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Biomedical subjects

Mikkael A Sekeres

Publications and source records attributed to Mikkael A Sekeres.

13 recordsLinked to original sources
PubMed2026

Quizartinib for patients with newly diagnosed FLT3-ITD-positive AML who received maintenance therapy in QuANTUM-First.

QuANTUM-First demonstrated improved overall survival (OS) in patients with newly diagnosed acute myeloid leukemia with FMS-like receptor tyrosine kinase 3-internal tandem duplication (FLT3-ITD) treated with quizartinib + standard chemotherapy. Herein, we evaluated the impact of postconsolidation/posttransplant single-agent maintenance therapy on clinical outcomes in patients receiving maintenance, focusing on measurable residual disease (MRD) status at maintenance onset. OS, event-free survival, and relapse-free survival were prespecified exploratory analyses. Cumulative incidence of relapse, analyses by allogeneic hematopoietic cell transplant (allo-HCT), and analyses by MRD status were post hoc and not powered for statistical significance. Samples for FLT3-ITD MRD analysis were collected from patients with composite complete remission ≤30 days before receiving maintenance and assessed using an ultrasensitive amplicon-based assay. More patients who had received an allo-HCT and quizartinib treatment received maintenance (71%) vs placebo (55%); OS benefit was not demonstrated among these patients. In patients who did not undergo allo-HCT, quizartinib maintenance was associated with a significant OS benefit (hazard ratio [HR], 0.401; 95% confidence interval [CI], 0.192-0.838), including a benefit in patients who were MRD negative at the start of maintenance (OS HR, 0.194; 95% CI, 0.056-0.676). Patients who were MRD negative at the completion of consolidation achieved 89.1% (95% CI, 70.0-96.4) survival at 3 years with quizartinib maintenance in the absence of allo-HCT. These data suggest that for patients who achieve FLT3-ITD MRD negativity after induction and consolidation with quizartinib, maintenance with quizartinib provides a significant survival benefit and, in some patients, may eliminate the need for allo-HCT. This trial was registered at www.clinicaltrials.gov as NCT02668653.

Humans↗
PubMed2006

Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another myeloproliferative condition characterized by JAK2 V617F mutation.

JAK2 V617F mutation recently was identified as a pathogenic factor in typical chronic myeloproliferative diseases (CMPD). Some forms of myelodysplastic syndromes (MDS) show a significant overlap with CMPD (classified as MDS/MPD), but the diagnostic assignment may be challenging. We studied blood or bone marrow from 270 patients with MDS, MDS/MPD, and CMPD for the presence of JAK2 V617F mutation using polymerase chain reaction, sequencing, and melting curve analysis. The detection rate of JAK2 V617F mutants for polycythemia vera, chronic idiopathic myelofibrosis, and essential thrombocythemia (n = 103) was similar to the previously reported results. In typical forms of MDS (n = 89) JAK2 V617F mutation was very rare (n = 2). However, a higher prevalence of this mutation was found in patients with MDS/MPD-U (9 of 35). Within this group, most of the patients harboring JAK2 V617F mutation showed features consistent with the provisional MDS/MPD-U entity refractory anemia with ringed sideroblasts and thrombocytosis (RARS-T). Among 9 RARS-T patients, 6 showed the presence of JAK2 V617F mutation, and in 1 patient without mutation, aberrant, positive phospho-STAT5 staining was seen that is typically present in association with JAK2 V617F mutation. In summary, we found that RARS-T reveals a high frequency of JAK2 V617F mutation and likely constitutes another JAK2 mutation-associated form of CMPD.

Alleles↗
PubMed2006

Immunomodulation in myelodysplastic syndromes.

The myelodysplastic syndromes (MDS) - bone-marrow stem-cell malignancies that share pathogenetic overlap with acute myeloid leukemia - are characterized by peripheral-blood cytopenias and, in more advanced subtypes, varied degrees of maturation arrest. Premature apoptosis of bone-marrow cellular elements contributes to ineffective hematopoiesis, which is exacerbated by stromal production of inflammatory cytokines. Abrogation of the effects of these cytokines represents an area of active clinical research, particularly in the treatment of low-risk MDS. Agents such as thalidomide, lenalidomide, and infliximab have shown promising efficacy and tolerability in clinical trials, and may represent a springboard for future treatment combinations.

Humans↗
PubMed2006

Non-transplant therapy for older adults with acute myeloid leukemia.

