Age and acute myeloid leukemia

Appelbaum, Frederick R.; Gundacker, Holly; Head, David R.; Slovak, Marilyn L.; Willman, Cheryl L.; Godwin, John; Anderson, Jeanne E.; Petersdorf, Stephen H.

doi:10.1182/blood-2005-09-3724

Cited by 1,164 publications

(1,063 citation statements)

References 22 publications

Supporting

Mentioning

993

Contrasting

Unclassified

Order By: Relevance

“…Within the acute myeloid leukemia ex chronic myelomonocytic leukemia patient group, univariate survival analysis also identified increasing age as being associated with worse survival, similar to published results for de novo acute myeloid leukemia. 34,35 Although there were too few cases to attempt formal statistical comparisons regarding the NPM1 or FLT3 gene mutations, survival of the acute myeloid leukemia ex chronic myelomonocytic leukemia cases containing the NPM1 mutation were generally favorable compared with the other patients. This finding, as well as the rapid progression of NPM1-mutated chronic myelomonocytic leukemia patients to acute myeloid leukemia in our series and in another published series, 24 suggests that cases diagnosed as chronic myelomonocytic leukemia with an NPM1 mutation may actually represent early de novo acute myeloid leukemia exhibiting dysplastic features and monocytosis mimicking chronic myelomonocytic leukemia.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathologic analysis of acute myeloid leukemia arising from chronic myelomonocytic leukemia

Courville

Kourda

et al. 2013

Modern Pathology

View full text Add to dashboard Cite

Acute myeloid leukemia arising from chronic myelomonocytic leukemia is currently classified as acute myeloid leukemia with myelodysplasia-related changes, a high-risk subtype. However, the specific features of these cases have not been well described. We studied 38 patients with chronic myelomonocytic leukemia who progressed to acute myeloid leukemia. We compared the clinicopathologic and genetic features of these cases with 180 patients with de novo acute myeloid leukemia and 34 patients with acute myeloid leukemia following myelodysplastic syndromes. We also examined features associated with progression from chronic myelomonocytic leukemia to acute myeloid leukemia by comparing the progressed chronic myelomonocytic leukemia cases with a cohort of chronic myelomonocytic leukemia cases that did not transform to acute myeloid leukemia. Higher white blood cell count, marrow cellularity, karyotype risk score, and Revised International Prognostic Scoring System score were associated with more rapid progression from chronic myelomonocytic leukemia to acute myeloid leukemia. Patients with acute myeloid leukemia ex chronic myelomonocytic leukemia were older (Po0.01) and less likely to receive aggressive treatment (P ¼ 0.02) than de novo acute myeloid leukemia patients. Most cases showed monocytic differentiation and fell into the intermediate acute myeloid leukemia karyotype risk group; 55% had normal karyotype and 17% had NPM1 mutation. Median overall survival was 6 months, which was inferior to de novo acute myeloid leukemia (17 months, P ¼ 0.002) but similar to post myelodysplastic syndrome acute myeloid leukemia. On multivariate analysis of all acute myeloid leukemia patients, only age and karyotype were independent prognostic variables for overall survival. Our findings indicate that acute myeloid leukemia following chronic myelomonocytic leukemia displays aggressive behavior and support placement of these cases within the category of acute myeloid leukemia with myelodysplasia-related changes. The poor prognosis of these patients may be related to an older population and lack of favorable-prognosis karyotypes that characterize many de novo acute myeloid leukemia cases.

show abstract

Section: Discussionmentioning

confidence: 99%

Clinicopathologic analysis of acute myeloid leukemia arising from chronic myelomonocytic leukemia

Courville

Kourda

et al. 2013

Modern Pathology

View full text Add to dashboard Cite

show abstract

“…Risk Stratification TRM vs. resistance It is important to re-emphasize that the major cause of therapeutic failure in AML is resistance to treatment rather than treatment-related mortality (TRM) [1,2]. Although various criteria for TRM exist, Walter et al [3] using data from 2,238 MD Anderson Cancer Center (MDA) and 1,127 Southwest Oncology Group (SWOG) patients given 3 days of an anthracycline 1 either standard doses of ara-C (100 mg/m 2 daily X 7, i.e.…”

Section: Instructions On Receiving Creditmentioning

confidence: 99%

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

2013

View full text Add to dashboard Cite

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.

show abstract

“…2 However, these advances have been limited to subpopulations, with the majority of AML patients relying on modifications to doses and schedules of the standard of care cytarabine and anthracycline chemotherapy induction regimens (7 + 3) or improvements in hematopoietic stem cell transplantation methodologies. 3 AML has been a target for the therapeutic use of monoclonal antibodies or antibody-drug conjugates (ADCs), partly due the accessibility of the malignant cells and expression of well-defined cell surface antigens. To date, most development efforts with ADCs for AML have focused on targeting CD33, a transmembrane receptor expressed on cells of myeloid lineage, as exemplified by the approval of anti-CD33 Mylotarg® (gemtuzumab ozogamicin) in 2000, which was the first anti-cancer ADC on the market.…”

Section: Introductionmentioning

confidence: 99%

Preclinical pharmacokinetics and pharmacodynamics of DCLL9718A: An antibody-drug conjugate for the treatment of acute myeloid leukemia

Leipold¹,

Figueroa²,

Masih³

et al. 2018

mAbs

View full text Add to dashboard Cite

Few treatment options are available for acute myeloid leukemia (AML) patients. DCLL9718A is an antibody-drug conjugate that targets C-type lectin-like molecule-1 (CLL-1). This receptor is prevalent on monocytes, neutrophils, and AML blast cells, and unlike CD33, is not expressed on hematopoietic stem cells, thus providing possible hematopoietic recovery. DCLL9718A comprises an anti-CLL-1 IgG1 antibody (MCLL0517A) linked to a pyrrolobenzodiazepine (PBD) dimer payload, via a cleavable disulfide-labile linker. Here, we characterize the in vitro and in vivo stability, the pharmacokinetics (PK) and pharmacodynamics (PD) of DCLL9718A and MCLL0517A in rodents and cynomolgus monkeys. Three key PK analytes were measured in these studies: total antibody, antibody-conjugated PBD dimer and unconjugated PBD dimer. In vitro, DCLL9718A, was stable with most (> 80%) of the PBD dimer payload remaining conjugated to the antibody over 96 hours. This was recapitulated in vivo with antibody-conjugated PBD dimer clearance estimates similar to DCLL9718A total antibody clearance. Both DCLL9718A and MCLL0517A showed linear PK in the non-binding rodent species, and non-linear PK in cynomolgus monkeys, a binding species. The PK data indicated minimal impact of conjugation on the disposition of DCLL9718A total antibody. Finally, in cynomolgus monkey, MCLL0517A showed target engagement at all doses tested (0.5 and 20 mg/kg) as measured by receptor occupancy, and DCLL9718A (at doses of 0.05, 0.1 and 0.2 mg/kg) showed strong PD activity as evidenced by notable reduction in monocytes and neutrophils.

show abstract

Age and acute myeloid leukemia

Cited by 1,164 publications

References 22 publications

Clinicopathologic analysis of acute myeloid leukemia arising from chronic myelomonocytic leukemia

Clinicopathologic analysis of acute myeloid leukemia arising from chronic myelomonocytic leukemia

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

Preclinical pharmacokinetics and pharmacodynamics of DCLL9718A: An antibody-drug conjugate for the treatment of acute myeloid leukemia

Contact Info

Product

Resources

About