Fludarabine in the treatment of chronic lymphocytic leukemia: a review

Figures & data

Figure 1 Metabolism and mechanisms of actions of fludarabine.

Abbreviations: A, adenosine; dA, deoxyadenosine; F-ara-A, 9-β-D-arabinosyl-2-fluoroadenine; MP, DP, TP refer to nucleoside 5’-monophosphates, diphosphates and triphosphates, respectively.

Table 1 Results of clinical trials on B-CLL with fludarabine monotherapy

References	Comp study	No of evaluable patients	Prior therapy	Treatment regimen	Clinical response		Survival/duration of response
					CR (%)	OR (%)
Keating et al^Citation32	no	68	yes	FAMP 25–30 mg/m^2 iv × d1–5 q 4 wk	13	57	16 mo median OS
Keating et al^12,34	no	33	no	FAMP 30 mg/m^2 iv × d1–5 q 4 wk	33	79	33 mo median PFS
Clavio et al^Citation35	no	32	no	FAMP 25 mg/m^2 iv × d1–5 q 4 wk	16	100	na
Sorensen et al^Citation33	no	703	yes	FAMP 25 mg/m^2 iv × d1–5 q 4 wk	3	32	12.6 mo median OS
Stelitano et al^Citation36	no	47	yes (64%)	FAMP 25 mg/m^2 iv × d1–5 q 4 wk or FAMP 25 mg/m^2 iv × d1–4 q 3 wk	34	74	35.7 mo median OS 18 mo median TTR
Leporrier et al^Citation41	yes	924	no	FAMP 25 mg/m^2 iv × d1–5 q 4–6 wk (n = 336)	40	71	69 mo median OS
				CAP (n = 237)	15	58	70 mo median OS
				CHOP (n = 351)	30	72	67 mo median OS
Rai et al^Citation39	yes	509	no	FAMP 25 mg/m^2 iv × d1–5 q 4 wk (n = 179)	20	63	25 mo median DFS, 20 mo median PFS, 66 mo median OS
				CHL 40 mg/m^2 os × d1 q 4 wk (n = 193)	4	37	14 mo median DFS and e PFS, 56 mo median OS
				FAMP 10–20 mg/m^2 iv × d1–5+CHL 15–20 mg/m^2 os × d1 q 4 wk (n = 137)	20	61	55 mo median OS
Jhonson et al^Citation40	yes	100	no	FAMP 20 mg/m^2 iv × d1–5 q 4w (n = 52)	23	48	na
				CAP (n = 48)	17	60
Spriano et al^Citation42	yes	115	no	FAMP 25 mg/m^2 iv × d1–5 q 4 wk	47	70	28 mo median PFS
				CHL 30 mg/m^2 d1 and 15+PDN 40 mg/m^2 im on days 1–5 and 15–19	31	65	21 mo median PFS
Rossi et al^Citation38	no	81	no	FAMP 40 mg/m^2 os × d1–5 q 4 wk	12.3	80.2	841 d median PFS
Boogaerts^Citation37	no	78	yes	FAMP 40 mg/m^2 os × d1–5 q 4 wk	17.9	51.3	na
Eichhorst^Citation43	yes	206	yes	FAMP 25 mg/m^2 iv × d1–5 q 4 wk	8	86	18.7 mo median PFS, 45.9 mo median OS
				CHL 0.4 mg/kg dose escalation up to 0.8 mg/kg every 15 day for up to 12 months	0	59	17.8 mo median PFS, 63.6 mo median OS

Abbreviations: Comp, comparative; CR, complete remission; OR, overall response; DFS, disease-free survival; OS, overall survival; PFS, progresión-free survival; FAMP, fludarabine; PDN, prednisone; CHL, chlorambucil; CAP, cyclophosmphamide + doxorubicin + prednisone; CHOP, vincristine + doxorubicine + cyclophosmphamide + prednisone; d, days; mo, months; wk, weeks; q, every; iv, intravenous; os, oral; im, intramuscular; na, not applicable.

