PUBLISHED: 01-01-2013
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Results of clinical studies are often contradictory in real time, and in other instances therapies may be adopted due to information from clinical studies where the data may be premature or resulting from small studies. Much of the data may have inherent selection biases, and their interpretation may be confusing and difficult. The hematological literature is full of such examples, and this review will describe some such instances in the hope of introducing both a cautionary note and encouraging more precise description of study conditions as well as an appreciation of the importance of allowing data from clinical studies to mature. Several examples will be drawn from clinical studies in lymphomas, leukemia, and bone marrow transplantation.
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ETV6 mutations in early immature human T cell leukemias.
J. Exp. Med.
PUBLISHED: 12-12-2011
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Early immature T cell acute lymphoblastic leukemias (T-ALLs) account for ~5-10% of pediatric T-ALLs and are associated with poor prognosis. However, the genetic defects that drive the biology of these tumors remain largely unknown. In this study, analysis of microarray gene expression signatures in adult T-ALL demonstrated a high prevalence of early immature leukemias and revealed a close relationship between these tumors and myeloid leukemias. Many adult immature T-ALLs harbored mutations in myeloid-specific oncogenes and tumor suppressors including IDH1, IDH2, DNMT3A, FLT3, and NRAS. Moreover, we identified ETV6 mutations as a novel genetic lesion uniquely present in immature adult T-ALL. Our results demonstrate that early immature adult T-ALL represents a heterogeneous category of leukemias characterized by the presence of overlapping myeloid and T-ALL characteristics, and highlight the potential role of ETV6 mutations in these tumors.
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Prognostic factors in adult acute leukemia.
Hematol. Oncol. Clin. North Am.
PUBLISHED: 11-19-2011
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The prognostic factors in acute leukemia have undergone a major change over the past decade and are likely to be further refined in the coming years. While age is the single most important prognostic factor in both AML and in ALL, recurring cytogenetic abnormalities and molecular markers have become crucial for the prognosis of patients and for new directions in the development of targeted therapies. No less important is the development of a personalized approach for therapy as determined by the response to therapy using increasingly sensitive technologies. The assessment of MRD is rapidly superseding other prognostic factors in ALL and, somewhat lacking behind, coming into its own in AML. The next decade should see further refinement of response-driven prognostication, to include epigenetics as well as pharmacogenetics and pharmacodynamics of individual drugs used and the responses to them. It is hoped that these refinements and better predictors of response will also lead to a significantly improved overall outcome of patients with both AML and ALL.
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Incidence of therapy-related myeloid neoplasia after initial therapy for chronic lymphocytic leukemia with fludarabine-cyclophosphamide versus fludarabine: long-term follow-up of US Intergroup Study E2997.
Blood
PUBLISHED: 07-29-2011
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Chemotherapy-related myeloid neoplasia (t-MN) is a significant late toxicity concern after cancer therapy. In the randomized intergroup phase 3 E2997 trial, initial therapy of chronic lymphocytic leukemia with fludarabine plus cyclophosphamide (FC) compared with fludarabine alone yielded higher complete and overall response rates and longer progression-free, but not overall, survival. Here, we report t-MN incidence in 278 patients enrolled in E2997 with a median 6.4-year follow-up. Thirteen cases (4.7%) of t-MN occurred at a median of 5 years from initial therapy for chronic lymphocytic leukemia, 9 after FC and 4 after fludarabine alone. By cumulative incidence methodology, rates of t-MN at 7 years were 8.2% after FC and 4.6% after fludarabine alone (P = .09). Seven of the 9 cases of t-MN after FC occurred without additional therapy. Abnormalities involving chromosomes 5 or 7 were found in 10 cases, which suggests alkylator involvement. These data suggest that FC may induce more t-MN than fludarabine alone.
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The increased risk for pneumocystis pneumonia in patients receiving rituximab-CHOP-14 can be prevented by the administration of trimethoprim/sulfamethoxazole: a single-center experience.
Acta Haematol.
PUBLISHED: 07-27-2011
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Recent studies suggest an increased risk for Pneumocystis jirovecii pneumonia (PJP) in adults receiving short-interval rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) therapy for diffuse large cell B cell lymphoma (DLBCL). This retrospective study evaluates precise PJP incidence and the efficacy of anti-PJP prophylaxis in DLBCL. Patients with DLBCL, aged ?18 years and treated between December 2004 and December 2010, were included. Details of treatment-related respiratory infections, focusing on PJP incidence, risk factors and prophylaxis, were assessed. A total of 132 patients were analyzed; 47 were treated with rituximab-CHOP therapy every 21 days (R-CHOP-21) and 85 were treated every 14 days (R-CHOP-14). The incidence of treatment-related respiratory infections was higher in patients receiving R-CHOP-14. PJP was diagnosed in 5 patients: 4 in the R-CHOP-14 (6.6%) and 1 in the R-CHOP-21 cohort (2.6%), using triplex polymerase chain reaction (PCR) for PJ in bronchoalveolar fluid. None of the patients receiving P.jirovecii prophylaxis (n = 33) developed PJP, compared with 6.6% of those treated with R-CHOP-14 without such prophylaxis. An older age and R-CHOP administered every 14 rather than every 21 days increased the PJP risk. Trimethoprim/sulfamethoxazole prophylaxis is found to be highly efficient in preventing this life-threatening complication and, therefore, should be recommended for patients receiving the R-CHOP-14 regimen.
