Clinical evaluation of effects of KRN8601 (rhG-CSF) on neutropenia]

Clinical effects of KRN8601 (recombinant human granulocyte colony-stimulating factor:rhG-CSF) were studied in 26 patients with chronic neutropenia including 4 Kostmann's disease, 1 Shwachman's syndrome, 1 Lonsdale's syndrome, 1 glycogen storage disease Ib-associated, 6 chronic benign, 5 chronic hypoplastic, 2 cyclic, 4 autoimmune and 2 miscellaneous neutropenia. The patients were given rhG-CSF intravenously at doses of 20-540 micrograms/m2 or subcutaneously at doses 20-400 micrograms/m2, over the periods of 2-32 weeks. Increases in neutrophil counts occurred after rhG-CSF administration in 23 of the 26 patients. Patients with Kostmann's disease, Shwachman's syndrome and chronic hypoplastic neutropenia responded poorly compared to patients with other types of neutropenia. There were no serious side effects which caused interruption of the study. These results indicated a beneficial effect of KRN8601 in various types of chronic neutropenia.     

Treatment of aplastic anemia with KRN8601 (rhG-CSF)]

Thirty-nine patients with severe or moderate aplastic anemia received treatment with recombinant human granulocyte colony-stimulating factor (rhG-CSF). The first group of eight patients received rhG-CSF in doses of 100 to 400 micrograms/m2/d by a daily 30-minute intravenous infusion for one or two weeks. Doses up to 400 micrograms/m2/d were well tolerated and resulted in increases of neutrophil counts in 5 out of 8 patients. We gave rhG-CSF (400 micrograms/m2/d) to the second group of 26 patients by a daily 30-minute intravenous infusion for two weeks. The treatment resulted in an increase of neutrophil counts in 15 out of 26 patients (3.1 to 29.5 fold). Further, higher doses (800 or 1,200 micrograms/m2/d) were administered in 5 patients who did not respond to the dose of 400 micrograms/m2/d. The treatment increased the neutrophil counts in 3 out of 5 patients. The third group of five patients received rhG-CSF subcutaneously in doses of 20 to 400 micrograms/m2/d. An increase of neutrophil counts was noted in all five patients. Differential counts of bone marrow aspirate revealed an increase of myeloid: erythroid ratios. However, the responses were transient and neutrophil counts returned to basal levels within 1 approximately 2 weeks after discontinuing treatment. No severe toxicity due to rhG-CSF was observed. These results suggest that rhG-CSF is effective on stimulating granulopoiesis in patients with aplastic anemia. This treatment will be particularly useful for the patient with aplastic anemia suffering from bacterial or fungal infections.     

Clinical study of three myelodysplastic syndrome (MDS) patients with BOOP-like pulmonary disease]

Three cases of myelodysplastic syndrome (MDS) associated with BOOP-like pulmonary disease were reported. They were diagnosed from transbronchial biopsies and clinical features. In two cases, chest radiographs showed ground glass opacities or air space consolidation in both lung fields, and air space consolidation in the right lower lobe in the other case. BALF showed a marked increase of lymphocytes in one case, and organizing pneumonia and alveolitis, and alveolar spaces filled with foamy macrophages were identified histologically. Although no steroid therapy was employed, all three cases improved. However, one patient suffered a relapse 6 months later and thereafter did not respond to corticosteroid therapy.     

原发骨髓增生异常综合征患者IPSS及染色体核型的临床分析

目的:比较原发性骨髓增生异常综合征(MDS)患者WHO(2001)分型与FAB分型的IPSS染色体核型分析及预后的相关性分析。方法:经FAB标准确诊的原发MDS的患者重新按WHO标准分型,对2种结果的IPSS及染色体异常与各亚型的关系进行分析。结果:按FAB分型各亚型的IPSS及染色体异常无显著性差异,按WHO分型的难治性细胞减少伴多系增生异常(RCMD)与难治性贫血(RA)患者染色体异常率有统计学意义(66.6%,41.7%,P<0.01),RAEB-2高危组比例明显高于RAEB-1组(25%,0%,P<0.01)。结论:原发MDS的WHO分型与FAB分型相比,前者与预后的相关性更好。     

