The National MDS Natural History Study: design of an integrated data and sample biorepository to promote research studies in myelodysplastic syndromes.

Myelodysplastic syndromes (MDS), a spectrum of heterogeneous hematopoietic stem cell diseases, vary in clinical severity, response to therapy, and propensity toward progression to acute myeloid leukemia. These are acquired clonal disorders resulting from somatic mutations within the hematopoietic stem or progenitor cell population. Understanding the natural history and the risk of developing leukemia and other adverse outcomes is dependent on access to well-annotated biospecimens linked to robust clinical and molecular data. To facilitate the acquisition and distribution of MDS biospecimens to the wider scientific community and support scientific discovery in this disease, the National MDS Natural History study was initiated by the National Heart, Lung, and Blood Institute (NHLBI) and is being conducted in collaboration with community hospitals and academic medical centers supported by the National Cancer Institute (NCI). The study will recruit up to 2000 MDS patients or overlapping myeloproliferative neoplasms (MDS/MPN) and up to 500 cases of idiopathic cytopenia of undetermined significance (ICUS). The National MDS Natural History Study (NCT02775383) will offer the world's largest disease-focused tissue biobank linked to longitudinal clinical and molecular data in MDS. Here, we report on the study design features and describe the vanguard phase of 200 cases. The study assembles a comprehensive clinical database, quality of life results, laboratory data, histopathology slides and images, genetic information, hematopoietic and germline tissues representing high-quality biospecimens and data from diverse centers across the United States. These resources will be available to the scientific community for investigator-initiated research.

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.

Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation.

PURPOSE: Age has long been used as a major factor for assessing suitability for allogeneic hematopoietic cell transplantation (HCT). The HCT-comorbidity index (HCT-CI) was developed as a measure of health status to predict mortality risk after HCT. Whether age, comorbidities, or both should guide decision making for HCT is unknown. PATIENTS AND METHODS: Data from 3,033 consecutive recipients of HLA-matched grafts from five institutions contributed to this analysis. Patients were randomly divided into a training set to develop weights for age intervals and a validation set to assess the performance of prognostic models. RESULTS: In the training set, patients age 20 to 39 years, 40 to 49 years, 50 to 59 years, and ≥ 60 years had hazard ratios for nonrelapse mortality (NRM) of 1.21 (P = .29), 1.48 (P = .04), 1.75 (P = .004), and 1.84 (P = .005), respectively, compared with those age younger than 20 years. Consequently, age ≥ 40 years was assigned a weight of 1 to be added to the HCT-CI to constitute a composite comorbidity/age index. In the validation set, the composite comorbidity/age score had statistically significantly higher c-statistic estimates for prediction of NRM (0.664 v 0.556; P < .001) and survival (0.682 v 0.560; P < .001) compared with age, respectively. Patients with comorbidity/age scores of 0 to 2 had comparable mortality risks regardless of conditioning regimens. Patients with scores of 3 to 4 and ≥ 5 had statistically significant higher mortality risks after high-dose versus nonmyeloablative regimens. CONCLUSION: Age is a poor prognostic factor. The proposed composite measure allows integration of both comorbidities and age into clinical decision making and comparative-effectiveness research of HCT.

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.

Incidence of myelodysplastic syndromes within a nonprofit healthcare system in western Washington state, 2005-2006.