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A 10-year experience with treatment of high and standard risk Hodgkin disease: six cycles of tailored BEACOPP, with interim scintigraphy, are effective and female fertility is preserved.
Am. J. Hematol.
PUBLISHED: 07-27-2011
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Therapy of Hodgkin lymphoma (HL) is designed to prolong survival and minimize toxicity. A total of 124 patients with newly diagnosed HL and adverse prognostic factors were prospectively studied between July, 1999 and August, 2005. Patients with early unfavorable and advanced disease were eligible for the study. Patients were assigned to therapy based on international prognostic score (IPS). Those with IPS ? 3 received three cycles of escalated BEACOPP (EB). All others received two cycles of standard BEACOPP (SB). Subsequent therapy was prospectively assigned according to early interim GA(67) or positron emission tomography (PET)/computerized tomography (CT). Four cycles of EB or SB were administered following a positive or negative scan, respectively. Complete remission rate, 10-year progression free (PFS), and overall survival (OS) were 97, 87, and 88%, respectively, at a median follow-up of 89 months (5-144). PFS and OS were similar in both groups. Fertility status was assessed in 38 females aged <40 years; 94% of females younger than 40 years preserved their cyclic ovarian function. Nineteen conceived during follow-up for 30 pregnancies, delivering 24 babies. Deliveries were reported up to 7 years from diagnosis. Predictive value of negative interim Ga(67) or PET/CT was 87 and 93%, respectively. Six cycles of tailored BEACOPP, for patients with adverse prognostic factors, provide encouraging long-term PFS and OS, and fertility is preserved in most females.
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Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid.
Blood
PUBLISHED: 06-08-2011
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The incidence of early death in a large population of unselected patients with acute promyelocytic leukemia (APL) remains unknown because of the paucity of outcome data available for patients treated outside of clinical trials. We undertook an epidemiologic study to estimate the true rate of early death with data from the Surveillance, Epidemiology, and End Results (SEER) program. A total of 1400 patients with a diagnosis of APL between 1992 and 2007 were identified. The overall early death rate was 17.3%, and only a modest change in early death rate was observed over time. The early death rate was significantly higher in patients aged ? 55 years (24.2%; P < .0001). The 3-year survival improved from 54.6% to 70.1% over the study period but was significantly lower in patients aged ? 55 years (46.4%; P < .0001). This study shows that the early death rate remains high despite the wide availability of all-trans retinoic acid and appears significantly higher than commonly reported in multicenter clinical trials. These data highlight a need to educate health care providers across a wide range of medical fields, who may be the first to evaluate patients with APL, to have a major effect on early death and the cure rate of APL.
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Classifying cytogenetics in patients with acute myelogenous leukemia in complete remission undergoing allogeneic transplantation: a Center for International Blood and Marrow Transplant Research study.
Biol. Blood Marrow Transplant.
PUBLISHED: 05-26-2011
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Cytogenetics play a major role in determining the prognosis of patients with acute myelogenous leukemia (AML). However, existing cytogenetics classifications were developed in chemotherapy-treated patients and might not be optimal for patients undergoing allogeneic hematopoietic cell transplantation (HCT). We studied 821 adult patients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) who underwent HCT for AML in first or second complete remission between 1999 and 2004. We compared the ability of the 6 existing classifications to stratify patients by overall survival. We then defined a new scheme specifically applicable to patients undergoing HCT using this patient cohort. Under this scheme, inv(16) is favorable, a complex karyotype (4 or more abnormalities) is adverse, and all other classified abnormalities are intermediate in predicting survival after HCT (5-year overall survival, 64%, 18%, and 50%, respectively; P = .0001). This scheme stratifies patients into 3 groups with similar nonrelapse mortality, but significantly different incidences of relapse, overall and leukemia-free survival. It applies to patients regardless of disease status (first or second complete remission), donor type (matched related or unrelated), or conditioning intensity (myeloablative or reduced intensity). This transplantation-specific classification could be adopted for prognostication purposes and to stratify patients with AML and karyotypic abnormalities entering HCT clinical trials.
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Leukemia-free survival as a surrogate end point for overall survival in the evaluation of maintenance therapy for patients with acute myeloid leukemia in complete remission.
Haematologica
PUBLISHED: 05-05-2011
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In trials designed to evaluate new therapies for hematologic malignancies, end points such as leukemia-free survival are often used as surrogates for overall survival in acute leukemia. We aimed to assess whether leukemia-free survival is an acceptable statistical surrogate for overall survival when applied to remission maintenance therapy for acute myeloid leukemia.
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Assessment of the consistency and robustness of results from a multicenter trial of remission maintenance therapy for acute myeloid leukemia.
Trials
PUBLISHED: 03-23-2011
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Data from a randomized multinational phase 3 trial of 320 adults with acute myeloid leukemia (AML) demonstrated that maintenance therapy with 3-week cycles of histamine dihydrochloride plus low-dose interleukin-2 (HDC/IL-2) for up to 18 months significantly improved leukemia-free survival (LFS) but lacked power to detect an overall survival (OS) difference.
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Autologous transplantation gives encouraging results for young adults with favorable-risk acute myeloid leukemia, but is not improved with gemtuzumab ozogamicin.