Extended cytogenetic follow-up of patients with myelodysplastic syndrome (MDS)

The prognostic significance of clonal karyotype status in myelodysplastic syndrome (MDS) is assessed after an extended follow-up period of 5 years. There are three karyotype, single abnormalities or multiple abnormalities at the time of referral. However, there is no correlation between the size of the abnormal clone and prognosis. Karyotype status has independent prognostic significance in 'high risk' MDS so that patients with a refractory anaemia with excess of blasts (RAEB)/RAEB in transformation (RAEB-t) and a normal karyotype survive significantly longer than those with an abnormal karyotype (P < 0.001) and do not differ significantly from patients with refractory anaemia (RA). Significant differences in survival according to karyotype status are also seen in patients with chronic myelomonocytic leukaemia (P < 0.001) but not in those with primary acquired sideroblastic anaemia and RA. Among patients studied sequentially, those who retained a normal karyotype survived significantly longer than those who developed an abnormality on follow-up (P < 0.001). The risk of leukaemic transformation was also increased in patients who presented with or subsequently developed a clonal karyotype abnormality compared with those who remained normal (P < 0.05).     

Clinical experience with decitabine in North American patients with myelodysplastic syndrome

Recent evidence demonstrates that epigenetic silencing of genes is associated with myelodysplasia and that a worse prognosis may be correlated with hypermethylation of certain genes, such as the cyclin-dependent kinase inhibitor p15. 5-Aza-2'-deoxycytidine (decitabine, DAC) is a nucleoside analog, which, at low doses, acts as a hypomethylating agent and is fivefold to tenfold more active than 5-azacytidine (azacitidine, Vidaza)--currently the only approved drug for treatment of myelodysplastic syndrome (MDS). Clinical studies have demonstrated that decitabine has activity in patients with MDS. Preliminary results of a phase III multicenter North American trial comparing low-dose decitabine to supportive care verified that therapy with decitabine resulted in higher response rates, improved quality of life, and prolonged time to leukemic transformation and/or death. However, further elucidation of its mechanism of action is required, as clinical response to decitabine does not correlate with demethylation of the p15 gene promoter or the repetitive DNA element LINE. Decitabine appears to upregulate both hypermethylated and nonmethylated genes. Ongoing studies aim to determine the optimal dose, schedule, and route of administration of decitabine, and to evaluate whether efficacy can be improved by using it in combination with other agents, such as histone deacetylase inhibitors.     

Clinical significance of regulatory T cells in patients with myelodysplastic syndrome

Objective: Foxp3⁺ regulatory T cells (Tregs) play a central role in maintaining immune tolerance. Their expansion in malignant diseases leads to the suppression of host anti‐tumour responses. In this study, we evaluated the clinical significance of Tregs in patients with myelodysplastic syndrome (MDS). Patients and Methods: We analysed the number of CD4⁺ CD25⁺ Foxp3⁺ Tregs using three‐colour flow cytometry in the peripheral blood of 26 patients with MDS classified according to the World Health Organization classification method into four cases of refractory anaemia and refractory anaemia with ringed sideroblasts (RA/RARS), 15 cases of refractory cytopenia with multilineage dysplasia (RCMD), three cases of refractory anaemia with excess blast‐1 (RAEB‐1) and four cases of refractory anaemia with excess blast‐2 (RAEB‐2). Eighteen healthy volunteers were included as the control group. Results: The mean absolute numbers of Tregs in the RA/RARS group (0.06 × 10⁹/L; 95% CI, 0.02–0.10 × 10⁹/L) and RAEB group (0.06 × 10⁹/L; 95% CI, 0.02–0.10 × 10⁹/L) were significantly higher than that of the control group (0.03 × 10⁹/L; 95% CI, 0.02–0.03 × 10⁹/L) (P < 0.05). However, in the RCMD group, there was no significant difference in the mean absolute number of Tregs (0.03 × 10⁹/L; 95% CI, 0.02–0.04 × 10⁹/L) compared with the control group. Regarding the mean level of the CD8/Foxp3 ratio, there were significant decreases in the RA/RARS group (2.8; 95% CI, 0.7–4.9; P < 0.01), RCMD group (3.4; 95% CI, 2.0–4.4; P < 0.001) and RAEB group (2.1; 95% CI, 1.7–2.5; P < 0.001) compared with the control group (6.1; 95% CI, 5.1–7.0). Conclusions: The expansion of natural CD4⁺ Tregs may contribute to the suppression of CD8 through the Th1‐mediated immune response in MDS. The low CD8/Foxp3 ratio is a characteristic feature in MDS. To determine whether the expansion of CD4⁺ Tregs contributes to the progression of MDS subtypes into more aggressive subtypes, more MDS cases and further follow‐up are required.     

