Abstract

Chronic myelogenous leukemia (CML) in children is relatively rare. Because of a lack of robust clinical study evidence, management of CML in children is not standardized and often follows guidelines developed for adults. Children and young adults tend to have a more aggressive clinical presentation than older adults, and prognostic scores for adult CML do not apply to children. CML in children has been considered to have the same biology as in adults, but recent data indicate that some genetic differences exist in pediatric and adult CML. Because children with CML may receive tyrosine kinase inhibitor (TKI) therapy for many decades, and are exposed to TKIs during a period of active growth, morbidities in children with CML may be distinct from those in adults and require careful monitoring. Aggressive strategies, such as eradication of CML stem cells with limited duration and intensive regimens of chemotherapy and TKIs, may be more advantageous in children as a way to avoid lifelong exposure to TKIs and their associated adverse effects. Blood and marrow transplantation in pediatric CML is currently indicated only for recurrent progressive disease, and the acute and long-term toxicities of this option should be carefully evaluated against the complications associated with lifelong use of TKIs.

Introduction

The median age at diagnosis of chronic myelogenous leukemia (CML) is 60 to 65 years in Western registries,1  and CML is rare among children and adolescents. CML constitutes 2% of all leukemias in children younger than 15 years and 9% of all leukemias in adolescents between 15 and 19 years, with an annual incidence of 1 and 2.2 cases per million in these 2 age groups, respectively.2  Because of the low incidence of CML and a lack of robust clinical trial data in children and adolescents, practice standards for the management of pediatric CML are not as established as for adult patients.3 

After the introduction of the tyrosine kinase inhibitor (TKI) imatinib approximately 15 years ago,4  the treatment paradigm for CML changed considerably. The second-generation TKIs5,6  dasatinib and nilotinib produce more rapid and deeper molecular responses compared with imatinib in adults. These second-generation TKIs are now included as first-line treatments for chronic phase CML (CML-CP) in the most recent adult CML guidelines from European Leukemia Net (ELN)7  and the National Comprehensive Cancer Network (NCCN).8  Continuing TKI treatment indefinitely has become a standard practice for adult patients with CML-CP, and the feasibility of discontinuing TKI in patients who achieve complete molecular remission (CMR) is also being explored.9  Indications for hematopoietic stem cell transplant (HSCT), the only established curative treatment of CML, are now very limited.

Many pediatric oncologists follow treatment guidelines that are designed for adult patients, despite the absence of data supporting the extrapolation of adult guidelines to children. In some countries, children with CML are treated by adult oncologists. Yet, there are clear differences between CML in children and adults in terms of disease presentation and progression, along with differences in the underlying CML biology and host factors, which should be considered when treating pediatric patients with CML.

Differences in adult and pediatric CML may be related to host factors and CML leukemia cell biology

A number of studies have reported clinical findings in children3,10,11  and young adults12  with CML that suggest either a different leukemia cell or host biology compared with CML in adults.13  Although it might be reasonable to assume that CML in an 8-month-old,11  which may also involve congenital factors, will have a different biology from CML in a 70-year-old, there is little data to support this, and the biology of CML in children has been assumed to be identical to that in adults. It is clear that there are also host differences in adult patients compared with young, rapidly developing pediatric and adolescent patients that may affect CML development, response to treatment, and adverse effects of treatment.

CML biology is different in pediatric and adult disease

Both pediatric and adult patients with CML have the fusion gene BCR-ABL1, with breakpoints occurring in the same major breakpoint cluster regions (M-BCR) in the BCR gene on chromosome 22 and dispersed over a wide intronic distance (covering >200 kb) in the ABL1 gene.14  Krumbholz et al have shown that breakpoint distribution in BCR is different in pediatric CML compared with adult CML.15  Given the different incidences of CML in children and adolescents vs adult patients, it is possible that distinct mechanisms account for initiation of chromosomal translocation in each cohort. On the genomic level, children with CML-CP exhibit a different breakpoint distribution pattern in the BCR gene and a higher proportion of breakpoints within Alu repeat regions compared with adults with CML-CP. DNA fusion sites within the BCR major breakpoint cluster region are significantly enriched in the centromere in adult CML, whereas pediatric CML exhibits a second cluster in the telomeres, largely overlapping with an extended Alu repeat region.15  The latter distribution is similar to the pattern observed in adult Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) with M-BCR rearrangement.16,17  These differences in the genomic landscape may contribute to the more aggressive clinical characteristics in pediatric CML compared with adult CML.

Within the M-BCR, the vast majority of CML patients exhibit transcript phenotypes with an e13a2 or an e14a2 junction (b2a2 and b3a2, respectively, in older nomenclature). Both RNA variants can occur either alone or simultaneously depending on alternative splicing of the e14a2 transcript, which is influenced by intronic and exonic DNA polymorphisms.16-18  There are conflicting reports on the influence of these transcript phenotypes on hematologic findings at diagnosis. The majority of,13  but not all,12  studies in adults with CML showed that high platelet counts are observed more often in patients expressing the e14a2 transcript. Similar studies using small cohorts of pediatric patients with CML19,20  found no clear patterns; however, transcript variants in pediatric patients were comparable with those in adults in a larger series that included 146 pediatric patients.13 

The transcript phenotype also exerts an influence on the kinetics of treatment response to TKIs.21  The clinical significance of transcript type on the rate of response to imatinib was evaluated in a large cohort of adult patients in CP, of whom 44%, 41%, and 14% exhibited e14a2, e13a2, and both transcripts, respectively. Hanfstein et al found a significant difference in median time to achieve a major molecular response (MMR) with imatinib in adult patients (n = 1105) with different transcripts. Patients who had the e13a2 transcript had significantly longer median time to MMR (18.4 months) compared with those with e14a2 (14.2 months).22  Suttorp et al also found a faster response to imatinib in patients harboring the e14a2 transcript in a small cohort of children with CML.23  Although the reason for these findings remains open to speculation (eg, higher immunogenicity of the additional 25 amino acid residues encoded by exon e14), further analysis of transcript types in children with CML is needed to validate these findings and evaluate the potential role in guiding management decisions.

Clinical presentation and disease progression are different in adult and pediatric CML

Children and adolescents, as well as young adults,12  in CML-CP tend to have clinical presentations with more aggressive features,12,24,25  although the impact on prognosis is debatable. The characteristics of pediatric CML have been reported in several studies, summarized in Table 1.12,24-28  The proportion of pediatric patients diagnosed with advanced-stage disease (accelerated phase [AP] or blast phase [BP]) is higher than for adult patients.3,10,11,29,30  Among children, the median size of the spleen is 8 cm below the costal margin (range, 0-25 cm).11  This number is not very different from that of adults31 ; however, it is proportionally larger in children because the age-based normal size of the spleen in children is smaller than in adults. The median baseline white blood cell count in children with CML was approximately 250 × 109/L in an international registry of 200 children with CML (median age, 11.6 years [range, 8 months to 18 years]),11  which is higher than the range of 80 × 109/L to 150 × 109/L in adults.32  The disease maintains these aggressive clinical features after childhood, with young adults presenting with more aggressive disease compared with those diagnosed as older adults. The GIMEMA CML Working Party recently analyzed 2784 patients ≥18 years of age25  and found that young adults (18-29 years) had splenomegaly and a larger spleen more often than did older adults.25  In addition, young adults had lower complete cytogenetic response and MMR rates compared with older adults.25  In a study by Millot et al, a higher proportion of children treated with imatinib failed to achieve BCR-ABL1 transcript levels ≤10% compared with adult patients.27  It remains to be determined whether second-generation TKIs can achieve better response rates. Efficacy of nilotinib and dasatinib in children with newly diagnosed CML has been studied in phase 2 trials but the results have not been published (Table 2).33-38 

