Demonstration of additional benefit in adding lenalidomide to azacitidine in patients with higher-risk myelodysplastic syndromes

Lenalidomide and azacitidine are active in MDS patients, and may complement each other by targeting the bone marrow microenvironment and the malignant clone. A recent Phase I trial testing the lenalidomide and azacitidine combination yielded encouraging results; however, lenalidomide’s contribution was unclear. In this study, 18 higher-risk MDS patients were treated with the combination for seven cycles, after which lenalidomide was discontinued in eight patients who achieved a complete response, with azacitidine monotherapy continuing until disease progression. We report on three patients who relapsed on monotherapy with excess blasts at 12, 19, and 24 months, in whom lenalidomide was then resumed in combination with azacitidine. Each patient, one with normal cytogenetics at relapse; one with a 18 abnormality; and one with del(4q25), recaptured a complete response that was sustained for 5, 7, and 7+ months. We conclude that the addition of lenalidomide to azacitidine provides additional clinical benefit over azacitidine monotherapy.     

Therapy with low‐dose azacitidine for MDS in children and young adults: a retrospective analysis of the EWOG‐MDS study group

Low‐dose azacitidine is efficient and safe in the therapy of malignant myeloid disorders in adults but data in children are lacking. We present a retrospective analysis of 24 children and young adults with myelodysplastic syndrome (MDS) who received azacitidine at the time of first diagnosis or relapse after allotransplant (2 children were treated with azacitidine both initially and for relapse). Diagnoses were refractory cytopenia of childhood (N = 4), advanced primary MDS (N = 9) and secondary MDS (N = 11). The median duration of treatment was four cycles. Azacitidine was well tolerated, but cytopenias led to dose reduction in five cases. Treatment was discontinued in one child because of impaired renal function. Sixteen MDS patients were treated with azacitidine at first diagnosis. One complete clinical remission was observed and one child showed complete marrow remission; six children experienced stable disease with haematological improvement. Ten children received azacitidine for relapsed MDS after transplant: of these, seven experienced stable disease for 2–30 cycles (median 3), including one patient with haematological improvement for seven cycles. In summary, azacitidine is effective in some children with MDS and appears to be a non‐toxic option in palliative situations to prolong survival.     

Rapid loss of response after withdrawal of treatment with azacitidine: a case series in patients with higher‐risk myelodysplastic syndromes or chronic myelomonocytic leukemia

In patients with myelodysplastic syndromes (MDS), the likelihood of having a sustained response to azacitidine is increased by maximizing treatment duration. This is important as prognosis postrelapse is poor. There is also the concern that early termination of treatment may result in rapid disease progression. We reviewed outcomes in 13 patients who discontinued azacitidine (decitabine in one patient) while still responding to the treatment. Most patients rapidly relapsed; median time to progression was 5.4 months. Reasons for treatment discontinuation included comorbidities, infections, and patient choice. These findings illustrate the risk of prematurely terminating azacitidine therapy in MDS.     

Successful treatment by azacitidine therapy of intestinal Behçet’s disease associated with myelodysplastic syndrome

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic stem cell diseases. It has been reported that several autoimmune diseases are associated with MDS. Recently, the co-occurrence of MDS with trisomy 8 and rare disorders of the immune system, such as Behçet’s disease (BD), has been described. Prognosis in the older-onset group of MDS-associated BD is unfavorable. Here, we report a case of MDS-associated intestinal BD treated successfully by azacitidine therapy. A 59-year-old Japanese male suffering from recurrent high fever, melena, and oral and genital ulcerations was diagnosed with MDS with trisomy 8 and intestinal BD by endoscopic and bone marrow examinations. Immunosuppressive therapies, including infliximab, were ineffective. Due to his severe emphysema, the patient was considered ineligible for stem cell transplantation, and azacitidine therapy was initiated. With the exception of fever, the symptoms of intestinal BD improved, and severe malnutrition and anemia were ameliorated. Fluorescence in situ hybridization analyses of the bone marrow before the eighth cycle revealed that the trisomy 8 had not decreased. To our knowledge, this is the first report of azacitidine therapy for MDS-associated BD. We suggest that azacitidine may control intestinal BD by mechanisms other than those responsible for its effect in MDS.     