Blood
PUBLISHED: 03-17-2011
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We report the results of a prospective, randomized phase 3 trial evaluating the use of gemtuzumab ozogamicin (GO) in an intensive consolidation approach in 657 patients 17-60 years of age. Patients in first complete remission (CR1) after cytarabine and standard- or high-dose daunorubicin induction received 2 cycles of consolidation with high-dose cytarabine followed by peripheral blood progenitor cell collection. The 352 patients who entered consolidation were randomized to receive GO (n = 132) or not (n = 138) and then proceeded to autologous hematopoietic cell transplantation (HCT). GO was given to 67 patients. Median follow-up was 50.9 months. Results of the intention-to-treat analysis demonstrated a 4-year disease-free survival (DFS) of 33.6% versus 35.9% (P = .54) and an overall survival (OS) of 41.3% versus 41.9% (P = .52) for those randomized to receive GO versus no GO, respectively. Patients with favorable- and intermediate-risk acute myeloid leukemia (AML) treated with high-dose daunorubicin and autologous HCT had 4-year DFS rates of 60% and 40% and OS rates of 80% and 49.3%, respectively. For younger AML patients in CR1, autologous HCT should be considered in favorable- and intermediate-cytogenetic risk patients who do not have an allogeneic donor. The addition of a single dose of GO in this setting did not improve outcomes.
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Low incidence of long-term respiratory impairment in Hodgkin lymphoma survivors.
Ann. Hematol.
PUBLISHED: 01-27-2011
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Introduction of new chemotherapy regimens over the last decade resulted in 90% survival in patients with Hodgkin lymphoma (HL), which enhances significance of abrogating chemotherapy-related long-term toxicities in young subjects. The present trial evaluated incidence of long-term respiratory complications associated with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) or bleomycin sulfate, etoposide phosphate, doxorubicin hydrochloride (Adriamycin), cyclophosphamide, vincristine sulfate (Oncovin), procarbazine hydrochloride, and prednisone (BEACOPP). Sixty-seven HL patients, 21 treated with ABVD and 46 with BEACOPP, underwent prospective respiratory evaluation. Median follow-up from chemotherapy completion to respiratory assessment was 61 months. Abnormal lung function tests (LFT) were found in nine patients (13.6%)-three with functional dyspnea and six asymptomatic-with reduced DLCO (?70%), VC, and TLC. Previous history of bleomycin pulmonary toxicity was found to be the only statistically significant factor for chronic respiratory impairment (75% vs. 10%, p?=?0.007, relative risk (RR)?=?28; 95% CI, 2.5-313). However, abnormal LFT tended to occur more frequently in patients receiving mantle field irradiation (18% vs. 9%, RR?=?2.2), those who experienced respiratory infection (25% vs. 13%, RR?=?2.25), and patients treated with ABVD compared to BEACOPP (19% vs. 11%, RR?=?1.9). Long-term respiratory impairment in HL survivors is unusual and rarely results in functional discomfort. BEACOPP is "respiratory safe," being associated with a nonsignificant risk for long-term respiratory dysfunction.
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Induction and postremission strategies in acute myeloid leukemia: what is new?
Curr. Opin. Hematol.
PUBLISHED: 01-20-2011
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Induction followed by postremission therapy is recognized as the main road toward cure in acute myeloid leukemia (AML). Induction approach has not changed substantially for many years. Despite identifying numerous heterogeneous factors in AML, bench-derived insights are sluggishly translated into clinical protocols. In the current review, advances in intensified dose induction protocols, risk stratification, and disease monitoring are presented. Some promising as well as disappointing agents used for tailoring and targeting therapies in AML are also discussed.
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Interpreting data on transplant selection and outcome in adult acute lymphoblastic leukemia (ALL).
Biol. Blood Marrow Transplant.
PUBLISHED: 01-04-2011
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Until 10 to 15 years ago allogeneic transplants were performed in acute lymphoblastic leukemkia (ALL) mostly for advanced disease. They were rarely performed in first remission except for patients who were positive for the Philadelphia chromosome. Over the past decade, allogeneic transplants are being increasingly performed also for select patients in first remission, and the use of matched unrelated donors has vastly increased the availability of the donor pool for ALL patients. The data for reduced-intensity conditioning (RIC) transplants are at their infancy for ALL, but are likely to come into their own over the next decade, given the vast potential of offering this also to older patients or those with comorbidities. Despite the plethora of data, reports from various study groups differ in their enthusiasm for transplantation in many instances, and published data are often contradictory. Much of the data may have inherent selection biases and their interpretation may be confusing and difficult. The study conditions should be carefully described for physicians and patients to be able to adequately interpret the data.
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Treatment of patients with acute promyelocytic leukemia: a consensus statement on risk-adapted approaches to therapy.
Clin Lymphoma Myeloma Leuk
PUBLISHED: 12-01-2010
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The integration of all-trans-retinoic acid (ATRA) with anthracycline chemotherapy into up-front regimens for acute promyelocytic leukemia (APL) has produced striking improvements in clinical outcomes, making APL one of the most curable forms of hematologic malignancies in adults. In addition, arsenic trioxide has proven efficacy in relapse and when combined with ATRA in frontline regimens has demonstrated high efficacy in a number of trials and the potential to replace chemotherapy, which would thereby reduce chemotherapy-related adverse events. Cure in APL is also largely dependent on timely and effective supportive care measures that counteract such life-threatening emergencies as coagulopathy and APL differentiation syndrome. The risk of mortality during induction and the risk of relapse following frontline therapy are related to the individuals initial clinical presentation and relapse-risk score at diagnosis; however, these risks are now quite low even in high-risk patients as long as appropriate therapy is initiated expeditiously. Multiple European and North American trials have investigated risk-adapted approaches to the treatment of APL and have reported high success rates. Further refinement of risk-adapted strategies is ongoing and will likely contribute to better patient care. A roundtable conference was conducted to discuss risk-adapted therapy for APL and to develop a consensus statement and approach for clinical oncologists. Expert opinions and evidence-based strategies presented during the roundtable are summarized herein.