Table 1

Comparison of age-dependent differences in CML characteristics

   Organomegaly
 
Blood counts (median) Transcript phenotype
 
Risk profiles Outcomes 
Ref. Cohort age (y)* Patients (No.) Median spleen size (cm BCM) WBC (cells/µL) Platelets (cells/µL) Hgb (g/dL) Blasts in PB (%) b3a2 (%) High-risk Sokal score (%) High-risk EUTOS score (%) CCA (%) CML progression (%) Response to treatment at defined time point after start of TKI 
26  1-18 72 217 405 10.0 n.r. 16 19 n.r. n.a. <10% at 3 mo: 64%§ 
27  0.8-16.7 25 252 n.r. n.r. n.r. n.r. 52 n.r. n.r. 0.0 <10% at 3 mo: 63%§ 
1.9-17.3 15 13 378 n.r. n.r. n.r. n.r. 80 n.r. n.r. 13.3 >10% at 3 mo: 37%§ 
28  2.8-17.9 47 n.r. 171 577 9.9 n.r. 72 n.r. n.r. n.r. 3.0 CCyR at 12 mo: 96% 
MMR at 12 mo: 67% 
12  16-29 120 144 430 11.1 52 26 18 8.7 >10% at 3 mo: 42%§ 
30-44 383 106 369 11.8 61 24 16 7.3 >10% at 3 mo: 42%§ 
45-59 495 74 364 12.6 58 22 11 5.3 >10% at 3 mo: 26%§ 
>60 526 57 381 12.5 62 24 6.1 >10% at 3 mo: 25%§ 
24  15-28 61 39% 30.5 332 12.2 n.r. n.r. CCyR at 12 mo: 83% 
MMR at 18 mo: 65% 
CMR 23% 
30-85 407 23% 27.4 343 12.3 n.r, n.r. n.r. CCyR at 12 mo: 88% 
MMR at 18 mo: 78% 
CMR 41% 
25  18-30 329 4.5 62 370 11.8 54 20 18 14 CCyR at 60 mo: 80% 
MMR at 60 mo: 71% 
30-39 444 5.0 66 355 12.1 44 15 CCyR at 60 mo: 90% MMR at 60 mo: 86% 
40-49 613 3.0 54 380 12.0 21  
50-59 693 2.0 57 350 12.2 25 10  
60-69 473 1.8 54 333 12.3 47 28 CCyR at 60 mo: 90% 
>70 232 1.0 71 345 12.1 0.7 36 MMR at 60 mo: 88% 
   Organomegaly
 
Blood counts (median) Transcript phenotype
 
Risk profiles Outcomes 
Ref. Cohort age (y)* Patients (No.) Median spleen size (cm BCM) WBC (cells/µL) Platelets (cells/µL) Hgb (g/dL) Blasts in PB (%) b3a2 (%) High-risk Sokal score (%) High-risk EUTOS score (%) CCA (%) CML progression (%) Response to treatment at defined time point after start of TKI 
26  1-18 72 217 405 10.0 n.r. 16 19 n.r. n.a. <10% at 3 mo: 64%§ 
27  0.8-16.7 25 252 n.r. n.r. n.r. n.r. 52 n.r. n.r. 0.0 <10% at 3 mo: 63%§ 
1.9-17.3 15 13 378 n.r. n.r. n.r. n.r. 80 n.r. n.r. 13.3 >10% at 3 mo: 37%§ 
28  2.8-17.9 47 n.r. 171 577 9.9 n.r. 72 n.r. n.r. n.r. 3.0 CCyR at 12 mo: 96% 
MMR at 12 mo: 67% 
12  16-29 120 144 430 11.1 52 26 18 8.7 >10% at 3 mo: 42%§ 
30-44 383 106 369 11.8 61 24 16 7.3 >10% at 3 mo: 42%§ 
45-59 495 74 364 12.6 58 22 11 5.3 >10% at 3 mo: 26%§ 
>60 526 57 381 12.5 62 24 6.1 >10% at 3 mo: 25%§ 
24  15-28 61 39% 30.5 332 12.2 n.r. n.r. CCyR at 12 mo: 83% 
MMR at 18 mo: 65% 
CMR 23% 
30-85 407 23% 27.4 343 12.3 n.r, n.r. n.r. CCyR at 12 mo: 88% 
MMR at 18 mo: 78% 
CMR 41% 
25  18-30 329 4.5 62 370 11.8 54 20 18 14 CCyR at 60 mo: 80% 
MMR at 60 mo: 71% 
30-39 444 5.0 66 355 12.1 44 15 CCyR at 60 mo: 90% MMR at 60 mo: 86% 
40-49 613 3.0 54 380 12.0 21  
50-59 693 2.0 57 350 12.2 25 10  
60-69 473 1.8 54 333 12.3 47 28 CCyR at 60 mo: 90% 
>70 232 1.0 71 345 12.1 0.7 36 MMR at 60 mo: 88% 

BCM, below costal margin; CCA, complex cytogenetic aberrations in addition to Philadelphia chromosome; CCyR, complete cytogenetic response (no Ph+ chromosome detectable); CML, chronic myelogenous leukemia; CMR, complete molecular response (no BCR-ABL1 transcript detectable by RT-PCR; for details on sensitivity of PCR see text of referred publication); EUTOS, European Treatment and Outcome Study; Hgb, hemoglobin; MMR, major molecular response (transcript ratio BCR-ABL1/ABL1 < 0.1%); PB, peripheral blood; n.a., not applicable because of short follow-up; n.r., not reported; TKI, tyrosine kinase inhibitor; WBC, white blood cells.

*

Only trials reporting on cohorts of >30 patients and adult trials with data presented by age cohorts are included in the table.

The percentage of patients showing both transcripts (b3a2 and b2a2) was added to the cohort expressing only transcript b3a2.

Length of follow-up time differs among the trials, thus age-dependent comparisons can only be made for subcohorts within a given trial.

§

Percentage of the cohort achieving a transcript ratio higher or lower (as indicated) than 10% BCR-ABL1/ABL1 at month 3.

Proportion of patients with enlarged spleen of any measured size.

Includes patients who were treated with second-generation TKIs.

Table 2

Studies of TKI therapy for pediatric CML

TKI Sponsor and collaborator Phase Year published Author and references 
Imatinib COG 2004 Champagne33  
Imatinib COG 2012 Champagne34  
Imatinib French 2011 Millot35  
Dasatinib COG 2011 Aplenc36  
Dasatinib BMS/ITCC 2013 Zwaan37  
Dasatinib BMS Unpublished www.clinicaltrials.gov (#NCT00777036)38  
Nilotinib Novartis Unpublished www.clinicaltrials.gov (#NCT01077544) 
Nilotinib Novartis/COG/ITCC Unpublished www.clinicaltrials.gov (#NCT01844765) 
TKI Sponsor and collaborator Phase Year published Author and references 
Imatinib COG 2004 Champagne33  
Imatinib COG 2012 Champagne34  
Imatinib French 2011 Millot35  
Dasatinib COG 2011 Aplenc36  
Dasatinib BMS/ITCC 2013 Zwaan37  
Dasatinib BMS Unpublished www.clinicaltrials.gov (#NCT00777036)38  
Nilotinib Novartis Unpublished www.clinicaltrials.gov (#NCT01077544) 
Nilotinib Novartis/COG/ITCC Unpublished www.clinicaltrials.gov (#NCT01844765) 

BMS, Bristol-Myers Squibb; CML, chronic myelogenous leukemia; COG, Children’s Oncology Group; ITCC, Innovative Therapies for Children with Cancer Consortium.

Existing prognostic scores used in adults do not apply to children with CML

The Sokal, Hasford, and EUTOS scores are used to predict the outcomes of adult CML patients32,39,40  and to guide treatment. The Sokal score39  was established using cohorts treated with busulfan or hydroxyurea, whereas the Hasford score32  was considered to be the best predictor of survival in patients on interferon α. More recently, the EUTOS score40  was implemented as a simple calculation using just 2 parameters (spleen size and percentage of blood basophils) to categorize patients as low- or high-risk and predict progression-free survival based on the surrogate marker of early cytogenetic response to imatinib at 18 months. The Sokal and Hasford scores predict molecular response, risk of progression to AP or BP, and overall survival in adult patients treated with imatinib, and thus remain useful as prognostic markers in the TKI era.