Table 2 Results of clinical trials on B-CLL with fludarabine in combination with alkylating agents

References	Comp study	No of evaluable patients	Prior therapy	Treatment regimen	Clinical response		Survival/duration of response
					CR (%)	OR (%)
FAMP + CHL
Elias et al^Citation54	no	17	yes	FAMP 10–20 mg/m^2 iv × d1–5 + CHL 15–20 mg/m^2 iv × d1 q 4 wk	6	53	na
Weiss et al^Citation55	no	15	yes	FAMP 10–20 mg/m^2 iv × d1–5 +CHL 20 mg/m^2 iv × d1 and d15 q 4 wk	7	27	na
FAMP + CTX
O’Brien et al^Citation57	no	128	Yes (some)	FAMP 30 mg/m^2 iv × d1–3 + CTX 300–500 mg/m^2 iv × d1–3 q 4–6 wk	17	74	12–38 mo median OS
Hallek et al^Citation120	no	32	Yes (some)	FAMP 30 mg/m^2 iv × d1–3 +CTX 250 mg/m^2 iv × d1–3 q 4 wk	16	90	na
Eichhorst et al^Citation59	yes	328	no	FAMP 25 mg/m^2 iv × d1–5 q 4 wk (n = 164)	7	83	20 mo median DFS
				FAMP 30 mg/m^2 iv × d1–3 +CTX 250 mg/m^2 iv × d1–3 q 4 wk (n = 164)	24	94	48 mo median DFS
Flinn et al^Citation61	yes	278	no	FAMP 20 mg/m^2 iv × d1–5 +CTX 600 mg/m^2 iv × d1	23	74	32 mo median PFS, OS 79% at 2 yrs
				FAMP 25 mg/m^2 iv × d1–5 q 4 wk	7	59	19 mo median PFS, OS 80% at 2 yrs
Catovsky et al^Citation62	yes	777	no	FAMP 25 mg/m^2 iv or 40 mg/m^2 os × d1–5 q 4 wk	15	80	PFS 36%, OS 2% at 5 yrs
				FAMP 25 mg/m^2 iv x d1–3 or 24 mg/m^2 os × d1–5 +CTX 250 mg/m^2 iv × d1–3 or 150 mg/m^2 os d1–5 q 4 wk	38	95	PFS 10%, OS 54% at 5 yrs
				CHL 10 mg/m^2 os × d1–7 q 4 wk	7	72	PFS 10%, OS 59% 5 yrs
Cazin et al^Citation63	no	76	no	FAMP 30 mg/m^2 os × d1–5 +CTX 200 mg/m^2 os + d1–5 q 4 wk	53	80	median OS not reached at 7 yrs 5 yrs median PFS
Laurenti et al^Citation64	no	37	no	FAMP 30 mg/m^2 os × d1–3+ CTX 250 mg/m^2 os × d1–3 q 4 wk	40	77	23 mo median PFS 38 mo median TTR OS 89% at 30 mo
Flinn et al^Citation58	no	36	no	FAMP 20 mg/m^2 iv × d1–5+ CTX 600 mg/m^2 iv × dl + G-CSF 5 mg/kg × d8–18/22 q 4 wk	42	64	DFS 92.9% 1 yr, 27 mo median DoR

Abbreviations: Comp, comparative; CR, complete remission; OR, overall response; DFS, disease free survival; OS, overall survival; PFS, progression free survival; TTR, time to retreatment; DoR, duration of response; FAMP, fludarabine; CTX, cyclophosphamide; CHL, chlorambucil; d, days; mo, months; wk, weeks; q, every; iv, intravenous; os, oral; na, not available.

Table 3 Results of clinical trials on B-CLL with fludarabine in combination with anthracyclines or anthracenedione

References	Comp study	No of evaluable patients	Prior therapy	Treatment regimen	Clinical response		Survival/duration of response
					CR (%)	OR (%)
FAMP+Dox+PDN
Robertson et al^Citation68	no	29	yes	FAMP 30 mg/m^2 d1–3 or 25–30 mg/m^2 d1–4+Dox 50 mg/m^2 d1 ± PDN 30 mg/m^2 d1–5 q 4 wk	10	46	28 mo median OS
FAMP+EPI
Rummel et al^Citation69	no	38	yes (some)	FAMP 25 mg/m^2 d1–5+EPI 25/mg/m^2 d4–5 q 4 wk	32	82	19 mo median PFS
Rummel et al^Citation70	yes	150	yes (some)	FAMP 25 mg/m^2 d1–5+EPI	29	88	30 mo median EFS, 76 mo median OS
				25/mg/m^2 d4–5 q 4 wk FAMP 25/mg/m^2 d1–5 q 4 wk	9	73	19 mo median EFS, 63 mo median OS
FAMP+MIT
Tsimberidou et al^Citation121	no	88	yes (some)	FAMP 30 mg/m^2 × d1–3 + MIT 10 mg/m^2 d1	20 1st line 7 2nd line	83 1st line 55 2nd line	2 yrs median PFS
FAMP +CTX + MIT + ara-C + Dex
Mauro et al^Citation67	no	31	yes	FAMP 25 mg/m^2 iv d at 0, 24 and 48 h+Ara-C 1 g/m^2 iv at 4 h or at 4 h and 28 h+MIT 10 mg/m^2 iv at 6 h+Dex 20 mg iv d on d1–3 q 4 wk	60	70	28 mo median PFS, OS 68% at 67 mo
FAMP+CTX+MIT
Bosch et al^Citation65	no	60	yes	FAMP 25 mg/m^2 iv × d1–3+CYC 600 mg/m^2 iv × d1 or 200 mg/m^2 iv × d1–3+ MIT 6–8 mg/m^2 × d1 q 4 wk	50	78	19 mo median DoR, 42 mo median OS
Bosch et al^Citation66	no	69	no	FAMP 25 mg/m^2 iv × d1–3+ CTX 200 mg/m^2 iv × d1–3+ MIT 6 mg/m^2 × d1 q 4 wk	64	90	37 mo median PFS

