Comparative clinical effectiveness of azacitidine versus decitabine in older patients with myelodysplastic syndromes

The hypomethylating agents (HMAs) azacitidine and decitabine are both approved for treatment of myelodysplastic syndromes (MDS) in the USA. In Europe, decitabine is not approved due to lack of survival advantage in randomized trials. The two drugs have not been compared in clinical trials. We identified patients diagnosed with MDS between 2004 and 2011 from the Surveillance, Epidemiology, and End Results (SEER)‐Medicare linked database in the USA who received ≥ 10 doses of either HMA. We estimated survival from HMA initiation with Kaplan–Meier methods and used multivariate Cox proportional hazards models to adjust for covariates. Analyses controlled for histological subtype and we conducted a subset analysis limited to patients with refractory anaemia with excess blasts (RAEB). In 2025 HMA‐treated patients, median survival was 15 months with no difference in survival based on the HMA received in adjusted analysis (decitabine versus azacitidine, hazard ratio = 1·06, 95% confidence interval: 0·94–1·19, P = 0·37). For RAEB patients (n = 523), median survival was 12 months, with no significant difference based on HMA received. No significant survival difference was found between azacitidine and decitabine in patients with MDS, including RAEB. Importantly, population‐based survival of azacitidine‐treated RAEB patients was substantially shorter than in the AZA‐001 clinical trial (11 versus 24·5 months).     

Bone marrow hypocellularity does not affect tolerance or efficacy of azacitidine in patients with higher‐risk myelodysplastic syndromes

The efficacy and tolerance of azacitidine in higher‐risk myelodysplasia with hypocellular bone marrow (BM) are unknown. This post hoc AZA‐001 trial analysis assessed whether baseline BM cellularity affected the overall survival (OS) advantage demonstrated with azacitidine versus conventional care regimens (CCR). Baseline BM biopsies of <30% cellularity were considered hypocellular with data evaluable from 299 patients (azacitidine n = 154, CCR n = 145); 13% (n = 39) hypocellular, 87% (n = 260) non‐hypocellular. Patient characteristics were balanced between cellularity and treatment groups. Most patients (90–100%) had 2–3 cytopenias at baseline. Median (range) azacitidine treatment cycle lengths were 35·5 (28–54) and 33·0 (15–75) d in hypocellular and non‐hypocellular groups, respectively. At 33 months, median OS was not reached (NR) [95% confidence interval (CI): 19·2, NR] in hypocellular patients receiving azacitidine versus 16·9 months (95% CI: 11·1, 19·3) with CCR (P = 0·001); and in non‐hypocellular patients, it was 21·1 months (95% CI: 16·2, 34·7) versus 15·3 months (95% CI: 9·3, 17·6) (P = 0·012). Azacitidine tolerance was similar regardless of cellularity. Grade 3–4 thrombocytopenia and neutropenia occurred similarly in hypocellular patients treated with azacitidine versus CCR (80% vs. 92% and 88% vs. 75%). Azacitidine OS results are consistent with those from AZA‐001, regardless of cellularity, and demonstrate its safety and efficacy in higher‐risk myelodysplasia with hypocellular BM.     

Prolonged survival with improved tolerability in higher‐risk myelodysplastic syndromes: azacitidine compared with low dose ara‐C

In the phase III AZA‐001 trial, low‐dose cytarabine (LDara‐C), the most widely used low‐dose chemotherapy in patients with higher‐risk myelodysplastic syndrome (MDS) who are ineligible for intensive treatment, was found to be associated with poorer survival compared with azacitidine. This analysis further compared the efficacy and the toxicity of these two drug regimens. Before randomization, investigators preselected patients to receive a conventional care regimen, one of which was LDara‐C. Of 94 patients preselected to LDara‐C, 45 were randomized to azacitidine and 49 to LDara‐C. Azacitidine patients had significantly more and longer haematologicalal responses and increased red blood cell transfusion independence. Azacitidine prolonged overall survival versus LDara‐C in patients with poor cytogenetic risk, presence of ?7/del(7q), and French‐American‐British subtypes refractory anaemia with excess blasts (RAEB) and RAEB in transformation. When analyzed per patient year of drug exposure, azacitidine treatment was associated with fewer grade 3–4 cytopenias and shorter hospitalisation time than LDara‐C in these higher‐risk MDS patients.     