Acute myeloid leukemia is a disease of older adults, with a median age at diagnosis of 68 years. This group represents a high-risk population, because inherent disease characteristics predict for resistance to chemotherapy and advanced age is accompanied by high treatment-related mortality. Standard remission-induction and postremission therapy can result in a median disease-free survival of 10 months and rare long-term survival. Efforts to improve outcomes have not made a major impact on complete remission rates of 40% to 60%, or on overall survival. Newer therapies, divided into aggressive and nonaggressive approaches, focus on targeting the disease biology specific to older adults and on maximizing quality of life. Clinical trials should be considered at every stage of treatment in this group of patients.

Acute Disease↗
PubMed2005

Daptomycin-resistant Enterococcus faecium in a patient with acute myeloid leukemia.

Daptomycin is a lipopeptide antimicrobial used for the treatment of aerobic gram-positive skin and soft tissue infections. We describe a patient with acute myeloid leukemia whose febrile neutropenia was treated with daptomycin and who later developed daptomycin-resistant Enterococcus faecium infection. Defervescence and negative blood cultures ensued after treatment with linezolid. Guidelines for testing daptomycin susceptibillities of enterococci include breakpoints only for vancomycin-susceptible Enterococcus faecalis, making interpretation of minimum inhibitory concentrations for common clinical infections difficult. No enterococcal cross-resistance has been reported among daptomycin, linezolid, or quinupristin-dalfopristin, and these agents may be viable alternatives.

Acute Disease↗
PubMed2005

Arsenic trioxide as a treatment for myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) is a heterogeneous bone marrow disorder primarily affecting older adults, for whom the only curative therapy, bone marrow transplantation, is rarely an option. New therapies, or novel applications of historical therapies, are desperately needed. Arsenic trioxide (ATO), which acts through pro-apoptotic, antiproliferative, and anti-angiogenesis mechanisms, has been used successfully to treat a variety of hematologic malignancies, including MDS. As monotherapy or in combination with other agents, it can effect hematologic improvement in 22% to 26% of patients, with tolerable side effects. MDS patients whose cells express the EVI1 mutation in particular may derive benefit from this therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Lenalidomide (Revlimid, CC-5013) in myelodysplastic syndromes: is it any good?

The myelodysplastic syndromes (MDS) can be divided into "early" and "advanced" disease by evaluation of prognostic variables such as the number of cytopenias, karyotype, and percentage of myeloblasts. Patients with an isolated interstitial deletion of chromosome 5q31 represent a distinct subset who may derive particular benefit from immunomodulatory drugs. Goals of therapy for early MDS focus on hematologic improvement and maximizing quality of life. Thalidomide, the prototype of the immunomodulatory drugs, yields major erythroid responses in some patients with early MDS, but dose-limiting neurologic toxicities limit its potential clinical benefit. Lenalidomide, a more potent and non-neurotoxic derivative, has shown promising results in early MDS, yielding hematologic improvement in almost half of patients, and transfusion independence with cytogenetic remissions in approximately two thirds of patients harboring the chromosome 5q31 deletion.

Aged↗
PubMed2004

Differences in prognostic factors and outcomes in African Americans and whites with acute myeloid leukemia.

Whites have a more favorable prognosis than African Americans for a number of cancers. The relationship between race and outcome is less clear in acute myeloid leukemia (AML). Using data from 7 Cancer and Leukemia Group B studies initiated from 1985 to 1997, we conducted a retrospective cross-sectional analysis of 2570 patients (270 African American and 2300 white) with de novo AML who received induction chemotherapy. African Americans were younger than whites (48 versus 54 years, P <.001). African Americans also had different cytogenetic risk group distributions than whites (P <.001): they were more commonly classified in the favorable (23% versus 14%) and unfavorable (31% versus 23%) groups, and less commonly classified in the intermediate group (47% versus 63%). African American men had a lower complete remission (CR) rate (54%, compared with 64% for white men, 65% for white women, and 70% for African American women, P =.001) and a worse overall survival compared with all other patients (P =.004), when known risk factors are taken into account. African Americans and whites with AML differ with respect to important prognostic factors. African American men have worse CR rates and overall survival than whites and African American women, and should be considered a poor-risk group.

Acute Disease↗
PubMed2004

Acute myeloid leukemia.

