Efficacy and toxicity of cladribine for the treatment of refractory acute myeloid leukemia: a meta-analysis

Figures & data

Figure 1 PRISMA flow diagram of the study selection process.

Abbreviations: AML, acute myeloid leukemia; ALL, acute lymphoid leukemia.

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

Study	No. of patients	Median age in years (range)	Gender (F/M)	Induction chemotherapy	BM blast (%)	CR (%)	ORR (%)	Overall survival	DFS	ED (early death) (%)	Days for neutrophils <0.5 g/L	Days for platelets <20g/L	Infection/Fever (%)
Wrzesien et al, 2005^Citation15	43	44 (20–66)	21/22	CLAG-M:2-CdA 5 mg/m^2 iv d 1–5, Ara-C 2 g/m^2 iv d 1–5, MIT 10 mg/m^2 iv d 1–3, G-CSF 300 µg sc d 0–5, in cases of PR, the second induction course was recommended.	39.8(6–97)	49	49	23.7 weeks (3–174+ weeks)	26.2 weeks (0.5–138+ weeks)	2(5%)	20 days (13–35 days)	24 days (12–104 days)	49
Van et al, 1998^Citation17	19	57 (18–66)	9/10	5 patients: 2-CdA 0.1 mg/kg d1–7; 14 patients: 2-CdA 0.1 mg/kg d1–7+DNR 50 mg/m^2 d5–7.	NA	0	5	56 days	510+ days	2(10.5%)	NA	22 days (1–300 days)	94.7
Bao et al, 2018^Citation12	55	51 (33–69)	31/24	CLAG:cladribine 5 mg/m^2/day d1–5, cytarabine 2 g/m^2/day d1–5, filgrastim 300 µg/day d0–5.	43.2(25.1–61.8)	61.7	78.7	12.0 months (8.4–15.6 months)	NA	NA	NA	NA	NA
Wierzbowska et al, 2008^Citation16	114	45 (20–66)	53/61	CLAG-M:2-CdA 5 mg/m^2 iv d 1–5, Ara-C 2 g/m^2 iv d 1–5,MIT 10 mg/m^2 iv d 1–3, G-CSF 300 µg sc d 0–5, in cases of PR, the second induction course was recommended.	44(6–97)	58	NA	9 months	NA	8(7%)	24 days (13–35 days)	23 days (15–104 days)	45
Wrzesien-Kus et al, 2003^Citation13	58	45 (18–67)	30/28	2-CdA 5 mg/m^2 iv d1–5,Ara-C 2 g/m^2 iv d1–5, G-CSF 300 µg sc d0–5. In cases of partial remission (PR), the second induction course was administered.	77(30–100)	50	NA	34 weeks (1–206+ weeks)	17 weeks (1–202+ weeks)	NA	17 days (2–52 days)	14 days (3–52 days)	40
Robak et al, 2000^Citation14	20	44 (20–62)	10/10	2-CdA 5 mg/m^2 iv d1–5, Ara-C 2 g/m^2 iv d1–5, G-CSF 300 µg sc d0–5. In case of partial remission the second identical course was performed.	NA	50	60	24 weeks (1.0–96.3 weeks)	22.5 weeks (3.5–53 weeks)	NA	17 days	NA	90
Gordon et al, 2000^Citation11	15	69 (29–75)	7/8	2-CdA 17 mg/m^2 iv d1–5	NA	0	NA	57 days (28–271 days)	NA	NA	NA	NA	NA
Jain et al, 2016^Citation21	46	55 (19–65)	NA	Cladribine 5 mg/m^2 iv d1–5, Ara-C 1,000 mg/m^2 iv d1–5, idarubicin 10 mg/m^2 iv d1–3	44(8–94)	22	39	8.8 months	10.3 months	7%	NA	NA	NA
Chen et al, 2015^Citation22	14	42 (18–65)	2/12	Cladribine 5 mg/m^2 iv d1–5, cytarabine 1.0 g/m^2 iv d1–5, topotecan 1.25 mg/m^2 iv d1–5 and G-CSF 300 µg sc on days until neutrophile granulocyte recovery	NA	58.3	66.7	NA	8.6 months (2–16 months)	NA	13 days (2–21 days)	12 days (2–21 days)	NA
Komrokji et al, 2011^Citation23	38	62 (26–79)	16/22	Cladribine, 5 mg/m^2 iv d2–6; Cytarabine, 2 gm/m^2 iv d2–6; G-CSF: 300 mcg SC d1–6. IM 400 mg orally bid d2–15. Re-induction was allowed if patient had partial response (PR).	NA	26	37	11.1 months (4.8–13.4 months)	4.9 months (1.6–11.7 months)	2(5.3%)	NA	NA	58

Abbreviations: BM, bone marrow; NA, not available; M, mitoxantrone; IM, imatinib mesylate.

