Minimizing risk of hypomethylating agent failure in patients with higher-risk MDS and practical management recommendations

In Europe, azacitidine is the only hypomethylating agent approved for the treatment of patients with int-2-/high-risk myelodysplastic syndromes, offering significantly improved survival compared with conventional care. However, not all patients treated with azacitidine respond to treatment, and the vast majority of responders subsequently relapse. Currently, no standard care regimens have been established for patients after failure of azacitidine. Here, we discuss treatment options after loss of response or progression on azacitidine. In addition, we briefly consider optimization of first-line treatment along with potential biomarkers for identifying and monitoring response during treatment with azacitidine.     

Does addition of erythropoiesis stimulating agents improve the outcome of higher-risk myelodysplastic syndromes treated with azacitidine?

We studied a retrospective cohort of 282 higher-risk MDS treated with azacitidine, including 32 patients who concomitantly received an ESA for a median of 5.8 months after azacitidine onset. Forty-four percent of ESA and 29% of no-ESA patients reached HI-E (p=0.07); 48% and 20% achieved transfusion independence (p=0.01). Median OS was 19.6 months in the ESA and 11.9 months in the no-ESA groups (p=0.04). Addition of an ESA significantly improved OS (p=0.03) independently of azacitidine schedule and duration, and of our proposed azacitidine risk score (Blood 2011;117:403-11). Adding an ESA to azacitidine in higher-risk MDS should be studied prospectively.     

Azacitidine in CMML: Matched-pair analyses of daily-life patients reveal modest effects on clinical course and survival

Recent data suggest that azacitidine may be beneficial in CMML. We report on 48 CMML-patients treated with azacitidine. Overall response rates were high (70% according to IWG-criteria, including 22% complete responses). Monocyte count and cytogenetics adversely affected survival, whereas age, WHO-type, FAB-type, and spleen size did not. Matched-pair analyses revealed a trend for higher two-year-survival for azacitidine as compared to best supportive care (62% vs. 41%, p = 0.067) and longer OS for azacitidine first-line vs. hydroxyurea first-line (p = 0.072, median OS 27.7 vs. 6.2 months). This report reinforces existing evidence that azacitidine is safe and efficacious in both myelodysplastic and myeloproliferative CMML.     

Effectiveness and Safety of Therapeutic Regimens for Elderly Patients With Acute Myeloid Leukemia: A Systematic Literature Review

Acute myeloid leukemia (AML) is the second most common leukemia among adults. Although the median age at diagnosis is 67 years, with approximately one third of patients aged 75 years or older, limited treatment options exist for the elderly, who have 5-year survival rates of only 5%. A systematic review was conducted to examine effectiveness and safety outcomes of treatment regimens in elderly (≥60 years old) patients with AML. Published literature on the topic was scant, and the review included only 22 articles examining outcomes. Twelve studies examined treatment-specific outcomes; most of these examined azacitidine or intensive chemotherapy (IC). An international randomized controlled trial found that azacitidine significantly improved overall survival relative to conventional regimens including IC and low-dose cytarabine in patients aged > 65 years. Similar results in favor of azacitidine were demonstrated in 2 other studies. IC was generally associated with longer survival versus lower-intensity therapy or best supportive care. Findings suggest that azacitidine is a viable option for elderly AML patients who are ineligible for IC, and emerging agents used in combination with azacitidine could have a major impact in this difficult-to-treat population.     

In vitro assessment of cytochrome P450 inhibition and induction potential of azacitidine

Purpose

To assess the potential inhibitory and inductive effects of azacitidine on cytochrome P450 isozymes in vitro.

Methods

The inhibitory effects of azacitidine on various CYP isozymes were determined in human liver microsomes. In addition, the ability of azacitidine to induce CYP enzymes in cultured human hepatocytes was evaluated.

Results

Azacitidine did not inhibit CYP2B6-, CYP2C8-, CYP2C9-, CYP2C19-, CYP2D6-, and CYP3A4-mediated activities in human liver microsomes up to a concentration of 100 μM, while weak inhibition (<30% inhibition) of CYP1A2 and CYP2E1 activities was observed at 100 μM azacitidine. In vitro azacitidine did not induce CYP1A2, CYP2C19, or CYP3A4/5 activities in cultured human hepatocytes.

Conclusions

Azacitidine is not an inhibitor or inducer of the cytochrome P450 isozymes tested; therefore, clinically relevant pharmacokinetic drug–drug interactions are unlikely to occur between azacitidine and co-administered substrates of these CYP isozymes.     

