Prognostic Significance of the European LeukemiaNet Standardized System for Reporting Cytogenetic and Molecular Alterations in Adults With Acute Myeloid Leukemia

Mrózek, Krzysztof; Marcucci, Guido; Nicolet, Deedra; Maharry, Kati; Becker, Heiko; Whitman, Susan P.; Metzeler, Klaus H.; Schwind, Sebastian; Wu, Yue-Zhong; Kohlschmidt, Jessica; Pettenati, Mark J.; Heerema, Nyla A.; Block, AnneMarie W.; Patil, Shivanand R.; Baer, Maria R.; Kolitz, Jonathan E.; Moore, Joseph O.; Carroll, Andrew J.; Stone, Richard; Larson, Richard A.; Bloomfield, Clara D.

doi:10.1200/jco.2012.43.4738

Cited by 352 publications

(297 citation statements)

References 47 publications

(3 reference statements)

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“…The opposite is true in patients with other combinations of NPM1 and FLT3 or in patients who are CEBPA-. Examining 1550 CALGB patients with de novo AML Mrozek et al [9] have confirmed the independent prognostic significance of the ELN classification ("favorable" vs. intermediate 1 vs. intermediate 2 vs. adverse) in patients aged < 60, although the two intermediate groups had similar outcomes in older patients.…”

Section: European Leukemianet (Eln) System Verified In Independent Damentioning

confidence: 87%

Acute myeloid leukemia: 2013 update on risk‐stratification and management

2013

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Disease overviewAcute myeloid leukemia (AML) results from accumulation of abnormal blasts in the marrow. These cells interfere with normal hematopoiesis, can escape into the peripheral blood, and infiltrate CSF and lung. It is likely that many different mutations, epigenetic aberrations, or abnormalities in micro RNA expression can produce the same morphologic disease with these differences responsible for the very variable response to therapy, which is AMLs principal feature.DiagnosisThis rests on demonstration that the marrow or blood has > 20% blasts of myeloid lineage. Blast lineage is assessed by multiparameter flow cytometry, with CD33 and CD13 being surface markers typically expressed by myeloid blasts. It should be realized that clinical/prognostic considerations, not the blast % per se, should be the main factor determining how a patient is treated.Risk StratificationTwo features determine risk: the probability of treatment‐related mortality (TRM) and, more important, even in patients aged >75 with Zubrod performance status 1, the probability of resistance to standard therapy despite not incurring TRM. The chief predictor of resistance is cytogenetics, with a monosomal karyotype (MK) denoting the disease is essentially incurable with standard therapy even if followed by a standard allogeneic transplant (HCT). The most common cytogentic finding is a normal karyotype(NK) and those of such patients with an NPM1 mutation but no FLT3 internal tandem duplication (ITD), or with a CEBPA mutation, have a prognosis similar to that of patients with the most favorable cytogenetics (inv 16 or t[8;21]) (60–70% cure rate). In contrast, NK patients with a FLT3 ITD have only a 30–40% chance of cure even after HCT. Accordingly analyses of NPM1, FLT3, and CEBPA should be part of routine evaluation, much as is cytogenetics. Risk is best assessed considering several variables simultaneously rather than, for example, only age. Increasing evidence indicates that other mutations and abnormalities in microRNA (miRNA) expression also affect resistance as do post treatment factors, in particular the presence of minimal residual disease. These newer mutations and MRD are discussed in this update.Risk‐adapted therapyPatients with inv (16) or t(8;21) or who are NPM1+/FLT3ITD—can receive standard therapy (daunorubicin + cytarabine) and should not receive HCT in first CR. It seems likely that use of a daily daunorubicin dose of 90 mg/m2 will further improve outcome in these patients. There appears no reason to use doses of cytarabine > 1 g/m2 (for example bid X 6 days), as opposed to the more commonly used 3 g/m2. Patients with an unfavorable karyotype (particularly MK) are unlikely to benefit from standard therapy (even with dose escalation) and are thus prime candidates for clinical trials of new drugs or new approaches to HCT; the latter should be done in first CR. Patients with intermediate prognoses (for example NK and NPM and FLT3ITD negative) should also receive HCT in first CR and can plausibly receive either investigational or standard induction therapy, with the same prognostic information about standard therapy leading one patient to choose the standard and another an investigational option. This update discusses results with newer agents: quizartinib and crenolanib, gemtuzumab ozogamicin, clofarabine and cladribine, azacitidine and decitabine, volasertib, and means to prevent relapse after allogeneic transplant.The diagnosis of AML essentially is made as it was in 2012. Thus this review will emphasize new developments in risk stratification and treatment using as references many papers published in 2012. Am. J. Hematol. 88:318–327, 2013. © 2013 Wiley Periodicals, Inc.

