Andrea Kuendgen

Time-Dependent Prognostic Scoring System for Predicting Survival and Leukemic Evolution in Myelodysplastic Syndromes

PURPOSE The aims of this study were to identify the most significant prognostic factors in myelodysplastic syndromes (MDS) taking into account both their values at clinical onset and their changes in time and to develop a dynamic model for predicting survival and leukemic evolution that can be applied at any time during the course of the disease. PATIENTS AND METHODS We studied a learning cohort of 426 MDS patients diagnosed at the Department of Hematology, San Matteo Hospital, Pavia, Italy, between 1992 and 2004, and a validation cohort of 739 patients diagnosed at the Heinrich-Heine-University Hospital, Düsseldorf, Germany, between 1982 and 2003. All patients were reclassified according to WHO criteria. Univariable and multivariable analyses were performed using Cox models with time-dependent covariates. RESULTS The most important variables for the prognostic model were WHO subgroups, karyotype, and transfusion requirement. We defined a WHO classification-based prognostic scoring system (WPSS) that was able to classify patients into five risk groups showing different survivals (median survival from 12 to 103 months) and probabilities of leukemic evolution (P < .001). WPSS was shown to predict survival and leukemia progression at any time during follow-up (P < .001), and its prognostic value was confirmed in the validation cohort. CONCLUSION WPSS is a dynamic prognostic scoring system that provides an accurate prediction of survival and risk of leukemic evolution in MDS patients at any time during the course of their disease. This time-dependent system seems particularly useful in lower risk patients and may be used for implementing risk-adapted treatment strategies.

Impact of the degree of anemia on the outcome of patients with myelodysplastic syndrome and its integration into the WHO classification-based Prognostic Scoring System (WPSS)

Background Anemia is an established negative prognostic factor in myelodysplastic syndromes but the relationship between its degree and clinical outcome is poorly defined. We, therefore, studied the relationship between severity of anemia and outcome in myelodysplastic syndrome patients. Design and Methods We studied 840 consecutive patients diagnosed with myelodysplastic syndromes at the Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, and 504 patients seen at the Heinrich-Heine-University Hospital, Düsseldorf, Germany. Hemoglobin levels were monitored longitudinally and analyzed by means of time-dependent Cox’s proportional hazards regression models. Results Hemoglobin levels lower than 9 g/dL in males (HR 5.56, P=0.018) and 8 g/dL in females (HR=5.35, P=0.026) were independently related to reduced overall survival, higher risk of non-leukemic death and cardiac death (P<0.001). Severe anemia, defined as hemoglobin below these thresholds, was found to be as effective as transfusion-dependency in the prognostic assessment. After integrating this definition of severe anemia into the WHO classification-based Prognostic Scoring System, time-dependent regression and landmark analyses showed that the refined model was able to identify risk groups with different survivals at any time during follow up. Conclusions Accounting for severity of anemia through the WHO classification-based Prognostic Scoring System provides an objective criterion for prognostic assessment and implementation of risk-adapted treatment strategies in myelodysplastic syndrome patients.

Risk stratification based on both disease status and extra-hematologic comorbidities in patients with myelodysplastic syndrome

The incidence of myelodysplastic syndromes increases with age and a high prevalence of co-morbid conditions has been reported in these patients. So far, risk assessment in myelodysplastic syndromes has been mainly based on disease status. We studied the prognostic impact of comorbidity on the natural history of myelodysplastic syndrome with the aim of developing novel tools for risk assessment. The study population included a learning cohort of 840 patients diagnosed with myelodysplastic syndrome in Pavia, Italy, and a validation cohort of 504 patients followed in Duesseldorf, Germany. Information on comorbidity was extracted from detailed review of the patients’ medical charts and laboratory values at diagnosis and during the course of the disease. Univariable and multivariable survival analyses with both fixed and time-dependent covariates were performed using Cox’s proportional hazards regression models. Comorbidity was present in 54% of patients in the learning cohort. Cardiac disease was the most frequent comorbidity and the main cause of non-leukemic death. In multivariable analysis, comorbidity had a significant impact on both non-leukemic death (P=0.01) and overall survival (P=0.02). Cardiac, liver, renal, pulmonary disease and solid tumors were found to independently affect the risk of non-leukemic death. A time-dependent myelodysplastic syndrome-specific comorbidity index (MDS-CI) was developed for predicting the effect of comorbidity on outcome. This identified three groups of patients which showed significantly different probabilities of non-leukemic death (P<0.001) and survival (P=0.005) also in the validation cohort. Landmark survival analyses at fixed time points from diagnosis showed that the MDS-CI can better define the life expectancy of patients with myelodysplastic syndrome stratified according to the WHO-classification based Prognostic Scoring System (WPSS).Comorbidities have a significant impact on the outcome of patients with myelodysplastic syndrome. Accounting for both disease status by means of the WPSS and comorbidity through the MDS-CI considerably improves risk stratification in myelodysplastic syndromes.

Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia

Valproic acid (VPA) inhibits histone deacetylase activity and induces differentiation of acute myeloid leukemia (AML) blasts in vitro. We observed clinical responses to VPA in patients with myelodysplastic syndrome (MDS) and AML. Here, we report follow-up data on 75 patients. Of these, 66 were started on VPA monotherapy, with later addition of all-trans retinoic acid (ATRA) in patients who did not respond or relapsed. Nine patients were treated with VPA + ATRA from the start. Median treatment duration was 4 months for VPA and 2 months for ATRA. Hematological improvement, according to international working group criteria for MDS, was observed in 18 patients (24%). Median response duration was 4 months. ATRA exerted no additional effect in patients receiving the combination from the start or benefited primary VPA nonresponders. However, of ten VPA responders who relapsed, four achieved a second response after addition of ATRA. Response rates were strongly dependent on disease type according to WHO classification. We found a response rate of 52% in MDS patients with a normal blast count (refractory sideroblastic anemia, refractory cytopenia with multilineage dysplasia, and refractory sideroblastic cytopenia with multilineage dysplasia). The response rate was 6% in refractory anemia with excess blasts (I + II), 16% in AML, and 0% in chronic myelomonocytic leukemia. Bone marrow blast count was the only variable that predicted responses. We conclude that VPA is clinically useful in low-risk MDS. For patients with high-risk MDS, VPA may be combined with chemotherapy or demethylating drugs. If patients relapse after an initial response to VPA, ATRA has the potential to induce a prolonged second response.

Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia

The natural course of chronic myelomonocytic leukemia (CMML) is highly variable but a widely accepted prognostic scoring system for patients with CMML is not available. The main aim of this study was to develop a new CMML-specific prognostic scoring system (CPSS) in a large series of 558 patients with CMML (training cohort, Spanish Group of Myelodysplastic Syndromes) and to validate it in an independent series of 274 patients (validation cohort, Heinrich Heine University Hospital, Düsseldorf, Germany, and San Matteo Hospital, Pavia, Italy). The most relevant variables for overall survival (OS) and evolution to acute myeloblastic leukemia (AML) were FAB and WHO CMML subtypes, CMML-specific cytogenetic risk classification, and red blood cell (RBC) transfusion dependency. CPSS was able to segregate patients into 4 clearly different risk groups for OS (P < .001) and risk of AML evolution (P < .001) and its predictive capability was confirmed in the validation cohort. An alternative CPSS with hemoglobin instead of RBC transfusion dependency offered almost identical prognostic capability. This study confirms the prognostic impact of FAB and WHO subtypes, recognizes the importance of RBC transfusion dependency and cytogenetics, and offers a simple and powerful CPSS for accurately assessing prognosis and planning therapy in patients with CMML.

Valproic Acid for the Treatment of Myeloid Malignancies

Valproic acid (VPA) has been used as an anticonvulsant for decades. Recently, it was demonstrated that VPA also acts as a histone deacetylase inhibitor and induces differentiation and apoptosis in a variety of malignant cells in vitro. The effect of VPA on tumor cells differs according to cell type, degree of differentiation, and underlying genetic alterations. Clinical trials with VPA have focused on acute myeloid leukemia and the myelodysplastic syndromes. When it was used as monotherapy or in combination with all‐trans retinoic acid, which synergizes in vitro, VPA achieved hematologic improvement in a subset of patients. Similar to other inhibitors of histone deacetylases, complete or partial remissions rarely were observed. In this report, the authors reviewed the in vitro and in vivo data obtained with VPA, and they considered possible combination regimens aimed at improving therapeutic efficacy. Cancer 2007.

Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: results of the AML Study Group (AMLSG).