Phase I and II study of azacitidine in Japanese patients with myelodysplastic syndromes

Azacitidine, an inhibitor of DNA methyltransferase, is reported to have antileukemic efficacy and is approved for the treatment of myelodysplastic syndromes in Western countries. We have conducted a Phase I/II study of azacitidine in Japanese patients with myelodysplastic syndromes to evaluate its pharmacokinetics, efficacy, and safety. In all, 53 patients received 75 mg/m(2) azacitidine subcutaneously or intravenously once daily for seven consecutive days on a 28-day cycle. The C(max) following intravenous administration was approximately 3.7-fold higher than that following subcutaneous administration, whereas the area under the plasma concentration-time curve from time zero to infinity was comparable for subcutaneous and intravenous administration. The bioavailability of azacitidine following subcutaneous administration was 91.1%, indicating that azacitidine is nearly completely absorbed after subcutaneous administration. The hematologic improvement and hematologic response rates were 54.9% (28/51) and 28.3% (15/53), respectively, and there were no differences between the two routes of administration. Azacitidine was generally well tolerated and clinically manageable in Japanese patients with myelodysplastic syndromes. Adverse events occurred in ≥ 20% of patients included hematologic toxicity, gastrointestinal events, and general disorders, such as malaise. Grade 3/4 adverse events that occurred in ≥ 50% of patients were all due to hematologic toxicity. The safety profile of azacitidine was generally similar for both routes of administration, with the exception of injection site reactions observed following subcutaneous administration. These results indicate that azacitidine can be expected to be a useful therapeutic agent in Japanese patients with myelodysplastic syndromes.     

阿扎胞苷联合CAG方案再诱导治疗儿童复发难治急性髓系白血病临床观察

目的:探讨阿扎胞苷联合CAG（阿糖胞苷+阿柔比星+粒细胞集落刺激因子）方案再诱导儿童复发难治急性髓系白血病（AML）的疗效和安全性。方法:回顾性分析2018年11月至2019年8月福建医科大学附属协和医院收治的3例接受阿扎胞苷联合CAG方案再诱导治疗的复发难治AML患儿的临床资料,分析疗效、预后及不良反应发生情况。结果:3例患儿中,2例为复发AML（分别距开始治疗18个月和8个月后复发）,1例为难治AML（2个疗程标准化疗不能达完全缓解）。在2个疗程阿扎胞苷联合CAG方案再诱导后,2例达完全缓解,1例达部分缓解,之后均桥接造血干细胞移植（HSCT）。随访16~21个月（距首次阿扎胞苷联合CAG方案再诱导的时间）,患儿均为无白血病生存。除了血液学不良反应及感染外,阿扎胞苷未增加其他不良反应。结论:阿扎胞苷联合CAG方案诱导儿童复发难治AML有较高的再缓解率和安全性,及时桥接HSCT可取得较好的预后。     

Poor Outcome of Patients With Myelodysplastic Syndrome After Azacitidine Treatment Failure

BackgroundLimited data have been reported describing the outcome and prognosis of patients with MDS in whom treatment with azanucleosides has failed. We report our single-institutional experience of patients with higher-risk MDS in whom therapy with azacitidine has failed.Patients and MethodsThis was a retrospective study of MDS patients treated at the Moffitt Cancer Center in whom azacitidine treatment regimens had failed. Patients were identified through the Moffitt database, and clinical data were extracted. Azacitidine failure was defined as failure to achieve hematologic improvement or better after at least 4 cycles of therapy, loss of response, or disease progression during therapy. The objectives were to characterize response to salvage therapies after azacitidine failure and to estimate the overall survival. All responses were defined according to the International Working Group 2006 criteria, and survival was estimated using the Kaplan-Meier method.ResultsA total of 59 patients in whom azacitidine treatment had failed were identified. The median age at treatment failure was 68 years, and most were Caucasian male patients. Thirteen patients received intensive chemotherapy with an overall response rate of 31%. Six patients were treated with decitabine, and none responded. Median overall survival of the entire cohort after azacitidine failure was 5.8 months (95% confidence interval, 1.3-10.3 months), with an estimated 12-month survival of 17%.ConclusionPatients with higher-risk MDS in whom azacitidine treatment has failed have a poor prognosis and low probability of response to salvage treatments. The standard of care after azanucleoside failure should be enrollment in clinical trials.     

Invasive fungal infections in AML/MDS patients treated with azacitidine: a risk worth considering antifungal prophylaxis?