Management and supportive care measures for adverse events in patients with myelodysplastic syndromes treated with azacitidine*

Objective: Myelodysplastic syndrome (MDS) treatment can initially worsen patients’ clinical condition and they may discontinue therapy before achieving benefit. We present previously unpublished data from two large phase III trials describing common adverse events (AEs) associated with azacitidine and methods to manage them. Methods: In the Cancer and Leukemia Group B (CALGB) 9221 study, patients with any French‐American‐British (FAB) subtype of MDS were randomized to azacitidine or best supportive care (BSC). After 56 d, patients randomized to BSC with disease progression could cross over to receive azacitidine. In the AZA‐001 study, patients with higher‐risk MDS (FAB‐defined refractory anemia with excess blasts (RAEB), RAEB in transformation, or chronic myelomonocitic leukaemia and IPSS int‐2 or high) were randomized to azacitidine or to conventional care regimens (CCR), which included low‐dose ara‐C, BSC, or intensive chemotherapy. In both studies, azacitidine dose was 75 mg/m²/d SC for 7 d every 28 d. AEs were graded per National Cancer Institute’s Common Toxicity Criteria version 2.0 (AZA‐001) or CALGB Expanded CTC (CALGB 9221). Results: In safety‐evaluable patients in AZA‐001 (N = 175) or CALGB 9221 (N = 150), the most common AEs with azacitidine included hematologic (eg, cytopenias) and non‐hematologic administration‐related events (eg, injection‐site reactions and gastrointestinal disorders). Most AEs were transient and resolved during ongoing therapy (> 83%). Hematologic AEs, most frequently observed during early treatment cycles, decreased during subsequent cycles and were usually managed with dosing delays (23–29%). Gastrointestinal symptoms were primarily managed with anti‐emetics and laxatives. Conclusion: Hematologic and non‐hematologic AEs with azacitidine decreased in frequency as treatment continued. Awareness of the onset, duration and management of AEs can facilitate treatment, permitting patients to continue therapy for maximum benefit.     

Azacitidine for treatment of patients with myelodysplastic syndromes (MDS): practical recommendations of the German MDS Study Group

Myelodysplastic syndromes (MDS) are a group of common bone marrow disorders characterized by ineffective hematopoiesis, peripheral cytopenias, and a substantial risk of progression to acute myeloid leukemia (AML). For many years, the main treatment option for MDS was best supportive care which alleviates symptoms, but has no effect on the natural course of the disease. Recently, demethylating agents have become available as a promising new treatment for patients with MDS. In two randomized clinical trials, the demethylating agent azacitidine has demonstrated a reduced risk of transformation to AML, improvement of peripheral blood values, an improved quality of life, and a definite survival advantage compared to conventional care regimens for patients with International Prognostic Scoring System score of intermediate-2 or high-risk MDS. This review aims to provide practical recommendations for the use of azacitidine and the management of its side effects in patients with MDS, assuring safe administration and best efficacy of treatment.     

Myelodysplastic features in patients with long-term HIV infection and haemophilia

HIV-related bone marrow changes are consistent with myelodysplastic features (MDF). Their pathogenesis may differ from primary myelodysplastic syndromes (MDS) and is associated with various factors including the virus itself or the antiretroviral therapy. In order to evaluate the differences between HIV-related MDF and MDS, the morphological changes in peripheral blood and bone marrow, cytogenetic analysis and the response to anaemia treatment were studied in 158 HIV+ patients with haemophilia and the results were compared with those of 61 patients with primary MDS (31 with RA, 10 with RARS, 11 with RAEB, three with RAEB-t and six with CMML). The eligibility criteria for patients with MDS were primary MDS, Hb levels < 10 g dL(-1), and no significant organ disease. The peripheral blood and bone marrow examination revealed MDF in 44 HIV-infected haemophilic patients (27.8%). The median time from seroconversion was 12.5 years and the mean time under AZT therapy was 44.1 months. Nineteen of these patients (43.1%) had Hb levels < 10 g dL(-1), while neutropenia and thrombocytopenia were observed in 29.5% and 25%, respectively. Every patient of this study with Hb < 10 g dL(-1) received erythropoietin (Epo). There were statistically significant morphological alterations between HIV-related MDF and MDS: hypocellularity, plasmatocytosis and eosinophilia were more pronounced in HIV haemophiliacs with MDF, while dysplasia of erythroblasts, megakaryocytes and granulocytes was more frequent in MDS patients. No HIV haemophilic patient with MDF had more than 5% blasts in the bone marrow nor did any develop RAEB or acute leukaemia during the period of this study. The cytogenetic analysis was normal in HIV-infected patients with haemophilia whereas 42.6% of patients with MDS had an abnormal karyotype. Complete erythroid response was achieved with Epo administration in 84.2% of HIV+ haemophilic patients with anaemia compared to 19.7% of patients with MDS. These data suggest that bone marrow changes in long-term HIV patients have different characteristics from primary MDS and constitute the entity for which the name HIV-myelopathy has been proposed in the literature.     

