Efficacy and safety of oral decitabine/cedazuridine in the chronic myelomonocytic leukaemia subpopulations from phase 2 and 3 studies

Summary

DNA methyltransferase inhibitors (DNMTis) are commonly used in treating chronic myelomonocytic leukaemia (CMML); however, data from prospective studies of DNMTis in CMML are limited. The present analysis evaluated the efficacy, safety and pharmacodynamics of the oral DNMTi decitabine/cedazuridine in the subset of patients with CMML from the phase 2 and 3 trials, which led to the approval of this agent for myelodysplastic syndromes and CMML in the United States and Canada. Potential prognostic factors also were analysed. In all, 34 patients with CMML were screened and 33 were treated. Most patients (76% [n = 25]) had myelodysplastic type‐CMML and 77% (n = 24/31 with DNA available for sequencing) had intermediate‐2 or high‐risk disease noted by CMML‐specific prognostic scoring systems. The overall response rate was 76%, with 21% (n = 7) of patients achieving a complete response. Nearly half of the 11 patients who were red blood cell‐transfusion dependent at baseline (46%) attained transfusion independence for ≥12 weeks, which was associated with survival. Median overall and transformation‐free survival were 35.7 and 28.3 months, respectively, and the safety profile was similar to that previously reported for decitabine. This analysis described the use of decitabine/cedazuridine in CMML from consecutive, prospective, randomised trials and illustrated a median survival of nearly 3 years.

A retrospective analysis of patients with chronic myelomonocytic leukaemia treated with oral decitabine 35 mg + cedazuridine 100 mg suggested favourable outcomes, particularly in higher risk patients. The results provide a rationale for further prospective study of oral decitabine/cedazuridine to identify subgroups of this population who would benefit most from this therapy.

INTRODUCTION

Chronic myelomonocytic leukaemia (CMML) is a haematological malignancy characterised by persistent monocytosis and the risk of transformation to acute myeloid leukaemia (AML; ~15% over 3–5 years) in the presence of both dysplastic bone marrow changes (myelodysplastic syndrome [MDS]) and proliferative clinical features (myeloproliferative neoplasm [MPN]). ¹ , ² This malignancy has an estimated incidence of 4 cases/100 000 persons/year, which is predicted to increase due to permissive diagnostic criteria in revisions of recent classification schema. ¹ , ³ The only potential cure remains allogeneic haematopoietic stem‐cell transplantation (HSCT), for which many patients are not eligible due to advanced age (median 73–75 years at diagnosis), comorbidities or the absence of a donor. ² CMML is the most common overlap MDS/MPN and patients often have splenomegaly, proliferative constitutional symptoms, bone marrow dysplasia with associated cytopenias and resultant fatigue, infection and bleeding. Although patients with CMML often have both proliferative and dysplastic features, in an effort to further delineate therapy decisions, patients are considered to have ‘dysplastic‐type’ CMML (myelodysplastic [MD]‐CMML; white blood cell count <13 × 10⁹/L) or ‘proliferative‐type’ CMML (myeloproliferative [MP]‐CMML; white blood cell count ≥13 × 10⁹/L). ¹ Age‐associated comorbidities amplify the detriment to health‐related quality of life for patients with CMML.

Symptoms, actionable cytopenias, elevated marrow blast percentage (>5) and high‐risk molecular features all drive the indications for the treatment of high‐risk MDS/MPN. ⁴ , ⁵ Somatic mutations have been shown to affect CMML prognosis or response to DNA methyltransferase inhibitor (DNMTi) therapy. Three CMML prognostic scoring systems identified ASXL1 as negatively impacting overall survival (OS): the Groupe Francophone des Myelodysplasies system, the Mayo Molecular Model and the clinical/molecular CMML‐specific prognostic scoring system (CPSS‐Mol). ⁶ , ⁷ , ⁸ NRAS, RUNX1 and SETBP1, as well as ASXL1 and the presence of ≥2 mutations, predicted worse survival in a cohort of patients with CMML used to validate the CPSS‐Mol. ⁸ The presence of mutated TP53 or SRSF2, as well as of ≥3 mutations, predicted shorter survival after DNMTi therapy in patients with MDS or MDS/MPN, including those with CMML. ⁹ Oncogenic rat sarcoma (RAS) pathway mutations such as KRAS and NRAS are associated with CMML and contribute to AML transformation. ²

Whereas there is limited availability of DNMTis for the treatment of CMML in the EU and UK (parenteral azacitidine is approved for chronic MD‐CMML2 in the EU), parenteral azacitidine and decitabine and oral decitabine/cedazuridine (DEC‐C) are approved by the U.S. Food & Drug Administration and Health Canada for the treatment of CMML. Few prospective data support the use of these agents for CMML, however, and most of the data come from trials of DNMTis in MDS that included patients with CMML. The pivotal North American Cancer and Leukemia Group B study (N = 191) included 14 patients with CMML, with 7 assigned to azacitidine and 7 to best supportive care. ¹⁰ The randomised prospective phase 3 European AZA‐001 study (N = 358) included 11 patients with CMML (all MDS‐CMML), with 6 assigned to azacitidine and 5 to conventional care. ¹¹ Haematological response and improvement rates (complete response [CR] + partial response [PR] + haematological improvement [HI]) for the full study cohorts of patients receiving azacitidine in these studies were 60% ¹⁰ and 78%, respectively, ¹¹ whereas response rates (CR + PR) were 23% ¹⁰ and 29%. ¹¹

