A systematic review and meta-analysis of the efficacy and adverse events of azacitidine-plus-lenalidomide treatment for patients with acute myeloid leukemia, myelodysplastic syndromes and chronic myelomonocytic leukemia¹

1 Supplemental data for this article can be accessed https://doi.org/10.1080/16078454.2019.1631425.

Figures & data

Figure 1. Flow/chart of literature review process.

Table 1. Baseline characteristics of studies included in the meta/analysis.

References	No.	Sex (M/F)	Median age (years, range)	Diseases	Cytogenetics	Period of study	Median follow up (months, range)	Median cycles (cycles, range)	Study design
Scherman 2012 [10]	8	5/3	66.5 (23–76)	– 4 MDS, RAEB-2 – 4 secondary AML	– 5q del complex: 4 – Non-5q: 4	August 2008–March 2010	15 (0–18)	4.5 (1–13)	Retrospective cohort
Sekeres 2012 [11]	36	23/13	68 (47–68)	– RA: 2 – CMMoL-2: 3 – RAEB-1: 10 – RAEB-2: 21	Data available 19 patients and 1 patient NG – Normal: 8 – 5q del complex: 3 – Non-5q: 7	May 2005–April 2011	11.5 (3–55)	5 (1–7)	Retrospective-prospective cohort
Plabecker 2013 [12]	20	11/9	69 (45–78)	– AML: 5 – Secondary AML: 1 – MDS, RAEB-2: 9 – MDS, RAEB-1: 3 – MDS, RCMD: 1 *Available data 19	– 5q del alone: 3 – 5q del complex: 16	No data	15.3 (0.4–33.7)	2 (1–6)	Prospective cohort
Pollyea 2013 [13]	42	27/15	74 (62–86)	– AML: 26 – Secondary AML (7 MDS turn; 9 t-AML): 16	– Normal: 18 – Intermediate: 28 – Unfavorable: 8 – Monosomal karyotype: 5 **No specific of 5q chromosome	April 2009–June 2011	22 (0.25–30)	Mean 4.7 cycles	Prospective cohort
Ramsingh 2013 [14]	5	3/2	75 (65–81)	– AML: 4 – Secondary AML: 1	– Normal: 1 – Non Del 5: 4	No data	No data	2 (1–4)	Prospective cohort
Dinardo 2015 [15]	88	No data	67 (32–88)	– MDS/CMML 45 – AML/RAEB-T 43	– Normal/-Y: 24 – Del 5 alone: 2 – Del 5 complex: 24 – Non Del 5: 33 – No metaphase: 5	Dec 30, 2009–June 17, 2013	14.25 (2.5–43)	Overall: 3 (1 –1. 16) Phase 2a: 2 (1–12) Phase 2b: 5 (1–16)	Prospective cohort
Narayan 2015 [17]	32	18/14	73.5 (61–86)	Previously treated AML and MDS – De novo AML 3 – Secondary AML 18 – T-AML 5 – MDS, RAEB-2: 6	– No data	August 2011–February 2013	NR	2 (1–11)	Prospective cohort
Mittelman 2016 [16]	25	17/8	76.3 (60–87)	– MDS, RCMD: 3 MDS, RCMS-RS: 1 MDS, 5q: 1 MDS, RAEB 1: 3 MDS, RAEB 2: 15 CMML: 2	– Normal/-Y: 10 – Del 5 alone: 3 – Del 5 complex: 4 – Non Del 5: 6 – no metaphase: 2	NR	6.3 (0.1–29.4)	No data	Prospective cohort
Sekeres 2017 [18]	93	61/32	70 (51–86)	Azacitidine + lenalidomide – 14 (17) CMML-1 – 5 (6) CMML-2 – 22 (27) MDS RAEB-1 – 40 (49) MDS RAEB 2	– Normal: 27 – 5q del: 26 – Non-5q: 32	June 2012–June 2014	23 (1–43)	23 weeks	Prospective cohort
Medeiros 2018 [19]	39	22/17	76 (66–87)	Newly Dx AML – Prior MDS 5	No data – 4 patients had del(5/5q)	April 27, 2012–May 1, 2015	No data	2 (0–19.5)	Prospective cohort

Notes: Abbreviations – AML, acute myeloid leukemia; CMML, chronic myelomonocytic leukemia; del, deletion; F, female; M, male; MDS, myelodysplastic syndrome; NR, not reported; RA, refractory anemia; RAEB, refractory anemia with excess blasts; RARS, refractory anemia with ringed sideroblasts; RCMD, refractory cytopenia with multilineage dysplasia.