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Phase II study of interleukin-4 in indolent B-cell non-Hodgkin lymphoma and B-cell chronic lymphocytic leukemia: a study of the Eastern Cooperative Oncology Group (E5Y92).
J. Immunother.
PUBLISHED: 10-16-2010
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Recombinant interleukin (IL)-4, 5??g/kg thrice weekly for 3 weeks followed by a 2-week rest period (1 cycle) was administered to 32 eligible previously treated B-cell chronic lymphocytic leukemia (7 patients) or low-grade B-cell lymphoma patients (25 patients). Two cycles were given before response was evaluated. IL-6 serum levels were evaluated before therapy in all patients and at 12 weeks on study in 7 patients. None of the chronic lymphocytic leukemia patients responded. A partial response was observed in 3 lymphoma patients of 1.2, 3.0, and 3.5 months duration and stable disease (median 1.5?mo) was observed in another 7 lymphoma patients. The median survival from registration on study was 29.7 months with 7 patients alive at the time of analysis for a median follow-up of 72.8 months. Toxicity was generally mild with no grade 4 nonhematologic toxicity observed. Recombinant IL-4 treatment was well tolerated in this study but had minimal antitumor activity.
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Does microgranular variant morphology of acute promyelocytic leukemia independently predict a less favorable outcome compared with classical M3 APL? A joint study of the North American Intergroup and the PETHEMA Group.
Blood
PUBLISHED: 09-21-2010
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Few studies have examined the outcome of large numbers of patients with the microgranular variant (M3V) of acute promyelocytic leukemia (APL) in the all-trans retinoic acid era. Here, the outcome of 155 patients treated with all-trans retinoic acid-based therapy on 3 clinical trials, North American Intergroup protocol I0129 and Programa para el Estudio de la Terapéutica en Hemopatía Maligna protocols LPA96 and LPA99, are reported. The complete remission rate for all 155 patients was 82%, compared with 89% for 748 patients with classical M3 disease. The incidence of the APL differentiation syndrome was 26%, compared with 25% for classical M3 patients, and the early death rate was 13.6% compared with 8.4% for patients with classical M3 morphology. With a median follow-up time among survivors of 7.6 years (range 3.6-14.5), the 5-year overall survival, disease-free survival, and cumulative incidence of relapse for patients with M3V were 70%, 73%, and 24%, respectively. With a median follow-up time among survivors of 7.6 years (range 0.6-14.3), the 5-year overall survival, disease-free survival, and cumulative incidence of relapse among patients with classical M3 morphology were 80% (P = .006 compared with M3V), 81% (P = .07), and 15% (P = .005), respectively. When outcomes were adjusted for the white blood cell count or the relapse risk score, none of these outcomes were significantly different between patients with M3V and classical M3 APL.
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Zosuquidar, a novel modulator of P-glycoprotein, does not improve the outcome of older patients with newly diagnosed acute myeloid leukemia: a randomized, placebo-controlled trial of the Eastern Cooperative Oncology Group 3999.
Blood
PUBLISHED: 08-17-2010
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Zosuquidar, which modulates P-glycoprotein (P-gp) with minimal delay of anthracycline clearance, may reverse P-gp-mediated resistance in acute myeloid leukemia without increased toxicity. A total of 449 adults older than 60 years with acute myeloid leukemia or high-risk myelodysplastic syndrome enrolled in a randomized placebo-controlled double-blind trial (Eastern Cooperative Oncology Group 3999). Overall survival was compared between patients receiving conventional-dose cytarabine and daunorubicin and either zosuquidar (550 mg; 212 patients) or placebo (221 patients). Median and 2-year overall survival values were 7.2 months and 20% on zosuquidar and 9.4 months and 23% on placebo, respectively (P = .281). Remission rate was 51.9% on zosuquidar and 48.9% on placebo. All cause mortality to day 42 was not different (zosuquidar 22.2% vs placebo 16.3%; P = .158). In vitro modulation of P-gp activity by zosuquidar and expression of P-gp, multidrug resistance-related protein 1, lung resistance protein, and breast cancer resistance protein, were comparable in the 2 arms. Poor-risk cytogenetics were more common in P-gp(+) patients. P-gp expression and cytogenetics were correlated, though independent prognostic factors. We conclude that zosuquidar did not improve outcome in older acute myeloid leukemia, in part, because of the presence P-gp independent mechanisms of resistance. This trial is registered at www.clinicaltrials.gov as #NCT00046930.
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Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710.
