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.     

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.     

A phase II trial of interleukin-2 in myelodysplastic syndromes

Patients with myelodysplastic syndromes (MDS) show a decrease in the number and function of natural killer (NK) cells, including lymphokine activated killer (LAK) cell activity. Interleukin-2 (IL-2) stimulates the proliferation and activity of these lymphocytes. Anecdotal clinical experience has shown haematological and cytogenetic improvement in myelodysplasia by low-dose IL-2 treatment.
A total of 10 patients with MDS were treated with 1 million units of IL-2 subcutaneously daily for 12 weeks. Even though improvement in CD16⁺/CD56⁺ cell numbers was seen in a majority of the patients, the haematological status and transfusion requirements remained unchanged. There was minimal toxicity from this therapy.     

Cost-effectiveness analysis of azacitidine for myelodysplastic syndromes in Japan

The aim of this study was to assess the cost-effectiveness of azacitidine therapy for patients with myelodysplastic syndromes. A Markov model was developed to estimate the total additional direct cost and quality adjusted life years (QALYs) gained with azacitidine therapy versus best-supportive care in patients with high-risk MDS. The cost-effectiveness of azacitidine was evaluated with incremental cost-effectiveness ratio, which represents the additional cost per QALY gained from the more effective treatment. Azacitidine therapy was 1.83 million yen more costly per patient but yielded an additional 0.353 QALYs. The ICER (Increment of Cost-effectiveness Ratio) was 5.18 million yen per QALY. In conclusion, because the ICER was less than the threshold for acceptable cost-effectiveness in Japan, azacitidine therapy for MDS patient was assumed to be cost-effective.     

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.     

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.     

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.     

Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine

Prognostic factors for response and survival in higher-risk myelodysplastic syndrome patients treated with azacitidine (AZA) remain largely unknown. Two hundred eighty-two consecutive high or intermediate-2 risk myelodysplastic syndrome patients received AZA in a compassionate, patient-named program. Diagnosis was RA/RARS/RCMD in 4%, RAEB-1 in 20%, RAEB-2 in 54%, and RAEB-t (AML with 21%-30% marrow blasts) in 22%. Cytogenetic risk was good in 31%, intermediate in 17%, and poor in 47%. Patients received AZA for a median of 6 cycles (1-52). Previous low-dose cytosine arabinoside treatment (P = .009), bone marrow blasts > 15% (P = .004), and abnormal karyotype (P = .03) independently predicted lower response rates. Complex karyotype predicted shorter responses (P = .0003). Performance status ≥ 2, intermediate- and poor-risk cytogenetics, presence of circulating blasts, and red blood cell transfusion dependency ≥ 4 units/8 weeks (all P < 10(-4)) independently predicted poorer overall survival (OS). A prognostic score based on those factors discriminated 3 risk groups with median OS not reached, 15.0 and 6.1 months, respectively (P < 10(-4)). This prognostic score was validated in an independent set of patients receiving AZA in the AZA-001 trial (P = .003). Achievement of hematological improvement in patients who did not obtain complete or partial remission was associated with improved OS (P < 10(-4)). In conclusion, routine tests can identify subgroups of patients with distinct prognosis with AZA treatment.     

Anti‐thymocyte globulin plus etanercept as therapy for myelodysplastic syndromes (MDS): a phase II study

Immunosuppressive therapies have proven valuable in treating patients with myelodysplastic syndromes (MDS). We evaluated the combination of equine anti‐thymocyte globulin (ATGAM^®) and the soluble tumour necrosis factor receptor, etanercept (Enbrel^®), in a phase II trial. Twenty‐five patients with MDS [4‐refractory anaemia (RA), 2‐RA with ring sideroblasts, 15‐refractory cytopenia with multilineage dysplasia (RCMD), 3‐RCMD and ring sideroblasts, 1‐RA with excess blasts type 1] in International Prognostic Staging System risk groups low (n = 11) or intermediate‐1 (n = 14) were enrolled. All patients were platelet or red cell transfusion‐dependent. Nineteen patients completed therapy with ATG at 40 mg/kg per day for four consecutive days, followed by etanercept, 25 mg subcutaneous twice a week for 2 weeks, every month for 4 months. Thirteen patients had haematological improvement (HI)‐erythroid, 2 HI‐neutrophil, and 6 HI‐platelet. One patient with a co‐existing diagnosis of multiple sclerosis and rheumatoid arthritis had a complete remission. The overall response by intent to treat analysis among the 25 patients was 56% (95% confidence interval 35–56%). Four patients did not complete their first course of therapy and one patient did not survive to the 8‐week post‐treatment assessment. Among patients who completed treatment and survived to the 8‐week assessment, 70% had at least haematological responses lasting for at least 5 to more than 36 months. Thus, combination therapy with ATG and etanercept was active and safe in patients with MDS.     

