Brivio E, Pennesi E, Willemse ME, et al. Bosutinib in resistant and intolerant pediatric patients with chronic phase chronic myeloid leukemia: results from the phase I part of study ITCC054/COG AAML1921. J Clin Oncol. 2024;42(7):821-831.

Chronic myeloid leukemia (CML) accounts for 3% of pediatric leukemia cases in the U.S. and is driven by the fusion oncogene BCR-ABL1, created by the Philadelphia chromosome (Ph) t(9;22)(q34;q11.2) translocation.1  Pediatric CML is primarily treated with tyrosine kinase inhibitors (TKIs) that target BCR: ABL protein. The first-generation TKI imatinib and the second-generation TKIs dasatinib and nilotinib are approved in pediatric Ph-positive CML and have significantly improved prognosis (Table).2-5 

Table

Tyrosine kinase inhibitors approved for use in pediatric Ph-positive CML

DrugFDA approval yearRecommended doseCCyRMMRNotable toxicities
First generation 
Imatinib2,3  2003 340 mg/m2/dose, once daily Newly diagnosed (3 years) Hematologic, rash, arthralgia/myalgia, growth impairment
Compared to adults, lower incidence of edema 
86% 74% 
Second generation 
Dasatinib4  2017 60 mg/m2/dose, once daily Newly diagnosed (2 years) Nausea, diarrhea, rash
Compared to adults, no pleural, pericardial effusions, or pulmonary arterial hypertension 
96% 70% 
Resistant/intolerant (2 years) 
81% 55% 
Nilotinib5  2021 240 mg/m2/dose, twice daily Newly diagnosed (2 years) Hyperbilirubinemia, ALT elevation, rash, vomiting, growth impairment
Compared to adults, no cardiovascular events or grade 3/4 hyperglycemia 
84% 68% 
Resistant/intolerant (2 years) 
81.8% 57.6% 
Bosutinib14  2023 Newly diagnosed: 300 mg/m2/dose, once daily
Resistant/intolerant: 400 mg/m2/dose, once daily 
Resistant/intolerant (1 year) Compared to adults, GI and dermatologic toxicity; no cardiovascular toxicity 
92.9% 46.5% 
DrugFDA approval yearRecommended doseCCyRMMRNotable toxicities
First generation 
Imatinib2,3  2003 340 mg/m2/dose, once daily Newly diagnosed (3 years) Hematologic, rash, arthralgia/myalgia, growth impairment
Compared to adults, lower incidence of edema 
86% 74% 
Second generation 
Dasatinib4  2017 60 mg/m2/dose, once daily Newly diagnosed (2 years) Nausea, diarrhea, rash
Compared to adults, no pleural, pericardial effusions, or pulmonary arterial hypertension 
96% 70% 
Resistant/intolerant (2 years) 
81% 55% 
Nilotinib5  2021 240 mg/m2/dose, twice daily Newly diagnosed (2 years) Hyperbilirubinemia, ALT elevation, rash, vomiting, growth impairment
Compared to adults, no cardiovascular events or grade 3/4 hyperglycemia 
84% 68% 
Resistant/intolerant (2 years) 
81.8% 57.6% 
Bosutinib14  2023 Newly diagnosed: 300 mg/m2/dose, once daily
Resistant/intolerant: 400 mg/m2/dose, once daily 
Resistant/intolerant (1 year) Compared to adults, GI and dermatologic toxicity; no cardiovascular toxicity 
92.9% 46.5% 

Abbreviations: ALT, alanine aminotransferase; CCyR, complete cytogenetic response; MMR, major molecular response.