NCCN guidelines (version 1.2015) recommend the use of dasatinib or nilotinib in intermediate- or high-risk patients based on the Sokal score or Hasford score.8  Yet, the validity of these scores has not been formally evaluated in the pediatric population and their prognostic significance may not apply to these patients. The Sokal39  and Hasford32  scores were defined in cohorts that included small numbers of children and adolescents, and the EUTOS score40  was derived using only data from adults (≥18 years). Using the Sokal score,39  which is based on age, spleen size, platelet counts, and blast count, a 10-year-old with CML would have a lower risk than a 60-year-old patient with the same spleen size and blood cell counts. No data support this conclusion. The difference in spleen size by age in children should be taken into consideration when applying prognostic scores for CML. Suttorp et al attempted to validate the 3 scoring systems, as well as a modified “Sokal young score,”41  in 90 children (median age, 11.6 years [range, 1-18) on imatinib.26  There was high discordance among the 4 scoring methods, which validates the concerns raised about using these scores for risk assessment or to make treatment decisions for children with CML.

In adult patients, early molecular and cytogenetic response has been shown to correlate with long-term survival.42  Millot et al evaluated the significance of early response in 40 children with newly diagnosed CML who were treated with imatinib,27  and the result was comparable with that in adult patients.42  Children with a BCR-ABL1/ABL ratio ≤10% after 3 months of imatinib had higher rates of complete cytogenetic response and MMR at 12 months than did patients with a BCR-ABL1/ABL ratio >10%. This finding needs to be confirmed in a larger cohort of pediatric patients, but the early response could identify a subset of patients who require alternative treatment strategies.27 

Host factors may underlie the different TKI adverse effects seen in children with CML

Imatinib is known to have several off-target effects43  and has been shown to dysregulate bone remodeling and change bone mineral density in adult patients.43,44  Children have immature skeletons and longer life expectancies than adult patients, and the current standard practice of continuing TKI indefinitely can lead to significant long-term morbidities in growing children, as has been shown in juvenile animal models.45,46  In children, various groups have reported substantial growth abnormalities associated with imatinib in children with CML.47-55  There is less experience with second- and third-generation TKIs in children, but dasatinib also seems to have a similar effect on growth.48  It appears that prepubertal children are affected more significantly,29  and though they may experience “catch-up” growth in puberty, their final height is lower than the predicted midparental height.47  Some reports suggest that the growth hormone/IGF-1 axis is affected by TKIs,45,48,56,57  and cotreatment with growth hormone or recombinant IGF-1 may improve the final adult height in children receiving TKIs; however, no study has demonstrated the safety or efficacy of this strategy.

TKIs may also have adverse effects on pregnancy outcomes because of the teratogenic potential of the drug.58  Although the data are sparse,8  it is generally recommended that female patients of childbearing age avoid pregnancy while taking a TKI and that TKI treatment should be withheld during pregnancy if the patient is in deep molecular remission.58-61  It is strongly recommended that teenage girls with CML be counseled early about reproductive considerations to increase their adherence to long-term treatment.

Perhaps a more important question for children and adolescents with CML is whether TKI treatment has a long-term effect on future fertility. There is very little evidence on the effect of early TKI exposure on later fertility in humans, and the results of animal studies vary.57,60,62,63  Nevertheless, a few case reports describe a decrease in markers of fertility in a teenage male64  and a young adult female65  who received imatinib. Studies with long-term follow-up in children treated with TKIs are needed.

Other morbidities observed in adults, such as thyroid dysfunction66  and cardiovascular toxicity,67-69  have not been reported in children to date; however, because children with CML may receive TKI therapy for much longer periods of time than adults, they may also develop unanticipated comorbidities, and careful follow-up is imperative. Although it will be important to gather more data in prospective studies, we recommend that pediatric patients who are treated with TKIs off protocol are at least monitored for height, weight, and Tanner stage on every visit, in addition to periodic bone age and dual-energy x-ray absorptiometry scans, and that an endocrinology consultation is pursued if there are abnormal patterns (Table 3).3 

Table 3

Recommendations for monitoring and supportive care in children with CML receiving TKI therapy

• Accurate measurement of height and weight at each visit and close monitoring of growth velocity. Consider bone scan and DEXA scan and refer to endocrinology if there is evidence of an abnormal growth pattern. 
• Tanner staging at each visit. Consider checking gonadotropins and sex steroids and refer to endocrinology if there is evidence of a pubertal delay. 
• Thyroid function (TSH, free T4) 4 to 6 weeks after start of TKI and annually thereafter. 
• Counseling on reproductive considerations for young women of childbearing age. 
• Annual echocardiogram and electrocardiogram. 
• Live vaccines are not recommended. Inactivated vaccines may be given safely, but their efficacy has not been proven. 
• Accurate measurement of height and weight at each visit and close monitoring of growth velocity. Consider bone scan and DEXA scan and refer to endocrinology if there is evidence of an abnormal growth pattern. 
• Tanner staging at each visit. Consider checking gonadotropins and sex steroids and refer to endocrinology if there is evidence of a pubertal delay. 
• Thyroid function (TSH, free T4) 4 to 6 weeks after start of TKI and annually thereafter. 
• Counseling on reproductive considerations for young women of childbearing age. 
• Annual echocardiogram and electrocardiogram. 
• Live vaccines are not recommended. Inactivated vaccines may be given safely, but their efficacy has not been proven. 

DEXA, dual-energy x-ray absorptiometry; T4, thyroxine; TSH, thyroid-stimulating hormone.

TKIs appear to cause immune dysfunction to some degree,70  which interferes with routine immunizations in children. Live vaccines are not recommended.3  It is safe to give inactivated vaccines, although humoral responses may be impaired, as in any immunocompromised patient.

Pediatric CML may require a different approach to TKI treatment

The goals of CML therapy are the same for adults and children: disease remission, reduced risk of progression, and survival.71  However, the treatment of CML in children must take into account the added challenge of achieving these goals while minimizing toxicities for 6 or 7 decades. Although cure is the ideal goal for all patients regardless of age, for older adults, it may be sufficient to approach CML as a chronic disease, with the goal of maintaining patients in CML-CP for a few decades with TKIs. In the GIMEMA study,25  the percentage of young adults who were treated with TKI and had cumulative probability of progression to AP and BP at 8 years was 16% (95% confidence interval [CI], 8-31), which was higher than in adults (5%; 95% CI, 3-8) or elderly (7%; 95% CI, 4-11). Children have a much longer life expectancy and thus potentially longer exposure to TKI therapy, yet there are no data on the long-term efficacy of TKI therapy beyond 15 years. Furthermore, as discussed before, prolonged treatment with TKIs has potentially major long-term effects and different effects in the still-growing child compared with the adult. These adverse effects can be cumulatively higher in the pediatric CML population with lifetime exposure to TKIs. Further complicating the issue are reports from pediatric oncologists who observe poor adherence more frequently in adolescents compared with older adults or younger children,72,73  making extended use of TKIs a less viable option in these patients. When selecting a TKI, it is important to consider adherence. Twice-daily dosing of nilotinib may be more challenging for pediatric patients than once-daily dosing of imatinib or dasatinib. Formulations of TKI with better palatability may also improve adherence among pediatric patients and should be developed. Other methods to improve adherence, such as direct supervision or various reminder systems,74  may be needed in patients with suboptimal responses to TKIs. Another factor that needs to be considered is the cumulative cost of TKI therapy in children who may need decades of treatment, although this may become less of an issue in the near future with the introduction of generic products.75 

Taking into account all of these issues, it is clear that an important goal of pediatric CML management should be the avoidance of lifelong treatment with TKIs. One potential solution is to stop TKIs after a certain period of deep molecular remission.9,76-78  Use of this approach in children and adolescents with CML is supported by the results of the prospective Stop Imatinib (STIM) study in adults (≥18 years of age), which evaluated the feasibility of discontinuing imatinib in patients who maintained a CMR for at least 2 years on imatinib.9  Sixty-nine of 100 patients enrolled had at least 12 months of follow-up (median, 24 months [range, 13-30]) and 42 of 69 patients (61%) experienced relapse. The probability of remaining in CMR at 12 months for these 69 patients was 41% (95% CI, 29-52). All patients who had a molecular relapse responded to reintroduction of imatinib. Despite these results, there is limited information on the longer-term (>5 years) outcomes of CML patients in CMR after cessation of TKI.9,77  Intermittent TKI dosing79  may be a potential approach to reducing long-term morbidity in pediatric CML while sustaining molecular remission.46,54  More studies are needed to evaluate this approach.