A randomised phase 3 study of IV decitabine (N = 170) included 17 patients with CMML, 7 of whom received decitabine. ¹² Decitabine 15 mg/m² IV was administered over 3 h every 8 h for 3 days (comprising 1 treatment cycle, which was repeated every 6 weeks, depending on recovery from myelosuppression). In the intent‐to‐treat analysis, the response rate (CR + PR) for patients receiving decitabine was 17% (n = 1/6) in patients with CMML, the same rate as for the full cohort who received decitabine. A study of an alternative decitabine dosing regimen (daily for 5 days every 28 days; N = 99) included 11 patients with CMML, all of whom received decitabine. ¹³ Response rates (CR + marrow CR [mCR] + PR + HI) were 51% in the full cohort and 73% in the CMML subgroup. ¹³ Phase 2 and 3 studies of oral DEC‐C reported CR rates of 21% ¹⁴ and 25% (evaluable patients), ¹⁵ respectively, and similar response rates including HI (CR + mCR + PR + HI) of 60% (phase 2) ¹⁴ and 62% (phase 3; intention‐to‐treat analysis). ¹⁵ Findings from other phase 2 trials ¹⁶ , ¹⁷ , ¹⁸ and from retrospective series ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ of DNMT is in CMML largely confirm the range of response rates reported in the aforementioned studies.

The DACOTA is a Randomized Phase III study of Decitabine (DAC) with or without Hydroxyurea (HY) versus HY alone in patients with advanced proliferative CMML study—was a phase 3 trial and the largest completed study of a DNMTi in MP‐CMML (N = 170; 84 of whom received decitabine)—compared IV decitabine with hydroxyurea in treatment‐naïve patients with MP‐CMML. ²⁵ The study reported no significant difference in OS between treatment arms despite a significantly higher response rate (CR + mCR + HI) with decitabine (63% vs. 35%). Compared with hydroxyurea, decitabine reduced the risk of CMML progression and AML transformation, but was associated with a higher risk of death due to causes other than CMML progression or AML transformation. Grade ≥3 infections and cardiovascular adverse events were more common with decitabine.

The phase 2 study of oral DEC‐C (80 treated patients) included 17 patients with CMML, all of whom received the DNMTi (ClinicalTrials.gov NCT02103478). ¹⁴ The phase 3 study of oral DEC‐C (133 treated patients) included 16 patients with CMML, all of whom received oral DEC‐C (NCT03306264). ¹⁵ These studies led to U.S. Food & Drug Administration and Health Canada approval of oral DEC‐C for CMML and were designed primarily to compare the pharmacokinetic and pharmacodynamic effects of oral DEC‐C with IV decitabine, an established therapy for CMML. The oral bioavailability of both azacitidine and decitabine is low due to first‐pass elimination by the enzyme cytidine deaminase, ²⁶ , ²⁷ and the use of cedazuridine—a novel, oral cytidine deaminase inhibitor—in phase 2 and 3 studies established the pharmacologic equivalence of oral DEC‐C with IV decitabine. ¹⁴ , ¹⁵ The present analysis reported the combined clinical experience—response, survival, safety and pharmacodynamics—for the subset of patients with CMML in the prospective phase 2 and 3 trials of oral DEC‐C. The effect of clinical features, number of genetic variants, CPSS‐Mol score, treatment response and grade 4 neutropenia on OS were evaluated.

METHODS

Study eligibility

Study designs, eligibility criteria and methods for the phase 2 and 3 studies of oral DEC‐C were nearly identical, and have been published previously. ¹⁴ , ¹⁵ These pivotal studies both randomised patients to DEC‐C. The study design in these trials encapsulated intrapatient pharmacokinetics by allowing patients to receive either standard‐of‐care IV decitabine followed by oral DEC‐C or oral DEC‐C followed by IV decitabine, for the first two cycles. After cycle 2, all patients received only DEC‐C. Each study compared the pharmacokinetics and pharmacodynamics of oral DEC‐C with those of IV decitabine. Eligible patients were adults (aged ≥18 years) who were deemed candidates to receive IV decitabine (i.e. all French‐American‐British subtypes of previously treated or untreated MDS, or CMML that scored intermediate‐1 or ‐2, or high risk on the International Prognostic Scoring System), ²⁸ with Eastern Cooperative Oncology Group performance status 0 or 1 (phase 3) or 0 to 2 (phase 2). In both the phase 2 and 3 studies, one prior treatment cycle with decitabine or azacitidine was permitted for practical considerations. The protocols are available at https://vicc.org/sites/default/files/drupalfiles/2023‐10/Oral_decitabine_cedazuridine_vs_intravenous_decitabine_protocol.pdf.

An institutional review board or independent ethics committee at each of the 37 participating study centres in Canada (7 sites) and the United States (30 sites) approved the protocols and associated amendments. ¹⁴ , ¹⁵ The studies were conducted in accordance with the protocols, the International Council for Harmonisation Good Clinical Practice guidelines and applicable local requirements. Each patient provided informed consent. Clinical response was assessed by independent review committees. The authors assume responsibility for the accuracy and completeness of the data and analyses.