The aim of this study is to analyse the risk of invasive fungal infection (IFI) and the need for antifungal prophylaxis in patients with acute myeloid leukaemia and myelodysplastic syndromes (AML/MDS) treated with azacitidine. We retrospectively analysed the incidence of IFI according to EORTC‐MSG criteria in 121 consecutive AML/MDS patients receiving 948 azacitidine courses (median 5, range 1–43) between June 2007 and June 2015. Four cases of IFI (two possible, one probable aspergillosis and one proven candidemia) occurred in this series. The incidence rate of proven/probable IFI was 0.21% per treatment cycle and 1.6% per patient treated for the whole series, and 0.73% per treatment cycle and 4.1% per patient treated in those with severe neutropenia. Two patients died from IFI, leading to an IFI‐attributable mortality rate of 1.65% per patient and 0.21% per treatment cycle. The numbers needed to treat with prophylaxis to prevent one case of IFI are 238 azacitidine cycles or 30 patients throughout their whole treatment course, and 137 azacitidine cycles or 24 patients among those with severe neutropenia. AML/MDS patients treated with azacitidine, including those with severe prolonged neutropenia, have a very low risk of IFI which does not justify the use of antifungal prophylaxis.     

FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension

On May 19, 2004, azacitidine (5-azacytidine; Vidaza(trade mark); Pharmion Corporation, Boulder, CO, http://www.pharmion.com) for injectable suspension received regular approval by the U.S. Food and Drug Administration (FDA) for the treatment of all subtypes of myelodysplastic syndrome (MDS). This report summarizes the basis for this approval. Effectiveness was demonstrated in one randomized, controlled trial comparing azacitidine administered s.c. with best supportive care (observation group) and in two single-arm studies, one in which azacitidine was administered s.c. and in the other in which it was administered i.v. The dose of azacitidine, 75 mg/m2/day for 7 days every 28 days, was the same in all three studies. In the randomized trial, study participants were well matched with respect to age, sex, race, performance status, MDS subtype, and use of transfusion during the 3 months before study entry. Patients in the observation arm were permitted by protocol to cross over to azacitidine treatment if their disease progressed according to prespecified criteria. During the course of the study, more than half of the patients in the observation arm did cross over to the azacitidine treatment arm. The primary efficacy end point was the overall response rate. Response consisted of complete or partial normalization of blood cell counts and of bone marrow morphology. The response rate in the azacitidine arm was about 16%; there were no responses in the observation arm. The response rates in the two single-arm studies were similar (13% and 19%). The responses were sustained, with median durations of 11 months and 17 months respectively. Responding patients who were transfusion dependent at study entry lost the need for transfusions. In addition, about 19% of patients had less than partial responses (termed improvement), and two-thirds of them became transfusion independent. Common adverse events associated with azacitidine treatment were gastrointestinal (nausea, vomiting, diarrhea, constipation, and anorexia), hematologic (neutropenia, thrombocytopenia), fevers, rigors, ecchymoses, petechiae, injection site events, arthralgia, headache, and dizziness. Liver function abnormalities occurred in 16% of patients with intercurrent hepatobiliary disorders and in two patients with previously diagnosed liver cirrhosis. Renal failure occurred in patients during sepsis and hypotension. There were no deaths attributed to azacitidine. Azacitidine, the first drug approved by the U.S. FDA for MDS, has a favorable safety profile and provides a clinical benefit of eliminating transfusion dependence and complete or partial normalization of blood counts and bone marrow blast percentages in responding patients.     

Patterns of Infection in Patients With Myelodysplastic Syndromes and Acute Myeloid Leukemia Receiving Azacitidine as Salvage Therapy. Implications for Primary Antifungal Prophylaxis

Incidence, etiology, and outcome of infectious episodes in patients with myeloid neoplasms receiving azacitidine are uncertain, with no prospective data available in this group of patients. The aim of the current study was to analyze the incidence and factors related to the probability of infection in a cohort of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) treated with azacitidine who did not receive any type of antimicrobial prophylaxis. Significantly, the group of patients who received prior intensive chemotherapy had more infectious episodes (P = 10^-4), and particularly, invasive aspergillosis (P = .015), than patients who received frontline azacitidine. Primary antifungal prophylaxis might be recommended in MDS and AML patients receiving azacitidine as salvage therapy after intensive regimens.     

Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes.