Unfortunately, stopping TKI treatment in the subset of patients who are in molecular remission does not address the issue that the majority of children would probably need to remain on TKIs.9  TKIs do not target the leukemic stem cells that may play a significant role in TKI resistance.80-83  Because of the factors outlined here, there is a compelling argument for conducting trials in children and adolescents to study combinations of TKIs with other agents such as JAK2 inhibitors83,84  and interferon-α85,86  that do affect leukemic stem cells. With the goal of avoiding lifelong TKI treatment, strategies that permanently eliminate the CML clone—for example, using limited duration, more intensive chemotherapy in combination with TKIs, similar to approaches used in recent trials of Ph+ ALL87 —may be intriguing options for treatment of pediatric CML.

BMT for CML-CP may have a bigger role in children than in adults with CML

Until the availability of TKIs, blood and marrow transplantation (BMT) was once the optimal curative choice for children and adolescents with CML.88  With its more aggressive clinical features and evidence of biological and host differences, pediatric CML cannot be easily categorized using adult criteria or treated using adult guidelines. As the only established therapeutic approach that can achieve a lifelong remission in CML, allogeneic BMT may allow pediatric CML patients to avoid lifelong TKI therapy. Until treatment approaches with TKIs, potentially in combination with other agents, can be optimized to achieve durable remission, BMT will continue to be considered the only curative option.

The risks vs benefits of BMT in children with CML can be viewed as similar to those for some nonmalignant diseases, such as sickle cell anemia or thalassemia, where the morbidity and mortality of long-term therapies to control the disease are weighed against the potentially more toxic, but curative modality of allogeneic BMT. Children with thalassemia are maintained on transfusion therapy and chelation therapy and can live for decades with low levels of toxicity and morbidity; however, cumulative side effects result in a shortened life span. Similarly, the risks of TKI, although low, include rare, serious, and life-threatening complications such as pancreatitis and pulmonary arterial hypertension. Surveys of patients with sickle cell disease give some insight into patient perceptions of the risks vs benefits of a higher risk curative therapy such as BMT weighed against maintenance with lower-toxicity but noncurative therapies such as TKIs: 72% of patients surveyed were willing to accept a ≥5% mortality risk and 57% were willing to accept a ≥10% risk of graft-versus-host disease (GVHD) to undergo curative HSCT.89  With its long history, the complications of allogeneic BMT in younger patients have been well established and include acute and chronic GVHD, infertility, pulmonary fibrosis, endocrine failure, growth and development issues, and metabolic syndrome. Although it may be preferable to wait until patients reach the age of legal majority, transplant-related mortality (TRM) increases as early as 16 years of age90  for umbilical cord blood donor BMT, which shrinks the window for decision-making.

The current outcomes of BMT for CML-CP in adults and children has been reported to be as high as 90% in a few studies,91,92  whereas other studies showed lower numbers (Table 4).88,91,93,94  Late outcomes of BMT (>2 years) for CML have been evaluated in the Bone Marrow Transplant Survivor study,95  although only 5% of the patients were <21 years of age. In that study, overall health was excellent, very good, or good in 78% of patients. The major factors associated with long-term complications were chronic GVHD and, to a lesser extent, use of an unrelated donor.95 

Table 4

Results of HSCT in children (≤18 y of age) with CML in first chronic phase

Author Year Patients (No.) Disease phase at HSCT Donor source Overall survival Notes 
Cwynarski93  2003 314 CP1, n = 253 MSD 75% (CP1, MSD, n = 156) EBMT registry data 
Other, n = 61 VUD 65% (CP1, VUD, n = 97) 
Suttorp91  2009 176 CP1, n = 158 MRD At 5 y:  
Other, n = 18 MUD 87 ± 11% (MSD, n = 41) 
52 ± 9% (MUD, n = 71) 
45 ± 16% (MMD, n = 55) 
Muramatsu94  2010 125 CP1, n = 88 Unrelated 59.3% at 5 y  
Other, n = 37 
Chaudhury88  2014 177 CP1 and hematologic remission  71% (95% CI, 65-77) at 5 y CIBMTR data 
Author Year Patients (No.) Disease phase at HSCT Donor source Overall survival Notes 
Cwynarski93  2003 314 CP1, n = 253 MSD 75% (CP1, MSD, n = 156) EBMT registry data 
Other, n = 61 VUD 65% (CP1, VUD, n = 97) 
Suttorp91  2009 176 CP1, n = 158 MRD At 5 y:  
Other, n = 18 MUD 87 ± 11% (MSD, n = 41) 
52 ± 9% (MUD, n = 71) 
45 ± 16% (MMD, n = 55) 
Muramatsu94  2010 125 CP1, n = 88 Unrelated 59.3% at 5 y  
Other, n = 37 
Chaudhury88  2014 177 CP1 and hematologic remission  71% (95% CI, 65-77) at 5 y CIBMTR data 

Only studies with >100 cases are listed.

CI, confidence interval; CIBMTR, Center for International Blood and Marrow Transplant Research; CP1, first chronic phase; EBMT, European Group for Blood and Marrow Transplantation; HSCT, hematopoietic stem cell therapy; MMD, mismatched donor; MRD, matched-related donor; MSD, matched-sibling donor; MUD, matched-unrelated donor; VUD, volunteer-unrelated donor.

Since the advent of the TKIs, however, the application of allogeneic BMT in pediatric and adolescent patients has decreased dramatically because of a decrease in early complications associated with TKIs compared with BMT. Yet the complications of allogeneic BMT have also decreased since 2000, with better management of sinusoidal obstruction syndrome, infections, and GVHD.96  Nevertheless, patients who undergo BMT have a distinct risk of mortality associated with the procedure. The 1-year TRM for higher-risk acute leukemia in CR is 10% and the TRM rate in the CML IV study92  was 7% (4/56) for allogeneic BMT in CR1. It should be pointed out that the median age for BMT patients in the CML IV study was 37 years and thus does not accurately represent the pediatric cohort. A recent paper on outcomes in a small group of pediatric patients with CML undergoing HSCT28  reported a TRM of 0% after a median follow-up of 52 months. Moreover, the US Patient Survival Report from the Health Resources and Services Administration (HRSA) (http://bloodcell.transplant.hrsa.gov/research/transplant_data/us_tx_data/survival_data/survival.aspx) also reported a 100-day TRM of 0% for related donor BMT and 5% for unrelated donor BMT in patients with CML CR1 and <21 years of age. An increased use of reduced-intensity allogeneic BMT has resulted in a decrease in transplant-related mortality, although the risk of GVHD may be higher.97  The use of alemtuzumab, antithymocyte globulin, and post-transplantation cyclophosphamide has also resulted in a significant decrease in both acute and chronic GVHD.98-102 

With the current focus on the short-term responses to TKI and its few associated toxicities, there is no consensus on the role for allogeneic BMT, including human leukocyte antigen–identical sibling donor transplants, for CML-CP responsive to TKI therapy. Compliance and cost can limit access to TKI therapy, but donor availability for BMT is also an issue.