A phase II study of 5‐day intravenous azacitidine in patients with myelodysplastic syndromes

The approved 7‐day schedule of subcutaneous azacitidine for myelodysplastic syndrome is associated with injection site reactions and bruising and may be inconvenient because of the need for weekend doses. Although pharmacokinetic data with IV azacitidine suggests equivalence, there are no efficacy data published. Patients with all myelodysplastic syndromes (MDS) FAB subtypes were enrolled and received 75 mg/m²/d of azacitidine by 20‐min intravenous infusion for 5 days in every 28 days. Global methylation studies were performed at baseline and prior to Cycle 3. Twenty‐five patients were enrolled and 22 were evaluable. Median age was 69.5 years; 9 (41%) patients had lower‐risk disease (IPSS Low or Int‐1) and 13 (59%) had higher‐risk disease (IPSS Int‐2 or High). Twenty‐seven percent of patients responded (5 CRs and 1 PR). The median time to response was 108 days. The median PFS was 339 days (11.3 months), the median OS was 444 days (14.8 months) and the median duration of response (DOR) was 450 days (15.0 months). Global methylation studies suggest a greater degree of demethylation in responders. This regimen appeared to offer a PR + CR rate and median DOR somewhat similar to what has been reported with the 7‐day subcutaneous regimen; however, OS was shorter. Am. J. Hematol. 2009. © 2009 Wiley‐Liss, Inc.     

A retrospective study evaluating the impact of infectious complications during azacitidine treatment

Azacitidine has become an available therapy for high-risk myelodysplastic syndromes. Infectious complications (IC) may impede the success of therapy. Since most patients are managed in an outpatient setting, often with low level of clinical and microbiological documentation, the impact of IC remains unclear. We retrospectively evaluated the clinical course of 77 patients with MDS treated with azacitidine between 2004 and 2015 (median age 69 years). Clinical workup included severity and type of IC, days in the hospital and with antimicrobial therapy, response to azacitidine, and overall survival (OS). In total, 614 azacitidine cycles were administered, 81 cycles with at least one IC. The median number of administered cycles was 6 (range 1–43). Median OS after the start of azacitidine was 17 months (range 1–103). Infection rates were higher in the first 3 cycles with bacterial infections leading. The better patients’ hematological response to azacitidine with less IC occurred, and fewer days with antimicrobial treatment were needed. Compared to progressive disease, stable disease made no significant improvement in occurrence of IC and days in the hospital. Older age was associated with more IC and longer time in the hospital. Comorbidities or IPSS-R had no influence on IC. The incidence of IC correlated with hematological response and age. Stable disease led to longer OS, but incidence of IC was comparable to progressive disease and survival seemed to be bought by a considerable number of IC. IC rates were highest in the first 3 cycles. We recommend response evaluation after 4–6 cycles.     

Response to Cyclosporine Therapy in Patients with Myelodysplastic Syndrome: A Clinical Study of 12 Cases and Literature Review

Cyclosporine (CyA) was administered to 12 patients with myelodysplastic syndrome (MDS), and a response (major erythroid response, according to International Working Group criteria) was observed in 7 patients (58.3%). The median duration of response was 18 months (range, 3-22 months). Two patients are still responding and continuing to take CyA. Three patients stopped because of malignancy complications. To identify variables associated with responsiveness to CyA therapy, we analyzed the treatments of 72 MDS patients, comprising the 12 new patients and 60 patients previously described in the literature. Responses were observed in 44 of the 72 patients (61.1%). Univariate analyses revealed that higher daily dose of CyA (P for trend test, .007) and shorter disease duration (median, 5 months versus 17.5 months, P = .04) were factors significantly associated with response. No significant associations were observed between response and bone marrow features such as erythroid hypoplasia or hypoplastic marrow. Multivariate analysis also demonstrated that high CyA dose (>5 mg/kg per day) was significantly associated with response (P = .02). The present study showed that CyA therapy is useful for MDS patients with any marrow cellularity. Shorter disease duration is a pretreatment variable correlated with response, and a higher CyA dose results in a higher response rate.     

