Overall survival of patients with CLL treated with ibrutinib in the first line compared to second-line ibrutinib after chemotherapy/chemoimmunotherapy

Figures & data

Figure 1. Schematic overview of three scenarios and their data sources.

1L, first line; 2L, second line; CT/CIT, chemotherapy/chemoimmunotherapy.

Table 1. Baseline characteristics for cohorts of Scenarios 1, 2, and 3.

		Scenario 1		Scenario 2		Scenario 3
Treatment strategies		1L ibrutinib (N = 135)	1L Clb-2L ibrutinib^a (N = 131)	1L ibrutinib (N = 145)	1L CT/CIT-2L ibrutinib^a (N = 1481)	1L ibrutinib (N = 145)	1L CT/CIT-2L ibrutinib^a (N = 1350)
Baseline variable^b		n	n	n	n	n	n
Age, years	<70	40 (30%)	38 (29%)	48 (33%)	816 (55%)	48 (33%)	778 (55%)
	70–74	49 (36%)	46 (35%)	50 (34%)	300 (20%)	50 (34%)	254 (19%)
	75–79	24 (18%)	23 (18%)	24 (17%)	203 (14%)	24 (17%)	180 (13%)
	80+	22 (16%)	24 (18%)	23 (16%)	162 (11%)	23 (16%)	138 (10%)
Sex	Female	47 (35%)	52 (40%)	52 (36%)	514 (35%)	52 (36%)	462 (34%)
	Male	88 (65%)	79 (60%)	93 (64%)	967 (65%)	93 (64%)	888 (66%)
ECOG PS score	0	60 (44%)	54 (41%)	63 (43%)	344 (23%)	63 (43%)	290 (21%)
	1	65 (48%)	67 (51%)	67 (46%)	482 (33%)	67 (46%)	415 (31%)
	2+	10 (7%)	10 (8%)	10 (7%)	225 (15%)	10 (7%)	215 (16%)
	Unknown	0	0	5 (3%)	430 (29%)	5 (3%)	430 (32%)
Rai stage	0/1	34 (25%)	30 (23%)	–	–	–	–
	2	41 (30%)	40 (31%)	–	–	–	–
	3	28 (21%)	29 (22%)	–	–	–	–
	4	32 (24%)	32 (24%)	–	–	–	–
Binet/Rai stage^c	A/0	–	–	30 (21%)	241 (16%)	30 (21%)	216 (16%)
	B/1–2	–	–	66 (46%)	408 (28%)	66 (46%)	347 (26%)
	C/3–4	–	–	48 (33%)	430 (29%)	48 (33%)	385 (29%)
	Unknown	–	–	1 (1%)	402 (27%)	1 (1%)	402 (30%)
Del11q	No	100 (74%)	95 (73%)	109 (75%)	1033 (70%)	109 (75%)	938 (69%)
	Yes	29 (21%)	25 (19%)	30 (21%)	335 (23%)	30 (21%)	310 (23%)
	Unknown	6 (4%)	11 (8%)	6 (4%)	113 (8%)	6 (4%)	102 (8%)
Del17p^d	No	–	–	134 (92%)	1229 (83%)	134 (92%)	1104 (82%)
	Yes	–	–	9 (6%)	138 (9%)	9 (6%)	137 (10%)
	Unknown	–	–	2 (1%)	114 (8%)	2 (1%)	109 (8%)
IGHV status	Other^e	23 (17%)	25 (19%)	23 (16%)	25 (2%)	23 (16%)	0
	Mutated	40 (30%)	42 (32%)	46 (32%)	421 (28%)	46 (32%)	379 (28%)
	Unmutated	58 (34%)	59 (45%)	60 (41%)	740 (50%)	60 (41%)	681 (50%)
	Unknown	14 (10%)	5 (4%)	16 (11%)	295 (20%)	16 (11%)	290 (21%)
Geographic region	US	31 (23%)	28 (21%)	–	–	–	–
	Non-US	104 (77%)	103 (79%)	–	–	–	–
Race	White	119 (88%)	124 (95%)	–	–	–	–
	Other	16 (12%)	7 (5%)	–	–	–	–
Bulky disease	<5cm	80 (59%)	90 (69%)	–	–	–	–
	≥5cm	54 (40%)	39 (30%)	–	–	–	–
	Unknown	1 (1%)	2 (2%)	–	–	–	–
High β-2 macroglobulin (mg/L)	≤3.5	41 (30%)	33 (25%)	–	–	–	–
	>3.5	85 (63%)	88 (67%)	–	–	–	–
	Unknown	9 (7%)	10 (8%)	–	–	–	–
Creatinine clearance (mL/min)	<30	2 (1%)	2 (2%)	–	–	–	–
	30 to <60	58 (43%)	64 (49%)	–	–	–	–
	≥60	75 (56%)	65 (50%)	–	–	–	–
LDH (unit/L)	≤250	97 (72%)	101 (77%)	–	–	–	–
	>250	38 (28%)	30 (23%)	–	–	–	–