Efficacy and safety of a 5‐day regimen of azacitidine for patients with high‐risk myelodysplastic syndromes

Although a 7‐day (d) regimen of azacitidine (AZA) is the standard treatment of high‐risk myelodysplastic syndromes (MDS), AZA is difficult to administer during weekends in an outpatient setting. We retrospectively investigated the outcome of a 5‐d regimen of AZA in patients with high‐risk MDS. High‐risk MDS was defined as MDS with intermediate‐2‐ or high‐risk MDS according to the International Prognostic Scoring System. Every months AZA was given at 75 mg/m² per day for 5–7 d in hospital for first cycle and 5 d in outpatient for second cycle and later. Between April 2011 and December 2013, AZA treatment was initiated in 25 patients (men, 22; women, 3; median age, 75 yr; age range, 59–86 yr). The median number of AZA cycles was 10 (range, 1–24). Twenty patients received more than three cycles of AZA and 13 (52%) achieved any hematological improvement (HI). The median time to first response was two cycles (1–3). The most common non‐hematological adverse events were neutropenia in 21 patients and thrombocytopenia in 17 patients. Nineteen patients died. The main cause of death was disease progression (five patients) and infectious complications (11 patients). The median overall survival was 13.2 months. The 5‐d AZA regimen showed a good continuation rate of more than three cycles and an equivalent HI with the 7‐d regimen.     

Platelet doubling after the first azacitidine cycle is a promising predictor for response in myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML) patients in the Dutch azacitidine compassionate named patient programme

The efficacy of azacitidine in the treatment of high‐risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML) (20–30% blasts) has been demonstrated. To investigate the efficacy of azacitidine in daily clinical practice and to identify predictors for response, we analysed a cohort of 90 MDS, CMML and AML patients who have been treated in a Dutch compassionate named patient programme. Patients received azacitidine for a median of five cycles (range 1–19). The overall response rate (complete/partial/haematological improvement) was 57% in low risk MDS, 53% in high risk MDS, 50% in CMML, and 39% in AML patients. Median overall survival (OS) was 13·0 (9·8–16·2) months. Multivariate analysis confirmed circulating blasts [Hazard Ratio (HR) 0·48, 95% confidence interval (CI) 0·24–0·99; P = 0·05] and poor risk cytogenetics (HR 0·45, 95% CI 0·22–0·91; P = 0·03) as independent predictors for OS. Interestingly, this analysis also identified platelet doubling after the first cycle of azacitidine as a simple and independent positive predictor for OS (HR 5·4, 95% CI 0·73–39·9; P = 0·10). In conclusion, routine administration of azacitidine to patients with variable risk groups of MDS, CMML and AML is feasible, and subgroups with distinct efficacy of azacitidine treatment can be identified.     

Transformation of chronic myelomonocytic leukemia to acute lymphoblastic leukemia: Case report and review of the literature of lymphoblastic transformation of myelodysplastic syndrome

If chronic myelomonocytic leukemia (CMML) transforms into an acute leukemic phase, the blast crisis is invariably myeloid. Occasionally, the other subtypes of myelodysplastic syndrome (MDS) (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation) have been noted to transform into acute lymphoblastic leukemia (ALL). We now report a case of CMML that transformed into ALL and we review the literature of 13 other cases of MDS with ALL transformation. Such cases provide suggestive clinical evidence that MDS can involve a pluripotent stem cell. © 1955 Wiley-Liss, Inc.     

Pathological splenic rupture: a rare complication of chronic myelomonocytic leukemia

Chronic myelomonocytic leukemia (CMML) is an uncommon disorder characterized by monocytosis of the peripheral blood, absence of the Philadelphia chromosome, fewer than 20% blasts, and one or more lineages showing dysplastic features. Splenomegaly is frequently seen and may be massive. A 56-year-old man with stable CMML and moderate splenomegaly presented to the emergency department with generalized abdominal pain and abrupt drop in hemoglobin. Abdominal imaging revealed splenic rupture and emergency splenectomy was undertaken, with complete recovery. Atraumatic rupture of the spleen has rarely been reported as a complication of CMML or other myelodysplastic disorders. This report should alert physicians to consider this diagnosis in patients with CMML and acute abdominal pain.     

Spanish Guidelines for the use of targeted deep sequencing in myelodysplastic syndromes and chronic myelomonocytic leukaemia

The landscape of medical sequencing has rapidly changed with the evolution of next generation sequencing (NGS). These technologies have contributed to the molecular characterization of the myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), through the identification of recurrent gene mutations, which are present in >80% of patients. These mutations contribute to a better classification and risk stratification of the patients. Currently, clinical laboratories include NGS genomic analyses in their routine clinical practice, in an effort to personalize the diagnosis, prognosis and treatment of MDS and CMML. NGS technologies have reduced the cost of large-scale sequencing, but there are additional challenges involving the clinical validation of these technologies, as continuous advances are constantly being made. In this context, it is of major importance to standardize the generation, analysis, clinical interpretation and reporting of NGS data. To that end, the Spanish MDS Group (GESMD) has expanded the present set of guidelines, aiming to establish common quality standards for the adequate implementation of NGS and clinical interpretation of the results, hoping that this effort will ultimately contribute to the benefit of patients with myeloid malignancies.     