DNMTi treatment

An initial phase 2 cohort received oral cedazuridine 100 mg and decitabine 35 mg as separate medications. ¹⁴ Once it was confirmed that decitabine exposure with this regimen was comparable to that of IV decitabine (20 mg/m²/day for 5 days by 1‐h infusion; standard dose), the latter phase 2 cohort was randomised to receive a fixed‐dose combination of oral DEC‐C or IV decitabine using the same doses as previously given separately. The phase 3 trial also randomised patients to the same fixed‐dose combination or IV decitabine for the first two cycles; from cycle 3 onwards, all patients received the fixed‐dose combination. ¹⁵

Patients in both studies were randomly allocated to one of two sequences for the first two 28‐day treatment cycles: either oral DEC‐C daily for 5 days in cycle 1, followed by IV decitabine daily for 5 days in cycle 1 (sequence A) or the reverse order (sequence B). ¹⁴ , ¹⁵ All patients received oral DEC‐C from cycle 3 forward. In both studies, treatment continued until disease progression, unacceptable toxicity, study withdrawal or other reasons for discontinuation. Treatment with DEC‐C could be delayed or the dose reduced if judged necessary for haematological or non‐haematological recovery, as standard with parenteral DNMTi. ¹⁴ , ¹⁵

Somatic mutation testing

DNA was isolated from whole blood collected prior to treatment. Molecular abnormalities were identified using a next‐generation sequencing haematological malignancy panel of 179 genes. ²⁹ The prevalence of mutations with variant allele frequency (VAF) >2% and of mutations associated with poor risk in CMML (ASXL1, KRAS, NRAS, RUNX1, SETBP1, SRSF2 and TP53; mean + standard deviation VAF) was calculated, along with the number of mutations in each patient.

Measurement of endpoints

The primary end‐point for both the phase 2 and phase 3 studies was pharmacokinetic exposure equivalence between IV decitabine and oral DEC‐C. ¹⁴ , ¹⁵ The present analysis reported clinical response, red blood cell (RBC)‐ and platelet‐transfusion independence for ≥8 or ≥12 consecutive weeks, transformation‐free survival and OS, rates of HSCT transplantation, rates of and times to AML transformation and safety. Clinical response assessment (i.e. CR, mCR, PR and HI) was based on International Working Group 2006 MDS response criteria. ³⁰ The relationship between CPSS‐Mol and OS was evaluated. Pharmacodynamic assessment via DNA demethylation (measured roughly by long interspersed nuclear element‐1 methylation [LINE‐1] analysis) also was reported. ³¹ Efficacy and safety data were calculated for all patients who received any treatment, as well as by MD‐ and MP‐CMML subtypes as defined in the 2022 World Health Organization (WHO) classification. ¹

LINE‐1 demethylation was assessed in the first two cycles. Efficacy and safety end‐points were calculated using all data through the final cut‐offs: 16 September 2020 for the phase 2 study and 7 June 2021 for the phase 3 study.

Statistical analyses

All efficacy and safety data, as well as all CMML subtype analyses, were summarised using descriptive statistics. Survival was estimated using Kaplan–Meier analysis. The effects of selected baseline variables, number of mutations, clinical response measures and grade 4 neutropenia on OS was assessed using a Cox proportional hazards model analysis of maximum likelihood using univariate analysis. As noted previously, efficacy and safety data were calculated for the full treated population. Pharmacodynamics was calculated for all patients who received any treatment and for whom LINE‐1 methylation data were available from the baseline of cycle 1 or 2, and on either day 8, 15 or 22 of that same cycle. Of those three postbaseline measurements, maximum change from baseline was reported for cycles 1 and 2.

Role of the funding source

This work was funded by Astex Pharmaceuticals, Inc., now Taiho Oncology, Inc., which was involved in study design and data collection and analysis.

RESULTS

Patients and treatment

In all, 34 patients were screened, and 33 were randomised, treated and included in the efficacy and safety analyses (Figure 1). Table 1 lists baseline demographics and disease characteristics. Median age was 71 years, and most patients (>78%) were men. More than half of patients (61%) had an Eastern Cooperative Oncology Group performance status ≥1. Median neutrophil count was 2.49 × 10⁹/L and was lower in patients with MD‐CMML. Median haemoglobin and platelet count were 100.50 g/L and 65.5 × 10⁹/L respectively. Both values were lower for patients with MP‐CMML versus MD‐CMML.

FIGURE 1.

Patient disposition. BM, bone marrow; DEC, decitabine; DEC‐C, DEC‐cedazuridine; MD‐CMML, myelodysplastic‐chronic myelomonocytic leukaemia; MP‐CMML, myeloproliferative‐CMML; SC, stem cell.

TABLE 1.

Baseline demographics.