Clinical outcome in three patients with myelodysplastic syndrome showing polyclonal hematopoiesis

The clinical outcome of 3 myelodysplastic syndrome (MDS) patients with polyclonal hematopoiesis is reported. All patients were heterozygous for the phosphoglycerate kinase (PGK) gene. The presence of polyclonal hematopoiesis was determined by the X-chromosome-linked restriction fragment length polymorphism-methylation method using the PGK gene as a marker. The patients were initially diagnosed as having refractory anemia (RA), RA with ring sideroblasts (RARS), and RA with an excess of blasts (RAEB), respectively. Their pancytopenia persisted during the follow-up period of 11.4 years for the RA patient, 19.5 years for the RARS patient and 0.8 years for the RAEB patient. Although the RARS patient continues to be in good health, leukemic transformation occurred in the other 2 patients. A karyotype change from 46,XX to 45,XX,t(3;21),-7 was observed at the time of disease progression in the RA patient. The coexistence of a monoclonal MDS clone and normal bone marrow cells is thought to be the most probable reason for the polyclonal hematopoiesis of these patients.     

Increased prevalence of GSTM(1) null genotype in patients with myelodysplastic syndrome: a case-control study

BACKGROUND AND OBJECTIVE: Myelodysplastic syndromes (MDS) are clonal disorders of bone marrow stem cells characterized by ineffective hematopoiesis leading to blood cytopenia; they often progress to acute myeloid leukemia (AML). The glutathione S-transferases (GST) detoxify various agents, including those implicated in MDS. Both GSTM(1) and GSTT(1) genes have "null" alleles and are polymorphic. We studied the impact of GTM(1) and GSTT(1) null genotypes on the MDS susceptibility, disease severity and laboratory indices with prognostic value for the syndrome. MATERIAL AND METHODS: In a hospital-based case-control study we analyzed lymphocyte DNA samples from 54 patients with MDS and 60 cancer-free controls matched for age, sex, smoking habits and origin. A multiplex polymerase chain reaction was used to genotype both GSTM(1) and GSTT(1) simultaneously. The chi(2) test was used for statistical evaluation of the data and the odds ratios and attributable risk and population attributable risk were also calculated. RESULTS: A significantly increased frequency of GSTM(1) null genotype was found among MDS patients (57.4%) compared to controls (33.3%) (p < 0.01), while the frequency of GSTT(1) null genotype was not significantly higher in MDS patients (11.1% vs. 6.66%). Neither GSTM(1) and GSTT(1) null genotype was associated with a particular category of the French-American-British (FAB) classification in the patients studied. Additionally, GSTM(1) null genotype was associated with a significant decrease in the absolute number of neutrophils among the MDS patients. CONCLUSIONS: Individuals with GSTM(1) null genotype may have increased susceptibility to MDS. Null genotypes do not seem to have be associated with FAB classification while they may be associated with putative prognostic factors.     