Prolonged TKI therapy increases patients’ risk for long-term adverse effects (AEs), including endocrinopathies and linear growth impairment from off-target kinase inhibition — particularly when TKIs are started before puberty.6  A preclinical animal model found limited impact on bone growth, despite continuous exposure to the dual SRC/ABL inhibitor bosutinib.7  The U.S. Food and Drug Administration (FDA) initially approved bosutinib for adult patients with resistant/intolerant CML,8-10  then for newly diagnosed CML after the phase III BFORE study showed improved responses compared to imatinib.11,12  The phase IV BYOND study also demonstrated ongoing tolerability to and response with bosutinib.13  The durable responses and toxicity profile, along with a potential for less growth impairment, provided rationale for the phase I/II multicenter, single-arm, open-label ITCC-054/COG AAML1921 study (NCT04258943) of bosutinib in pediatric patients with CML.14  Based on these study findings, described in more detail below, the FDA approved bosutinib for pediatric patients with newly diagnosed and resistant/intolerant CML in September 2023.15 

In the phase I portion of the study, 28 patients (age range: 1-18 years) were treated at U.S. and European sites between November 2016 and August 2022. Eligible patients had Ph-positive CML that was resistant or intolerant to at least one previous TKI. Patients with known T315I and V299L resistance mutations were excluded. Upon bosutinib approval for adults with newly diagnosed CML in December 2017, the protocol was amended to allow newly diagnosed pediatric patients in the study’s phase II portion. The study’s primary objective was to define the recommended phase II dose (RP2D) based on tolerability and pharmacokinetic (PK) information. Tolerability was defined as a dose that resulted in dose-limiting toxicity (DLT) in none in six patients or one in 10 patients, using the 6+4 design, and PK targets were derived from population PK data for adults treated with bosutinib.

The RP2D for pediatric patients with resistant/intolerant CML was once-daily 400 mg/m2 (maximum: 600 mg/m2). For patients with newly diagnosed CML, the RP2D was once-daily 300 mg/m2 (maximum: 500 mg/m2). These findings were extrapolated from pediatric resistant/intolerant CML safety and PK data and adult target exposure data.

Twenty-seven patients (median age: 12 years; range: 1-17 years) with chronic-phase CML were evaluable for DLT. Patients were resistant (82%) or intolerant (18%) to prior therapy and had received one (n=16/28; 57%) or two (n=9/28; 32%) prior TKIs. The last TKI received included: imatinib (n=13), dasatinib (n=13), and nilotinib (n=2). Prior to enrollment, 16 patients (57%) had complete cytogenetic response (CCyR). Regarding molecular response (MR), four patients had ≥MR3, 10 had MR2, seven had MR1, and five had no MR.

There were no DLTs at 300 mg/m2 once daily (n=6 patients), one DLT (Grade 3 nausea/vomiting and diarrhea) at 350 mg/m2 once daily (n=11), one DLT (Grade 3 transaminase elevation and rash, grade 2 hyperbilirubinemia) at 400 mg/m2 once daily (n=10). Both patients with DLTs resumed lower dose bosutinib. Most common AEs were gastrointestinal (GI) toxicities: diarrhea (93%), abdominal pain (71%), vomiting (68%) or nausea (61%), and dermatologic toxicities: maculopapular rash (39%) or other skin disorders (43%). Most common grade 3/4 AEs were transaminase elevation (18%), maculopapular rash (11%), vomiting (11%), and diarrhea (11%). Some patients had prolonged low-grade GI toxicity, primarily diarrhea. QTC prolongation and cardiac AEs were not observed. Eleven patients had dose reduction, seven of whom stopped treatment due to intolerance (GI toxicity, neutropenia, rash); eight patients discontinued treatment due to insufficient response at the investigator’s discretion.

By six months of therapy, all patients experienced a complete hematologic response. By 12 months, nearly all attained CCyR (92.9%; 95% CI, 76.5-99.1) and nearly half attained major MR (46.4%; 95% CI, 27.5-66.1). Five patients achieved MR4/MR4.5. These response rates are comparable to other phase I/II trials of second-generation TKIs in pediatric patients with CML (Table).

With prolonged exposure to TKIs and off-target effects on growth and development, treatment of pediatric CML requires a balance of disease control and long-term toxicity. Ideally, pediatric patients should achieve a deep and durable response so that TKI treatment can discontinue. This objective is being investigated in the Children’s Oncology Group AAML18P1 study about stopping TKIs (NCT03817398). Inhibitors that work by alternative mechanisms may have less off-target toxicity; for example, a pediatric dose-finding study is evaluating asciminib, a BCR-ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP) (NCT04925479). In summary, phase I of ITCC-054/COG AAML1921 established pediatric dosing for bosutinib with efficacy in patients with CML that is resistant/intolerant to earlier-generation TKIs. The phase II portion of the trial has completed enrollment of newly diagnosed and treatment-resistant/intolerant patients, with followup investigation underway. Gastrointestinal toxicity was the predominant AE. A preclinical model suggests bosutinib is associated with less growth toxicity than all other TKIs currently on the market, but long-term follow-up is required to determine the clinical applicability of this finding.

