p53 immunohistochemistry as an ancillary tool for rapid assessment of residual disease in TP53-mutated acute myeloid leukemia and myelodysplastic syndromes.

OBJECTIVES: Measurable residual disease flow cytometry (MRD-FC) and molecular studies are the most sensitive methods for detecting residual malignant populations after therapy for TP53-mutated acute myeloid leukemia and myelodysplastic neoplasms (TP53+ AML/MDS). However, their sensitivity is limited in suboptimal aspirates or when the immunophenotype of the neoplastic blasts overlaps with erythroids or normal maturing myeloid cells. In this study, we set out to determine if p53 immunohistochemistry (IHC) correlates with MRD-FC and next-generation sequencing (NGS) in the posttherapy setting and to determine the utility of p53 IHC to detect residual disease in the setting of negative or equivocal MRD-FC. METHODS: We retrospectively identified 28 pre- and posttherapy bone marrow biopsy specimens from 9 patients with TP53+ AML/MDS and a p53 overexpressor phenotype by IHC (strong 3+ staining at initial diagnosis). Next-generation sequencing and/or MRD-FC results were collected for each specimen. RESULTS: Using a threshold of more than ten 2-3+ cells in any one 400× field, p53 IHC detected residual disease with a sensitivity of 94% and a specificity of 89%. The threshold used in this study showed a high degree of concordance among 6 blinded pathologists (Fleiss κ = 0.97). CONCLUSIONS: Our study suggests that p53 IHC can be used as a rapid tool (within 24 hours) to aid in the detection of residual disease that may complement MRD-FC or NGS in cases in which the flow cytometry immunophenotype is equivocal and/or the bone marrow aspirate is suboptimal.

Classification, risk stratification and response assessment in myelodysplastic syndromes/neoplasms (MDS): A state-of-the-art report on behalf of the International Consortium for MDS (icMDS).

The guidelines for classification, prognostication, and response assessment of myelodysplastic syndromes/neoplasms (MDS) have all recently been updated. In this report on behalf of the International Consortium for MDS (icMDS) we summarize these developments. We first critically examine the updated World Health Organization (WHO) classification and the International Consensus Classification (ICC) of MDS. We then compare traditional and molecularly based risk MDS risk assessment tools. Lastly, we discuss limitations of criteria in measuring therapeutic benefit and highlight how the International Working Group (IWG) 2018 and 2023 response criteria addressed these deficiencies and are endorsed by the icMDS. We also address the importance of patient centered care by discussing the value of quality-of-life assessment. We hope that the reader of this review will have a better understanding of how to classify MDS, predict clinical outcomes and evaluate therapeutic outcomes.

Comparison of Patient Age Groups in Transplantation for Myelodysplastic Syndrome: The Medicare Coverage With Evidence Development Study.

Importance: In 2010, the US Centers for Medicare & Medicaid Services (CMS) indicated that data regarding efficacy of allogeneic hematopoietic stem cell transplantation (HCT) in the CMS beneficiary population with myelodysplastic syndrome (MDS) were currently insufficient, but that coverage would be provided for patients enrolled in a clinical study that met its criteria for Coverage with Evidence Development (CED). Objective: The Center for International Bone Marrow Transplant Research (CIBMTR) submitted a study concept comparing the outcomes of patients aged 55 to 64 years vs aged 65 years or older who met those criteria, effectively providing coverage by CMS for HCT for MDS. Design, Setting, and Participants: Data on patients aged 65 years or older were prospectively collected and their outcomes compared with patients aged 55 to 64 years. Patients were enrolled in the study from December 15, 2010, to May 14, 2014. The results reported herein were analyzed as of September 4, 2017, with a median follow-up of 47 months. The study was conducted by the CIBMTR. It comprises a voluntary working group of more than 420 centers worldwide that contribute detailed data on allogeneic and autologous HCT and cellular therapies. Interventions: Patients with MDS received HCT according to institutional guidelines and preferences. Main Outcomes and Measures: The primary outcome was overall survival (OS); secondary outcomes included nonrelapse mortality (NRM), relapse-free survival, and acute and chronic graft vs host disease. Results: During the study period, 688 patients aged 65 years or older underwent HCT for MDS and were compared with 592 patients aged 55 to 64 years. Other than age, there were no differences in patient and disease characteristics between the groups. On univariate analysis, the 3-year NRM rate was 28% vs 25% for the 65 years or older group vs those aged 55 to 64 years, respectively. The 3-year OS was 37% vs 42% for the 65 years or older group vs the 55 to 64 years age group, respectively. On multivariable analysis after adjusting for excess risk of mortality in the older group, age group had no significant association with OS (HR, 1.09; 95% CI, 0.94-1.27; P = .23) or NRM (HR, 1.19; 95% CI, 0.93-1.52; P = .16). Conclusions and Relevance: Older patients with MDS undergoing HCT have similar OS compared with younger patients. Based on current data, we would recommend coverage of HCT for MDS by the CMS. Trial Registration: ClinicalTrials.gov identifier: NCT01166009.