^aIncludes all patients that initiated chlorambucil or CT/CIT in the first line, respectively.

^bVariables for which no baseline characteristics were available (“–” in the table) were not used in the analyses.

^cAs described by Salles et al.¹⁴.

^dDel17p was an exclusion criterion in the RESONATE-2 study.

^eOther: patients who were polyclonal or had no amplification.

1L, first line; 2L, second line; CIT, chemoimmunotherapy; Clb, chlorambucil; CT, chemotherapy; del11q, deletion of the long arm of chromosome 11; del17p, deletion of the short arm of chromosome 17; ECOG PS, Eastern Cooperative Oncology Group performance status; IGHV, immunoglobulin heavy-chain variable region; LDH, lactate dehydrogenase; US, United States.

Table 2. Treatment regimens for cohorts of Scenarios 1, 2, and 3.

		Scenario 1		Scenario 2		Scenario 3
Treatment strategies		1L ibrutinib (N = 135)	1L Clb-2L ibrutinib^a (N = 131)	1L ibrutinib (N = 145)	1L CT/CIT-2L ibrutinib^a (N = 1481)	1L ibrutinib (N = 145)	1L CT/CIT-2L ibrutinib^a (N = 1350)
Treatment regimens		n	n	n	n	n	n
1L treatment regimen	Ibrutinib	135 (100%)	0	145 (100%)	0	145 (100%)	0
	Chlorambucil	0	131 (100%)	0	195 (13%)	0	64 (5%)
	FCR	0	0	0	540 (37%)	0	540 (40%)
	BR	0	0	0	270 (18%)	0	270 (20%)
	Anti-CD20 + chlorambucil	0	0	0	120 (8%)	0	120 (9%)
	Other anti-CD20–based^b	0	0	0	285 (19%)	0	285 (21%)
	Other^c	0	0	0	71 (5%)	0	71 (5%)
2 L treatment regimen	Ibrutinib	0	81 (62%)	1 (1%)	123 (8%)	1 (1%)	42 (3%)
	Other^d	23 (17%)	14 (11%)	25 (17%)	479 (32%)	25 (17%)	465 (35%)
	FCR	3 (2%)	4 (3%)	3 (2%)	73 (5%)	3 (2%)	69 (5%)
	BR	3 (2%)	2 (1.5%)	3 (2%)	49 (3%)	3 (2%)	47 (4%)
	Other anti-CD20–based^e	4 (3%)	2 (1.5%)	5 (3%)	221 (15%)	5 (3%)	232 (17%)
	Other non-R^f	13 (10%)	6 (5%)	14 (10%)	136 (9%)	14 (10%)	117 (9%)
	No subsequent treatment	112 (83%)	36 (27%)	119 (82%)	879 (59%)	119 (82%)	843 (62%)

^aIncludes all patients who initiated chlorambucil or CT/CIT in the first line, respectively.