Platelet count doubling after the first cycle of azacitidine therapy predicts eventual response and survival in patients with myelodysplastic syndromes and oligoblastic acute myeloid leukaemia but does not add to prognostic utility of the revised IPSS

Reliable clinical or molecular predictors of benefit from azacitidine therapy in patients with myelodysplastic syndromes (MDS) are not defined. Doubling of platelet count at start of second cycle of azacitidine therapy compared to baseline was associated with achieving response and survival advantage in a Dutch cohort. To validate this observation, we analysed a larger cohort of North American patients, whose data was collected in a prospective clinical trial with a longer median follow‐up. We found a significant association between platelet count doubling after first cycle of azacitidine therapy and probability of achieving objective response. Among patients with MDS or oligoblastic acute myeloid leukaemia (<30% bone marrow blasts, n = 102), there was a statistically significant reduction in risk of death for patients who achieved platelet count doubling (n = 23, median OS, 21·0 months) compared to those who did not (n = 79, median OS, 16·7 months, adjusted hazard ratio (no/yes)=1·88, 95% confidence interval, 1·03–3·40, P = 0·04). Nonetheless, the addition of this platelet count doubling variable did not improve the survival prediction provided by the revised International Prognostic Scoring System or the French Prognostic Scoring System. Identification of reliable and consistent predictors for clinical benefit for azacitidine therapy remains an unmet medical need and a top research priority.     

Comparison of various criteria in predicting treatment response and prognosis of patients with myelodysplastic syndrome treated with azacitidine

This study was performed to identify whether cytogenetics, International Prognostic Scoring System (IPSS), or World Health Organization Classification-Based Prognostic Scoring System are predictive of the efficacy of azacitidine in patients with myelodysplastic syndrome (MDS). We retrospectively reviewed the clinical records of 113 patients with MDS treated with azacitidine. The “response alternating disease natural history,” “cytogenetic response,” and “hematologic improvement” were assessed by serial bone marrow biopsy, cytogenetic study, and hemogram analyses. The complete and partial remission rates were 17.6% and 3.9% in 51 evaluable patients. There were no significant differences in response rate in the different cytogenetic/IPSS/WPSS groups. The overall hematologic response (HR) rate was 49.6%, and the HR rate was significantly greater in patients classed as “very high” risk according to the WPSS compared with other patient groups. The 1-year overall survival (OS) rate was higher among patients with HR compared with those without HR (80.9% vs 63.3%, p?=?0.046), and the 1-year OS rate among patients classed as being at high risk by each criteria was similar to that of patients classed as being at low risk. The hazard ratio of death among patients with HR compared with those without HR was 0.17 (95% CI 0.04–0.69) for high?+?very high risk group based on WPSS. Patients in the WPSS high-risk group had an increased HR rate compared with other patient groups, and the achievement of HR was associated with a significant increase in OS. Azacitidine showed similar efficacy in all patient groups, even in patients with poor cytogenetics and in high-risk groups.     

Comparison of 7-day azacitidine and 5-day decitabine for treating myelodysplastic syndrome

Two DNA methyltransferase inhibitors, azacitidine and decitabine, are currently approved for the treatment of myelodysplastic syndrome (MDS). Choosing between these drugs is an important practical issue. In this retrospective study, patients receiving AZA-7d (azacitidine 75 mg/m² subcutaneously?×?7 days, n?=?75) or DEC-5d (decitabine 20 mg/m² intravenously?×?5 days, n?=?74) were compared. The rates of hematologic response (complete response [CR]/partial response [PR]/marrow CR) were 12.0 % (AZA-7d) vs. 29.7 % (DEC-5d) (P?=?0.008), and the overall response rates (CR/PR/marrow CR/hematologic improvement) were 52.0 % (AZA-7d) vs. 63.5 % (DEC-5d) (P?=?0.155). Grade 3 or higher neutropenia occurred more frequently with DEC-5d (79.6 %) than with AZA-7d (72.2 %) (P?=?0.040). Overall survival probabilities at 2 years were 42.1 % (AZA-7d) vs. 42.2 % (DEC-5d) (P?=?0.944). Subgroup analysis revealed that AZA-7d associated with higher survival rates than DEC-5d in patients whose MDS duration exceeded 1 year or who had poor performance status. In conclusion, both AZA-7d and DEC-5d regimens were effective in treating patients with MDS. However, the two regimens differed in terms of clinical responses and toxicities. One hypomethylating regimen may be superior to the other regimen in particular subgroups.     