Clinical significance of phenotypic features of blasts in patients with myelodysplastic syndrome

Knowledge of the blast phenotype in myelodysplastic syndrome (MDS) would be valuable, as in other malignancies, but remains sparse. This is mainly because MDS blasts are a minor population in clinical samples, making analysis difficult. Thus, for this blast phenotype study, we prepared blast-rich specimens (using a new density centrifugation reagent for harvesting blasts) from blood and marrow samples of 95 patients with various MDS subtypes and 21 patients with acute leukemia transformed from MDS (AL-MDS). Flow cytometry revealed that a high proportion of the enriched blast cells (EBCs) from almost all patients showed an immunophenotype of committed myeloid precursors (CD34(+)CD38(+)HLA-DR(+)CD13(+)CD33(+)), regardless of the disease subtype. The cytochemical reaction for myeloperoxidase was negative in 58% of the cases. Thus, the EBC phenotype is more immature in MDS than in de novo acute myeloid leukemia. MDS EBCs often coexpressed stem cell antigens and late-stage myeloid antigens asynchronously, but rarely expressed T- and B-lymphoid cell-specific antigens. Markers for myeloid cell maturation (CD10 and CD15) were more prevalent on EBCs from low-risk MDS (refractory anemia [RA] and RA with ringed sideroblasts), whereas markers for myeloid cell immaturity (CD7 and CD117) were more prevalent on EBCs from high-risk MDS (chronic myelomonocytic leukemia, RA with excess blasts [RAEB], and RAEB in transformation) and AL-MDS. A shift to a more immature phenotype of EBCs, accompanying disease progression, was also documented by sequential phenotyping of the same patients. Further, CD7 positivity of EBCs was an independent variable for a poor prognosis in MDS. These data represent new, valuable information regarding MDS.     

Clinical application of recombinant human colony-stimulating factor (rhG-CSF) in bone marrow transplantation]

Human granulocyte colony-stimulating factor (G-CSF) specifically stimulates granulocyte production and enhances functions of mature granulocytes. It also proliferates myeloid leukemic cells. The molecule was purified and molecularly cloned in 1986. In this study, 51 patients received single daily injections with recombinant human (rh) G-CSF (2-20 micrograms/kg) after bone marrow transplantation were compared with control 36 patients. Blood neurophilic recovery was accelerated remarkably by rhG-CSF administration without any adverse effects including delay in reticulocyte and platelet recoveries. Furthermore, the duration for the management in laminar airflow room and febrile days greater than or equal to 38 degrees C were shortened in rhGS-CSF treated group. In 6 patients with myeloid leukemia in relapse, we also tested the effects of the rhG-CSF-combined conditioning regimen. In all the patients tested, the leukemic cells responded to rhG-CSF. Clinically no relapse was observed and 3 patients are well on day 224-357 for the time being. These findings indicate that rhG-CSF is very useful in bone marrow transplantation.     

Pulmonary thromboembolism associated with myelodysplastic syndrome]

We present a 65-year-old female with myelodysplastic syndrome (MDS) who has attended our O.P.D. since 1983. In early December, 1990, dyspnea on effort developed which then progressed to dyspnea at rest at the end of December. She was admitted on January 8 with orthopnea. Chest X-ray films revealed loss of vascular shadows of the right lung. Blood gas analysis showed hypoxemia and hypocapnemia. Abnormalities in the coagulation-fibrinolytic system (increased TAT (thrombin-anti-thrombin III complex) and alpha 2-PIC (plasmin inhibitor complex)), possibly due to MDS, were detected. The diagnosis of pulmonary thromboembolism was made by pulmonary perfusion scintigram and pulmonary arteriography. After commencement of anticoagulation therapy on January 15, the subjective symptoms, blood gas analysis, pulmonary scintigram, and disorders of the coagulation-fibrinolytic system improved. The patient was discharged on March 5, 1991. The present case of myelodysplastic syndrome was associated with abnormalities of the coagulation-fibrinolytic system and was complicated by pulmonary thromboembolism.     