Drs. Zarnegar-Lumley and Pommert indicated no relevant conflicts of interest.

1
Hijiya
N
,
Suttorp
M
.
How I treat chronic myeloid leukemia in children and adolescents
.
Blood
.
2019
;
133
(
22
):
2374
2384
.
2
Suttorp
M
,
Schulze
P
,
Glauche
I
, et al
.
Front-line imatinib treatment in children and adolescents with chronic myeloid leukemia: results from a phase III trial
.
Leukemia
.
2018
;
32
(
7
):
1657
1669
.
3
Champagne
MA
,
Fu
CH
,
Chang
M
, et al
.
Higher dose imatinib for children with de novo chronic phase chronic myelogenous leukemia: a report from the Children’s Oncology Group
.
Pediatr Blood Cancer
.
2011
;
57
(
1
):
56
62
.
4
Gore
L
,
Kearns
PR
,
de Martino
ML
, et al
.
Dasatinib in pediatric patients with chronic myeloid leukemia in chronic phase: results from a phase II trial
.
J Clin Oncol
.
2018
;
36
(
13
):
1330
1338
.
5
Hijiya
N
,
Maschan
A
,
Rizzari
C
, et al
.
Phase 2 study of nilotinib in pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia
.
Blood
.
2019
;
134
(
23
):
2036
2045
.
6
Samis
J
,
Lee
P
,
Zimmerman
D
, et al
.
Recognizing endocrinopathies associated with tyrosine kinase inhibitor therapy in children with chronic myelogenous leukemia
.
Pediatr Blood Cancer
.
2016
;
63
(
8
):
1332
1338
.
7
Tauer
JT
,
Hofbauer
LC
,
Jung
R
, et al
.
Micro-osmotic pumps for continuous release of the tyrosine kinase inhibitor bosutinib in juvenile rats and its impact on bone growth
.
Med Sci Monit Basic Res
.
2013
;
19
:
274
278
.
8
Cortes
JE
,
Kantarjian
HM
,
Brümmendorf
TH
, et al
.
Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib
.
Blood
.
2011
;
118
(
17
):
4567
4576
.
Published correction appears in Blood. 2013;122(14):2524
.
9
Khoury
HJ
,
Cortes
JE
,
Kantarjian
HM
, et al
.
Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure
.
Blood
.
2012
;
119
(
15
):
3403
3412
.
10
Kantarjian
HM
,
Cortes
JE
,
Kim
DW
, et al
.
Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors
.
Blood
.
2014
;
123
(
9
):
1309
1318
.
Published correction appears in Blood. 2014;124(6):981
.
11
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
.
12
Brümmendorf
TH
,
Cortes
JE
,
Milojkovic
D
, et al
.
Bosutinib versus imatinib for newly diagnosed chronic phase chronic myeloid leukemia: final results from the BFORE trial
.
Leukemia
.
2022
;
36
(
7
):
1825
1833
.
13
Hochhaus
A
,
Gambacorti-Passerini
C
,
Abboud
C
, et al
.
Bosutinib for pretreated patients with chronic phase chronic myeloid leukemia: primary results of the phase 4 BYOND study
.
Leukemia
.
2020
;
34
(
8
):
2125
2137
.
14
Brivio
E
,
Pennesi
E
,
Willemse
ME
, et al
.
Bosutinib in resistant and intolerant pediatric patients with chronic phase chronic myeloid leukemia: results from the phase I part of study ITCC054/COG AAML1921
.
J Clin Oncol
.
2024
;
42
(
7
):
821
831
.
15
FDA approves bosutinib for pediatric patients with chronic myelogenous leukemia
.
FDA
.
Published online September 27, 2023
. Accessed March 27, 2024 .