	MD‐CMML (n = 25)	MP‐CMML (n = 8)	Total (n = 33)
Age, years
Mean (SD)	70.6 (9.57)	73.4 (8.02)	71.2 (9.18)
Median (range)	72.0 (44–82)	69.5 (66–86)	71.0 (44–86)
Male sex, n (%)	18 (72)	8 (100)	26 (78.8)
Race, n (%)
White	21 (84)	8 (100)	29 (88)
Black	2 (8)	0	2 (6)
Asian	1 (4)	0	1 (3)
Not reported	1 (4)	0	1 (3)
Median weight, kg (range)	87.0 (62.3–123.7)	88.5 (73.1–100.2)	87 (62.3–123.7)
Mean BSA, m2 (SD)	2.04 (0.20)	2.11 (0.12)	2.05 (0.19)
ECOG performance status, n (%)
0	9 (36)	4 (50)	13 (39)
1	16 (64)	2 (25)	18 (55)
2	0	2 (25)	2 (6)
Risk stratification, n	23	7	30
CPSS‐Mol, n (%) a
Low‐Int1	7 (28)	0 (0)	7 (21)
Int2‐high	17 (68)	7 (88)	24 (73)
Missing	1 (4)	1 (13)	2 (6)
p‐value			0.14
Prior anticancer therapy, n (%)
Yes	4 (16)	1 (13)	5 (15)
No	21 (84)	7 (88)	28 (85)
Prior DNMTi, n (%)
Azacitidine (1 cycle)	1 (4)	0	1 (3)
Decitabine	0	0	0
RBC‐transfusion dependent, n (%)	8 (32)	3 (38)	11 (33)
Platelet‐transfusion dependent, n (%)	1 (4)	1 (13)	2 (6)
BM blasts, n a	25	7	32
Median (range)	7 (2–19)	5 (1–10)	7 (1–9)
>5% BM blasts, n (%)	14 (56)	3 (43)	17 (53)
Baseline PB blasts, n a	23	8	31
Median (range)	0 (0–6)	1 (0–8)	1 (0–8)
WHO classification
CMML‐1	15 (60)	6 (75)	21 (64)
CMML‐2	10 (40)	2 (25)	12 (36)
Median haemoglobin, g/L (range)	101.5 (73.5–149.0)	97.0 (68.0–139.5)	100.5 (68.0–149.0)
Baseline haemoglobin
<80 g/L, n (%)	2 (8)	3 (38)	5 (15)
80–<100 g/L, n (%)	10 (40)	1 (13)	11 (33)
100–110 g/L, n (%)	6 (24)	2 (25)	8 (24)
≥110 g/L, n (%)	7 (28)	2 (25)	9 (27)
Median neutrophils, 109/L (range)	1.42 (0.16–8.71)	12.09 (4.95–43.81)	2.49 (0.16–43.81)
Baseline neutrophils
<0.5 109/L, n (%)	5 (20)	0	5 (15)
0.5–<1 109/L, n (%)	4 (16)	0	4 (12)
1–1.5 109/L, n (%)	4 (16)	0	4 (12)
>1.5–109/L, n (%)	12 (48)	8 (100)	20 (61)
Median platelets, 109/L (range)	66 (18–523)	41 (16–156)	66 (16–523)
Baseline platelets
<25 109/L, n (%) L	3 (12)	2 (25)	5 (15)
25–<50 109/L, n (%)	4 (16)	3 (38)	7 (21)
50–<75 109/L, n (%)	6 (24)	2 (25)	8 (24)
75–<100 109/L, n (%)	1 (4)	0	1 (3)
≥100 109/l, n (%)	11 (44)	1 (13)	12 (36)

Abbreviations: BM, bone marrow; BSA, body surface area; CMML, chronic myelomonocytic leukaemia; CPSS‐Mol, clinical/molecular CMML‐specific prognostic scoring system; DNMTi, DNA methyltransferase inhibitor; ECOG, Eastern Cooperative Oncology Group; Int, intermediate; MD, myelodysplastic; MP, myeloproliferative; PB, peripheral blood; RBC, red blood cells; SD, standard deviation; WHO, World Health Organization.

^a Calculated for patients with available data.

Few patients had received prior anticancer therapy (15% [n = 4]) and only 1 (4%) had experience with DNMTi therapy (Table 1). Prior treatments included ruxolitinib (n = 2), hydroxyurea (n = 3) and azacitidine (n = 1), with some patients having received more than one therapy. Eleven patients (33%; 8 with MD‐CMML and 3 with MP‐CMML) were RBC‐transfusion dependent at baseline. More than one‐third of patients (36% [n = 12]) were subtyped as CMML‐1 based on the 2022 WHO classification (<5% blasts in peripheral blood and <10% in bone marrow). More than three‐quarters of patients (76% [n = 25]) had MD‐CMML. All patients with MP‐CMML and 71% with MD‐CMML were intermediate‐2 or high‐risk by CPSS‐Mol scoring system (31/33 patients with data available for CPSS‐Mol score calculation).

All randomised patients received ≥2 cycles of treatment. Patients received a median of 10 cycles (range: 2–36). Nearly two‐thirds of patients (64%) had ≥1 delayed cycle; more than half (58%) had ≥1 dose‐reduced cycle. The most common reasons for cycle delays were related to myelosuppression and its clinical consequences, including the need to wait for blood counts to recover, as well as myelosuppression‐related adverse events such as neutropenia, thrombocytopenia and infections. Median durations of follow‐up were 23.4 months (range: 1.9–41.2) for the full study population, 27.2 months (range: 4.0–41.2) for patients with MD‐CMML, and 15.0 months (range: 1.9–40.2) for patients with MP‐CMML.