Clinical relevance of extra-hematologic comorbidity in the management of patients with myelodysplastic syndrome

Myelodysplastic syndromes occur mainly in older persons, and these patients are likely to have comorbidities that significantly worsen their survival. In this perspective article, Drs. Della Porta and Malcovati examine the relevance of comorbidities for clinical decision making in patients with myelodysplasti syndromes. See related paper on page 729.Malignancies have an increasing incidence with age. At present, 60% of cancers and two-thirds of cancer deaths occur over the age of 65 years in developed countries. This proportion is expected to increase markedly in the next decades as a consequence of the ageing of the population.¹One aspect of ageing is an increased prevalence of comorbidity. In a typical geriatric population, subjects aged 65 years and older suffer on average from three or more concomitant diseases. Similarly, older patients with malignancy present a high prevalence of comorbidity.² As a result, hematologists and oncologists will increasingly treat patients who have concomitant diseases.Comorbidity is recognized to have an unfavorable effect on life expectancy of patients with cancer, as well as to influence clinical decision making. There is a negative clinical effect per se in terms of competing risk of death with primary disease. Furthermore, presence of comorbidity significantly affects therapeutic strategies, being a major reason of undertreatment of patients. Finally, several studies showed that cancer patients with comorbidity have reduced tolerance to treatment and higher risk of complications, possibly resulting in a worse post-therapeutic outcome.^3,4The evaluation of the influence of comorbidity in cancer patients is made complex by many critical issues. The first important point to be considered is that, so far, clinical trials have provided little information on comorbidity. In fact, in only 20–40% of phase II and III studies are patients aged 65 years or older.⁵ As a consequence, clinicians are provided with a weak base of evidence when applying the results of these clinical investigations to patients with comorbidity. Therefore efforts aimed to integrate comorbidity in clinical studies and to promote the design of clinical trials focused on older patients are warranted.The second source of complexity consists in developing reliable tools to measure comorbidity and its effect on outcome.⁶ Available measures can be divided into two groups: general measures intended for use in general patient populations, and disease-specific measures.The most commonly used general comorbidity measure is the Charlson Comorbidity Index (CCI).⁷ It was developed to predict 1-year mortality in medical inpatients. Nineteen comorbid conditions are assigned weights based on the ratio of the mortality risk for patients with the comorbidity of interest versus the mortality risk for those without. The index was validated in a cohort of breast cancer patients, with the 10-year mortality rate as an endpoint. The CCI is widely used, has a good inter-rater and test-retest reliability, and predicts mortality in different clinical conditions. One weakness of these general tools is the assumption that each comorbidity computed in the measure has the same impact in different diseases and patient populations. In addition, they may include conditions that are complications of the major underlying disease rather than independent clinical entities, and generally do not account for the severity of the comorbidity, which may strongly affect the outcome.These limitations may be particularly relevant in patients with malignancies. In fact, for any given cancer, different comorbid conditions may have different effects. In addition the prognostic impact of a comorbidity may vary across types of malignancy and treatments, and may affect cancer care at multiple steps.³Disease-specific comorbidity measures are developed and tested in a single disease population, and intended for use only in that setting.⁸ They have a conceptual advantage in that they account for specific treatments and outcomes unique to the population of interest.⁶A major limitation in implementing either general or disease-specific measures is the data source used for their generation. Clinical trials that include detailed prospective information about patients and treatments are theoretically the best data sets to evaluate the impact of comorbid conditions. However, only a minority of all adult cancer patients are enrolled and the results cannot be easily applied to the general patient population.⁵ Cancer-specific registries provide the opportunity to collect information on comorbidity and self-reported outcomes from a more representative patient sample.