PURPOSE: This article summarizes data submitted to the U.S. Food and Drug Administration for marketing approval of azacitidine as injectable suspension (Vidaza, Pharmion Corporation, Boulder, CO) for treatment of patients with myelodysplastic syndrome. EXPERIMENTAL DESIGN: In one phase 3 controlled trial, 191 study subjects were randomized to treatment with azacitidine or to observation; an additional 120 patients were treated with azacitidine in two phase 2 single arm studies. The primary efficacy end point was the overall response rate, defined as complete or partial normalization of peripheral blood counts and bone marrow blast percentages for at least 4 weeks. RESULTS: In the controlled trial, the overall response rate was 15.7% in the azacitidine treatment group; there were no responders in the observation group (P < 0.0001). Response rates were similar in the two single arm studies. During response patients stopped being red cell or platelet transfusion dependent. Median duration of responses was at least 9 months. An additional 19% of azacitidine-treated patients had less than partial responses, most becoming transfusion independent. The most common adverse events attributed to azacitidine were gastrointestinal, hematologic, local (injection site), and constitutional. There were no azacitidine-related deaths. CONCLUSIONS: On May 19, 2004 the U.S. Food and Drug Administration approved azacitidine as injectable suspension for treatment of patients with the following myelodysplastic syndrome subtypes: refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia. Full prescribing information is available at http://www.fda.gov/cder/foi/label/2004/050794lbl.pdf. Azacitidine is the first agent approved for treatment of myelodysplastic syndrome.     

Phase II study of azacitidine to restore responsiveness of prostate cancer to hormonal therapy

Epigenetic alterations, including methylation of key tumor suppressor genes, may play a role in the progression of prostate cancer to a castration-refractory state. Azacitidine, an agent approved for the treatment of myelodysplastic syndromes, appears to exert its antineoplastic effects partly by hypomethylating DNA that leads to the reversal of gene silencing. It is hypothesized that the addition of azacitidine to complete androgen blockade may restore the responsiveness of progressive prostate cancer to hormonal therapy. A phase II trial was designed to evaluate the activity of azacitidine to primarily modulate PSA kinetics, with supportive secondary clinical endpoints. Correlative studies will be performed to detect the biologic activity of azacitidine (increased fetal hemoglobin, plasma DNA methylation) and examine any association with anti-tumor clinical activity.     

Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial

This study evaluated azacitidine as treatment of minimal residual disease (MRD) determined by a sensitive donor chimerism analysis of CD34(+) blood cells to pre-empt relapse in patients with CD34(+) myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT). At a median of 169 days after HSCT, 20/59 prospectively screened patients experienced a decrease of CD34(+) donor chimerism to <80% and received four azacitidine cycles (75?mg/m(2)/day for 7 days) while in complete hematologic remission. A total of 16 patients (80%) responded with either increasing CD34(+) donor chimerism to ≥80% (n=10; 50%) or stabilization (n=6; 30%) in the absence of relapse. Stabilized patients and those with a later drop of CD34(+) donor chimerism to <80% after initial response were eligible for subsequent azacitidine cycles. A total of 11 patients (55%) received a median of 4 (range, 1-11) additional cycles. Eventually, hematologic relapse occurred in 13 patients (65%), but was delayed until a median of 231 days (range, 56-558) after initial decrease of CD34(+) donor chimerism to <80%. In conclusion, pre-emptive azacitidine treatment has an acceptable safety profile and can substantially prevent or delay hematologic relapse in patients with MDS or AML and MRD after allogeneic HSCT.     

Secondary basophilic leukemia in Ph-negative myeloid neoplasms: A distinct subset with poor prognosis

During progression of myeloid neoplasms, the basophil compartment may expand substantially and in some of these patients, a basophilic leukemia is diagnosed. In patients with Ph-chromosome+ chronic myeloid leukemia, acceleration of disease is typically accompanied by marked basophilia. In other myeloid neoplasms, secondary leukemic expansion of basophils is rarely seen. We report on 5 patients who suffered from a myelodysplastic syndrome, myeloproliferative neoplasm, or acute leukemia and developed a massive expansion of basophils during disease progression. In 4 of 5 patients, peripheral blood basophil counts reached 40%, and the diagnosis “secondary basophilic leukemia” was established. As assessed by flow cytometry, neoplastic basophils expressed CD9, CD18, CD25, CD33, CD63, PD-L1, CD123, and CLL-1. In addition, basophils were found to display BB1 (basogranulin), 2D7, tryptase and KIT. In 4 of 5 patients the disease progressed quickly and treatment with azacitidine was started. However, azacitidine did not induce major clinical responses, and all patients died from progressive disease within 3 Y. In in vitro experiments, the patients´ cells and the basophilic leukemia cell line KU812 showed variable responses to targeted drugs, including azacitidine, venetoclax, hydroxyurea, and cytarabine. A combination of venetoclax and azacitidine induced cooperative antineoplastic effects in these cells. Together, secondary basophilic leukemia has a poor prognosis and monotherapy with azacitidine is not sufficient to keep the disease under control for longer time-periods. Whether drug combination, such as venetoclax+azacitidine, can induce better outcomes in these patients remains to be determined in future clinical studies.     