Efficacy

Response rate was 76% (25/33; CR + PR + mCR + HI), with 21% (7/33) of patients attaining CR and 15% (5/33) achieving mCR concurrently with HI (Table 2). Median time to best response was 2.3 months (range: 1–7). Median durations of best response were 9.4 months (range: 2–23) for the 23 patients for whom this parameter was reported, 10.1 months (range: 2–23) for patients with MD‐CMML (n = 19) and 6.5 months (range: 6–11) for those with MP‐CMML (n = 4). Median durations of CR were 9.4 months (range: 5–18) for the full cohort (n = 7) and patients with MD‐CMML (n = 5) and 8.6 months (range: 6–11) for those with MP‐CMML (n = 2).

TABLE 2.

Analysis of best response. ^a

Response, n (% [95% CI])	MD‐CMML (n = 25)	MP‐CMML (n = 8)	Total (N = 33)
Complete response	5 (20 [6.8, 40.7])	2 (25 [3.2, 65.1])	7 (21 [9.0, 38.9])
Partial response	0	0	0
Marrow complete response	12 (48 [27.8, 68.7])	2 (25 [3.2, 65.1])	14 (42 [25.5, 60.8])
Marrow complete response with haematological improvement	4 (16 [4.5, 36.1])	1 (13 [0.3, 52.7])	5 (15 [5.1, 31.9])
Haematological improvement	3 (12 [2.5, 31.2])	1 (13 [0.3, 52.7])	4 (12 [3.4, 28.2])
Erythroid response	1 (4 [0.1, 20.4])	1 (13 [0.3, 52.7])	2 (6 [0.7, 20.2])
Neutrophil response	1 (4 [0.1, 20.4])	0	1 (3 [0.1, 15.8])
Platelet response	1 (4. [0.1, 20.4])	1 (12.5 [0.3, 52.7])	2 (6 [0.7, 20.2])
Total responders b	20 (80 [59.3, 93.2])	5 (63 [24.5, 91.5])	25 (76 [57.7, 88.9])
Progressive disease	3 (12 [2.5, 31.2])	0	3 (9 [1.9, 24.3])
No response c	1 (4 [0.1, 20.4])	3 (37 [8.5, 75.5])	4 (12 [3.4, 28.2])
Not evaluable	1 (4 [0.1, 20.4])	0	1 (3 [0.1, 15.8])

Abbreviations: CI, confidence interval; CMML, chronic myelomonocytic leukaemia; MD, myelodysplastic; MP, myeloproliferative.

^a International Working Group response criteria 2006. ³⁰

^b Total of all response categories.

^c Includes stable disease.

Almost two‐thirds of patients (64%; n = 7/11) who were RBC‐transfusion dependent at baseline attained transfusion independence for ≥8 weeks. Nearly half of patients (46%) who were RBC‐transfusion dependent at baseline attained transfusion independence for ≥12 weeks. Two patients (6%) were platelet‐transfusion dependent at baseline; both attained transfusion independence for ≥8 weeks and 1 maintained transfusion independence for ≥12 weeks. Three patients (9%; 3/33) underwent HSCT after responding to DEC‐C; all had MD‐CMML. The rate of AML transformation was 21% (n = 7); the median time to AML transformation was 8 months (range: 1–27).

Median OS (mOS) and transformation‐free survival (mTFS) were 35.7 and 28.3 months, respectively (Figure 2A), with a median follow‐up of 29.7 months. In all, 21% (7/33) of patients progressed to AML, including 20% (5/25) of those with MD‐CMML and 25% (2/8) of those with MP‐CMML. In all, 42% (14/33) died during the study: 40% (10/25) with MD‐CMML and 50% (4/8) with MP‐CMML. Stratifying by the CPSS‐Mol risk classification system, mOS and mTFS were not reached in the low/intermediate‐1 risk group (Figure 2B,C). Conversely, the intermediate‐2/high‐risk group had an mOS of 28.3 months (95% confidence interval 13.5, not evaluable) and an mTFS of 20.7 months (8.0, 35.7).

FIGURE 2.

Kaplan–Meier curves for (A) overall survival (OS) and transformation‐free survival (TFS), and for (B) overall and (C) transformation‐free survival stratified by clinical/molecular chronic myelomonocytic leukaemia‐specific prognostic scoring system. CI, confidence interval; Int, intermediate; NE, not evaluable.

Somatic mutations and response

The distribution of the mutations of interest with VAF >2% and their VAF percentages in the study cohort are illustrated in Figure 3A,B, and a comprehensive study mutation analysis appears in Figure S1. Among high‐risk gene variants, a mutation in histone modification (ASXL1) had the highest mutation rate (48.5%), followed by mutations affecting splice factors (SRSF2: 45.5%), transcription factors (RUNX1: 36.4%; and SETBP1: 9.1%), cell signalling (NRAS: 18.7%; and KRAS: 6.1%), and DNA damage response (TP53: 9.1%). ² When risk stratified by CPSS‐Mol, 77% of evaluable patients were intermediate‐2 or high risk (Table 1). All evaluable patients with MP‐CMML and 71% with MD‐CMML were intermediate‐2 or high risk. More than 85% of patients had ≥4 mutations (Figure 3C).