¹ However, such a systematic data collection is extremely demanding, and available only in a minority of clinical settings. In the light of these drawbacks, retrospective studies, despite potential biases related to data recording, represent a valuable source of information, which is relatively accessible and provides more results that can be generalized than those from clinical trials.The third critical issue in the evaluation of the prognostic effect of comorbidity in patients with malignancy is the selection of the outcomes of interest. In fact, each comorbid condition may have different impacts on the outcome of the underlying malignancy, as well as on the eligibility of specific treatments and on their efficacy. In addition, outcomes such as the quality of life are turning out to be important endpoints.⁹A further level of complexity is that comorbidity must be integrated in a more comprehensive geriatric assessment.¹⁰ Comorbidities are not simply additive or synergistic in affecting the prognosis, but also strongly interact with other patient characteristics such as functional and nutritional status, cognition, psychological state and social support. Moreover, even in the absence of a clinically-evident disease, ageing may be associated with a progressive loss of the organ functional reserve needed to maintain physiological homeostasis under stress, resulting in a condition of frailty.During the last decade, oncologists and geriatricians have begun to work together to integrate these principles into cancer care. Older patients with cancer are more likely to require functional assistance than those without cancer. In this clinical setting, a comprehensive geriatric assessment was demonstrated to predict survival as well as therapy-related toxicity and mortality.Information on the role of comorbidity in cancer patients is mainly derived from studies on solid tumor populations, while their impact in hematologic malignancies is still largely unknown.Myelodysplastic syndromes (MDS) are one of the most common hematologic malignancies in Western countries.¹¹ Its incidence in the general population is about 3.5-4 per 100,000 person-year. However, over the age of 70 years, incidence rises from 15 to 50 per 100,000 person-year.^12,13 Thus, it is very likely that comorbidity may emerge as a relevant clinical problem in patients with MDS.In this issue of Haematologica/the hematology journal,¹⁴ Zipperer and colleagues address the relevant issue of the prognostic impact of comorbidity on the natural history of MDS. The study by the Düsseldorf group documents for the first time the high prevalence of comorbidity in MDS patients and shows that comorbidity significantly worsens the prognosis of these subjects.It is well-known that age has a significant effect on survival of the MDS population: the older the patient, the worse the prognosis.^15,16 The effect of demographic predictors is mainly noticeable in patients with low-risk MDS. In high-risk patients, age does not affect the natural history of the disease, while its effect may be relevant in limiting the eligibility for intensive treatments (Figure 1). The role of extra-hematologic comorbidity in determining these outcomes is to be clarified.Open in a separate windowFigure 1.Cumulative probability of survival among 840 patients given a diagnosis of myelodysplastic syndrome at the Department of Hematology and Oncology, Policlinico San Matteo, Pavia Italy, 1992–2007 who are younger than 50 vs. >50 years of age. (A) Patients with refractory anemia or refractory cytopenia with multilineage dysplasia according to WHO criteria. (B) Patients with refractory anemia with excess blasts (types 1 and 2).Causes of death in MDS patients may be related to the consequences of the progression of the disease into acute leukemia, or to clinical events outside leukemic evolution. The impact of comorbidity is as expected noticeable on non-leukemic death, which is mainly due to cardiac failure, infection, hemorrhage and hepatic cirrhosis (Figure 2).¹⁵ In agreement with these data, cardiac disease and infections are reported by Zipperer and colleagues as the most common comorbidity in MDS patients.Open in a separate windowFigure 2.Cumulative probability of survival (A) and risk of non-leukemic death (B) among 840 patients given a diagnosis of myelodysplastic syndrome at the Department of Hematology and Oncology, Policlinico San Matteo, Pavia Italy, 1992–2007 according to the presence of extra-hematologic comorbidity at the time of diagnosis.The occurrence of non-leukemic death (NLD) is significantly different among the WHO categories, with a higher incidence in low-risk subgroups.