Flow cytometry immunophenotypic findings in chronic myelomonocytic leukemia and its utility in monitoring treatment response

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm, characterized by persistent monocytosis. Due to the lack of unique surface markers expressed by neoplastic monocytes and the frequent CD34‐negative blast immunophenotype, the diagnostic value of flow cytometric immunophenotyping (FCI) in CMML is rarely studied. In this study, by using a multicolor FCI assay, we assessed bone marrow (BM) immunophenotypical alterations in 118 CMML patients and follow‐up BM samples in 35 of these patients. The median BM monocytes as determined by FCI were 14% (1–63%), correlated with morphologic count (P = 0.0004). FCI alterations in monocytes were observed in 96% and granulocytes in 83% of cases. The percentage of CD34⁺ myeloblasts by FCI was low [median 0.6% (0.02–12.6%)], but exhibiting frequent aberrancies [median 6 (2–12)]. CD34⁺ B‐cell precursors were absent in 93% of cases. In 35 patients with follow‐up BM samples assessed, the CD34⁺ myeloblasts showed persistent FCI aberrancies in all 29 patients treated with hypomethylating agents and 3 patients on observation, but became normal in 3 patients following stem cell transplant. In conclusion, CMML exhibit numerous FCI alterations in monocytes, granulocytes, and more profound/frequent in CD34⁺ myeloblasts. These findings provide solid evidence for using FCI as an ancillary test in CMML diagnosis and also, in assessment of treatment responses.     

A phase II study of addition of pracinostat to a hypomethylating agent in patients with myelodysplastic syndromes who have not responded to previous hypomethylating agent therapy

Hypomethylating agents (HMAs) are standard of care for higher-risk myelodysplastic syndromes (MDS). However, less than half of patients achieve objective responses and most eventually lose their response. Pracinostat is a pan-histone deacetylase inhibitor with demonstrated activity in advanced myeloid malignancies. This phase II study explored the benefit of adding pracinostat to HMAs in MDS patients who did not respond to single-agent HMA treatment. The goal was to estimate the clinical improvement rate [complete remission (CR), marrow CR, partial response (PR) and haematological improvement]. Group 1 included patients with primary/secondary HMA failures; Group 2 included those who did not achieve response but had stable disease (SD) after single-agent HMAs. Forty-five patients (39 Group 1, 6 Group 2) received a median of 3 cycles. Among all patients, 1 (2%) had CR, 7 (16%) had marrow CR and 18 (40%) had SD; disease progression occurred in 3 (7%). Median overall survival was 5·7/5·6 months for Group 1/2. Grade ≥3 adverse events occurred in 38 patients (84%) leading to treatment discontinuation in 12 (33%). Adding pracinostat to HMAs did not improve outcomes in patients previously treated with HMAs. Frequent dose modifications/early discontinuation resulted in suboptimal drug exposure. A reduced pracinostat dose may improve tolerability and efficacy.     

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 in the ‘real‐world’: an evaluation of 1101 higher‐risk myelodysplastic syndrome/low blast count acute myeloid leukaemia patients in Ontario,Canada

The outcome of myelodysplastic syndrome (MDS) patients with uniformly higher‐risk disease treated with azacitidine (AZA) in the ‘real‐world’ remains largely unknown. We evaluated 1101 consecutive higher‐risk MDS patients (International Prognostic Scoring System intermediate‐2/high) and low‐blast count acute myeloid leukaemia (AML; 21–30% blasts) patients treated in Ontario, Canada. By dosing schedule, 24·7% received AZA for seven consecutive days, 12·4% for six consecutive days and 62·9% by 5‐2‐2. Overall, median number of cycles was 6 (range 1–67) and 8 (range 6–14) when restricted to the 692 (63%) patients who received at least 4 cycles. The actuarial median survival was 11·6 months [95% confidence interval (CI) 10·7–12·4) for the entire cohort and 18·0 months (landmark analysis; 95% CI 16·6–19·1 months) for those receiving at least 4 cycles. There was no difference in overall survival (OS) between the 3 dosing schedules (P = 0·87). In our large ‘real‐world’ evaluation of AZA in higher‐risk MDS/low‐blast count AML, we demonstrated a lower than expected OS. Reassuringly, survival did not differ by dosing schedules. The OS was higher in the 2/3 of patients who received at least 4 cycles of treatment, reinforcing the necessity of sustained administration until therapeutic benefits are realised. This represents the largest ‘real‐world’ evaluation of AZA in higher‐risk MDS/low‐blast count AML.     

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.     