FIGURE 3.

Distribution of (A) mutations of interest (variant allele frequency [VAF] >2%) in the study population and (B) VAF (mean + standard deviation); and (C) number of mutations/patient: N = 33. Figures on pie chart slices reflect percentages and numbers of patients, with numbers of mutations represented by colours of pie slices.

Pharmacodynamics

Maximum changes from baseline in LINE‐1 methylation were a median of −11.3% (range: −23.6% to 4.2%) from baseline to day 8 of cycle 1 (n = 32) and −8.8% (range: −23.6% to 0.39%) from baseline to day 8 of cycle 2 (n = 27; Figure S2).

Safety

All patients had ≥1 adverse event and most (94% [n = 31]) had ≥1 adverse event of grade ≥3 severity (Table 3). The most common adverse events (overall and grade ≥3) were related to myelosuppression (neutropenia, thrombocytopenia and anaemia). Most patients (82% [n = 27]) had ≥1 treatment‐emergent adverse event deemed treatment related and most (70% [n = 23]) had ≥1 treatment‐related event of grade ≥3 severity (Table S1). All of the five most common treatment‐related adverse events, and all such events observed in >24% of patients, were related to myelosuppression: neutropenia, thrombocytopenia, anaemia, fatigue and leucopenia. The next four most common treatment‐related adverse events (none of grade >2) were gastrointestinal: nausea, constipation, decreased appetite and diarrhoea. All these events, plus febrile neutropenia, were noted in >10% of patients. Other adverse events deemed treatment related were observed in <10% of the study population. All of the five most common grade ≥3 treatment‐related adverse events, and all such events observed in ≥10% of the study population, were related to myelosuppression and were consistent with the overall populations studied in the phase 2 and 3 studies. ¹⁴ , ¹⁵

TABLE 3.

Most common treatment‐emergent adverse events. ^a

Patients, n (%)	MD‐CMML (n = 25)	MP‐CMML (n = 8)	Total (N = 33)
≥1 TEAE regardless of relation to treatment b	25 (100)	8 (100)	33 (100)
Neutropenia	17 (68)	5 (63)	22 (67)
Thrombocytopenia	17 (68)	5 (63)	22 (67)
Anaemia	14 (56)	1 (13)	15 (46)
Constipation	11 (44)	3 (38)	14 (42)
Fatigue	10 (40)	3 (38)	13 (39)
Leucopenia	8 (32)	2 (25)	10 (30)
Arthralgia	9 (36)	0	9 (27)
Cough	7 (28)	2 (25)	9 (27)
Decreased appetite	8 (32)	1 (13)	9 (27)
Diarrhoea	8 (32)	1 (13)	9 (27)
Febrile neutropenia	8 (32)	1 (13)	9 (27)
Nausea	7 (28)	2 (25)	9 (27)
Dyspnoea	7 (28)	1 (13)	8 (24)
Contusion	7 (28)	0	7 (21)
Headache	7 (28)	0	7 (21)
≥1 Grade ≥3 TEAE regardless of relation to treatment c	23 (92)	8 (100)	31 (94)
Neutropenia	15 (60)	5 (63)	20 (61)
Thrombocytopenia	13 (52)	5 (63)	18 (55)
Anaemia	11 (44)	1 (13)	12 (37)
Febrile neutropenia	8 (32)	1 (13)	9 (27)
Leucopenia	6 (24)	2 (25)	8 (24)
Cellulitis	2 (8)	0	2 (6)
Dyspnoea	2 (8)	0	2 (6)
Fatigue	2 (8)	0	2 (6)
Pneumonia	1 (4)	1 (13)	2 (6)
Sepsis	1 (4)	1 (13)	2 (6)

Abbreviations: CMML, chronic myelomonocytic leukaemia; MD, myelodysplastic; MP, myeloproliferative.

^a Treatment‐emergent adverse events (TEAEs) were coded using Medical Dictionary for Regulatory Activities Version 22.0 and are listed in descending order of incidence in the treated population.

^b ≥20% of treated population.

^c ≥5% of treated population.

Two patients permanently discontinued oral DEC‐C and one discontinued IV decitabine due to an adverse event. The conditions leading the two patients to discontinue oral DEC‐C were failure to thrive due to social circumstances and sepsis respectively. Intravenous decitabine was discontinued due to pulmonary haemorrhage. At least one serious adverse event was reported in more than half of patients (64% [n = 21]); treatment‐related serious adverse events were noted in 15% of patients (n = 5; Table S2). Two deaths occurred during the study: one patient with MD‐CMML died due to sepsis and one with MP‐CMML died due to pulmonary haemorrhage.

Predictors of survival

Cox proportional hazard analysis indicated that of the variables assessed, only posttreatment RBC‐transfusion independence for ≥12 weeks was associated with OS (Figure 4). In this small sample size, baseline clinical variables, number of genetic mutations (≥ or <4) and neutropenia were associated with no statistically significant impact on survival.

FIGURE 4.

Effect of oral decitabine–cedazuridine therapy on overall survival. Proportional hazards model analysis of maximum likelihood estimates. CI, confidence interval; CMML, chronic myelomonocytic leukaemia; CPSS, CMML‐specific prognostic scoring system; CPSS‐MOL, molecular CPSS; CR, complete response; HI, haematological improvement; mCR, marrow CR; MD, myelodysplastic; MP, myeloproliferative; RBC, red blood cell; TI, transfusion independent; WBC, white blood cell.