^15,17 In these patients the cumulative probability of leukemic death tends to increase several years after the diagnosis, while the probability of non-leukemic death increases constantly from the time of diagnosis, and appears to competitively replace leukemic death as the major cause of death in these patients. Conversely, considering high-risk patients, the leukemic death rate rapidly increases to exceed the level of non-leukemic deaths (Figure 3).Open in a separate windowFigure 3.Cumulative probability of death attributed to disease complications/disease progression and to comorbidity by competing risk analysis among 840 patients given a diagnosis of myelodysplastic syndrome at the Department of Hematology and Oncology, Policlinico San Matteo, Pavia Italy, 1992–2007. (A) Patients with refractory anemia or refractory cytopenia with multi-lineage dysplasia according to WHO criteria; (B) Patients with refractory anemia with excess blasts (types 1 and 2). This analysis allows an estimate to be made of the cumulative incidence of a specified failure mode, compared to its competing risk over time.Therefore, from a clinical point of view, problems related to the presence of comorbidity appear to be very different in low- and high-risk MDS. In low-risk patients they increase the risk of death, while in high-risk patients who mostly die from leukemic evolution, comorbidity seems to mainly influence eligibility for intensive treatment, treatment tolerance and post-therapeutic outcome.In MDS there is a high prevalence of patients suffering from symptomatic anemia, and the onset of a regular transfusion requirement has been found to be associated with reduced survival.^11,15 Anemia has been recognized as a negative prognostic factor in the general population, as well as in many pathological conditions, in particular involving the cardiovascular system. Preliminary data suggested that in patients with MDS low hemoglobin levels are associated with increased cardiac remodeling and risk of NLD.¹⁵ Therefore it may be hypothesized that cardiac comorbidity in MDS patients may have not just an additive detrimental effect per se but actively interacts with anemia in determining the clinical course of the disease. In addition, the role of secondary iron overload in determining clinical organ dysfunction represents an interesting area of investigation. To date there is limited evidence on the role of iron in organ damage in patients with MDS. However, secondary iron overload as measured by serum ferritin was found to be associated with reduced survival in transfusion-dependent patients with MDS, with a more evident effect in patients with refractory anemia that have the longest median survival and are, therefore, more prone to developing the toxic effect of iron overload.¹⁵The study by Zipperer and colleagues also addresses the relevant issue of the measurement of comorbidity in MDS. The application of a general comorbidity measure such as the CCI⁷ to MDS patients failed to provide prognostic information. One possible reason is that most of the comorbid conditions included in the CCI are rarely observed in MDS patients. Moreover, common comorbidity like myocardial infarction or congestive heart failure, which are very relevant for anemic MDS patients, have a low weight in the CCI. Finally, the score does not account for the degree of severity of these conditions.Recent findings showed that comorbidity assessment predicts post-transplantation outcome in MDS, and a hematopoietic cell transplantation (HCT)-specific comorbidity index (HCT-CI) was generated with the aim of improving sensitivity and specificity of CCI in this setting.¹⁸ The most relevant modifications with respect to CCI were the inclusion of additional diseases clinically relevant for transplantation, and the introduction of objective laboratory and functional data in comorbidity definition. These modifications resulted in a significantly increased sensitivity in identifying patients with comorbid conditions compared to CCI, as well as in a more accurate prognostic stratification of these patients. HCT-CI was specifically validated in MDS patients receiving allogeneic transplantation.¹⁹However, according to evidence-based guidelines²⁰ no more than 20% of MDS patients are eligible for intensive treatments with a curative aim (Malcovati L, unpublished data, 2005). Therefore, the results obtained in such a highly selected subset of patients cannot be easily applicable to the whole MDS population. Nevertheless, in the study of Zipperer and colleagues, HCT-CI allows a successful identification of a high proportion of MDS patients with relevant comorbidity. The score also provides prognostic information on untreated subjects with IPSS intermediate-2 and high-risk, but fails to stratify the outcome of low-risk patients. Overall, HCT-CI appears to be only partially adequate to study the clinical significance of comorbidity in MDS. Investigations aimed at defining MDS-specific comorbidity measures are warranted.The improvement of clinical decision making in MDS demands a continuous effort to refine patient- and disease-specific prognostic factors. The accurate evaluation of extra-hematologic comorbidity must be part of the prognostic assessment of patients with MDS. This is expected to result in a more accurate selection of optimal candidates to intensive therapeutic procedures in high-risk disease. In addition, the prevention of non-hematologic complications is mandatory, especially in subjects with low-risk MDS, in order not to worsen their life expectancy or to preclude the eligibility of younger patients for intensive treatments.     