A pilot study of antithymocyte globulin (ATG) in the treatment of patients with 'low-risk' myelodysplasia

We report 30 'low-risk' patients with myelodysplasia (MDS) (defined as < 10% bone marrow blasts) who were treated with antithymocyte globulin (ATG). In total, 20 patients were evaluable at the study end-point (response to treatment at 6 months). The diagnosis in these 20 patients was refractory anaemia (RA) in 13, RA with excess blasts in four, and RA with ringed sideroblasts in three. Median age was 54.5 years (range, 31-73 years). There were two cases of secondary MDS. The bone marrow was hypocellular in eight cases and cytogenetics were abnormal in four cases. All patients received lymphoglobuline (horse ATG; Sangstat, France) at a dose of 1.5 vials/10 kg/day for 5 d. The treatment was well tolerated. Three patients in the study died (disease progression, invasive aspergillosis and lung carcinoma respectively); 10 out of 20 evaluable patients (50%) responded to treatment and became transfusion independent; eight out of 13 (62%) patients with RA responded. The median duration of response was 15.5 months (2-42+ months) at the time of analysis.     

Myelodysplasia: the good, the fair and the ugly

The myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders. The molecular pathogenesis of the disease is poorly understood and a large number of fundamental biologic questions remain. This heterogeneity presents challenges in selecting therapy for individual patients as well as for evaluating response to treatment. Only a small number of randomized clinical trials have been conducted, although three new drugs (azacitidine, lenalidomide, and decitabine) have been approved for use in the last few years. Response to most therapies occurs slowly, and sometimes months elapse before response can be evaluated. The response rates for most drugs used or studied for MDS range from <10%-20%. Some therapies seem more promising than others: immunosuppression with antithymocyte globulin results in extended durations of benefit in responders; lenalidomide induces a very high erythroid response rate in patients with del 5q- karyotype. The DNA hypomethylating agents, azacitidine and decitabine, can be of significant benefit for a fraction of patients and further investigation is needed to determine whether higher response rates occur in particular subgroups of MDS patients. Further refinements of dose and schedule of administration are also under investigation.     

Successful treatment of acute myelomonocytic leukemia developed from essential thrombocythemia with cytarabine plus etoposide

A 77-year-old man was diagnosed as having essential thrombocythemia (ET) in 1994. He had been treated with hydroxyurea (HU) for six years, and 9 years after the diagnosis of ET, he then developed acute myelomonocytic leukemia (AMMoL) following myelodysplastic syndrome (MDS). Since he suffered from ischemic heart disease, we chose the ara-C+VP-16 therapy. Two courses of the ara-C+VP-16 therapy resulted in partial remission in the bone marrow and a prolonged hematological response. This case seemed rare, since in previous reports, prognosis of ET patients developing MDS and AML was very poor and most of the patients expired within six months.     

Azacitidine in 302 patients with WHO-defined acute myeloid leukemia: results from the Austrian Azacitidine Registry of the AGMT-Study Group

Data on efficacy and safety of azacitidine in acute myeloid leukemia (AML) with >30 % bone marrow (BM) blasts are limited, and the drug can only be used off-label in these patients. We previously reported on the efficacy and safety of azacitidine in 155 AML patients treated within the Austrian Azacitidine Registry (clinicaltrials.gov identifier NCT01595295). We herein update this report with a population almost twice as large (n?=?302). This cohort included 172 patients with >30 % BM blasts; 93 % would have been excluded from the pivotal AZA-001 trial (which led to European Medicines Agency (EMA) approval of azacitidine for high-risk myelodysplastic syndromes (MDS) and AML with 20–30 % BM blasts). Despite this much more unfavorable profile, results are encouraging: overall response rate was 48 % in the total cohort and 72 % in patients evaluable according to MDS-IWG-2006 response criteria, respectively. Median OS was 9.6 (95 % CI 8.53–10.7)?months. A clinically relevant OS benefit was observed with any form of disease stabilization (marrow stable disease (8.1 months), hematologic improvement (HI) (9.7 months), or the combination thereof (18.9 months)), as compared to patients without response and/or without disease stabilization (3.2 months). Age, white blood cell count, and BM blast count at start of therapy did not influence OS. The baseline factors LDH >225 U/l, ECOG ≥2, comorbidities ≥3, monosomal karyotype, and prior disease-modifying drugs, as well as the response-related factors hematologic improvement and further deepening of response after first response, were significant independent predictors of OS in multivariate analysis. Azacitidine seems effective in WHO-AML, including patients with >30 % BM blasts (currently off-label use). Although currently not regarded as standard form of response assessment in AML, disease stabilization and/or HI should be considered sufficient response to continue treatment with azacitidine.     

Etanercept in the treatment of adult patients with Still's disease

OBJECTIVE: To evaluate the safety and efficacy of etanercept in the treatment of adult patients with Still's disease. METHODS: Twelve adult patients who met criteria for Still's disease and had active arthritis were enrolled in a 6-month open-label trial of etanercept given in biweekly doses of 25 mg. The mean disease duration at study entry was 10.7 years. All patients had been treated unsuccessfully with other disease-modifying antirheumatic drugs. Efficacy was evaluated according to American College of Rheumatology (ACR) improvement criteria, and adverse events were recorded. RESULTS: Ten patients successfully completed the study; 2 withdrew due to disease flare. In 4 patients, the dosage of etanercept was increased from 25 mg biweekly to 25 mg 3 times per week. Seven patients met ACR 20% response criteria. Of these 7 responders, 4 met ACR 50% response criteria and 2 met ACR 70% response criteria. Among the 3 patients with systemic features of Still's disease (fever and rash), improvement in these features was seen in 1; the arthritis did not improve in any of these 3 patients. Except in the 2 patients who withdrew due to disease flare (rash, fever, and arthritis), no other significant adverse events occurred. CONCLUSION: In this initial study of etanercept therapy for Still's disease in the adult, this treatment resulted in improvement in the arthritis and was well tolerated. Additional trials should be performed to elucidate the effects of tumor necrosis factor inhibitors in Still's disease.     

Etanercept treatment improves longitudinal growth in prepubertal children with juvenile idiopathic arthritis

OBJECTIVE: Anti-tumor necrosis factor (TNF) therapy is known to decrease disease activity of juvenile idiopathic arthritis (JIA), but its effect on longitudinal growth in relation to puberty is not clear. We studied longitudinal growth in response to etanercept treatment in prepubertal and pubertal patients with JIA. METHODS: Out of 52 children treated with etanercept, we studied 20 prepubertal and 11 early/midpubertal patients adherent to treatment for at least 1 year. We collected data on growth and glucocorticoid medication and calculated each patient's height standard deviation score (SDS) in relation to the mid-parental height, the change of this value (DeltahSDS) from 1 to 0 and 0 to 1 year of treatment, and the change between the DeltahSDS values to assess growth improvement. RESULTS: In the prepubertal group, the relative height SDS (mean +/- standard error of the mean) was 1.8 +/- 0.2, 2.1 +/- 0.3, and 1.9 +/- 0.3, and in the pubertal group 1.1 +/- 0.4, 1.3 +/- 0.3, and 1.1 +/- 0.3 at 1, 0, and +1 year of treatment, respectively. The DeltahSDS before etanercept was 0.3 +/- 0.1 in prepubertal and 0.2 +/- 0.2 in pubertal patients. Over the first year with etanercept, DeltahSDS was +0.2 +/- 0.1 in prepubertal (p = 0.001 vs before etanercept; paired Student t-test) and +0.2 +/- 0.1 in pubertal patients (p = 0.071). Nevertheless, most prepubertal (17/20) and pubertal (8/11) patients had improved growth (DeltahSDS) in response to etanercept treatment when analyzed individually. The need for intraarticular glucocorticoid injections was negatively correlated to the improved growth (p = 0.001). CONCLUSION: TNF inhibition with etanercept improved growth in a majority of patients with JIA. Our data demonstrate that growth improvement with etanercept was independent of the pubertal growth spurt.     

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.