The field is ready to consider the possibility of long-term curative outcomes in pediatric CML, and accumulating evidence of the unique biology of the pediatric CML stem cell and host demand a re-evaluation of the role of single TKI as the optimal therapy and the possible role of BMT. The recent development of reduced-toxicity BMT, particularly human leukocyte antigen–identical sibling BMT, with its superior survival outcomes, may play a bigger role in the treatment of children with CML in the future. Unfortunately, there are no good prognostic criteria to identify pediatric CML-CP patients who have an expected event-free survival rate of <80% despite prolonged TKI treatment and who may benefit from BMT. For now, the only indications for allogeneic BMT in children and adolescents are for those who have failed TKI therapy, have experienced progression of CML while on a TKI, or have CML-BP. Better prognostic criteria for evaluating long-term survival and complications of CML-CP treated with TKI, as well as studies evaluating reduced-toxicity BMT for pediatric CML-CP, are needed.

Summary

CML in children has more aggressive clinical features, and recent work has begun to reveal differences in CML biology in adults and children that may account for the clinical differences in CML presentation, progression, and response to treatment. Clinicians need to be aware of the host factors in children that lead to different morbidities associated with TKI treatment. The prospect of decades-long TKI treatment raises the question of whether children in the first CML-CP should be offered BMT, but this should await further investigation. Clinical trials to test the feasibility of intermittent TKI therapy or stopping TKI treatment and to test new agents that target CML stem cells should be preferentially considered in children. International collaborative efforts and funding to conduct larger studies and construct a shared clinical database for pediatric CML are urgently needed to address unanswered questions and issues.

Acknowledgments

The authors thank Stacey Tobin for assistance in language editing and William J. Muller for valuable discussions regarding vaccination recommendations in immune compromised patients.

Authorship

Contribution: All authors wrote and edited the manuscript.

Conflict-of-interest disclosure: N.H. has served as an advisor for Pfizer and as a consultant for Sanofi. F.M. has served as an advisor for Pfizer and has been a speaker for ARIAD and Novartis. M.S. has received research funding from Novartis and Bristol-Myers Squibb and has provided expert testimony for Pfizer. The remaining authors declare no competing financial interests.

Correspondence: Nobuko Hijiya, 225 E. Chicago Ave, Box #30, Chicago, IL 60611; e-mail: nhijiya@luriechildrens.org or n-hijiya@northwestern.edu.

References

References
1
Gugliotta
 
G
Castagnetti
 
F
Apolinari
 
M
, et al. 
First-line treatment of newly diagnosed elderly patients with chronic myeloid leukemia: current and emerging strategies.
Drugs
2014
, vol. 
74
 
6
(pg. 
627
-
643
)
2
Ries LAG, Smith M, Gurney JG, et al, eds. Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975-1995. In: National Cancer Institute, vol. 99. Bethesda, MD: SEER Program; 1999:46-49
3
Hijiya
 
N
Millot
 
F
Suttorp
 
M
Chronic myeloid leukemia in children: clinical findings, management, and unanswered questions.
Pediatr Clin North Am
2015
, vol. 
62
 
1
(pg. 
107
-
119
)
4
Druker
 
BJ
Sawyers
 
CL
Kantarjian
 
H
, et al. 
Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome.
N Engl J Med
2001
, vol. 
344
 
14
(pg. 
1038
-
1042
)
5
Larson
 
RA
Hochhaus
 
A
Hughes
 
TP
, et al. 
Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up.
Leukemia
2012
, vol. 
26
 
10
(pg. 
2197
-
2203
)
6
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
, vol. 
119
 
5
(pg. 
1123
-
1129
)
7
Baccarani
 
M
Deininger
 
MW
Rosti
 
G
, et al. 
European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013.
Blood
2013
, vol. 
122
 
6
(pg. 
872
-
884
)
8
NCCN Clinical Practice Guidelines in Oncology.
2015
Chronic Myelogenous Leukemia: National Comprehensive Cancer Network
9
Mahon
 
FX
Réa
 
D
Guilhot
 
J
, et al. 
Intergroupe Français des Leucémies Myéloïdes Chroniques
Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial.
Lancet Oncol
2010
, vol. 
11
 
11
(pg. 
1029
-
1035
)
10
Millot
 
F
Traore
 
P
Guilhot
 
J
, et al. 
Clinical and biological features at diagnosis in 40 children with chronic myeloid leukemia.
Pediatrics
2005
, vol. 
116
 
1
(pg. 
140
-
143
)
11
Millot
 
F
Suttorp
 
M
Guilhot
 
J
, et al. 
The International Registry for Chronic Myeloid Leukemia (CML) in Children and Adolescents (I-CML-Ped-Study): objectives and preliminary results [abstract].
Blood
2012
, vol. 
120
 
21
 
Abstract 3741
12
Kalmanti
 
L
Saussele
 
S
Lauseker
 
M
, et al. 
German Chronic Myeloid Leukemia Study Group; Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung (SAKK)
Younger patients with chronic myeloid leukemia do well in spite of poor prognostic indicators: results from the randomized CML study IV.
Ann Hematol
2014
, vol. 
93
 
1
(pg. 
71
-
80
)
13
Adler
 
R
Viehmann
 
S
Kuhlisch
 
E
, et al. 
Correlation of BCR/ABL transcript variants with patients’ characteristics in childhood chronic myeloid leukaemia.
Eur J Haematol
2009
, vol. 
82
 
2
(pg. 
112
-
118
)
14
Suryanarayan
 
K
Hunger
 
SP
Kohler
 
S
, et al. 
Consistent involvement of the bcr gene by 9;22 breakpoints in pediatric acute leukemias.
Blood
1991
, vol. 
77
 
2
(pg. 
324
-
330
)
15
Krumbholz
 
M
Karl
 
M
Tauer
 
JT
, et al. 
Genomic BCR-ABL1 breakpoints in pediatric chronic myeloid leukemia.
Genes Chromosomes Cancer
2012
, vol. 
51
 
11
(pg. 
1045
-
1053
)
16
Branford
 
S
Hughes
 
TP
Rudzki
 
Z
Dual transcription of b2a2 and b3a2 BCR-ABL transcripts in chronic myeloid leukaemia is confined to patients with a linked polymorphism within the BCR gene.
Br J Haematol
2002
, vol. 
117
 
4
(pg. 
875
-
877
)
17
Meissner
 
RV
Dias
 
PM
Covas
 
DT
Job
 
F
Leite
 
M
Nardi
 
NB
A polymorphism in exon b2 of the major breakpoint cluster region (M-bcr) identified in chronic myeloid leukaemia patients.
Br J Haematol
1998
, vol. 
103
 
1
(pg. 
224
-
226
)
18
Saussele
 
S
Weisser
 
A
Müller
 
MC
, et al. 
Frequent polymorphism in BCR exon b2 identified in BCR-ABL positive and negative individuals using fluorescent hybridization probes.
Leukemia
2000
, vol. 
14
 
11
(pg. 
2006
-
2010
)
19
Aurer
 
I
Butturini
 
A
Gale
 
RP
BCR-ABL rearrangements in children with Philadelphia chromosome-positive chronic myelogenous leukemia.
Blood
1991
, vol. 
78
 
9
(pg. 
2407
-
2410
)
20
Hasan
 
SK
Sazawal
 
S
Kumar
 
B
, et al. 
Childhood CML in India: b2a2 transcript is more common than b3a2.
Cancer Genet Cytogenet
2006
, vol. 
169
 
1
(pg. 
76
-
77
)
21
Lucas
 
CM
Harris
 
RJ
Giannoudis
 
A
, et al. 
Chronic myeloid leukemia patients with the e13a2 BCR-ABL fusion transcript have inferior responses to imatinib compared to patients with the e14a2 transcript.
Haematologica
2009
, vol. 
94
 