Blood
PUBLISHED: 08-12-2010
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Arsenic trioxide (As(2)O(3)) is a highly effective treatment for patients with relapsed acute promyelocytic leukemia (APL); its role as consolidation treatment for patients in first remission has not been defined. We randomized 481 patients (age ? 15 years) with untreated APL to either a standard induction regimen of tretinoin, cytarabine, and daunorubicin, followed by 2 courses of consolidation therapy with tretinoin plus daunorubicin, or to the same induction and consolidation regimen plus two 25-day courses of As(2)O(3) consolidation immediately after induction. After consolidation, patients were randomly assigned to one year of maintenance therapy with either tretinoin alone or in combination with methotrexate and mercaptopurine. Ninety percent of patients on each arm achieved remission and were eligible to receive their assigned consolidation therapy. Event-free survival, the primary end point, was significantly better for patients assigned to receive As(2)O(3) consolidation, 80% compared with 63% at 3 years (stratified log-rank test, P < .0001). Survival, a secondary end point, was better in the As(2)O(3) arm, 86% compared with 81% at 3 years (P = .059). Disease-free survival, a secondary end point, was significantly better in the As(2)O(3) arm, 90% compared with 70% at 3 years (P < .0001). The addition of As(2)O(3) consolidation to standard induction and consolidation therapy significantly improves event-free and disease-free survival in adults with newly diagnosed APL. This trial was registered at clinicaltrials.gov (NCT00003934).
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NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 08-03-2010
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Relapse is a major cause of treatment failure after allogeneic hematopoietic stem cell transplantation (alloHSCT). Treatment options for relapse have been inadequate, and the majority of patients ultimately die of their disease. There is no standard approach to treating relapse after alloHSCT. Withdrawal of immune suppression and donor lymphocyte infusions are commonly used for all diseases; although these interventions are remarkably effective for relapsed chronic myelogenous leukemia, they have limited efficacy in other hematologic malignancies. Conventional and novel chemotherapy, monoclonal antibody therapy, targeted therapies, and second transplants have been utilized in a variety of relapsed diseases, but reports on these therapies are generally anecdotal and retrospective. As such, there is an immediate need for well-designed, disease-specific trials for treatment of relapse after alloHSCT. This report summarizes current treatment options under investigation for relapse after alloHSCT in a disease-specific manner. In addition, recommendations are provided for specific areas of research necessary in the treatment of relapse after alloHSCT.
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Influence of glutathione S-transferase A1, P1, M1, T1 polymorphisms on oral busulfan pharmacokinetics in children with congenital hemoglobinopathies undergoing hematopoietic stem cell transplantation.
Pediatr Blood Cancer
PUBLISHED: 07-31-2010
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Busulfan (BU), often used in high dose for myeloablation before hematopoietic stem cell transplantation (HSCT), has been implicated in certain HSCT toxicities, including the occurrence of hepatic veno-occlusive disease (HVOD). In addition to weight and age, gene polymorphisms in specific members of the glutathione-transferase (GST) gene family (A1, P1, M1, and T1), involved in BU metabolism, may play a role in the wide inter-patient variability in systemic BU concentrations.
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Lenalidomide and prednisone for myelofibrosis: Eastern Cooperative Oncology Group (ECOG) phase 2 trial E4903.
Blood
PUBLISHED: 07-22-2010
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A multicenter Eastern Cooperative Group (ECOG) phase 2 trial assessed whether adding prednisone to lenalidomide would improve previously reported responses in persons with myelofibrosis (MF). Forty-eight subjects with anemia (42 evaluable) received lenalidomide, 10 mg/d, with a 3-month low-dose prednisone taper. Ten subjects received 3 months, and 25 received 6 months of therapy. Myelosuppression was the main toxicity with 88% with ? grade 3 hematologic toxicity and 45% ? grade 3 nonhematologic toxicity. There were responses in 10 subjects (23%) using the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT)-defined clinical improvement of anemia in 8 (19%) and/or decreased spleen size in 4 (10%). Serial bone marrow analysis showed no resolution of disease-related fibrosis or angiogenesis. With a median follow-up of 2.3 years, 23 subjects are alive. Lenali-domide and prednisone for myelofibro-sis evaluated through a multicentered-cooperative group mechanism is only modestly active and myelosuppre-sive. This study was registered at http://clinicaltrials.gov as NCT00227591.
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Adult patients with acute myeloid leukemia who achieve complete remission after 1 or 2 cycles of induction have a similar prognosis: a report on 1980 patients registered to 6 studies conducted by the Eastern Cooperative Oncology Group.
Cancer
PUBLISHED: 07-15-2010
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Patients with newly diagnosed acute myeloid leukemia (AML) often have residual leukemia in the bone marrow 10 to 14 days after the start of induction therapy. Some cooperative groups administer a second cycle of similar induction therapy on Day 14 if there is residual leukemia. It is a common perception that the presence of residual leukemia at that point predicts a worse prognosis irrespective of the therapy received. The objective of this study was to determine whether patients who required a second cycle of induction (given on or about Day 14) to achieve complete remission (CR) had a worse prognosis than patients who achieved CR after only 1 cycle, because a worse prognosis may alter postremission therapy.
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Prognostic factors in adult acute lymphoblastic leukaemia.
Br. J. Haematol.
PUBLISHED: 06-22-2010
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Treatment of acute lymphoblastic leukaemia (ALL) in adults presents a formidable challenge. While overall results have improved over the past 3 decades, the long-term survival for patients aged less than 60 years is only in the range of 30-40% and is 10-15% if between 60 and 70 years and <5% for those over 70 years. The historic lack of clear-cut biological prognostic factors has led to over- or under-treatment of some patients. Response to initial therapy is an important prognosticator of outcome based on disease biology, as well as pharmacogenetics, which include the patients response to drugs given. The more widespread availability of allogeneic transplantation and reduced-intensity regimens for older patients have opened up this curative modality to a greater number of patients. Hopefully, those options, as well as novel cytogenetic and molecular markers, will enable a better selection of patients who undergo intensive therapies and finally break the 30-40% cure barrier for adults with ALL.
