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AZA or LEN plus AZA in MDS, CMML and low blast AML
Introduction
The myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), an MDS/myelopro- liferative neoplasm overlap syndrome, are a group of clon- al bone marrow disorders characterized by active but inef- fective and clonal hematopoiesis accompanied by mor- phological dysplasia and variable cytopenias. Cytogenetic abnormalities and/or recurrent somatic mutations are present in the majority of cases.1,2 The prognosis is variable with 30% of patients transforming to acute myeloid leukemia (AML).2,3 AML with a “low blast” count of 20- 29% has a similar prognosis to MDS with blasts of 10- 19%.4 The most widely used tool for stratifying clinical risk in MDS is the IPSS score.4,5
Azacitidine is approved and available for use in subsets of intermediate- to high-risk MDS. It is a nucleoside ana- logue that has direct cytotoxicity and gives rise to DNA hypomethylation through interference with DNA methyl- transferase.6 Clinical responses are manifest by an improvement in hematologic parameters and quality of life in a broad population of MDS patients including those with lower-risk disease but significant cytopenias.7,8 Overall survival is prolonged in those with higher-risk dis- ease.9 There is also an established role for azacitidine in low-blast count AML and elderly AML with >30% BM blasts.10,11 Azacitidine is an established standard of care in these patients, but even so the disease does not respond in many patients and survival remains suboptimal. Ball et al. reviewed a number of studies that combined hypomethy- lating agents (azacitidine and decitabine) with a number of different medication classes including small molecules, immunomodulators and monoclonal antibodies, but found a lack of survival advantage in these combinations compared to HMA monotherapy.12 Emerging data sug- gests molecular profiles may influence response to azaciti- dine.13
Lenalidomide is a thalidomide analogue and is both more potent and tolerable relative to thalidomide.14,15 Its efficacy in MDS is most pronounced in patients with 5q- MDS (low risk MDS).16 Targeted degradation of CK1a (encoded by the retained allele of CSNK1A1 at 5q32 in cells with 5q-) achieves cytogenetic remission and transfu- sion independence in the majority of patients.15 Clinically relevant responses are also seen in lower-risk disease without 5q-.17,18,19 In MDS without 5q-, the primary mech- anism of disease control with lenalidomide appears to be immunomodulation.14 Defective or reduced immune inter- action between host and tumor contributes to the patho- genesis of MDS. Lenalidomide overcomes this by reduc- ing pro-inflammatory cytokines, upregulation of T- and NK-cell activity and inhibition of angiogenic activity. These effects prevent apoptosis of healthy stem cells, improve erythropoiesis and direct immune responses against abnormal hematopoietic clones.14
The combination of a demethylating agent and an immunomodulatory drug has been explored in phase-I and -II studies in MDS, CMML and low blast AML in an attempt to improve outcomes. The ALLG MDS3 trial of azacitidine and thalidomide20 showed promising response rates, and a phase-II study by Sekeres et al.21 including the combination of azacitidine and lenalidomide in higher- risk MDS (blasts ≥ 5% or IPSS ≥1.5) or CMML resulted in an overall response rate of 49% compared to 38% azaciti- dine alone (P=0.14), with the subgroup of CMML patients
on combination therapy achieving an improved ORR compared to aza alone (68% vs. 28%, P=0.02). Other groups have gone on to review the safety and efficacy of this combination in similar disease groups; elderly AML patients and high risk MDS and AML with ≤30% blasts.22,23 Narayan et al. demonstrated a modest 25% response rate in elderly patients with previously treated AML and high-risk MDS. In these responders, the overall survival was 9.6 months compared to 4 months for non responders.22
We conducted an open-label, multicentre randomized phase-II study across 30 sites in Australia to assess the effi- cacy of azacitidine in combination with lenalidomide compared to standard azacitidine alone in the treatment of higher-risk MDS, CMML and low blast AML.
Methods
Study design and treatment
ALLG MDS4 was an open-label, multi-centre study conducted across 30 Australian sites. The study was registered at anzctr.org.au ACTRN12610000271000, was reviewed and approved by the Human Research Ethics Committees of each centre and conduct- ed according to the Declaration of Helsinki. All patients provided written informed consent prior to participation.
The primary objective was to demonstrate improved efficacy with the combination compared to azacitidine alone. Secondary objectives were to describe response rates, response duration, overall survival, tolerability and changes in quality of life, and to explore biomarkers of response and mechanism of action of azac- itidine and lenalidomide.
Patients were stratified according to IPSS (low-Int1 or Int2- high),5 by centre and by disease category (MDS, AML or CMML),24 and randomized 1:1 to either azacitidine alone at stan- dard dosing of 75mg/m2/d x 7 days (on a 5-2-2 interrupted sched- ule25) each 28 day cycle subcutaneously, or to the combination azacitidine plus lenalidomide. Patients on the combination arm received azacitidine alone at the above dose and schedule for the first 2 cycles, then commenced lenalidomide 10mg/d from day 1 of cycle 3 with a reduction in azacitidine dose with the combina- tion to 75mg/m2/d for 5 consecutive days per cycle as per phase 1 data available at the time.26 The rationale for this was to limit the expected myelotoxicity typically seen in the first 2 cycles of treat- ment with azacitidine and so to improve the deliverability of com- bination treatment. Lenalidomide was continued only until com- pletion of C12 due to limited data on longer-term combination toxicity. Azacitidine as a single agent was continued after the pri- mary endpoint assessment at 12 months, until disease progression or unacceptable toxicity. Patients were followed for transforma- tion to AML and survival until the last registered patient had been followed for a minimum 2 years after completion of the first 12 months of treatment.
Patient population
Patients were eligible with a diagnosis of non-proliferative CMML, AML with blasts <30% or MDS by WHO criteria;24 those with refractory cytopenia with unilineage dysplasia (RCUD) and refractory anemia with ringed sideroblasts (RARS) had to have at least one clinically significant cytopenia as defined in the protocol (refer Online Supplementary Appendix), consistent with early stud- ies of azacitidine in a broader group of patients with MDS.7 Patients were 18 years or older and could have either de novo or secondary disease. They must have received no prior chemother- apy for MDS or AML except low dose cytarabine or hydroxyurea,
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