^bOther anti-CD20–based treatment regimens include FCR-based (n = 104), BR-based (n = 14), anti-CD20 (n = 16), anti-CD20 + chemotherapy (n = 108), R-CHOP (n = 11), and anti-CD20 + other (n = 32) in Scenarios 2 and 3.

^cOther treatment regimens include alemtuzumab-based (n = 27) and other chemotherapy (n = 44) in Scenarios 2 and 3.

^dPatients who received other treatments than ibrutinib were censored at the time of 2L treatment initiation.

^eOther anti-CD20-based regimens include rituximab and obinutuzumab as monotherapy and in combination with other treatments (including FCR- and BR-based combinations) except the combinations listed separately. Patients receiving these regimens are censored at the time of 2L treatment initiation.

^fOther treatment regimens include all other treatment regimens without rituximab. Patients receiving these regimens are censored at the time of 2L treatment initiation.

1L, first line; 2L, second line; BR, bendamustine + rituximab; CIT, chemoimmunotherapy; Clb, chlorambucil; CT, chemotherapy; FCR, fludarabine + cyclophosphamide + rituximab; R, rituximab; R-CHOP, rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone.

Figure 2. Kaplan–Meier curves for Scenario 1 (A), Scenario 2 (B), and Scenario 3 (C). Overall survival analysis of observed data and adjusted data using the weighted Cox PH model.

1L, first line; 2L, second line; CT/CIT, chemotherapy/chemoimmunotherapy; CI, confidence interval; HR, hazard ratio; PH, proportional hazards.

Table 3. Summary of observed and adjusted overall survival.

Scenario	Overall survival	1L ibrutinib	1L CT/CIT-2L ibrutinib^a	HR [95% CI]	p-value
		N	N
1^b	Observed	106	104	0.35 [0.20–0.62]	.0003
	Weighted Cox PH model			0.35 [0.20–0.62]	.0003
2	Observed	119	807	0.42 [0.27–0.63]	<.0001
	Weighted Cox PH model			0.35 [0.21–0.61]	.0002
	Doubly robust Cox PH model			0.31 [0.18–0.55]	<.0001
3	Observed	119	692	0.42 [0.27–0.64]	<.0001
	Weighted Cox PH model			0.64 [0.39–1.04]	.0722
	Doubly robust Cox PH model			0.56 [0.33–0.94]	.0270

^a1L treatments for each scenario are described in Figure 1.

^bThe doubly robust method does not apply to Scenario 1. Scenario 1 uses randomized trial data and correction for baseline characteristics is not required.

1L, first line; 2L, second line; CI, confidence interval; CIT, chemoimmunotherapy; CT, chemotherapy; HR, hazard ratio; PH, proportional hazards.

Data availability statement

Data used for this study were based on the RESONATE-2 study and PHEDRA database. PHEDRA is a non-interventional, secondary-use project which collaborates with the owners of existing databases of electronic health records in the Europe, Middle East, and Africa (EMEA) region and gathers deidentified patient-level data on CLL, mantle cell lymphoma, and Waldenström macroglobulinemia centrally. The real-world databases utilized in this study are not owned by Janssen Pharmaceutica NV. The Lyon-Sud data included in this study are based on patient-level information collected by Lyon-Sud University Hospital in the French routine care setting. The CLLEAR data included in this study are based on patient-level information collected by contributing local hospitals at seven academic centers in the Czech Republic, located in Brno, Hradec Králové, Nový Jičín, Olomouc, Ostrava, Plzeň, and Prague. Requests for access to data from Lyon-Sud University Hospital and the CLLEAR registry should be sent directly to the respective owners of the databases. RESONATE-2 data sharing is governed by Pharmacyclics LLC, an AbbVie Company. Requests for access to individual participant data from clinical studies conducted by Pharmacyclics LLC, an AbbVie Company, can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu.