An indirect comparison between bosutinib, nilotinib and dasatinib in first-line chronic phase chronic myeloid leukemia

Figures & data

Table 1. Overview of the pivotal trials included in the MAIC.

Characteristic	BFORE (bosutinib, n = 249)†	ENESTnd (nilotinib, n = 282)	DASISION (dasatinib, n = 259)
Daily drug dose	400 mg	600 mg*	100 mg
Study design	Phase 3, randomized, open-label, multinational^5	Phase 3, randomized, open-label, multicentre^3	Phase 3, randomized, open-label, multinational^4
Key inclusion criteria	Adults^5 Molecular diagnosis (detection of BCR-ABL rearrangement) of CP-CML within 6 months of randomization^5 Adequate hepatic and renal function^5 ECOG performance status of 0 or 1^5	Adults, within 6 months after the diagnosis of Ph + CP-CML by conventional cytogenetic analysis of bone marrow^3 ECOG of 0, 1, or 2^3 Adequate organ function^3	Adults with Ph + CP-CML diagnosed by means of bone marrow cytogenetic studies performed within 3 months before study entry^4 ECOG performance status of 0–2^4 Adequate hepatic and renal function^4
Primary endpoint	Major molecular response at 12 months^5	Major molecular response at 12 months^3	Confirmed complete cytogenetic response by 12 months^4
Secondary efficacy endpoints	Complete cytogenetic response by 12 months^5 Major molecular response by 18 months^5 Duration of major molecular response^5 Duration of complete cytogenetic response^5 Event-free survival^5 Overall survival^5	Durable major molecular response at 24 months^10 Time to and duration of major molecular response^10 Complete cytogenetic response by 1 month^3 (also time to and duration of this response)^29 Progression to accelerated phase or blast crisis^3 A ≥4 and ≥4.5 log reduction in BCR-ABL transcripts at 6, 12, and beyond 12 months (also time to and duration of this reduction)^29 Rate of hematologic response^Citation29 Progression-free survival ≤5 years of follow-up^29 Event-free survival ≤5 years of follow-up^29 Overall survival ≤5 years of follow-up^29	Time in confirmed complete cytogenetic response overall^11 Major molecular response at any time^4 Time to confirmed complete cytogenetic response overall^4 Time to a major molecular response overall^4 Progression-free survival^4 Overall survival^4

*Based on a 300 mg twice daily dose.

†The molecular diagnosis (detection of BCR-ABL rearrangement) inclusion criterion from the BFORE study pertains to all the N = 268 randomized patients. However, only Ph + patients from the BFORE study were included in the current analysis.

Abbreviations. CP-CML, chronic-phase chronic myeloid leukemia; ECOG, Eastern Cooperative Oncology Group; Ph+, Philadelphia chromosome positive.

Table 2. Covariates included in the analyses per endpoint.

Endpoint	Comparison with nilotinib		Comparison with dasatinib
	Effect modifier	Prognostic factor	Effect modifier	Prognostic factor
MMR at 24 months	Gender, race, Sokal score	Race, Sokal score	–	–
MMR by 24 months	Gender	Race, Sokal score, ECOG	Gender	Sokal/Hasford score, race, ECOG, peripheral blood basophils
MR4 by 24 months	White-cell count	–	–	–
MR4 at 24 months	Race, platelet count, white-cell count	Sokal score	–	–
MR4.5 by 24 months	Race	Age, race, Sokal score, platelet count, white-cell count	Peripheral blood basophils, race	Age, race, Sokal/Hasford score, platelet count, white-cell count
MR4.5 at 24 months	Race	Age, Sokal score, platelet count, white-cell count	–	–
CCyR by 24 months	Gender, race, white-cell count, ECOG	Race, ECOG	Gender, ECOG, white-cell count, race	ECOG, race, peripheral blood basophils
Disease transformation at any time	Gender	Race, Sokal score, white-cell count, ECOG	Gender	Sokal/Hasford score, race, ECOG, white-cell count, peripheral blood basophils

Abbreviations. MMR, major molecular response; MR, deep molecular response; CCyR, complete cytogenetic response; ECOG, Eastern Cooperative Oncology Group.

Table 3. Summary statistics of baseline characteristics before and after the MAIC.

Variables	Bosutinib before the MAIC in the comparison with nilotinib/dasatinib N = 248/244	Nilotinib N = 282	Dasatinib N = 259	Bosutinib after the MAIC in the comparison with nilotinib/dasatinib ESS = 142–206/100–118
Median age (range), years	53 (18-84)/53 (18-84)	47 (18–85)	46 (18–84)	47/46
Male, %	58/57	56%	56%	56%/56%
Race, %
Asian	12%/12%	27%	42%	27%/42%
Black	4%/4%	4%	1%	4%/1%
White	78%/78%	60%	51%	60%/51%
Other	6%/6%	9%	6%	9%/6%
Sokal risk score/Hasford risk score*, %
Low	35%/35%	37%	33%	37%/33%
Intermediate	44%/44%	36%	48%	36%/48%
High	21%/21%	28%	19%	27%/19%
ECOG performance status, %
0	71%/71%	88%	82%	88%/82%
1	29%/29%	12%	18%	12%/18%
Median platelet count (range), 10^9/L	386 (72–2195)/385.5 (72–2195)	424 (90–3880)	448 (58–1880)	424/448
Median white blood cell count (range), 10^9/L	41 (1.5–525)/41 (1.5–525)	23 (2–247)	25.1 (2.5–493)	23/25.1
Median peripheral blood basophils (range), %	NR/4 (0–22)	NR	4 (0.27–8)	NR/4%

Peripheral blood blasts were not reported for nilotinib and peripheral blood blasts were not included as a covariate in the dasatinib analysis since the exact baseline value was not always known for patients in the BFORE trial (missing values were confirmed to be <15% [criteria for CP CML diagnosis] as the sum of the remaining differentials were >85% or bone marrow blasts were <15%).

*In the ENESTnd and the BFORE studies disease risk is reported using the Sokal score, while in the DASISION study it is reported using the Hasford score. The two scales have similar categories (low, intermediate and high), but are not entirely comparable. However, for the purpose of the current analysis, the two risk scores were assumed to be comparable.

Abbreviations. ECOG, Eastern Cooperative Oncology Group; NR, not reported; MAIC, matching-adjusted indirect comparison; ESS, effective sample size.

Table 4. Outcomes of the MAIC for the comparison of nilotinib versus bosutinib.

Outcome	Bosutinib before MAIC	Bosutinib after MAIC	Nilotinib (%)	OR (95% CI)
MMR at 24 months	60.9% (n = 248)*	61.5% (ESS = 190)**	61.7	1.01 (0.70–1.45)
MMR by 24 months	66.9% (n = 248)*	68.3% (ESS = 167)**	71	1.14 (0.77–1.69)
MR4 by 24 months	37.9% (n = 248)*	38.4% (ESS = 206)**	39	1.02 (0.71–1.47)
MR4 at 24 months	33.0% (n = 248)*	36.4% (ESS = 156)**	24.5	0.57 (0.38–0.84)
MR4.5 by 24 months	23.4% (n = 248)*	25.7% (ESS = 149)**	25	0.96 (0.63–1.47)
MR4.5 at 24 months	12.5% (n = 248)*	14.8% (ESS = 149)**	12.4	0.81 (0.48–1.39)
CCyR† by 24 months	81.9% (n = 248)*	81.2% (ESS = 151)**	86.9	1.54 (0.93–2.56)
Disease transformation at any time	2.4% (n = 248)*	2.6% (ESS = 142)**	0.7	0.26 (0.05–1.41)

*Based on the dataset used for conducting the MAIC between bosutinib and nilotinib (patients with missing data were excluded).

**Effective sample size (the actual sample size of the bosutinib dataset after the MAIC).

†CCyR was imputed from MMR in the BFORE study if no valid cytogenetic assessment was available.

Abbreviations. MMR, major molecular response; MR, deep molecular response; CCyR, complete cytogenetic response; MAIC, matching-adjusted indirect comparison; ESS, effective sample size.

Table 5. Outcomes of the MAIC for the comparison of dasatinib versus bosutinib.

Outcome	Bosutinib before MAIC	Bosutinib after MAIC	Dasatinib (%)	OR (95% CI)
MMR by 24 months	66.8% (n = 244)*	68.7% (ESS = 118)**	64	0.81 (0.54–1.22)
MR4.5 by 24 months	23.8% (n = 244)*	26.8% (ESS = 100)**	17	0.56 (0.35–0.90)
CCyR† by 24 months	81.6% (n = 244)*	82.9% (ESS = 110)**	86	1.27 (0.74–2.17)
Disease transformation at any time	2.5% (n = 244)*	3.6% (ESS = 110)**	2.3	0.63 (0.20–2.00)

*Based on the dataset used for conducting the MAIC between bosutinib and dasatinib (patients with missing data were excluded).

**Effective sample size (the actual sample size of the bosutinib dataset after the MAIC).

†CCyR was imputed from MMR in the BFORE study if no valid cytogenetic assessment was available.

Abbreviations. MMR, major molecular response; MR, deep molecular response; CCyR, complete cytogenetic response; MAIC, matching-adjusted indirect comparison; ESS, effective sample size.

Table A1. Specific inclusion/exclusion criteria*.