Abbreviations: Comp, comparative; CR, complete remission; OR, overall response; OS, overall survival; PFS, progression-free survival; DoR, duration of response; EFS, event-free survival; FAMP: fludarabine; CTX, cyclophosphamide; MIT, mitoxantrone; Dox, doxorubicinl; Dex, desametaxone; ara-C, cytarabine; EPI, epirubicin; PDN, prednisone; d, days; mo, months; wk, weeks; q, every; iv, intravenous; os, oral.

Table 4 Results of clinical trials on B-CLL with fludarabine with ara-C with or without cisplatin

References	Comp study	No of evaluable pts	Prior therapy	Treatement regimen	Clinical response		Survival/duration of response
					CR (%)	OR (%)
FAMP+ara-C Gandhi et al^Citation71	no	15	yes	FAMP 30 mg/m^2 d1 + ara-C 500–1000 mg/m^2 d1 q 4 wk	0	5	9 mo median OS
FAMP+ara-C+Cis Giles et al^Citation72	no	41	yes	FAMP 30 mg/m^2 d4 + Cis 25 mg/m^2 d1–4 ± ara-C 500 mg/m^2 d4 q 4 wk	0	19	6 mo median OS

Abbreviations: Comp, comparative; CR, complete remission; OR, overall response; OS, overall survival; FAMP, fludarabine; ara-C, cytarabine; Cis, cisplatin; d, days; mo, months; wk, weeks; q, every; iv, intravenous; os, oral.

Table 5 Results of clinical trials on B-CLL with fludarabine and monoclonal antibody