Development and validation of a model to predict platelet response to romiplostim in patients with lower‐risk myelodysplastic syndromes

Low endogenous erythropoietin levels and limited red blood cell transfusion history can predict response to erythropoiesis‐stimulating agents in anaemic patients with myelodysplastic syndromes (MDS). The relationship between endogenous thrombopoietin (THPO) levels and platelet response to romiplostim is unknown. Variables including baseline endogenous THPO levels, transfusion needs, and platelet response were analysed in a randomized trial of 250 thrombocytopenic, lower‐risk MDS patients (International Prognostic Scoring System low/intermediate‐1). A predictive scoring system was developed based on log–likelihood ratios and logistic coefficients. Patients with HI–P (haematological improvement – platelets) responses had lower mean baseline THPO levels (P = 0·0497) and were more likely to have <6 platelet units transfused in the past year (P = 0·0027), as did patients with platelet responses ≥50% of weeks on romiplostim (P = 0·001 and P = 0·0037, respectively). A model for predicting response to romiplostim was developed and validated in a separate MDS cohort (N = 72). Patients in low‐, intermediate‐, and high‐response groups had response rates of 17·4%, 29·6%, and 50·7%, respectively, for HI‐P, and 17·4%, 33·8%, and 65·2%, respectively, for ≥50% response. For thrombocytopenic patients with lower‐risk MDS, lower baseline THPO levels (<500 pg/ml) and limited platelet transfusion history predicted a greater likelihood of a subsequent platelet response to romiplostim.     

A phase 2 trial of high dose lenalidomide in patients with relapsed/refractory higher‐risk myelodysplastic syndromes and acute myeloid leukaemia with trilineage dysplasia

Limited therapies exist for patients with refractory and relapsed (RR ) higher‐risk myelodysplastic syndromes (HR ‐MDS ) and acute myeloid leukaemia with trilineage dysplasia (AML ‐TD ). High dose (HD ) lenalidomide (50 mg) has activity as frontline therapy in elderly AML but there is limited data in the RR setting. This phase II trial included patients with RR HR ‐MDS or AML ‐TD at 2 doses of lenalidomide (15 or 50 mg) on days 1–28 of 42‐day cycles. The primary endpoint was response rate using the 2006 International Working Group criteria. Overall survival (OS ) was estimated by Kaplan–Meier methods. Of 27 patients enrolled, 59% had HR ‐MDS and 31% AML ‐TD . No patient had isolated del5q; 41% had poor‐risk karyotype. Of 9 patients treated at 15 mg, 56% completed ≥2 cycles with no responses. Of 18 patients treated at 50 mg, 39% completed ≥2 cycles and 11% responded but all experienced grade 3/4 neutropenic fever/infection. The 60‐day mortality rate was 30%. Median OS was 114 days with 19% surviving ≥1 year. The study was terminated due to lack of robust clinical activity. In conclusion, lenalidomide at 15 mg is ineffective in RR myeloid malignancies. Continous high dosing schedules are poorly tolerated and minimally active. Further evaluation should be considered in upfront intensive chemotherapy‐ineligible patients.     

Erythropoiesis-stimulating agents are not associated with increased risk of thrombosis in patients with myelodysplastic syndromes

Background

There are limited reports of thrombosis among myelodysplastic syndrome patients exposed to erythropoiesis stimulating agents. It is not clear whether erythropoiesis stimulating agents are associated with an increased risk of thrombosis in myelodysplastic syndromes, as they are among patients with solid tumors.

Design and Methods

The association between use of erythropoiesis stimulating agent and transient thrombosis risk in patients with myelodysplastic syndromes was assessed in a case-crossover study nested within a cohort of incident myelodysplastic syndrome patients. Using the US Surveillance, Epidemiology, and End Results Medicare-linked database, cases with an incident diagnosis of deep vein thrombosis were identified. Using conditional logistical regression, the odds of exposure to erythropoiesis stimulating agents in the 12 weeks prior to the incident deep vein thrombosis (hazard period) was compared to the exposure odds in a prior 12-week comparison period.

Results

Within the cohort of eligibles with myelodysplastic syndromes (n=5,673) there were 212 incident cases of deep vein thrombosis events. Mean age was 76.2 (standard deviation=±8.6) years. Use of erythropoiesis stimulating agents was not associated with deep vein thrombosis in the crude nor the adjusted models (OR=1.21, 95% CI: 0.60, 2.43). Central venous catheter placement (OR=6.47, 95% CI: 2.37, 17.62) and red blood cell transfusion (OR=4.60, 95% CI: 2.29, 9.23) were associated with deep vein thrombosis.

Conclusions

Despite the link between use of erythropoiesis stimulating agents and thrombosis among patients with solid tumors, this study provides evidence that their safety profile may be different among patients with myelodysplastic syndromes.     

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.