Advances in our understanding of the pathophysiology of acute myeloid leukemia (AML) have not yet led to major improvements in disease-free and overall survival of adults with this disease. Only about one-third of those between ages 18-60 who are diagnosed with AML can be cured; disease-free survival is rare and current therapy devastating in older adults. In this chapter, challenges in the management of the adult with AML are discussed, including ongoing questions concerning the optimal choice of induction and postremission therapy such as the rationale for and role of allogeneic and autologous stem cell transplantation in a variety of settings, the special considerations pertaining to the older patient, and the development of new, so-called targeted therapies. In Section I, Dr. Richard Stone reviews state-of the-art therapy in AML in the era of change from a morphological to a genetically based classification system. Questions being addressed in ongoing randomized cooperative group trials include anthracycline dose during induction, the efficacy of drug-resistance modulators, and the utility of pro-apoptotic agents such as the anti-bcl-2 antisense oligonucloetide. Developmental therapeutics in AML include drug resistance modulation, anti-angiogenic strategies, immunotherapy, and signal transduction-active agents, particularly the farnesyl transferase inhibitors as well as those molecules that inhibit the FLT3 tyrosine kinase, activated via mutation in 30% of patients. In Section II Dr. Margaret O'Donnell discusses the role of stem cell transplantation in AML. Several advances including expanded donor pools, the movement toward peripheral blood stem cell collection, newer immunosuppressive drugs and antifungals, and particularly the advent of nonmyeloablative transplant have made the allogeneic option more viable. The subset-specific role for high-dose chemotherapy with autologous stem cell support and/or for allogeneic transplant in AML patients in first remission is outlined. Although preconceived notions about the role of transplant abound, the clinical data supporting a risk-adapted approach are covered. Finally, guidance concerning the use of nonmyeloablative or reduced-intensity allogeneic transplantation is provided. In Section III Dr. Mikkael Sekeres reviews the approach to the older patient with AML. Unique biological and therapeutic considerations make AML in this age group a vastly different disease than that in younger adults. The outcome data, including the role of specific anthracylines, hematopoietic growth factors, and drug-resistance modulators, are summarized. Communicating with older adults with AML and their families regarding selection of the optimal treatment strategy, often a stark choice between induction chemotherapy and palliative care, is covered.

Adult↗
PubMed2003

The impact of a physician awareness group and the first year of training on hematology-oncology fellows.

PURPOSE: To assess the impact of a Balint-like physician awareness group on hematology-oncology fellows' attitudes and measure changes in attitudes during the first fellowship year. PATIENTS AND METHODS: We used a modified crossover design in which one half of a fellowship class at a time was exposed to the group intervention over a 2-year period (2000 to 2002). Two 14-fellow classes were followed for 1 year each and were given three "attitudes" questionnaires, at the beginning, middle, and end of the academic year. RESULTS: Forty Balint group sessions were held during the 2-year study period; 82 questionnaires of the 84 administered (98%) were recovered. Instrument content and criterion validity were demonstrated, as was topic domain reliability. Overall, mean attitude scores increased following the group intervention, from 3.6 (95% CI, 3.5 to 3.7) to 3.7 (95% CI, 3.6 to 3.8; P =.09). Within domains, scores increased in a "fellow's views of him/herself as a physician," from 3.8 (95% CI, 3.6 to 3.9) to 4.1 (95% CI, 3.9 to 4.2; P =.008) and "comfort dealing with emotional patient/clinical situations," from 3.5 (95% CI, 3.3 to 3.7) to 3.7 (95% CI, 3.6 to 3.9; P =.11). Changes in responses to individual questions included: an increase in fellows' comfort with the technical aspects of being an oncologist (P <.03); an increase in fellows' comfort with discussing the stress of home at work (P <.023); and an increase among fellows in feeling pressed for time to discuss psychosocial issues with patients (P =.035). CONCLUSION: A physician awareness group was feasible and enhanced fellows' development as physicians. Further research is needed to determine how to incorporate such groups into oncology fellowships.

Adult↗
PubMed2002

Older adults with acute myeloid leukemia.

Acute myeloid leukemia (AML) occurs most frequently in older adults, with a median age range from 65 to 70 years. Both the disease and its treatment are distinct from their counterparts in young patients. Herein we characterize the intrinsic biologic features of AML as it occurs in the older population, review currently available therapeutic approaches, and discuss therapeutic strategies in development.

Acute Disease↗
PubMed2002

The challenge of acute myeloid leukemia in older patients.

Acute myeloid leukemia is a disease predominantly affecting older adults, with a median age at diagnosis of 65 years. Compared with younger adults or children with AML, older adults have a poor prognosis and represent a discrete population in terms of disease features, treatment-related complications, and overall outcome. Management of AML in this population often includes intensive, anthracycline-based chemotherapy, which can effect a 1.5- to 4-month survival advantage compared with nonintensive therapy but at a cost of early deaths, long length of hospital stay, and substantial transfusional support. Nonintensive therapy or palliative care remains an important option for many patients. Aggressive postremission therapy or the use of hematopoietic growth factor support does not appear to improve survival. Future directions include therapies targeted at immunomodulation, at angiogenesis, and in particular against intracellular signals that promote proliferation at the expense of differentiation.

Acute Disease↗