Myelodysplastic syndromes (MDS) incidence is unclear because of historical lack of population-based registration and possibly because of underdiagnosis. We conducted a study to evaluate completeness of MDS registration in the Seattle-Puget Sound region of the Surveillance, Epidemiology, and End Results (SEER) program-which has reported the highest rates among the SEER registries since mandatory reporting of MDS began in 2001. We identified incident MDS cases of any age that occurred within a nonprofit healthcare system in western Washington State in 2005 or 2006 through the local SEER registry or by relevant diagnostic code followed by medical chart review to classify these patients as unlikely, possible, or definite/probable MDS. We calculated age-standardized incidence rates for all identified MDS cases and for case groups based on identification method, and we summarized medical histories of the MDS patients. MDS incidence in our study population was estimated as 7.0 per 100,000 person-years in 2005-2006 when combining MDS cases identified by SEER and definite/probable cases identified by chart review, which was similar to the rate of 6.9 reported by our local SEER registry. The addition of possible MDS cases identified from chart review increased the rate to 10.2 per 100,000. MDS patients frequently had previous cancer diagnoses (25%) and comorbidities such as high blood pressure and diabetes. Our investigation suggests that although reporting of confirmed MDS diagnoses in our region appears complete, MDS incidence is likely underestimated because of omission of cases who are symptomatic but do not receive definitive diagnoses.

Longitudinal assessment of morbidity and acute graft-versus-host disease after allogeneic hematopoietic cell transplantation: retrospective analysis of a multicenter phase III study.

Because morbidity early after hematopoietic cell transplantation (HCT) results in large part from the development of acute graft-versus-host disease (GVHD), we previously proposed that a longitudinal assessment of morbidity involving the skin, liver, and gastrointestinal (GI) tract might provide a more complete, objective approach for comparing 2 arms of open-label randomized clinical trials for acute GVHD prevention. In this study, we determined both morbidity across time and GVHD across time in a retrospective analysis of a database from an open-label randomized clinical trial comparing tacrolimus/methotrexate and cyclosporine/methotrexate after myeloablative conditioning and marrow transplantation from HLA-matched unrelated donors. The results confirm differences in overall morbidity across time in patients with peak grade II-IV GVHD compared with those with grade 0-I GVHD, but no significant differences in morbidity associated with grade II GVHD compared with grade 0-I GVHD. We observed less skin morbidity and a trend toward less liver morbidity across time in the tacrolimus group (P = .04 and .09, respectively), but not for GI morbidity or overall morbidity, despite significantly decreased skin and liver stages and overall grades of GVHD across time in this group. Thus, our objective assessment of differences in morbidity (regardless of cause) as a measure of acute GVHD in a randomized clinical trial of acute GVHD prevention has only limited utility. The difficulty of demonstrating clinical benefits from objective parameters, such as survival and morbidity, and the subjectivity of grading acute GVHD emphasize the need for blinded assessments in clinical trials of GVHD prevention.

Hemopoietic cell transplantation for the myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are hemopoietic stem cell disorders, and hemopoietic stem cell transplantation is currently the only therapeutic modality with curative potential. Among patients with less advanced/low-risk MDS (<5% marrow blasts), 3-year survivals of 65--70% are achievable with HLA-identical related and unrelated donors. The overall probability of disease recurrence in these patients is <5%. Among patients with more advanced disease (>or=5% marrow blasts), the relapse probability is higher, ranging from 10--40%, and relapse-free survival is correspondingly lower. The criteria proposed by the International Prognostic Scoring System, derived from non-transplanted patients, also predict survival following transplantation. The development of reduced-intensity conditioning regimens and modification of conventional regimens, all aimed at optimizing the transplant approach, have permitted successful hemopoietic stem cell transplants even in patients 60--70 years of age. Improved survival with transplants from unrelated volunteer donors reflects to a large extent selection of donors on the basis of high resolution (allele-level) HLA typing. Graft-versus-host disease and associated problems remain major challenges after allogeneic transplantation. Autologous stem cell transplantation may be beneficial for selected patients who have obtained complete remissions with conventional chemotherapy.

Flow cytometry for diagnosis and assessment of prognosis in patients with myelodysplastic syndromes.

The Myelodysplastic Syndrome (MDS) comprises a spectrum of hematopoietic stem cell disorders. Identification of additional parameters that might distinguish different risk groups or entities would be useful. Flow cytometric studies have begun to characterize individual or composite immunophenotypic abnormalities as well as light scatter properties that may be helpful for diagnosis and of prognostic value for the natural course of the disease and for outcome after therapy. Here we review the current state of the art of the use of flow cytometry in patients with MDS.

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.