Efficacy and safety of lenalidomide for the treatment of acute myeloid leukemia: a systematic review and meta-analysis

Figures & data

Figure 1 Preferred reporting items for systematic reviews and meta-analyses flowchart describing the literature search strategy and study selection.

Abbreviations: AML, acute myeloid leukemia; MDS: myelodysplastic syndromes.

Table 1 Characteristics of the studies included in this meta-analysis

Study	No. ofpatients	Medianage inyears(range)	Gender(%female)	Treatment scheme	BM blast(%)	Previous treatmentwith eitherchemotherapy orHMAs	AML type	Overall survival
Blum et al (2010)^Citation18	31	63 (22–80)	–	Lenalidomide was given orally at escalating doses of 25–75 mg daily on days 1 through 21 of 28-day cycles.		–	Relapsed/refractory AML	–
Fehniger et al (2011)^Citation19	33	71 (60–88)	36%	Lenalidomide (50 mg/day in a single daily dose) on days 1–28 of a 28-day cycle for up to two cycles, followed by lenalidomide 10 mg/day in 28-day cycles up to 12 cycles.	53 (21–97)	None	Untreated AML	Median 4 months (95% CI, 3–9 months)
Griffiths et al (2016)^Citation30	45	64 (33–82)	44%	Cytarabine arabinoside 1.5 g/m^2/day over 3 hours on days 1–5 with initiation of daily. Lenalidomide (25–50 mg/day) on days 6–26 of a 28-day cycle.	–	Chemotherapy None	Relapsed/refractory AML Untreated AML	Median (95% CI) was 5.8 (2.5, 10.6) months
Medeiros et al (2018)^Citation20	54	76 (66–87)	40%	Lenalidomide (50 mg/day) on days 1–28 day for first two cycles, lenalidomide (25 mg/day) on days 1–28 day next two cycles, lenalidomide (10 mg/day) on days 1–28–day continuous cycles; azacitidine at 75 mg/m^2 daily for days 1–7, followed by lenalidomide 50 mg daily for days 8–28.	56 (22–95); 37 (12–84)			1--year survival rates was 21% with lenalidomide, and 44% with sequential azacitidine and lenalidomide
Narayan et al (2016)^Citation25	26	73.5 (61–86)	44%	Azacitidine at 75 mg/m^2 daily for days 1–7, followed by lenalidomide 50 mg daily for days 8–28, with a cycle length of 42 days, up to six cycles	32 (9–92)	HMAs, immunomodulatory therapy	Previously-treated AML	Median 5 months (95% CI, 3.7–8.6; range, 0.5–28.6 months)
Pollyea et al (2012)^Citation26	18	72 (62–86)	33%	Azacitidine 75 mg/m^2/day for 7 days followed by escalating doses (5 mg, 10 mg, 25 mg, and 50 mg) of lenalidomide for 21 days starting on day 8 of each cycle. This was followed by 14 days of observation, for a total 42-day cycle, up to 12 cycles.	64 (21–91)	None	Untreated AML	Median 8.2 months (range 0.7–16.0 months)
Pollyea et al (2013)^Citation27	45	74 (62–86)	34%	Azacitidine 75 mg/m^2/day for 7 days followed by escalating doses (5 mg, 10 mg, 25 mg and 50 mg) of lenalidomide for 21 days starting on day 8 of each cycle. This was followed by 14 days of observation, for a total 42-day cycle, up to 12 cycles.	50 (20–91)	None	Untreated AML	Median 20 weeks (range, 1–121+ weeks)
Ramsingh et al (2013)^Citation28	19	72 (63–81)	53%	Two 28-day induction cycles with lenalidomide 50 mg for days 1–28 and azacitidine given for days 1–5 at three-dose cohorts (25 mg/m^2, 50 mg/m^2 and 75 mg/m^2); maintenance cycles with lenalidomide 10 mg for days 1–28 and azacitidine 75 mg/m^2 for days 1–5, up to 12 cycles.	23 (2–81)	Chemotherapy	Untreated AML/relapsed/ refractory	–
Sekeres et al (2011)^Citation29	37	74 (60–94)	57%	Lenalidomide 50 mg daily for up to 28 days as induction therapy, maintenance lenalidomide at a dose of 10 mg daily for 21 days of a 28-day cycle, until disease progression or unacceptable toxicity.	38 (17–90)	None	Untreated AML	Median 2 months
Visani et al (2014)^Citation31	33	76 (70–85)	–	Lenalidomide (10 mg) was administered orally once daily (days 1–21); cytarabine (20 mg/m^2 twice daily) was administered subcutaneously (days 1–15), up to six cycles.	–	None	Untreated AML	–
Visani et al (2017)^Citation32	66	76 (70–85)	44%	Lenalidomide (10 mg) administered orally once daily (days 1–21) and cytarabine (10 mg/m^2) administered subcutaneously twice daily (days 1–15), up to six cycles.	60 (20–95)	None	Untreated AML	–

Abbreviations: AML, acute myeloid leukemia; BM, bone marrow; HMA, hypomethylating agent.