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Section: European Leukemianet (Eln) System Verified In Independent Damentioning

confidence: 87%

Acute myeloid leukemia: 2013 update on risk‐stratification and management

2013

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“…9 For the current analysis, cytogenetics were reclassified according to the European LeukemiaNet criteria. 1 The protocol contained a sequence of chemotherapy (Fludarabin 30 mg/m 2 , Amsacrine 100 mg/m 2 , Cytarabine 2000 mg/m 2 each given for 4 consecutive days), RIC for allogeneic transplantation (either 400 cGray TBI or IV Busulfan 6.4 mg/kg body weight (BW), followed by Cyclophosphamide 80-120 mg/kg BW and ATG-Fresenius 30-60 mg/kg BW, with the higher doses applied in unrelated transplantations) and planned aDLT. Cyclosporin A (targeted plasma trough level 150-200 ng/ml) and mycophenolate mofetil (15 mg/kg bid) were used for GvHD prophylaxis.…”

Section: Patients and Methods Patientsmentioning

confidence: 99%

“…In particular, patients with refractory disease or early relapse still have a poor prognosis. High-risk disease can further be defined by delayed response to chemotherapy, unfavorable karyotype or molecular genetics 1 and by a history of preceding neoplasia and/or chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Long-term results of adjuvant donor lymphocyte transfusion in AML after allogeneic stem cell transplantation

Jedlickova

Schmid

Koenecke

et al. 2015

Bone Marrow Transplant

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Adjuvant transfusion of donor lymphocytes (aDLT) may reduce the risk of relapse after allogeneic stem cell transplantation in high-risk AML. We performed a retrospective analysis on the safety and efficacy of aDLT in a cohort of 46 patients. To be eligible for aDLT, patients had to be in CR for at least 120 days from transplantation, off immunosuppression for ⩾ 30 days and free of GvHD. Thirty-four patients with similar disease characteristics and fulfilling the same selection criteria served as controls. Median follow-up among aDLT recipients was 7.2 years. Ten patients (22%) relapsed inspite of aDLT, as compared with 53% in the control group. Induction of GvHD was the main complication. However, non-relapse mortality was low with patients dying from infection (n = 2), severe chronic GvHD (n = 1) and secondary malignancy (n = 2). At the time of analysis, 31/46 aDLT recipients were alive in CR at a median of 5.7 years after first aDLT. Overall survival at 7 years after transplant was 67% as compared with 31% in the control group (P o 0.001). In conclusion, aDLT is safe, when given in escalating doses to a well predefined group of patients. Long-term survival can be achieved. INTRODUCTIONDespite advances in allogeneic transplantation (allogeneic stem cell transplantation; alloSCT), high-risk AML remains a disease with poor outcome, lacking optimal therapeutic strategy. In particular, patients with refractory disease or early relapse still have a poor prognosis. High-risk disease can further be defined by delayed response to chemotherapy, unfavorable karyotype or molecular genetics 1 and by a history of preceding neoplasia and/or chemotherapy.In the era of reduced intensity conditioning (RIC), high rates and a poor outcome of relapse after alloSCT (2 years overall survival (OS) 20%) 2,3 are the main causes for treatment failure in high-risk AML. Thus, effective strategies for preventing post-transplant relapse are urgently needed. As donor lymphocyte transfusion (DLT) enhances the graft-versus-leukemia (GVL) effect, it offers an attractive therapeutic option to decrease relapse-related mortality rates. The GVL potential of donor T-lymphocytes has been described in several preclinical 4,5 and clinical studies. [6][7][8] In particular, their use in the management of post-transplant relapses of chronic myeloid leukemia has been a story of success. However, despite of its desirable GVL effects, DLT may also increase the incidence and severity of GvHD. Thus, DLT protocols have to be optimized to minimize the risk of severe GvHD and maximize the benefit of the GVL effect.The establishment of RIC provided a basis for the employment of DLT in the post-transplantation period of AML therapy. There are several clinical studies supporting the positive role of DLT in the prophylaxis 9 and treatment of post-transplant relapse in AML. 2,10 Despite these encouraging data, the efficacy and the toxicity of DLT in the management of AML is still poorly assessed,

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“…For this review, we have focused only on the currently available genetic tests in clinical use and their interpretation. [18].…”

Section: Interpretation Of Various Key Genetic Changes In Hematologicmentioning

confidence: 99%

Current Role of Genetics in Hematologic Malignancies

Prakash

Kaur

Malhotra

et al. 2015

Indian J Hematol Blood Transfus

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Rapidly changing field of genetic technology and its application in the management of hematological malignancies has brought significant improvement in treatment and outcome of these disorders. Today, genetics plays pivotal role in diagnosis and prognostication of most hematologic neoplasms. The utilization of genetic tests in deciding specific treatment of various hematologic malignancies as well as for evaluation of depth of treatment response is rapidly advancing. Therefore, it is imperative for practitioners working in the field of hemato-oncology to have sufficient understanding of the basic concepts of genetics in order to comprehend upcoming molecular research in this area and to translate the same for patient care.

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Prognostic Significance of the European LeukemiaNet Standardized System for Reporting Cytogenetic and Molecular Alterations in Adults With Acute Myeloid Leukemia

Cited by 352 publications

References 47 publications

Acute myeloid leukemia: 2013 update on risk‐stratification and management

Acute myeloid leukemia: 2013 update on risk‐stratification and management

Long-term results of adjuvant donor lymphocyte transfusion in AML after allogeneic stem cell transplantation

Current Role of Genetics in Hematologic Malignancies

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