10
(pg. 
1362
-
1367
)
22
Hanfstein
 
B
Lauseker
 
M
Hehlmann
 
R
, et al. 
SAKK and the German CML Study Group
Distinct characteristics of e13a2 versus e14a2 BCR-ABL1 driven chronic myeloid leukemia under first-line therapy with imatinib.
Haematologica
2014
, vol. 
99
 
9
(pg. 
1441
-
1447
)
23
Suttorp
 
M
Thiede
 
C
Tauer
 
JT
Range
 
U
Schlegelberger
 
B
von Neuhoff
 
N
Impact of the type of the BCR-ABL fusion transcript on the molecular response in pediatric patients with chronic myeloid leukemia.
Haematologica
2010
, vol. 
95
 
5
(pg. 
852
-
853
)
24
Pemmaraju
 
N
Kantarjian
 
H
Shan
 
J
, et al. 
Analysis of outcomes in adolescents and young adults with chronic myelogenous leukemia treated with upfront tyrosine kinase inhibitor therapy.
Haematologica
2012
, vol. 
97
 
7
(pg. 
1029
-
1035
)
25
Castagnetti
 
F
Gugliotta
 
G
Baccarani
 
M
, et al. 
GIMEMA CML Working Party
Differences among young adults, adults and elderly chronic myeloid leukemia patients.
Ann Oncol
2015
, vol. 
26
 
1
(pg. 
185
-
192
)
26
Gurrea Salas
 
D
Glauche
 
I
Tauer
 
JT
Thiede
 
C
Suttorp
 
M
Can prognostic scoring systems for chronic myeloid leukemia as established in adults be applied to pediatric patients?
Ann Hematol
2015
, vol. 
94
 
8
(pg. 
1363
-
1371
)
27
Millot
 
F
Guilhot
 
J
Baruchel
 
A
, et al. 
Impact of early molecular response in children with chronic myeloid leukemia treated in the French Glivec phase 4 study.
Blood
2014
, vol. 
124
 
15
(pg. 
2408
-
2410
)
28
Giona
 
F
Putti
 
MC
Micalizzi
 
C
, et al. 
Long-term results of high-dose imatinib in children and adolescents with chronic myeloid leukaemia in chronic phase: the Italian experience.
Br J Haematol
2015
, vol. 
170
 
3
(pg. 
398
-
407
)
29
Suttorp
 
M
Millot
 
F
Treatment of pediatric chronic myeloid leukemia in the year 2010: use of tyrosine kinase inhibitors and stem-cell transplantation.
Hematol Am Soc Hematol Educ Program
2010
, vol. 
2010
 (pg. 
368
-
376
)
30
Mitra
 
D
Trask
 
PC
Iyer
 
S
Candrilli
 
SD
Kaye
 
JA
Patient characteristics and treatment patterns in chronic myeloid leukemia: evidence from a multi-country retrospective medical record chart review study.
Int J Hematol
2012
, vol. 
95
 
3
(pg. 
263
-
273
)
31
Savage
 
DG
Szydlo
 
RM
Goldman
 
JM
Clinical features at diagnosis in 430 patients with chronic myeloid leukaemia seen at a referral centre over a 16-year period.
Br J Haematol
1997
, vol. 
96
 
1
(pg. 
111
-
116
)
32
Hasford
 
J
Pfirrmann
 
M
Hehlmann
 
R
, et al. 
Writing Committee for the Collaborative CML Prognostic Factors Project Group
A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa.
J Natl Cancer Inst
1998
, vol. 
90
 
11
(pg. 
850
-
858
)
33
Champagne
 
MA
Capdeville
 
R
Krailo
 
M
, et al. 
Children’s Oncology Group phase 1 study
Imatinib mesylate (STI571) for treatment of children with Philadelphia chromosome-positive leukemia: results from a Children’s Oncology Group phase 1 study.
Blood
2004
, vol. 
104
 
9
(pg. 
2655
-
2660
)
34
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
, vol. 
57
 
1
(pg. 
56
-
62
)
35
Millot
 
F
Baruchel
 
A
Guilhot
 
J
, et al. 
Imatinib is effective in children with previously untreated chronic myelogenous leukemia in early chronic phase: results of the French national phase IV trial.
J Clin Oncol
2011
, vol. 
29
 
20
(pg. 
2827
-
2832
)
36
Aplenc
 
R
Blaney
 
SM
Strauss
 
LC
, et al. 
Pediatric phase I trial and pharmacokinetic study of dasatinib: a report from the children’s oncology group phase I consortium.
J Clin Oncol
2011
, vol. 
29
 
7
(pg. 
839
-
844
)
37
Zwaan
 
CM
Rizzari
 
C
Mechinaud
 
F
, et al. 
Dasatinib in children and adolescents with relapsed or refractory leukemia: results of the CA180-018 phase I dose-escalation study of the Innovative Therapies for Children with Cancer Consortium.
J Clin Oncol
2013
, vol. 
31
 
19
(pg. 
2460
-
2468
)
38
Zwaan
 
CM
Stork
 
L
Bertrand
 
Y
, et al. 
A phase 2 study of dasatinib therapy in children and adolescents with newly diagnosed chronic phase chronic myelogenous leukemia (CML-CP) or Philadelphia chromosome-positive (Ph+) leukemias resistant or intolerant to imatinib.
 
2012 American Society of Clinical Oncology Annual Meeting. Chicago, IL, 2012
39
Sokal
 
JE
Cox
 
EB
Baccarani
 
M
, et al. 
Prognostic discrimination in “good-risk” chronic granulocytic leukemia.
Blood
1984
, vol. 
63
 
4
(pg. 
789
-
799
)
40
Hasford
 
J
Baccarani
 
M
Hoffmann
 
V
, et al. 
Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score.
Blood
2011
, vol. 
118
 
3
(pg. 
686
-
692
)
41
Sokal
 
JE
Baccarani
 
M
Tura
 
S
, et al. 
Prognostic discrimination among younger patients with chronic granulocytic leukemia: relevance to bone marrow transplantation.
Blood
1985
, vol. 
66
 
6
(pg. 
1352
-
1357
)
42
Hanfstein
 
B
Müller
 
MC
Hehlmann
 
R
, et al. 
SAKK; German CML Study Group
Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML).
Leukemia
2012
, vol. 
26
 
9
(pg. 
2096
-
2102
)
43
Vandyke
 
K
Fitter
 
S
Dewar
 
AL
Hughes
 
TP
Zannettino
 
AC
Dysregulation of bone remodeling by imatinib mesylate.
Blood
2010
, vol. 
115
 
4
(pg. 
766
-
774
)
44
Vandyke
 
K
Fitter
 
S
Drew
 
J
, et al. 
Prospective histomorphometric and DXA evaluation of bone remodeling in imatinib-treated CML patients: evidence for site-specific skeletal effects.
J Clin Endocrinol Metab
2013
, vol. 
98
 
1
(pg. 
67
-
76
)
45
Ulmer
 
A
Tabea Tauer
 
J
Glauche
 
I
Jung
 
R
Suttorp
 
M
TK inhibitor treatment disrupts growth hormone axis: clinical observations in children with CML and experimental data from a juvenile animal model.
Klin Padiatr
2013
, vol. 
225
 
3
(pg. 
120
-
126
)
46
Geidel
 
P
Steinbronn
 
N
, et al. 
Cardiac failure in juvenile rats caused by continuous long-term exposure to the tyrosine kinase inhibitor dasatinib can be circumvented by an intermittent application schedule [abstract].
Blood
2013
, vol. 
122
 
21
 
Abstract 3984
47
Rastogi
 
MV
Stork
 
L
Druker
 
B
Blasdel
 
C
Nguyen
 
T
Boston
 
BA
Imatinib mesylate causes growth deceleration in pediatric patients with chronic myelogenous leukemia.
Pediatr Blood Cancer
2012
, vol. 
59
 