A phase I/II study of the combination of quizartinib with azacitidine or low-dose cytarabine for the treatment of patients with acute myeloid leukemia or myelodysplastic syndrome

The FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation in acute myeloid leukemia (AML) is associated with poor prognosis. We hypothesized that quizartinib, a selective and potent FLT3 inhibitor, with azacitidine (AZA) or low-dose cytarabine (LDAC) might improve the outcomes in patients with FLT3-ITD-mutated AML. In this open-label phase I/II trial, patients of any age receiving first-salvage treatment for FLT3-ITD AML or age >60 years with untreated myelodysplastic syndrome or AML were treated with quizartinib plus AZA or LDAC. Seventy-three patients were treated (34 frontline, 39 first salvage). With regard to previously untreated patients, the composite response (CRc) rate was 87% (n=13/15: 8 complete responses [CR], 4 CR with incomplete hematologic recovery [CRi], 1 CR without platelet recovery [CRp]) among the patients treated with quizartinib/AZA and 74% (n=14/19: 1 CR, 8 CRi, 5 CRp) among those treated with quizartinib/LDAC. The median overall survival was 19.2 months for the cohort treated with quizartinib/AZA cohort and 8.5 months for the patients treated with quizartinib/LDAC; the corresponding relapse-free survival figures were 10.5 and 6.4 months, respectively. With regard to previously treated patients, the CRc rate was 64% (n=16/25 in the quizartinib/AZA cohort and 29% (n=4/14)) in the quizartinib/LDAC cohort. The median overall survival for patients treated with quizartinib/AZA and quizartinib/LDAC was 12.8 versus 4 months, respectively. QTc prolongation grade 3 occurred in only one patient in each cohort. Quizartinib-based combinations, particularly with AZA, appear effective in both frontline and first salvage therapy for patients with FLT3-ITD-mutated AML and are well tolerated. ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT01892371","term_id":"NCT01892371"}}NCT01892371.     

Predicting infections in high‐risk patients with myelodysplastic syndrome/acute myeloid leukemia treated with azacitidine: Aretrospective multicenter study

Hypomethylating agents have become the standard therapy for patients with high‐risk myelodysplastic syndrome (MDS). In Israel, azacitidine (AZA) is routinely used. Yet, infectious complications are common during AZA therapy. The current study was aimed to evaluate the incidence and predisposing risk factors for infections in AZA‐treated patients. This retrospective study included patients treated with AZA in 18 Israeli medical institutions between 2008 and 2011. Data on 184 patients [157 high‐risk MDS and 27 acute myeloid leukemia (AML)], with a median age of 71.6 (range 29–92) were recorded. Overall, 153 infectious events were reported during 928 treatment cycles (16.5%) administered to 100 patients. One hundred fourteen, 114/153 (75%) events required hospitalization and 30 (19.6%) were fatal. In a univariate analysis, unfavorable cytogenetics, low neutrophil, hemoglobin (Hb) and platelet (PLT) counts were found to be associated with infections (24.4% vs. 12.9%, P < 0.0001; 27% vs. 13.5%, P < 0.0001; 20.4% vs. 11%, P < 0.0001 and 29.2% vs. 14.2%, P < 0.0001, respectively). In multivariate analysis, only low Hb level, low PLT count, and unfavorable cytogenetics remained significant. Prior to therapy, poor cytogenetics, PLT count below 20 × 10⁹/L and neutrophil count below 0.5 × 10⁹/L were predictive of the risk of infection during the first two cycles of therapy. In conclusion, patients with unfavorable cytogenetics, presenting with low neutrophil and PLT counts, are susceptible to infections. Evaluation of infection risk should be repeated prior to each cycle. Patients with poor cytogenetics in whom AZA is prescribed despite low PLT count are particularly at high risk for infections and infection prophylaxis may be considered. Am. J. Hematol. 88:130–134, 2013. © 2012 Wiley Periodicals, Inc.     

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.     

Immune-mediated complications in patients with myelodysplastic syndromes – clinical and cytogenetic features

Abstract: It has been recognized in recent years that some patients with myelodysplastic syndromes (MDS) develop immune-mediated complications (IMC), but little is known about the correlations to MDS-specific disease features. In a retrospective study of 82 MDS patients, we identified 10 (12%) with IMC (group A) and compared them to the remaining 72 cases (group B). Group A consisted of 5 patients with biopsy-verified skin vasculitis and 1 case each with temporal arteritis/polymyalgia rheumatica, necrotising panniculitis, Hashimoto's thyroiditis, autoimmune thrombocytopenia, and Sweet's syndrome. Survival times, sex ratio and distribution of MDS subtypes were similar in the two groups. The patients in group A were younger than those in group B (median 66 vs. 76 years, p<0.01). Four patients (40%) in group A had a history of previous genotoxic therapy for malignant disorders. The bone marrow karyotype was evaluated in 62 patients. Clonal chromosomal abnormalities were found more frequently in Group A than in group B (8/9 vs. 26/53, p = 0.03), and complex karyotypes, i.e., three or more aberrations, were also observed to be more common in group A (3/9 vs. 8/53). The results indicate that IMC preferentially develop in patients with secondary MDS, in younger MDS cases, and in patients with cytogenetic abnormalities.