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How I treat acute myeloid leukemia.
Blood
PUBLISHED: 06-17-2010
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More than one quarter of a million adults throughout the world are diagnosed annually with acute myeloid leukemia (AML). Despite considerable progress during the past 3 decades in the therapy of AML, two-thirds of young adults and 90% of older adults still die of their disease. The reported median age has increased over the past few decades, mostly because of a greater willingness of physicians to diagnose and treat older patients, and now is 72 years. The greatest challenge is in this age group. However, much improvement in therapy is needed for all adults with AML. Recent advances in allogeneic transplantation, a better understanding of prognostic factors, and development of targeted agents have only modestly improved overall outcome when large populations of patients are considered. Although an explosion in knowledge about the molecular pathogenesis of AML has outpaced treatment advances, such insights hold promise for the development of new therapies directed at specific molecular abnormalities that perturb malignant cell survival pathways. The current approach in 2010 to the management of this disease is presented through a discussion of illustrative cases.
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Comparable survival after HLA-well-matched unrelated or matched sibling donor transplantation for acute myeloid leukemia in first remission with unfavorable cytogenetics at diagnosis.
Blood
PUBLISHED: 06-10-2010
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We compared the outcomes of unrelated donor (URD, n = 358) with human leukocyte antigen (HLA)-matched sibling donor (MSD, n = 226) transplantations in patients with acute myeloid leukemia (AML) in first complete remission (CR1) having unfavorable cytogenetics at diagnosis. Unfavorable cytogenetic abnormalities were: complex (? 3 abnormalities), 32%; and noncomplex involving chromosome 7, 25%; chromosome 5, 9%; 11q or MLL rearrangements, 18%; t(6;9), 5%; and other noncomplex, 10%. URDs were HLA-well-matched (n = 254; 71%) or partially-matched (n = 104; 29%). Three-year leukemia-free survival (LFS) for MSD was 42% (95% confidence interval [CI], 35%-48%) compared with 34% (95% CI, 28%-41%) for HLA-well-matched URD and 29% (95% CI, 20%-39%) for partially-matched URD (P = .08). In multivariate analysis, HLA-well-matched URD and MSD yielded similar LFS (relative risk [RR] = 1.1, 95% CI, 0.86-1.40, P = .44) and overall survival (OS; RR = 1.06, 95% CI, 0.83-1.37, P = .63). LFS and OS were significantly inferior for HLA-partially-matched URD recipients, those with prior myelodysplastic syndrome, and those older than 50 years. All cytogenetic cohorts had similar outcomes. Patients with chronic graft-versus-host disease had a significantly lower risk of relapse (RR = 0.68, 95% CI, 0.47-0.99, P = .05). Hematopoietic cell transplantation (HCT) using HLA-well-matched URD and MSD resulted in similar LFS and OS in AML patients in CR1 with unfavorable cytogenetics. Outcomes of HCT from HLA-partially- matched URD were inferior.
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A functional dynamic scoring model to elucidate the significance of post-induction interim fluorine-18-fluorodeoxyglucose positron emission tomography findings in patients with Hodgkins lymphoma.
Haematologica
PUBLISHED: 04-21-2010
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The findings of interim fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET/CT) predict progression-free survival of patients with Hodgkins lymphoma. Historically, the assessment was based on a static all-or-none scoring system. However, the clinical significance of any positivity in interim FDG-PET/CT has not been defined.
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The TLX1 oncogene drives aneuploidy in T cell transformation.
Nat. Med.
PUBLISHED: 03-31-2010
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The TLX1 oncogene (encoding the transcription factor T cell leukemia homeobox protein-1) has a major role in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL). However, the specific mechanisms of T cell transformation downstream of TLX1 remain to be elucidated. Here we show that transgenic expression of human TLX1 in mice induces T-ALL with frequent deletions and mutations in Bcl11b (encoding B cell leukemia/lymphoma-11B) and identify the presence of recurrent mutations and deletions in BCL11B in 16% of human T-ALLs. Most notably, mouse TLX1 tumors were typically aneuploid and showed a marked defect in the activation of the mitotic checkpoint. Mechanistically, TLX1 directly downregulates the expression of CHEK1 (encoding CHK1 checkpoint homolog) and additional mitotic control genes and induces loss of the mitotic checkpoint in nontransformed preleukemic thymocytes. These results identify a previously unrecognized mechanism contributing to chromosomal missegregation and aneuploidy active at the earliest stages of tumor development in the pathogenesis of cancer.
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PHF6 mutations in T-cell acute lymphoblastic leukemia.
Nat. Genet.
PUBLISHED: 02-03-2010
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Tumor suppressor genes on the X chromosome may skew the gender distribution of specific types of cancer. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with an increased incidence in males. In this study, we report the identification of inactivating mutations and deletions in the X-linked plant homeodomain finger 6 (PHF6) gene in 16% of pediatric and 38% of adult primary T-ALL samples. Notably, PHF6 mutations are almost exclusively found in T-ALL samples from male subjects. Mutational loss of PHF6 is importantly associated with leukemias driven by aberrant expression of the homeobox transcription factor oncogenes TLX1 and TLX3. Overall, these results identify PHF6 as a new X-linked tumor suppressor in T-ALL and point to a strong genetic interaction between PHF6 loss and aberrant expression of TLX transcription factors in the pathogenesis of this disease.