Characteristic	BFORE (bosutinib, n = 249)	ENESTnd (nilotinib, n = 282)	DASISION (dasatinib, n = 259)
Daily drug dose	400 mg	600 mg*	100 mg
Key specific inclusion criteria	Molecular diagnosis of CP CML of ≤ 6 months (from initial diagnosis) Diagnosis of CP CML with molecular confirmation by detection of BCR-ABL rearrangement at screening (cytogenetic assessment for Philadelphia chromosome was not required for enrollment) Philadelphia chromosome status was to be identified at screening. Both Philadelphia positive (Ph+) and Philadelphia negative (Ph-) patients could be included Eastern Cooperative Oncology Group Performance Status score of 0 or 1 Adequate hepatic, renal and pancreatic function	Chronic myelogenous leukemia in chronic phase patients within the first 6 months of diagnosis. Standard conventional cytogenetic analysis was to be done on bone marrow. FISH could not be used Diagnosis of chronic myelogenous leukemia in chronic phase with confirmation of Philadelphia chromosome of (9:22) translocations Eastern Cooperative Oncology Group Performance Status score of 0, 1, or 2 Adequate end organ function Patients must have had potassium, magnesium, phosphorus and total calcium (corrected for serum albumin ≥ LLN (lower limit of normal) prior to the first dose of study medication	Chronic phase, Philadelphia Chromosome-positive chronic myeloid leukemia (CML) Previously untreated chronic CML Ph + or variants must be demonstrated by bone marrow cytogenetics. Eastern Cooperative Oncology Group Performance Status score of 0–2 Adequate hepatic and renal function
Key specific exclusion criteria	Any prior medical treatment for CML, including tyrosine kinase inhibitors (TKIs), with the exception of hydroxyurea and/or anagrelide treatment, which were permitted for up to 6 months prior to study entry (signature of ICF) if suitably approved for use in the subject's region Any past or current central nervous system (CNS) involvement, including leptomeningeal leukemia. Extramedullary disease only Concomitant use of or need for medications known to prolong the QT interval Uncontrolled hypomagnesemia or uncorrected hypokalemia, due to potential effects on the QT interval History of clinically significant or uncontrolled cardiac disease Known seropositivity to human immunodeficiency virus (HIV), current acute or chronic hepatitis B (hepatitis B surface-antigen positive), hepatitis C, cirrhosis or evidence of decompensated liver disease. Patients with resolved Hepatitis B can be included Recent or ongoing clinically significant GI disorder, e.g. Crohn's Disease, Ulcerative Colitis, or prior total or partial gastrectomy	Patients who are considered pH – because they do not have a confirmed cytogenetic diagnosis of Philadelphia chromosome with (9:22) translocation Previously documented T315I mutation Treatment with a tyrosine kinase inhibitor prior to study entry was not allowed except for no more than 2 weeks in duration of imatinib Any medical treatment for CML prior to study entry for longer than 2 weeks with the exception of hydroxyurea and/or anagrelide Known cytopathologically confirmed CNS infiltration Impaired cardiac function Severe or uncontrolled medical conditions (i.e. uncontrolled diabetes, active or uncontrolled infection) History of significant congenital or acquired bleeding disorder unrelated to cancer Use of therapeutic coumarin derivatives (i.e. warfarin, acenocoumarol, phenprocoumon) Patients receiving treatment with any medications with the potential to prolong the QT interval History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis Acute or chronic liver, pancreatic or severe renal disease considered unrelated to disease	Any other prior systemic treatments, with anti-CML activity except for anagrelide or hydroxyurea Known pleural effusion at baseline Uncontrolled or significant cardiovascular disease Significant bleeding disorder unrelated to CML Patients receiving drugs that are generally accepted to have a risk of causing Torsades de Pointes
Study locations†	North America, Europe, Asia, Africa, Australia	North America, South America, Europe, Africa, Asia	North America, South America, Europe, Asia, Australia

*Source: Study protocols^29–31.

†Source: clinicaltrials.gov.

Cortes JE, Gambacorti-Passerini C, Deininger MW, et al. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial. J Clin Oncol. 2018;36(3):231–237.

 PubMed Web of Science ®Google Scholar

Saglio G, Kim D-W, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362(24):2251–2259.

 PubMed Web of Science ®Google Scholar

Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic phase chronic myeloid leukemia. N Engl J Med. 2010;362(24):2260–2270.

 PubMed Web of Science ®Google Scholar

Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol. 2011;12(9):841–851.

 PubMed Web of Science ®Google Scholar

Protocol for: Saglio G, Kim D-W, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251–2259. DOI:https://doi.org/10.1056/NEJMoa0912614

 PubMed Web of Science ®Google Scholar

Kantarjian HM, Shah NP, Cortes JE, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2012;119(5):1123–1129.

 Google Scholar