Figure 2 Forest plot of the estimated proportions (95% CI) for overall response rate (ORR) in acute myeloid leukemia (AML) patients treated with lenalidomide.

Figure 3 Forest plot of the estimated proportions (95% CI) for complete remission (CR) in acute myeloid leukemia (AML) patients treated with lenalidomide.

Figure S1 Forest plots of the estimated proportions of grade 3 and 4 adverse events ([A] anemia, [B] thrombocytopenia, [C] neutropenia, and [D] neutropenic fever).

Figure S2 Forest plots of the estimated proportions of grade 3 and 4 adverse events ([A] infectious, [B] fatigue, and [C] electrolyte disturbance).

Figure S3 Forest plots of subgroup analysis of acute myeloid leukemia (AML) type ([A] untreated patients, [B] relapsed/refractory patients).

Figure S4 Forest plots of subgroup analysis of cytogenetic risk ([A] intermediate-risk patients, [B] unfavorable-risk patients).

Table S1 Assessment of study quality using a modified version of the Newcastle-Ottawa scale for cohort studies

Study population clearly defined and >95% AML	Patients consecutively enrolled in the study	Cohort included AML patients diagnosed according to WHO criteria	Assessment of outcome well performeda	Primary and secondary outcomes defined	Adverse events defined	Adequate follow up of cohorts
Blum et al (2010)^Citation1	✮	✮	✮	?	✮	?
Fehniger et al (2011)^Citation2	✮	✮	✮	✮	✮	✮
Griffiths et al (2016)^Citation3	✮	✮	✮	✮	✮	✮
Medeiros et al (2018)^Citation4	✮	✮	✮	✮	✮	✮
Narayan et al (2016)^Citation5	✮	✮	✮	✮	✮	✮
Pollyea et al (2012)^Citation6	✮	✮	✮	?	✮	✮
Pollyea et al (2013)^Citation7	✮	?	✮	?	✮	?
Ramsingh et al (2013)^Citation8	✮	✮	✮	?	✮	?
Sekeres et al (2011)^Citation9	✮	✮	✮	?	?	?
Visani et al (2017)^Citation11	✮	✮	✮	✮	✮	✮

Note:

a Independent blind assessment, reference to secure records or record linkage.

Abbreviations: AML, acute myeloid leukemia; ✮, yes; ?, no description.

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RamsinghGWesterveltPCashenAFA phase 1 study of concomitant high-dose lenalidomide and 5-azacitidine induction in the treatment of AMLLeukemia201327372572822828444

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BlumWKlisovicRBBeckerHDose escalation of lenalidomide in relapsed or refractory acute leukemiasJ Clin Oncol201028334919492520956622

 PubMed Web of Science ®Google Scholar

FehnigerTAUyGLTrinkausKA phase 2 study of high-dose lenalidomide as initial therapy for older patients with acute myeloid leukemiaBlood201111761828183321051557

 PubMed Web of Science ®Google Scholar

GriffthsEABradyWETanWA phase I study of intermediate dose cytarabine in combination with lenalidomide in relapsed/refractory acute myeloid leukemiaLeuk Res201643444826943703

 PubMed Web of Science ®Google Scholar

MedeirosBCMccaulKKambhampatiSRandomized study of continuous high-dose lenalidomide, sequential azacitidine and lenalidomide, or azacitidine in persons 65 years and over with newly-diagnosed acute myeloid leukemiaHaematologica2018103110110629097499

 PubMed Web of Science ®Google Scholar

NarayanRGarciaJSPercivalMESequential azacitidine plus lenalidomide in previously treated elderly patients with acute myeloid leukemia and higher risk myelodysplastic syndromeLeuk Lymphoma201657360961526374199

 PubMed Web of Science ®Google Scholar

PollyeaDAKohrtHEGallegosLSafety, effcacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemiaLeukemia201226589390122033493

 PubMed Web of Science ®Google Scholar

PollyeaDAZehnderJCoutreSSequential azacitidine plus lenalidomide combination for elderly patients with untreated acute myeloid leukemiaHaematologica201398459159623242596

 PubMed Web of Science ®Google Scholar

RamsinghGWesterveltPCashenAFA phase 1 study of concomitant high-dose lenalidomide and 5-azacitidine induction in the treatment of AMLLeukemia201327372572822828444

 PubMed Web of Science ®Google Scholar

SekeresMAGundackerHLancetJA phase 2 study of lenalidomide monotherapy in patients with deletion 5q acute myeloid leukemia: Southwest Oncology Group Study S0605Blood2011118352352821551228

 PubMed Web of Science ®Google Scholar

VisaniGFerraraFdi RaimondoFLow-dose lenalidomide plus cytarabine in very elderly, unfit acute myeloid leukemia patients: Final result of a phase II studyLeuk Res201762778328987821

 PubMed Web of Science ®Google Scholar