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Induction therapy in acute myeloid leukemia: intensifying and targeting the approach.
Curr. Opin. Hematol.
PUBLISHED: 01-21-2010
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Acute myeloid leukemia (AML) is a heterogeneous group of clonal disorders which is treated with similar regimens despite the heterogeneity. The treatment approach for many years has used combination chemotherapy, with usually an anthracycline and cytarabine as the foundation. In the present review we will present new data from recently completed trials that have demonstrated advances in the treatment of AML.
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Transplantation in adult ALL.
Hematology Am Soc Hematol Educ Program
PUBLISHED: 12-17-2009
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The value of the allogeneic graft-versus-leukemia effect in adult acute lymphoblastic leukemia (ALL) has now been conclusively demonstrated and confirmed. While this is true for adults in all age groups, it may not be the best clinical option for young adults for whom increasingly intensive pediatric protocols are clearly of benefit. On the other hand, there is potentially wider applicability of allogeneic donor transplantation for adults 25 to 45 years old, for whom matched unrelated donors may be as safe and effective as sibling donors, and for the patient older than 45 years for whom reduced-intensity conditioning may be a promising way forward. Since the treatment-related mortality of allogeneic transplantation remains significant, careful selection of patients is mandatory. Patients with the Philadelphia chromosome, those with t(4;11) and those with a complex karyotype remain transplant candidates, and allogeneic transplantation remains the best option for salvage, where achievable, in a remission beyond first. As in childhood ALL minimal residual disease studies may be extremely useful in predicting outcome and, therefore, strategy, but at present there are less definite data in adults. Clinical indications to harness the allogeneic effect will mature as the true value of pediatric protocols in adult patients and the safety and efficacy of a sibling, unrelated and reduced intensity transplant emerge in this disease.
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Optimal induction and post-remission therapy for AML in first remission.
Hematology Am Soc Hematol Educ Program
PUBLISHED: 12-17-2009
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Approximately 300,000 patients in the world are diagnosed annually with acute myeloid leukemia (AML). The median age at presentation has been steadily increasing over the past few decades and now is approaching 70 years. Although considerable progress has been made over the past 3 decades in the therapy of AML, two thirds of young adults still die of their disease. The therapy of AML, unlike acute lymphoblastic leukemia (ALL), is based on maximally tolerated induction and post-remission therapy, all given within a few months from diagnosis. While complete remission can be achieved in the majority of young patients, ultimate cure of the disease depends on disease eradication through the administration of post-remission therapy. This is most often done with intensive chemotherapy. Harnessing the immunologic effect of graft-versus-leukemia, as in allogeneic transplantation, has further improved the outcome for many patients. Treatment of older adults, representing the majority of patients with AML, remains quite unsatisfactory. While 40% to 50% can achieve a complete remission, less than 10% are long-term survivors, and the cure rate of older patients has only minimally improved over the past three decades. Significant progress in the treatment of this age group is urgently required. New and targeted agents have much promise, but a definitive clinical role for these has yet to be conclusively established.
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Is there a role for intensifying induction therapy in acute myeloid leukaemia (AML)?
Best Pract Res Clin Haematol
PUBLISHED: 12-05-2009
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Intensifying induction is not a new concept, but some recent and emerging information suggests that intensifying induction may be a relevant strategy for both young and older patients with acute myeloid leukaemia (AML). There are several potential strategies for intensifying induction therapy, including modulation of anthracyclines; modulation of ara-C; addition of other agents, including high-dose ara-C (HiDAC); addition of targeted or immunomodulatory agents, including gemtuzumab ozogamicin; or using timed-sequential therapy or very early intensification. It is clear that daunorubicin at a 45mgm(-2) dose is no longer acceptable as the standard for induction therapy in AML, but the optimal dose is unknown. No anthracycline dose attenuation should be made for older, fit adults, and modulation of induction can lead to significant survival benefit even without improving the initial response rate.
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T-cell acute lymphoblastic leukemia in adults: clinical features, immunophenotype, cytogenetics, and outcome from the large randomized prospective trial (UKALL XII/ECOG 2993).
Blood
PUBLISHED: 10-14-2009
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The biology and outcome of adult T-cell acute lymphoblastic leukemia are poorly understood. We present here the clinical and biologic features of 356 patients treated uniformly on the prospective trial (UKALL XII/ECOG 2993) with the aim of describing the outcome and identifying prognostic factors. Complete remission was obtained in 94% of patients, and 48% survived 5 years. Positivity of blasts for CD1a and lack of expression of CD13 were associated with better survival (P = .01 and < .001, respectively). NOTCH1 and CDKN2A mutations were seen in 61% and 42% of those tested. Complex cytogenetic abnormalities were associated with poorer survival (19% vs 51% at 5 years, P = .006). Central nervous system involvement at diagnosis did not affect survival (47% vs 48%, P = not significant). For 99 patients randomized between autograft and chemotherapy, 5-year survival was 51% in each arm. Patients with a matched sibling donor had superior 5-year survival to those without donors (61% vs 46%, chi(2), P = .02); this was the result of less relapse (25% vs 51% at 5 years, P < .001). Only 8 of 123 relapsed patients survive. This study provides a baseline for trials of new drugs, such as nelarabine, and may allow risk-adapted therapy in patients with poor-prognosis T-cell ALL.