References	Comp study	No of evaluable pts	Prior therapy	Treatment regimen	Clinical response		Survival/duration of response
					CR (%)	OR (%)
Byrd et al^Citation79	yes	104	no	FAMP 25 mg/m^2 iv d1–5 q 4 wk × 6 cycles followed by R 375 mg/m^2/w iv × 4 doses (n, 53)	47	90	PFS 28%, OS 96% at 23 mo
				FAMP 25 mg/m^2 iv d1–5 + R 375 mg/m^2 iv d1 followed by R 375 mg/m^2/wk iv × 4 doses (n, 51)	28	77	PFS 35%, OS 88% at 23 mo
Byrd et al^Citation82	yes	282	no	FAMP 25 mg/m^2 iv d1–5 q 4 wk+/– R 375 mg/m^2 iv × 6 cycles followed by R 375 mg/m^2/w iv × 4 doses (n,104)	38	84	PFS 67%, OS 93% at 2 yrs
				FAMP 25 mg/m^2 iv × d1–5 q 4 wk (n, 179)	20	63	PFS 45%, OS 81% at 2 yrs
Wierda et al^Citation80	no	177	yes	FAMP 25 mg/m^2 iv d1/2–3/4 + CTX 250 mg/m^2 iv d1/2–3/4 + R 375–500 mg/m^2 iv d1 q 4 wk	25	73	28 mo median PFS
Keating et al^Citation81	no	224	no	FAMP 25 mg/m^2 iv d1/2–3/4+CTX 250 mg/m^2 iv d1/2–3/4 +R 375–500 mg/m^2 iv d1 q 4 wk	70	95	TTF 69% at 4 yrs
Hallek et al^Citation85	yes	761 (for resp.)	no	FAMP 25 mg/m^2 iv d1/2–3/4+CTX 250 mg/m^2	52	95	PFS 76.6% and OS 91% at 2 yrs PFS
		787 (for PFS)		iv d1/2–3/4 +R 375–500 mg/m^2 iv d1 q 4 wk	27	88	62.3% and OS 88% at 2 yrs
		871 (for OS)		FAMP 25 mg/m^2 iv d1/2–3/4 +CTX 250 mg/m^2 iv d1/2–3/4
Foon et al^Citation86	no	48	no	FAMP 20 mg/m^2 d1–3+CTX 150 mg/m^2 d1–3 +R-500 mg/m^2 d1 and d14 q 4 wk; maintenance R-500 mg/m^2 q3 mo until progression	79	100	22.3 mo median PFS
Bosch et al^Citation88	no	72	no	FAMP 25 mg/m^2 iv d1/2–3/4 +CTX 250 mg/m^2 iv d1/2–3/4+MIT 6 mg/m^2 iv d 1 +R 375–500 mg/m^2 iv d1 q 4 wk	82	93	na
Tsimberidou et al^Citation87	no	50 (30 B-CLL20 RS)	yes	O 17.5, 20, or 25 mg/m^2 iv d1–4+FAMP 30 mg/m^2 iv d2–3+ ara-C 1 g/m^2 iv d2–3+R 375 mg/m^2 d1 or d3 q 4 wk	0 (B-CLL) 10 (RS)	36 (B-CLL) 50 (RS)	TTF 47%, OS 89% at 6 mo (B-CLL) TTF 54%, OS 59% at 6 mo (RS)
Kennedy et al^Citation93	no	6	yes	FAMP dose not applicable A dose not applicable	17	83	na
Elter et al^Citation94	no	36	yes	A 30 mg iv+FAMP 30 mg/m^2 iv d1–3 q 4 wk	31	83	35.6 mo median OS 12.9 mo median PFS
Wierda et al^Citation96	no	21	no	CTX 200 mg/m^2 d3–5+FAMP 20 mg/m^2 d3–5 A 30 mg iv d1, 3, 5 R 375–500 mg/m^2 d2 q 4 wk	71	95	na
Montillo et al^Citation97	no	19	yes	FAMP 40 mg/m^2 os d1–3+CTX 250/m^2 os d1–3+A 10–20 mg sc d1–3	37	79	na
Elter et al^Citation98	no	20	yes	FAMP 25 mg/m^2 iv d1–3 +CTX 200 mg/m^2 iv d1–3+A 30 mg sc d1–3	25	70	na
Byrd et al^Citation99	yes	31	yes	Lu 375–500 mg/m^2 +FAMP 25 mg/m^2 iv d1/2–3/4+ CTX 250 mg/m^2 iv d1/2–3/4 +R 375–500 mg/m^2 iv d1 q 4 wk. Comparison with FCR Wierda et al 2005	48	71	na

Abbreviations: Comp, comparative; RS, Richter’s syndrome; resp., response; CR, complete remission; OR, overall response; OS, overall survival; PFS, progression-free survival; TTF, time to treatment failure; FAMP, fludarabine; MIT, mitoxantrone; ara-C, cytarabine; R, Riuximab; O, oxaliplatin; A, alemtuzumab; Lu, lumiliximab; d, days; mo, months; wk, weeks; q, every; iv, intravenous; os, oral; sc, subcutaneous; pts, patients; na, not applicable.

Table 6 Reduced intensity conditioning FAMP-based regimen in allogeneic transplant for B-CLL

References	N° pts	Prior regimen(range)	Chemo-refractory	Prior auto-SCT	Related donor	FAMP-based conditioning	TRM	GVHD acute(grade 2–4)	GVHD chronic extnsive	Survival at 2 yrs
Dreger et al^Citation122	77	3 (0–8)	33%	13%	81%	79%	18% at 12 mo	34%	58%	OS 72% PFS 56%
Sorror et al^Citation123	64	4	53%		69%	83%	11% at 100 d	61%	50%	OS 60% PFS 52%
Brown et al^Citation124	46	5 (1–10)	57%	22%	33%	100%	17% at 24 mo	34%	43%	OS 54% PFS 34%
Delgado et al^Citation125	41	3 (1–8)	27%	27%	58%	100%	5% at 100 d	10% (grades 3–4)	33% (after DLI)	OS 51% PFS 45%
Schetelig et al^Citation126	30	3 (0–8)	46%		50%	100%	13% at 24 mo	56%	21%	OS 72% PFS 67%

Abbreviations: DLI, donor lymphocyte infusion; GVHD, graft versus host disease; OS, overall survival; PFS, progression-free survival; SCT, stem cell transplantation; TRM, transplantation-related mortality; FAMP, fludarabine; mo, months; d, days.

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