5
(pg. 
840
-
845
)
48
Hobernicht
 
SL
Schweiger
 
B
Zeitler
 
P
Wang
 
M
Hunger
 
SP
Acquired growth hormone deficiency in a girl with chronic myelogenous leukemia treated with tyrosine kinase inhibitor therapy.
Pediatr Blood Cancer
2011
, vol. 
56
 
4
(pg. 
671
-
673
)
49
Bansal
 
D
Shava
 
U
Varma
 
N
Trehan
 
A
Marwaha
 
RK
Imatinib has adverse effect on growth in children with chronic myeloid leukemia.
Pediatr Blood Cancer
2012
, vol. 
59
 
3
(pg. 
481
-
484
)
50
Schmid
 
H
Jaeger
 
BA
Lohse
 
J
Suttorp
 
M
Longitudinal growth retardation in a prepuberal girl with chronic myeloid leukemia on long-term treatment with imatinib.
Haematologica
2009
, vol. 
94
 
8
(pg. 
1177
-
1179
)
51
Mariani
 
S
Giona
 
F
Basciani
 
S
Brama
 
M
Gnessi
 
L
Low bone density and decreased inhibin-B/FSH ratio in a boy treated with imatinib during puberty.
Lancet
2008
, vol. 
372
 
9633
(pg. 
111
-
112
)
52
Kimoto
 
T
Inoue
 
M
Kawa
 
K
Growth deceleration in a girl treated with imatinib.
Int J Hematol
2009
, vol. 
89
 
2
(pg. 
251
-
252
)
53
Shima
 
H
Tokuyama
 
M
Tanizawa
 
A
, et al. 
Distinct impact of imatinib on growth at prepubertal and pubertal ages of children with chronic myeloid leukemia.
J Pediatr
2011
, vol. 
159
 
4
(pg. 
676
-
681
)
54
Giona
 
F
Mariani
 
S
Gnessi
 
L
, et al. 
Bone metabolism, growth rate and pubertal development in children with chronic myeloid leukemia treated with imatinib during puberty.
Haematologica
2013
, vol. 
98
 
3
(pg. 
e25
-
e27
)
55
Millot
 
F
Guilhot
 
J
Baruchel
 
A
, et al. 
Growth deceleration in children treated with imatinib for chronic myeloid leukaemia.
Eur J Cancer
2014
, vol. 
50
 
18
(pg. 
3206
-
3211
)
56
Narayanan
 
KR
Bansal
 
D
Walia
 
R
, et al. 
Growth failure in children with chronic myeloid leukemia receiving imatinib is due to disruption of GH/IGF-1 axis.
Pediatr Blood Cancer
2013
, vol. 
60
 
7
(pg. 
1148
-
1153
)
57
Ulmer
 
A
Tauer
 
JT
Suttorp
 
M
Impact of treatment with tyrosine kinase inhibitors (TKIs) on blood levels of growth hormone-related parameters, testosterone, and inhibin B in juvenile rats and pediatric patients with chronic myeloid leukemia (CML) [abstract].
Blood
2012
, vol. 
120
 
21
 
Abstract 3752
58
Pye
 
SM
Cortes
 
J
Ault
 
P
, et al. 
The effects of imatinib on pregnancy outcome.
Blood
2008
, vol. 
111
 
12
(pg. 
5505
-
5508
)
59
Berveiller
 
P
Andreoli
 
A
Mir
 
O
, et al. 
A dramatic fetal outcome following transplacental transfer of dasatinib.
Anticancer Drugs
2012
, vol. 
23
 
7
(pg. 
754
-
757
)
60
Apperley
 
J
CML in pregnancy and childhood.
Best Pract Res Clin Haematol
2009
, vol. 
22
 
3
(pg. 
455
-
474
)
61
Milojkovic
 
D
Apperley
 
JF
How I treat leukemia during pregnancy.
Blood
2014
, vol. 
123
 
7
(pg. 
974
-
984
)
62
Nurmio
 
M
Toppari
 
J
Zaman
 
F
, et al. 
Inhibition of tyrosine kinases PDGFR and C-Kit by imatinib mesylate interferes with postnatal testicular development in the rat.
Int J Androl
2007
, vol. 
30
 
4
(pg. 
366
-
376, discussion 376
)
63
Schultheis
 
B
Nijmeijer
 
BA
Yin
 
H
Gosden
 
RG
Melo
 
JV
Imatinib mesylate at therapeutic doses has no impact on folliculogenesis or spermatogenesis in a leukaemic mouse model.
Leuk Res
2012
, vol. 
36
 
3
(pg. 
271
-
274
)
64
Seshadri
 
T
Seymour
 
JF
McArthur
 
GA
Oligospermia in a patient receiving imatinib therapy for the hypereosinophilic syndrome.
N Engl J Med
2004
, vol. 
351
 
20
(pg. 
2134
-
2135
)
65
Christopoulos
 
C
Dimakopoulou
 
V
Rotas
 
E
Primary ovarian insufficiency associated with imatinib therapy.
N Engl J Med
2008
, vol. 
358
 
10
(pg. 
1079
-
1080
)
66
Kim
 
TD
Schwarz
 
M
Nogai
 
H
, et al. 
Thyroid dysfunction caused by second-generation tyrosine kinase inhibitors in Philadelphia chromosome-positive chronic myeloid leukemia.
Thyroid
2010
, vol. 
20
 
11
(pg. 
1209
-
1214
)
67
Giles
 
FJ
Mauro
 
MJ
Hong
 
F
, et al. 
Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: a retrospective cohort analysis.
Leukemia
2013
, vol. 
27
 
6
(pg. 
1310
-
1315
)
68
Atallah
 
E
Nilotinib cardiac toxicity: should we still be concerned?
Leuk Res
2011
, vol. 
35
 
5
(pg. 
577
-
578
)
69
Valent
 
P
Hadzijusufovic
 
E
Schernthaner
 
GH
Wolf
 
D
Rea
 
D
le Coutre
 
P
Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors.
Blood
2015
, vol. 
125
 
6
(pg. 
901
-
906
)
70
de Lavallade
 
H
Khoder
 
A
Hart
 
M
, et al. 
Tyrosine kinase inhibitors impair B-cell immune responses in CML through off-target inhibition of kinases important for cell signaling.
Blood
2013
, vol. 
122
 
2
(pg. 
227
-
238
)
71
Mahon
 
FX
Etienne
 
G
Deep molecular response in chronic myeloid leukemia: the new goal of therapy?
Clin Cancer Res
2014
, vol. 
20
 
2
(pg. 
310
-
322
)
72
Reaman
 
GH
Bonfiglio
 
J
Krailo
 
M
, et al. 
Cancer in adolescents and young adults.
Cancer
1993
, vol. 
71
 
10 Suppl
(pg. 
3206
-
3209
)
73
Millot
 
F
Claviez
 
A
Leverger
 
G
Corbaciglu
 
S
Groll
 
AH
Suttorp
 
M
Imatinib cessation in children and adolescents with chronic myeloid leukemia in chronic phase.
Pediatr Blood Cancer
2014
, vol. 
61
 
2
(pg. 
355
-
357
)
74
Bender
 
BG
Cvietusa
 
PJ
Goodrich
 
GK
, et al. 
Pragmatic trial of health care technologies to improve adherence to pediatric asthma treatment: a randomized clinical trial.
JAMA Pediatr
2015
, vol. 
169
 
4
(pg. 
317
-
323
)
75
Mathisen
 
MS
Kantarjian
 
HM
Cortes
 
J
Jabbour
 
EJ
Practical issues surrounding the explosion of tyrosine kinase inhibitors for the management of chronic myeloid leukemia.
Blood Rev
2014
, vol. 
28
 
5
(pg. 
179
-
187
)
76
Ross
 
DM
Branford
 
S
Seymour
 
JF
, et al. 
Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study.
Blood
2013
, vol. 
122
 