Modulation of angiogenesis in patients with myelodysplastic syndrome

Current investigations have revealed that angiogenesis plays a role in the pathogenesis of high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia, and in the mechanisms of disease progression. Secretion of cytokines and growth factors modulates angiogenesis in the marrow leading to increased vascularity and sustenance of the clonal population. For high-risk MDS patients older than 60 years who are not eligible for aggressive chemotherapy or stem cell transplant, there are few therapeutic options other than supportive treatment. Recent delineation of the pathobiology of MDS has resulted in the development of new agents and treatment modalities that impact on these mechanisms. One of the features of bone marrow pathology is the presence of new vessels, which appear to sustain growth and the hypercellularity of the marrow. Blocking angiogenesis may reduce the microvessel density of the marrow, cellularity, and disease progression. Angiogenesis can be targeted by inhibition of vascular endothelial growth factor (VEGF), which modulates new vessel growth, by the use of antibodies aimed at VEGF and its receptors, as well as receptor tyrosine kinases that block VEGF signaling. Other agents include inhibitors of farnesyl transferase and protein kinase C, which affect upstream modulators of growth factors and their receptor interactions; matrix metalloproteinases, which disrupt matrices and adhesion function promoting vessel growth; and other inhibitors with broader function, such as endostatin, thalidomide, and related analogues.     

Relapsing polychondritis in a patient with myelodysplastic syndrome]

Relapsing polychondritis is a rare disorder of uncertain origin characterized by recurrent inflammation of cartilage. A case of myelodysplastic syndrome (MDS) associated with relapsing polychondritis is reported. A 60-year-old man who had been diagnosed as MDS was admitted because of pain and swelling in the bilateral preauricular regions and cheek. A diagnosis of relapsing polychondritis was made by coexistence of auricular chondritis, arthropathy, ocular inflammation and audio-vestibular disturbance. He also developed ocular palsies and optic neuritis. He was treated with prednisolone, azathioprine, dapsone, and then with steroid pulse therapy. Moreover, plasmapheresis and high dose gamma-globulin therapy were undertaken. However, all these treatments were unsuccessful and he died of respiratory failure.     

Clinical significance of Th1/Th2 ratio in patients with myelodysplastic syndrome

In this study, we attempted to evaluate the clinical significance of T helper 1 (Th1)/T helper 2 (Th2) ratio in patients with myelodysplastic syndrome (MDS), five refractory anaemia (RA), four refractory anaemia with ringed sideroblasts (RARS), 31 refractory cytopenia with multilineage dysplasia (RCMD), nine refractory anaemia with excess blast-1 (RAEB-1) and seven refractory anaemia with excess blast-2 (RAEB-2). Intracellular interleukin-4 (Th2 cytokine) and interferon-gamma (Th1 cytokine) production was assessed in CD4+ T lymphocytes activated by phorbol 12-myristate 13-acetate and ionomycin using flow cytometry. Mean Th1/Th2 ratios in each MDS group were as follows: RA/RARS, 8.8 (95% CI, 5.8-11.8), RCMD, 14.7 (95% CI, 9.5-19.9), RAEB-1, 10.6 (95% CI, 4.6-16.6), RAEB-2, 12.8 (95% CI, 3.0-22.7) and control 12.8 (95% CI, 9.6-16.1). There were no significant differences in Th1/Th2 ratio in the RA/RARS, RCMD, RAEB-1 and RAEB-2 subgroups when compared to controls. Because Th1/Th2 ratio in the RCMD group was widely distributed, we divided RCMD patients according to Th1/Th2 ratio into three groups (low, normal and high Th1/Th2 groups). There were no differences in severity of cytopenia among the three above groups. However, the percentage of CD8 cells in the low Th1/Th2 group was significantly lower than those in the high group (P < 0.01). These data suggest that Th1/Th2 imbalance induces CD4/CD8 imbalance, and serves as a marker of the biological interplay in immune regulation.