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Failure of three novel regimens to improve outcome for patients with relapsed or refractory acute myeloid leukaemia: a report from the Eastern Cooperative Oncology Group.
Br. J. Haematol.
PUBLISHED: 10-05-2009
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The treatment of relapsed acute myeloid leukaemia (AML) remains unsatisfactory. We conducted a phase II randomized trial where patients received intermediate-dose cytarabine for 4 d followed by gemtuzumab ozogamicin on day 5 (Arm A), or combined with liposomal daunorubicin for 3 d (Arm B), or cytarabine given for 5 d combined with cyclophosphamide for 3 d and topotecan by continuous infusion for 5 d (Arm C). Eligible patients had primary refractory AML, a first relapse after a remission of <1 year, or a second or greater relapse. The primary objective of this trial was attainment of a conventional complete remission (CR) or a CR without platelet recovery (CRp) in at least 40% of patients. The CR/CRp rates for the 82 eligible patients were 3/26 (12%) in Arm A, 2/29 (7%) in Arm B, and 1/27 (4%) in Arm C. No patients who had relapsed within 6 months of initial CR or who had suffered multiple relapses responded. More than 95% of patients subsequently died of AML. No unexpected toxicities were encountered. We conclude that none of these three regimens were effective enough in the treatment of high-risk relapsed or refractory AML to warrant further study. This trial was registered at http://www.clinicaltrials.gov as #NCT00005962.
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Anthracycline dose intensification in acute myeloid leukemia.
N. Engl. J. Med.
PUBLISHED: 09-25-2009
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In young adults with acute myeloid leukemia (AML), intensification of the anthracycline dose during induction therapy has improved the rate of complete remission but not of overall survival. We evaluated the use of cytarabine plus either standard-dose or high-dose daunorubicin as induction therapy, followed by intensive consolidation therapy, in inducing complete remission to improve overall survival.
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Treatment of children with acute promyelocytic leukemia: results of the first North American Intergroup trial INT0129.
Pediatr Blood Cancer
PUBLISHED: 09-11-2009
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This report focuses on the children enrolled on the first North American Intergroup study of APL (INT0129). This study was designed to compare the rates of CR, disease-free survival (DFS), overall survival (OS) and toxicity of therapy with all-trans-retinoic acid (ATRA) for remission induction and/or maintenance compared to conventional chemotherapy in patients with previously untreated APL.
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Hematopoietic stem cell transplantation for adults with acute lymphoblastic leukemia.
Curr. Opin. Hematol.
PUBLISHED: 08-05-2009
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The long-term survival for patients with adult acute lymphoblastic leukemia (ALL) has not significantly changed over the past two decades and, as opposed to pediatric ALL, it is less than 40% despite high initial complete remission rate. These observations raise several important issues regarding the pathobiology of adult leukemic stem cells, the ability of adults to tolerate intensive treatment and the best postremission approach.
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Allogeneic induced human FOXP3(+)IFN-gamma(+) T cells exhibit selective suppressive capacity.
Eur. J. Immunol.
PUBLISHED: 07-28-2009
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Human induced CD4(+)CD25(+) T cells have been shown to express FOXP3, similar to naturally occurring Treg cells (nTreg). However, the suppressive capacity of these cells is still under debate. The current study was designed to investigate functional characteristics of CD25(+)FOXP3(+) derived from CD25(-) T cells. Stimulation of CD25(-) PBMC with allogeneic PBMC resulted in production of CD4(+)CD25(high) T cells. This process was more rapid and prominent when highly mature DC were used for stimulation. The resultant CD4(+)CD25(high) population concurrently exhibited regulatory markers FOXP3, CTLA-4, GITR, and inflammatory cytokines IL-2 and IFN-gamma. These human-induced FOXP3(+)IFN-gamma(+) T cells were shown, for the first time, to markedly inhibit alloreactive T-cell expansion, similar to nTreg. However, in contrast to nTreg, the induced CD4(+)CD25(+)FOXP3(+) cells did not suppress proliferation against a third party donor stimulus or CMV. This suggested that the cell population possessed a more selective suppressive capacity targeted against the original stimulus only. The induced human CD4(+)CD25(+)FOXP3(+) subset derived from CD25(-) T cells, while expressing inflammatory cytokines, exhibits a suppressive cell contact-dependent effect, restricted against T cells responding to the original stimulus. Such unique properties suggest that these cells are potentially ideal for the use as post-transplant GVH disease prophylaxis.
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Prognostic implications of NOTCH1 and FBXW7 mutations in adults with T-cell acute lymphoblastic leukemia treated on the MRC UKALLXII/ECOG E2993 protocol.
J. Clin. Oncol.
PUBLISHED: 07-27-2009
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Notch pathway activation by mutations in either NOTCH1 and/or FBXW7 is one of the most common molecular events in T-cell acute lymphoblastic leukemia (T-ALL) and, in pediatric disease, predicts for favorable outcome. Their prognostic significance in adult T-ALL is unclear. We sought to evaluate the outcome according to mutation status of patients with adult T-ALL treated on the United Kingdom Acute Lymphoblastic Leukaemia XII (UKALLXII)/Eastern Cooperative Oncology Group (ECOG) E2993 protocol.
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