Myelodysplastic syndromes, version 2.2015.

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) comprise a heterogeneous group of myeloid disorders with a highly variable disease course that depends largely on risk factors. Risk evaluation is therefore a critical component of decision-making in the treatment of MDS. The development of newer treatments and the refinement of current treatment modalities are designed to improve patient outcomes and reduce side effects. These NCCN Guidelines Insights focus on the recent updates to the guidelines, which include the incorporation of a revised prognostic scoring system, addition of molecular abnormalities associated with MDS, and refinement of treatment options involving a discussion of cost of care.

Role of reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation in older patients with de novo myelodysplastic syndromes: an international collaborative decision analysis.

PURPOSE: Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders that are more common in patients aged ≥ 60 years and are incurable with conventional therapies. Reduced-intensity conditioning (RIC) allogeneic hematopoietic stem-cell transplantation is potentially curative but has additional mortality risk. We evaluated RIC transplantation versus nontransplantation therapies in older patients with MDS stratified by International Prognostic Scoring System (IPSS) risk. PATIENTS AND METHODS: A Markov decision model with quality-of-life utility estimates for different MDS and transplantation states was assessed. Outcomes were life expectancy (LE) and quality-adjusted life expectancy (QALE). A total of 514 patients with de novo MDS aged 60 to 70 years were evaluated. Chronic myelomonocytic leukemia, isolated 5q- syndrome, unclassifiable, and therapy-related MDS were excluded. Transplantation using T-cell depletion or HLA-mismatched or umbilical cord donors was also excluded. RIC transplantation (n = 132) stratified by IPSS risk was compared with best supportive care for patients with nonanemic low/intermediate-1 IPSS (n = 123), hematopoietic growth factors for patients with anemic low/intermediate-1 IPSS (n = 94), and hypomethylating agents for patients with intermediate-2/high IPSS (n = 165). RESULTS: For patients with low/intermediate-1 IPSS MDS, RIC transplantation LE was 38 months versus 77 months with nontransplantation approaches. QALE and sensitivity analysis did not favor RIC transplantation across plausible utility estimates. For intermediate-2/high IPSS MDS, RIC transplantation LE was 36 months versus 28 months for nontransplantation therapies. QALE and sensitivity analysis favored RIC transplantation across plausible utility estimates. CONCLUSION: For patients with de novo MDS aged 60 to 70 years, favored treatments vary with IPSS risk. For low/intermediate-1 IPSS, nontransplantation approaches are preferred. For intermediate-2/high IPSS, RIC transplantation offers overall and quality-adjusted survival benefit.

Prospective assessment of effects on iron-overload parameters of deferasirox therapy in patients with myelodysplastic syndromes.

We report the first prospective study evaluating the effects of deferasirox on liver iron concentration (LIC), labile plasma iron (LPI) and pharmacokinetics (PK) along with serum ferritin values in patients with IPSS Low- and Intermediate-1 risk myelodysplastic syndromes (MDS) and evidence of iron overload. Twenty-four heavily transfused MDS patients were enrolled in a planned 52 weeks of therapy. PK studies showed dose-proportional total drug exposure. Data demonstrated that deferasirox was well tolerated and effectively reduced LIC, LPI and serum ferritin in the iron-overloaded patients with MDS who completed 24 and 52 weeks of therapy despite ongoing receipt of red blood cell transfusions.