Table 2. Azacitidine-plus-lenalidomide regimens used in the included studies.

References	Regimen
Scherman 2012 [11]	28-day cycle 3 patients – Azacitidine 75 mg/m2 i.v. or s.c. × 7 days – Lenalidomide 10 mg orally × 21 days
	5 patients – Azacitidine 75 mg/m2 i.v. or s.c. × 5 days – Lenalidomide 10 mg orally × 9 days (1); × 15 days (2); × 21 days (2)
Sekeres 2012 [11]	Phase 1: 28-day cycle – Azacitidine 75 mg/m2 i.v. or s.c. × 5 days or 10 days – Lenalidomide orally 5 or 10 mg × 14 days or 10 mg × 21 days
	Phase 2: 28-day cycle – Azacitidine 75 mg/m2 i.v. or s.c. × 5 days – Lenalidomide 10 mg orally × 21 days
Plabecker 2013 [12]	28-day cycle – Azacitidine 75 mg/m2/day s.c. × 5 days – Lenalidomide 10 mg oral × 14 days, escalating 5 mg increment to 25 mg, starting on day 6
	If SD or PR continue until 8 cycles or PD
	If CR or blast in marrow < 5% after ≥ 2 cycles and then continue in maintenance phase until 8 cycles or PD
	8-week cycle – Azacitidine 30 mg/m2/day s.c. for 5 days – Lenalidomide at MTD orally on day 6–19
Pollyea 2013 [13]	42-day cycle – Azacitidine 75 mg/m2/day i.v. or s.c. × 7 days – Lenalidomide orally escalating doses 5, 10, 25 and 50 mg orally × 21 days starting on day 8
Ramsingh 2013 [14]	Induction 2 cycles 28-day cycle – Azacitidine 25 (cohort 1), 50 (cohort 2), 75 (cohort 3) mg/m2/day i.v. × 5 days – Lenalidomide orally 50 mg orally × 21 days D1–21
	Maintenance until 12 cycles 28-day cycle – Azacitidine 75 mg/m2/day i.v. × 5 days – Lenalidomide orally 10 mg orally × 21 days D1–21
Dinardo 2015 [15]	28-day cycle – Azacitidine 75 mg/m2 i.v. × 5 days in all phases – Lenalidomide oral for 5 or 10 days, starting on day 6, dosing as below
	Phase 1: 3 + 3 dose escalation design – Lenalidomide 7 dose levels oral: 10, 15, 20, 25, 50, and 75 mg once a day × 5 days, and 75 mg × 10 days
	Phase 2:
	Phase 2a – Lenalidomide 50 mg orally for 10 days, starting on day 6
	Phase 2b: because of adverse events – Lenalidomide 25 mg orally for 5 days, starting on day 6 of each cycle
Narayan 2015 [17]	42-day cycle – Azacitidine 75 mg/m2/day i.v. or s.c. × 7 days – Lenalidomide oral 50 mg orally × 21 days starting on day 8
	If response after 6th cycle, would continue until PD
Mittleman 2016 [16]	Induction 6 cycles 28-day cycle – Azacitidine 75 mg/m2/day s.c. × 5 days – Lenalidomide orally 10 mg orally × 14 days D6–21
	Consolidation 6 cycles 28-day cycle – Azacitidine 75 mg/m2/day s.c. × 5 days
	Maintenance until 12 cycles 28-day cycle – Lenalidomide orally 10 mg orally × 21 days D1–21
Sekeres 2017 [18]	Azacitidine plus lenalidomide: 28-day cycle – Azacitidine 75 mg/m2 i.v. or s.c. × 7 days (7–0–0 or 5–2–2) – Lenalidomide 10 mg oral × 21 days
Medeiros 2018 [19]	Azacitidine plus lenalidomide: 42-day cycle – Azacitidine 75 mg/m2/day i.v. or s.c. × 7 days – Lenalidomide orally 50 mg orally × 21 days, starting on day 8

Figure 2. Forest plots of pooled overall CR rate (A) and overall response rate (B) after treatment with AZA/plus/LEN regimen.

Figure 3. Forest plots of pooled rate of grade 3–4 neutrophil toxicity (A) and grade 3–4 platelet toxicity (B) during treatment with AZA/plus/LEN regimen.

Figure 4. Forest plots of pooled febrile neutropenia rate (A), thrombotic event rate (B), acute renal failure rate (C) and treatment related mortality rate (D) during treatment with AZA/plus/LEN regimen.

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