Concise Drug Review: Azacitidine and Decitabine

The introduction of the hypomethylating agents azacitidine and decitabine has been a major advancement in the treatment of patients with higher-risk myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia who are ineligible for more intensive treatments. This concise drug review summarizes the current state of treatment with azacitidine and decitabine.     

Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes

BACKGROUND:

In the AZA‐001 trial, azacitidine (75 mg/m²/d subcutaneously for Days 1‐7 of every 28‐day cycle) demonstrated improved survival compared with conventional care regimens in patients with International Prognostic Scoring System‐defined intermediate‐2‐ or high‐risk myelodysplastic syndrome and World Health Organization‐defined acute myeloid leukemia with 20% to 30% bone marrow blasts.

METHODS:

This secondary analysis of the AZA‐001 phase 3 study evaluated the time to first response and the potential benefit of continued azacitidine treatment beyond first response in responders.

RESULTS:

Overall, 91 of 179 patients achieved a response to azacitidine; responding patients received a median of 14 treatment cycles (range, 2‐30). Median time to first response was 2 cycles (range, 1‐16). Although 91% of first responses occurred by 6 cycles, continued azacitidine improved response category in 48% of patients. Best response was achieved by 92% of responders by 12 cycles. Median time from first response to best response was 3.5 cycles (95% confidence interval [CI], 3.0‐6.0) in 30 patients who ultimately achieved a complete response, and 3.0 cycles (95% CI, 1.0‐3.0) in 21 patients who achieved a partial response.

CONCLUSIONS:

Continued azacitidine therapy in responders was associated with a quantitative increase in response to a higher response category in 48% of patients, and therefore may enhance clinical benefit in patients with higher‐risk MDS. Cancer 2011. © 2011 American Cancer Society.     

5'-Azacitidine for therapy-related myelodysplastic syndromes after non-Hodgkin lymphoma treatment

Therapy-related myelodysplastic syndromes are possible complications in patients treated for previous hematologic malignancies. Therapeutic strategies in these type of disorders are still not well defined: azacitidine has been recently approved for the treatment of higher risk myelodysplastic syndromes, but few data are published relating possible efficacy in therapy-related dysplastic disorders. We reported here 4 patients treated with azacitidine for therapy related dysplasia after chemotherapy for non-Hodgkin lymphoma.     

Cost-effectiveness in Canada of azacitidine for the treatment of higher-risk myelodysplastic syndromes

Objective

Our goal was to determine the economic value of azacitidine in Canada compared with conventional care regimens (ccrs), including best supportive care (bsc) and low- or standard-dose chemotherapy plus bsc in the treatment of higher-risk myelodysplastic syndromes (mdss) and acute myeloid leukemia (aml) with 20%–30% blasts.

Methods

The cost–utility model is a lifetime probabilistic Markov model with a 35-day cycle length consisting of 3 health states: mds; transformation to aml with more than 30% blasts; and death. A third-party public payer perspective was adopted. Overall survival was extrapolated beyond the time horizon of the aza-001 trial comparing azacitidine with ccr. Resource use was determined through a questionnaire completed by Canadian hematologists. Utility values were obtained from two studies in which EQ-5D health questionnaire values were mapped from the European Organization for Research and Treatment of Cancer qlq-C30 survey, and SF-6D scores were mapped from the Short Form 12, elicited from 191 and 43 patients in two different trials.

Results

In the base case, azacitidine had an incremental cost-effectiveness ratio (icer) of $86,182 (95% confidence limits: $69,920, $107,157) per quality-adjusted life year (qaly) gained relative to ccr. Comparing azacitidine with bsc, low-dose chemotherapy plus bsc, and standard-dose chemotherapy plus bsc, the icers were, respectively, $86,973, $84,829, and $2,152 per qaly gained. Results were most sensitive to the utility for azacitidine after 6 months of treatment and to overall survival.

Conclusions

The prolonged 9-month median overall survival with azacitidine relative to ccr fills a gap w hen treating patients with higher-risk mds and aml with 20%–30% blasts. The economic value of azacitidine is within the threshold of willingness-to-pay for third-party public payers for oncology treatments in Canada.