Current therapeutic approaches for patients with myelodysplastic syndromes.

The myelodysplastic syndromes (MDS) are a heterogeneous spectrum of disorders requiring selective therapy based on patients' specific clinical features, predominantly their prognostic subgroups, age and performance status. Guidelines for management of patients with MDS have been generated by a number of national panels. This review focuses on evidence-based data supporting therapeutic approaches, which have also been recommended by the US National Comprehensive Cancer Network MDS Panel, with discussion of accessibility of recommended drugs in the US and in other countries. For lower risk disease (International Prognostic Scoring System Low and Intermediate-1) therapy is aimed at haematological improvement whereas for higher risk disease (Intermediate-2 and High) treatment focuses on altering disease natural history. Recent information regarding additional clinical and biological features has provided useful parameters for assessing disease prognosis that aid risk-based management decisions. The rationale for use of low versus high intensity therapies with these agents, including allogeneic haematopoietic stem cell transplantation, is discussed in detail.

The costs of drugs used to treat myelodysplastic syndromes following National Comprehensive Cancer Network Guidelines.

Guidelines for management of patients with myelodysplastic syndromes (MDS) have been generated by the National Comprehensive Cancer Network (NCCN) Myelodysplastic Syndromes Panel. Because MDS is a heterogeneous spectrum of disorders, these patients have been categorized into prognostic subgroups, predominantly using the International Prognostic Scoring System (IPSS). Several drugs have been used to treat these patients, and their selection and sequential recommended use by the panel depend on disease characteristics and responses to treatment. Recombinant erythropoietin alfa and darbepoetin alfa have been the mainstay of therapy for treating anemia associated with MDS. The FDA has recently approved several other drugs for treating MDS, including azacytidine and decitabine for all stages of disease, lenalidomide for low-risk anemic patients with del(5q) chromosomal abnormality, and deferasirox for treating iron overload. For iron chelation, deferoxamine is also used occasionally. Treatment with immunosuppressive therapy (antithymocyte globulin and cyclosporin) has been therapeutically beneficial for a subset of younger patients with MDS. Because the financial cost of these therapies are substantial and have received only limited attention, this article evaluates the costs of specific drugs and their sequential use in the lower-risk IPSS (low and intermediate-1) subgroups based on the NCCN guidelines. Results estimate an average annual cost for potentially anemia-altering drugs of $63,577 per patient, ranging from $26,000 to $95,000, depending on the specific therapies. In patients for whom the therapies fail, annual costs for iron chelation plus red blood cell transfusions are estimated to average $41,412. The economic impact of drug therapy should be weighed against the patient's potential for improvement in clinical outcomes, quality of life, and transfusion requirements.

A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome.

Bone marrow transplantation (BMT) can cure myelodysplastic syndrome (MDS), although transplantation carries significant risks of morbidity and mortality. Because the optimal timing of HLA-matched BMT for MDS is unknown, we constructed a Markov model to examine 3 transplantation strategies for newly diagnosed MDS: transplantation at diagnosis, transplantation at leukemic progression, and transplantation at an interval from diagnosis but prior to leukemic progression. Analyses using individual patient risk-assessment data from transplantation and nontransplantation registries were performed for all 4 International Prognostic Scoring System (IPSS) risk groups with adjustments for quality of life (QoL). For low and intermediate-1 IPSS groups, delayed transplantation maximized overall survival. Transplantation prior to leukemic transformation was associated with a greater number of life years than transplantation at the time of leukemic progression. In a cohort of patients under the age of 40 years, an even more marked survival advantage for delayed transplantation was noted. For intermediate-2 and high IPSS groups, transplantation at diagnosis maximized overall survival. No changes in the optimal transplantation strategies were noted when QoL adjustments were incorporated. For low- and intermediate-1-risk MDS, delayed BMT is associated with maximal life expectancy, whereas immediate transplantation for intermediate-2- and high-risk disease is associated with maximal life expectancy.