Figure 2 Forest plot of the estimated proportions (95% CI) for complete remission (CR) rate in patients.

Figure 3 Forest plot of the estimated proportions (95% CI) for overall response rate (ORR) in patients.

Figure 4 Forest plots of the estimated proportions of complete remission (CR) rate by cladribine monotherapy (A), CLAG-based chemotherapy (B), CLAG/CLAG-M chemotherapy (C), standard CLAG chemotherapy (D).

Figure 5 Forest plots of the estimated proportions of complete remission (CR) rate by favorable risk (A), intermediate risk (B), unfavorable risk (C).

Figure 6 Forest plot of the estimated proportions (95% CI) for early death rate in patients.

Wrzesien-Kus A, Robak T, Wierzbowska A, et al. A multicenter, open, noncomparative, phase II study of the combination of cladribine (2-chlorodeoxyadenosine), cytarabine, granulocyte colony-stimulating factor and mitoxantrone as induction therapy in refractory acute myeloid leukemia: a report of the Polish Adult Leukemia Group. Ann Hematol. 2005;84:557–564. doi:10.1007/s00277-005-1046-015856358

 PubMed Web of Science ®Google Scholar

Van Den Neste E, Martiat P, Mineur P, et al. 2-Chlorodeoxyadenosine with or without daunorubicin in relapsed or refractory acute myeloid leukemia. Ann Hematol. 1998;76:19–23.9486920

 PubMed Web of Science ®Google Scholar

Bao Y, Zhao J, Li ZZ. Comparison of clinical remission and survival between CLAG and FLAG induction chemotherapy in patients with refractory or relapsed acute myeloid leukemia: a prospective cohort study. Clin Transl Oncol. 2018;20:870–880. doi:10.1007/s12094-017-1798-829181696

 PubMed Web of Science ®Google Scholar

Wierzbowska A, Robak T, Pluta A, et al. Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group. Eur J Haematol. 2008;80:115–126. doi:10.1111/j.1600-0609.2007.00988.x18076637

 PubMed Web of Science ®Google Scholar

Wrzesien-Kus A, Robak T, Lech-Marańda E, et al. A multicenter, open, non-comparative, phase II study of the combination of cladribine (2-chlorodeoxyadenosine), cytarabine, and G-CSF as induction therapy in refractory acute myeloid leukemia - a report of the Polish Adult Leukemia Group (PALG). Eur J Haematol. 2003;71:155–162.12930315

 PubMed Web of Science ®Google Scholar

Robak T, Wrzesień-Kuś A, Lech-Marańda E, Kowal M, Dmoszyńska A. Combination regimen of cladribine (2-chlorodeoxyadenosine), cytarabine and G-CSF (CLAG) as induction therapy for patients with relapsed or refractory acute myeloid leukemia. Leuk Lymphoma. 2000;39:121–129. doi:10.3109/1042819000905354510975390

 PubMed Web of Science ®Google Scholar

Gordon MS, Young ML, Tallman MS, et al. Phase II trial of 2-chlorodeoxyadenosine in patients with relapsed/refractory acute myeloid leukemia: a study of the Eastern Cooperative Oncology Group (ECOG), E5995. Leuk Res. 2000;24:871–875.10996206

 PubMed Web of Science ®Google Scholar

Jain P, Kantarjian HM, Ravandi F, et al. Cladribine combined with idarubicin and Ara-C (CLIA) as a frontline and salvage treatment for young patients (<65 yrs) with acute myeloid leukemia. Blood. 2018;132:4039.

 Web of Science ®Google Scholar

Chen X, Weng J, Wang Y, et al. Combination of cladribine, cytarabine and topotecan (CLAT) for relapsed or refractory acute myeloid leukemia. Blood. 2015;126:4897.

 Web of Science ®Google Scholar

Komrokji RS, Pinilla-Ibarz J, Yu D, et al. A phase II study of CLAG regimen in combination with imatinib mesylate in relapsed or refractory acute myeloid leukemia. Blood. 2011;118:2604. doi:10.1182/blood-2011-02-334870

 Web of Science ®Google Scholar