In this study, we evaluated the frequency and prognostic impact of DNMT3A mutations (DNMT3A(mut)) in 1770 younger adult patients with acute myeloid leukemia (AML) in the context of other genetic alterations and the European LeukemiaNet (ELN) classification. DNMT3A(mut) were found in 20.9% of AMLs and were associated with older age (P < .0001), higher white blood cell counts (P < .0001), cytogenetically normal AML (CN-AML; P < .0001), NPM1 mutations (P < .0001), FLT3 internal tandem duplications (P < .0001), and IDH1/2 mutations (P < .0001). In univariable and multivariable analyses, DNMT3A(mut) did not impact event-free, relapse-free (RFS), or overall survival (OS) in either the entire cohort or in CN-AML; a negative prognostic effect was found only in the ELN unfavorable CN-AML subset (OS, P = .011). In addition, R882 mutations vs non-R882 mutations showed opposite clinical effects-unfavorable for R882 on RFS (all: hazard ratio [HR], 1.29 [P = .026]; CN-AML: HR, 1.38 [P = .018]) and favorable for non-R882 on OS (all: HR, 0.77 [P = .057]; CN-AML: HR, 0.73 [P = .083]). In our statistically high-powered study with minimized selection bias, DNMT3A(mut) represent a frequent genetic lesion in younger adults with AML but have no significant impact on survival end points; only moderate effects on outcome were found, depending on molecular subgroup and DNMT3A(mut) type.

Current status of epigenetic treatment in myelodysplastic syndromes

Epigenetic deregulation plays an important role in cancer development. The great interest in epigenetics in hematology and oncology results from the fact that epigenetic, in contrast to genetic, alterations are, in principle, amenable to pharmacological reversal. Epigenetically active drugs currently within clinical trials include histone deacetylase inhibitors (HDACi) and DNA methyltransferase (DNMT) inhibitors. The first treatment approved by the Food and Drug Administration for the treatment of myelodysplastic syndromes (MDS) was the DNMT-inhibitor 5-azacytidine. Currently, two out of three drugs FDA approved for MDS therapy, 5-azacytidine and 5-aza-2′-deoxycytidine, are epigenetically active drugs. Recent clinical trials investigate new dosing schedules, routes of administration, and combination regimens. Several structurally distinct HDACi have been developed. Available data is mostly restricted to phase I trials. The largest experience in MDS and acute myeloid leukemia exists with the anticonvulsant valproic acid. This review summarizes the existing clinical experience on HDACi and DNMT inhibitors

The hematopoietic stem cell transplantation comorbidity index is of prognostic relevance for patients with myelodysplastic syndrome

So far, prognostic evaluation of patients with myelodysplastic syndrome has mainly been based on disease-related parameters like cytopenias, karyotype, or percentage of blast cells in the bone marrow. Patients’ characteristics reflecting comorbidities like cardiovascular diseases and impaired renal or liver function were not taken into account. In this study, the authors found that the Hematopoietic Cell Transplantation Comorbidity Index (HCTCI) may be useful for patients with myelodysplastic syndrome receiving best supportive care only. See perspective article on page 602. We studied the impact of comorbidities on survival and evaluated the prognostic utility of comorbidity scores in MDS patients, who received best supportive care and were assessable according to the Charlson Comorbidity Index (CCI) and the Hematopoietic Stem Cell Transplantation Comorbidity Index (HCTCI): 171 patients were identified in the Duesseldorf MDS Registry. The HCTCI captured more comorbidities. Both scoring systems had prognostic relevance, but the HCTCI more clearly distinguished between low-, intermediate- and high-risk patients. Median survival times of the different risk groups according to the HCTCI were 68, 34 and 25 months, respectively. The HCTCI showed prognostic impact in the IPSS intermediate- and high-risk group. On multivariate regression analysis, only the HCTCI remained a prognostic factor independent of IPSS. Considering their prognostic impact, comorbidities of MDS patients should receive appropriate attention in clinical trials as well as day-to-day clinical decision making.

Myelodysplastic Syndromes in Patients Younger Than Age 50

PURPOSE Myelodysplastic syndromes (MDS) mainly occur in the elderly but can affect younger individuals too. The latter require special consideration to identify suitable candidates for allogeneic stem-cell transplantation, a potentially curative approach carrying a high risk of treatment-related complications. PATIENTS AND METHODS We report the largest series of young MDS patients as yet, including 232 patients younger than 50 years. Their clinical characteristics and prognosis are compared with 2,496 patients older than 50 years. RESULTS Survival was significantly longer in the younger versus older age group (40 v 23 months, respectively; P < .00005). The difference arose from patients belonging to the low- and intermediate-I-risk categories of the International Prognostic Scoring System (median survival not reached v 45 months, respectively; P < .00005). In contrast, survival was identical for both age groups (8 months for both younger and older patients; P = .81) in the intermediate-II-and high-risk categories. Established classification systems and risk scores were applicable to young patients with primary MDS. Interestingly, a particularly large difference in median survival time was seen between the intermediate-I-and intermediate-II-risk groups (176 v 8 months, respectively). For low-risk patients, the overall survival rate was more than 86% at 20 years. CONCLUSION According to these results, aggressive treatment approaches should rarely be recommended to younger MDS patients belonging to the low and intermediate-I risk groups.