DISCUSSION

There is a paucity of prospective trials of DNMTi in patients with CMML, and this retrospective analysis describes the largest cohort of patients receiving oral DEC‐C, adding to the growing body of literature supporting the use of DNMTi therapy in this malignancy. Outside of MDS‐focused studies containing few patients with CMML, ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ data regarding DNMTi efficacy in CMML have been largely retrospective or from phase 2 studies. ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ Overall response rates in these investigations ranged from ~38% to 51%, ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²⁴ with mOS from 12 to 37 months ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ and CR rates of <20%, ¹⁶ , ¹⁷ , ¹⁹ , ²⁰ , ²⁴ 27% ¹⁸ and 45%. ²¹ A large retrospective cohort study reported that patients with higher risk disease (i.e. MP‐CMML, blasts ≥10%, 2016 WHO subtype CMML‐1 or −2) had significantly better survival after DNMTi therapy compared with hydroxyurea or intensive chemotherapy. ²³ Importantly, the DACOTA study remains the largest study of a DNMTi in MP‐CMML and illustrated significantly higher overall response and CR rates, but no improvement in mOS in patients treated with decitabine instead of hydroxyurea (18.4 vs. 21.9 months; p = 0.67) due to higher treatment‐related mortality in those receiving decitabine. ²⁵ This large study was conducted at many cancer treatment centres across France, Germany, and Italy.

Although patients with CMML in the present analysis were largely MD‐CMML, the population was higher risk according to the CPSS‐Mol risk classification system (Table 1), underscoring some optimism regarding the response and survival rates. Whereas mOS and mTFS were not reached in the CPSS‐Mol low/intermediate‐1 group, mOS and mTFS were 28.3 and 20.7 months, respectively, in the intermediate‐2/high‐risk group. The genomic parameters evaluated in this study were chosen based on those included in the CPSS‐Mol and findings from the literature suggesting their potential impact on prognosis following DNMTi therapy for CMML. ² , ⁶ , ⁷ , ⁸ , ⁹ This study, however, had an insufficient number of patients to allow correlation of survival with any single mutation.

The overall response rate (76%) and mOS (35.7 months) in this pooled analysis compare favourably with findings from earlier series, yet it is difficult to make comparisons to results from DACOTA. ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ The present analysis did not perform statistical comparisons of results for the MD‐CMML and MP‐CMML groups. The numerically smaller proportion of responders in the MP‐CMML group (63%) versus the MD‐CMML group (80%) could have resulted from the relatively small number of patients with MP‐CMML. Likewise, the limited number of patients presaged that the baseline variables, number of gene mutations, neutropenia and response characteristics would not have a statistically significant effect on survival. However, RBC transfusion independence attained during treatment correlated with improved OS in this analysis, underscoring suggestions from other recent studies in MDS and CMML that RBC transfusion independence may be a useful end‐point in these patients. ³²

Availability of an oral DNMTi reduces the treatment burden on patients who otherwise must travel to a medical facility 5 or 7 days of every 28–42 days to receive parenteral decitabine or azacitidine. Patients with CMML are generally of older age, heightening the value of being able to administer therapy at home. The safety profile for oral DEC‐C reported here in patients with CMML was similar to the overall safety profiles of the phase 2 and 3 studies of oral DEC‐C. ¹⁴ , ¹⁵ In addition, adverse events and serious adverse events were not dissimilar to those described in prior published reports testing parenteral azanucleosides. ¹⁰ , ¹¹

The present data were derived from two prospective trials, including a registrational study; however, this study shared the limitations of other investigations of DNMTi therapy in CMML in that they were derived from studies focused primarily on patients with MDS that included smaller numbers with CMML. Historically, MDS studies included CMML as early classification grouped CMML with MDS. Evolving classification of myeloid diseases by the WHO categorised CMML as an MDS/MPN in 2002. ³³ The lag in development of CMML‐specific clinical trials has, however, detracted from the development of CMML‐specific therapies. Thus, the present data from phase 2 and 3 registrational trials for DEC‐C complement a number of studies illustrating the activity of DNMTis in CMML and provide support for the use of an oral alternative DNMTi in CMML. The suggestions of favourable outcomes, particularly in CMML‐Mol higher risk patients who typically have poor mOS, justify the prospective study of oral DEC‐C in CMML with dedicated trials to help discern which subgroups of these patients will benefit most from oral DEC‐C as monotherapy or in combination with other agents, such as venetoclax.

AUTHOR CONTRIBUTIONS

M.R.S. was involved in study design, data collection, analysis and interpretation, and writing and editing the manuscript. O.O. was involved in study design, data collection, analysis and interpretation and editing the manuscript. G.J.R. was involved in study design, data collection and interpretation and editing the manuscript. H.A. was involved with data collection and assembly, provision of study material/patients and editing the manuscript. A.E.D., E.A.G., M.‐M.K., A.O., Y.S. and G.G.‐M. were involved with study conception and design, data collection, assembly, analysis and interpretation and editing the manuscript. K.‐H.D. and B.L. were involved with data collection, assembly, analysis and interpretation and editing the manuscript. A.M.Z. was involved with study conception and design, data collection, assembly, analysis and interpretation, provision of study material/patients and editing the manuscript. B.B. was involved with data collection, assembly, analysis and interpretation, provision of study material/patients and editing the manuscript. R.B. was involved with data collection and assembly and editing the manuscript. S.B. was involved with data analysis and interpretation and editing the manuscript. All authors had full access to all of the data in the study, take responsibility for the integrity of the data and the accuracy of the data analysis, and provided critical review of the manuscript for important intellectual content.