4
(pg. 
515
-
522
)
77
Rea
 
D
Rousselot
 
P
Guilhot
 
F
, et al. 
Discontinuation of second generation (2G) tyrosine kinase inhibitors (TKI) in chronic phase (CP)-chronic myeloid leukemia (CML) patients with stable undetectable BCR-ABL transcripts [abstract].
Blood
2012
, vol. 
120
 
21
 
Abstract 916
78
Rousselot
 
P
Charbonnier
 
A
Cony-Makhoul
 
P
, et al. 
Loss of major molecular response as a trigger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetectable disease.
J Clin Oncol
2014
, vol. 
32
 
5
(pg. 
424
-
430
)
79
La Rosée
 
P
Martiat
 
P
Leitner
 
A
, et al. 
Improved tolerability by a modified intermittent treatment schedule of dasatinib for patients with chronic myeloid leukemia resistant or intolerant to imatinib.
Ann Hematol
2013
, vol. 
92
 
10
(pg. 
1345
-
1350
)
80
Deininger
 
MW
Manley
 
P
What do kinase inhibition profiles tell us about tyrosine kinase inhibitors used for the treatment of CML?
Leuk Res
2012
, vol. 
36
 
3
(pg. 
253
-
261
)
81
Copland
 
M
Hamilton
 
A
Elrick
 
LJ
, et al. 
Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction.
Blood
2006
, vol. 
107
 
11
(pg. 
4532
-
4539
)
82
O’Hare
 
T
Zabriskie
 
MS
Eiring
 
AM
Deininger
 
MW
Pushing the limits of targeted therapy in chronic myeloid leukaemia.
Nat Rev Cancer
2012
, vol. 
12
 
8
(pg. 
513
-
526
)
83
Warsch
 
W
Walz
 
C
Sexl
 
V
JAK of all trades: JAK2-STAT5 as novel therapeutic targets in BCR-ABL1+ chronic myeloid leukemia.
Blood
2013
, vol. 
122
 
13
(pg. 
2167
-
2175
)
84
Gallipoli
 
P
Cook
 
A
Rhodes
 
S
, et al. 
JAK2/STAT5 inhibition by nilotinib with ruxolitinib contributes to the elimination of CML CD34+ cells in vitro and in vivo.
Blood
2014
, vol. 
124
 
9
(pg. 
1492
-
1501
)
85
Talpaz
 
M
Mercer
 
J
Hehlmann
 
R
The interferon-alpha revival in CML.
Ann Hematol
2015
, vol. 
94
 
Suppl 2
(pg. 
S195
-
S207
)
86
Burchert
 
A
Saussele
 
S
Eigendorff
 
E
, et al. 
Interferon alpha 2 maintenance therapy may enable high rates of treatment discontinuation in chronic myeloid leukemia.
Leukemia
2015
, vol. 
29
 
6
(pg. 
1331
-
1335
)
87
Schultz
 
KR
Carroll
 
A
Heerema
 
NA
, et al. 
Children’s Oncology Group
Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children’s Oncology Group study AALL0031.
Leukemia
2014
, vol. 
28
 
7
(pg. 
1467
-
1471
)
88
Chaudhury
 
S
Hijiya
 
N
Hu
 
Z
, et al. 
Outcomes of allogeneic hematopoietic stem cell transplantation in children and young adults with chronic myeloid leukemia: a CIBMTR cohort analysis [abstract].
Blood
2014
, vol. 
124
 
21
 
Abstract 2534
89
Meier
 
ER
Dioguardi
 
JV
Kamani
 
N
Current attitudes of parents and patients toward hematopoietic stem cell transplantation for sickle cell anemia.
Pediatr Blood Cancer
2015
, vol. 
62
 
7
(pg. 
1277
-
1284
)
90
Eapen
 
M
Klein
 
JP
Ruggeri
 
A
, et al. 
Center for International Blood and Marrow Transplant Research, Netcord, Eurocord, and the European Group for Blood and Marrow Transplantation
Impact of allele-level HLA matching on outcomes after myeloablative single unit umbilical cord blood transplantation for hematologic malignancy.
Blood
2014
, vol. 
123
 
1
(pg. 
133
-
140
)
91
Suttorp
 
M
Claviez
 
A
Bader
 
P
, et al. 
Allogeneic stem cell transplantation for pediatric and adolescent patients with CML: results from the prospective trial CML-paed I.
Klin Padiatr
2009
, vol. 
221
 
6
(pg. 
351
-
357
)
92
Saussele
 
S
Lauseker
 
M
Gratwohl
 
A
, et al. 
German CML Study Group
Allogeneic hematopoietic stem cell transplantation (allo SCT) for chronic myeloid leukemia in the imatinib era: evaluation of its impact within a subgroup of the randomized German CML Study IV.
Blood
2010
, vol. 
115
 
10
(pg. 
1880
-
1885
)
93
Cwynarski
 
K
Roberts
 
IA
Iacobelli
 
S
, et al. 
Paediatric and Chronic Leukaemia Working Parties of the European Group for Blood and Marrow Transplantation
Stem cell transplantation for chronic myeloid leukemia in children.
Blood
2003
, vol. 
102
 
4
(pg. 
1224
-
1231
)
94
Muramatsu
 
H
Kojima
 
S
Yoshimi
 
A
, et al. 
Outcome of 125 children with chronic myelogenous leukemia who received transplants from unrelated donors: the Japan Marrow Donor Program.
Biol Blood Marrow Transplant
2010
, vol. 
16
 
2
(pg. 
231
-
238
)
95
Baker
 
KS
Gurney
 
JG
Ness
 
KK
, et al. 
Late effects in survivors of chronic myeloid leukemia treated with hematopoietic cell transplantation: results from the Bone Marrow Transplant Survivor Study.
Blood
2004
, vol. 
104
 
6
(pg. 
1898
-
1906
)
96
Pulsipher
 
MA
Wayne
 
AS
Schultz
 
KR
New frontiers in pediatric Allo-SCT: novel approaches for children and adolescents with ALL.
Bone Marrow Transplant
2014
, vol. 
49
 
10
(pg. 
1259
-
1265
)
97
Chen
 
MH
Chiou
 
TJ
Lin
 
PC
, et al. 
Comparison of myeloablative and nonmyeloablative hematopoietic stem cell transplantation for treatment of chronic myeloid leukemia.
Int J Hematol
2007
, vol. 
86
 
3
(pg. 
275
-
281
)
98
van Besien
 
K
Kunavakkam
 
R
Rondon
 
G
, et al. 
Fludarabine-melphalan conditioning for AML and MDS: alemtuzumab reduces acute and chronic GVHD without affecting long-term outcomes.
Biol Blood Marrow Transplant
2009
, vol. 
15
 
5
(pg. 
610
-
617
)
99
Law
 
J
Cowan
 
MJ
Dvorak
 
CC
, et al. 
Busulfan, fludarabine, and alemtuzumab as a reduced toxicity regimen for children with malignant and nonmalignant diseases improves engraftment and graft-versus-host disease without delaying immune reconstitution.
Biol Blood Marrow Transplant
2012
, vol. 
18
 
11
(pg. 
1656
-
1663
)
100
Hatanaka
 
K
Fuji
 
S
Ikegame
 
K
, et al. 
Low incidences of acute and chronic graft-versus-host disease after unrelated bone marrow transplantation with low-dose anti-T lymphocyte globulin.
Int J Hematol
2012
, vol. 
96
 
6
(pg. 
773
-
780
)
101
Baron
 
F
Labopin
 
M
Niederwieser
 
D
, et al. 
Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European group for blood and marrow transplantation.
Leukemia
2012
, vol. 
26
 
12
(pg. 
2462
-
2468
)
102
Kanakry
 
CG
Tsai
 
HL
Bolaños-Meade
 
J
, et al. 
Single-agent GVHD prophylaxis with posttransplantation cyclophosphamide after myeloablative, HLA-matched BMT for AML, ALL, and MDS.
Blood
2014
, vol. 
124
 
25
(pg. 
3817
-
3827
)