CONFLICT OF INTEREST STATEMENT

M.R.S. has consulted for BMS, CTI, Forma, Geron, GSK, Karyopharm, Rigel, Ryvu and Treadwell, is an equity holder for Empath Biosciences, Karyopharm and Ryvu, received research funding from ALX Oncology, Astex and Incyte and received travel expenses from Ryvu and Taiho. O.O. received research funding from AbbVie, Astex, Immune‐Onc, Kartos, Loxo and Shattuck and served on advisory boards for AbbVie, Rigel and Servier, and on a data and safety monitoring board for Treadwell. G.J.R. has consulted for AbbVie, Amgen, AstraZeneca, BMS, Caribou, Celgene, Daiichi Sankyo, Ellipses, GSK, Geron, Glycomimetics, Janssen, Jasper, Jazz, Molecular Partners, Morphosys, Neogenomics, Novartis, Oncoprecision, Oncoverity, Pfizer, Rigel, Roche and Syndax and has received research funding from Janssen. H.A., K.‐H.D. and S.B. have nothing to declare. A.E.D. participated in advisory boards and/or had a consultancy with and received honoraria from Agios, BMS and Novartis and served on clinical trial committees or data and safety monitoring boards for AbbVie, Agios, BMS, Geron, Keros, Kura, Novartis, Servier and Shattuck. E.A.G. has received research funding from Astex/Taiho, Blueprint and Celldex, received research funding from and consulted and served on advisory committees for Alexion/AstraZeneca Rare Disease, BMS/Celgene and Genentech, consulted for and served on advisory committees for AbbVie, Apellis, CTI Biopharma, Novartis, Servier and Takeda, and received honoraria from AAMDSIF, Medicom Worldwide, Physician Educational Resource and Picnic Health. A.M.Z. has received research funding from AbbVie, ADC Therapeutics, Amgen, Aprea, Astex, AstraZeneca, BMS, Boehringer‐Ingelheim, Cardiff Oncology, Celgene, Incyte, Medimmune, Novartis, Otsuka, Pfizer, Takeda and Trovagene, consulted for AbbVie, Acceleron, Agios, Amgen, Aprea, Astellas, BeyondSpring, BMS, Boehringer‐Ingelheim, Cardiff, Cardinal Health, Celgene, Daiichi Sankyo, Epizyme, Geron, Gilead, Incyte, Ionis, Janssen, Jazz, Kura, Novartis, Pfizer, Seattle Genetics, Syndax, Taiho, Takeda, Trovagene and Tyme, received honoraria from AbbVie, Acceleron, Agios, Amgen, Aprea, Astellas, BeyondSpring, BMS, Boehringer‐Ingelheim, Cardiff, Cardinal, Celgene, Daiichi Sankyo, Epizyme, Geron, Gilead, Incyte, Ionis, Janssen, Jazz, Kura, Novartis, Otsuka, Pfizer, Seattle Genetics, Syndax, Taiho, Takeda, Trovagene and Tyme, received travel expenses from Cardiff, Novartis and Pfizer and had leadership roles in boards or committees for AbbVie, BMS, Celgene, Geron, Gilead, Kura and Novartis. B.B. has received advisory board honoraria from BMS, Celgene, Daiichi Sankyo, Kite, Novartis and Servier, and serves on the speakers bureau for AstraZeneca. R.B. has received research funding and honoraria from BMS and Taiho, and served on advisory boards for BMS and Keros. B.L. has received honoraria from and served on advisory committees and speakers bureaus for AbbVie, Amgen, BMS, Novartis and Pfizer and consulted for Novartis and Pfizer. M.‐M.K. has consulted for AbbVie, AstraZeneca, Beigene, Celgene, Incyte, Lilly, Roche and Taiho. A.O., Y.S. and H.N.K. are employees of Taiho. G.G.‐M. has consulted for Acceleron, received honoraria and research funding from AbbVie, Astex, BMS, Curis, Genentech and Novartis, received honoraria from Aprea and received research funding from Gilead.

Supporting information

Data S1.

Savona MR, Odenike O, Roboz GJ, Amin H, DeZern AE, Griffiths EA, et al. Efficacy and safety of oral decitabine/cedazuridine in the chronic myelomonocytic leukaemia subpopulations from phase 2 and 3 studies. Br J Haematol. 2025;207(2):432–444. 10.1111/bjh.20203

DATA AVAILABILITY STATEMENT

The data analysed in this study are on file with Taiho Oncology, Inc. and are not publicly available. The clinical data reported in this manuscript may be requested by qualified medical or scientific professionals who engage in rigorous independent scientific research. Please submit requests to Taiho Oncology, Inc. at medicalinformation@taihooncology.com.