Chronic myelogenous leukemia (CML) is a rare disease in children. There is little evidence of biological differences between CML in children and adults, although host factors are different. Children develop distinct morbidities related to the off-target effects of tyrosine kinase inhibitors. The goal of treatment in children should be cure rather than suppression of disease, which can be the treatment goal for many older adults. This article reviews data from the literature on the treatment of CML, discusses the issues that are unique to CML in children, and recommends management that takes these issues into consideration.
Key points
- •
There are few data showing biological differences between adult and pediatric chronic myelogenous leukemia (CML), but the clinical presentations are distinct and the host factors are different in adults and growing children, which raises issues specific to the care of pediatric patients with CML.
- •
Children have longer life expectancies than adults; therefore, the goal of CML treatment in children should be cure rather than disease suppression.
- •
Because of the possibility of decades-long tyrosine kinase inhibitor (TKI) treatment, which also occurs during periods of active growth, morbidity related to TKI therapy for CML is different in children than in adults. Careful monitoring of bone growth and other possible long-term morbidity is crucial.
- •
The role of hematopoietic stem cell transplant in the first chronic phase should be defined for pediatric patients with CML.
Introduction
Chronic myelogenous leukemia (CML) is diagnosed in approximately 6000 patients every year in the United States according to the Surveillance Epidemiology and End Results (SEER) Program. CML in children is usually considered to be rare, but it accounts for 10% to 15% of myeloid leukemia and is more common than acute promyelocytic leukemia, which accounts for 5% to 10% of cases. At one time, hematopoietic stem cell transplant (HSCT) was the only curative treatment of CML in children as well as in adults; however, the treatment landscape has changed drastically over the last 15 years since the introduction of the tyrosine kinase inhibitor (TKI) imatinib. Continuing TKI treatment indefinitely has become standard practice for adult patients in chronic phase (CP), and the feasibility of discontinuing TKI therapy in patients in deep molecular remission has been studied. However, because of a lack of data from large clinical studies, standardized treatment and interventions have not been established in the pediatric CML population. This article discusses some controversial issues and unanswered questions ( Table 1 ), as well as current recommendations, in the management of pediatric CML ( Boxes 1 and 2 , Fig. 1 ).
| Issues and Questions | Notes |
|---|---|
| Children have longer life expectancy than adults |
|
| Morbidities from TKIs in children are different from those in adults |
|
| Treatment should be designed for cure, rather than suppression, of the disease |
|
| HSCT may still play a role in children in first CP |
|
| Efficacy of newer TKIs has not been validated |
|
| Pediatric-specific treatment guidelines are lacking |
|
| CML scoring system has not been validated in children |
|
-
At diagnosis:
- 1.
Bone marrow (cytogenetics, FISH)
- 2.
Qualitative PCR for BCR-ABL1
- 3.
Consider HLA typing of the patient and siblings
-
During TKI treatment:
- 1.
Bone marrow every 3 months until complete cytogenetic remission (no Philadelphia chromosome is identified)
- 2.
RQ-PCR by peripheral blood every 3 months
- 3.
BCR-ABL1 mutation analysis if response is not optimal
Abbreviations: FISH, fluorescence in situ hybridization; HLA, human leukocyte antigen; RQ-PCR, real-time quantitative polymerase chain reaction.
- •
Height, weight and Tanner staging on every visit. If there are abnormal patterns, consult endocrinology and consider bone age and DEXA scan.
- •
Thyroid function after 4 to 6 weeks of TKI and repeat thereafter periodically.
- •
Echocardiogram and ECG annually.
- •
Inactivated vaccines may be given anytime during TKI treatment, although efficacy is not confirmed.
- •
Live vaccines are not recommended during TKI therapy. May be given after discontinuing TKI for several weeks when the patient is in deep molecular response.
Abbreviations: ECG, electrocardiogram; DEXA, dual-energy X-ray absorptiometry.
Introduction
Chronic myelogenous leukemia (CML) is diagnosed in approximately 6000 patients every year in the United States according to the Surveillance Epidemiology and End Results (SEER) Program. CML in children is usually considered to be rare, but it accounts for 10% to 15% of myeloid leukemia and is more common than acute promyelocytic leukemia, which accounts for 5% to 10% of cases. At one time, hematopoietic stem cell transplant (HSCT) was the only curative treatment of CML in children as well as in adults; however, the treatment landscape has changed drastically over the last 15 years since the introduction of the tyrosine kinase inhibitor (TKI) imatinib. Continuing TKI treatment indefinitely has become standard practice for adult patients in chronic phase (CP), and the feasibility of discontinuing TKI therapy in patients in deep molecular remission has been studied. However, because of a lack of data from large clinical studies, standardized treatment and interventions have not been established in the pediatric CML population. This article discusses some controversial issues and unanswered questions ( Table 1 ), as well as current recommendations, in the management of pediatric CML ( Boxes 1 and 2 , Fig. 1 ).
| Issues and Questions | Notes |
|---|---|
| Children have longer life expectancy than adults |
|
| Morbidities from TKIs in children are different from those in adults |
|
| Treatment should be designed for cure, rather than suppression, of the disease |
|
| HSCT may still play a role in children in first CP |
|
| Efficacy of newer TKIs has not been validated |
|
| Pediatric-specific treatment guidelines are lacking |
|
| CML scoring system has not been validated in children |
|
-
At diagnosis:
- 1.
Bone marrow (cytogenetics, FISH)
- 2.
Qualitative PCR for BCR-ABL1
- 3.
Consider HLA typing of the patient and siblings
-
During TKI treatment:
- 1.
Bone marrow every 3 months until complete cytogenetic remission (no Philadelphia chromosome is identified)
- 2.
RQ-PCR by peripheral blood every 3 months
- 3.
BCR-ABL1 mutation analysis if response is not optimal
Abbreviations: FISH, fluorescence in situ hybridization; HLA, human leukocyte antigen; RQ-PCR, real-time quantitative polymerase chain reaction.
- •
Height, weight and Tanner staging on every visit. If there are abnormal patterns, consult endocrinology and consider bone age and DEXA scan.
- •
Thyroid function after 4 to 6 weeks of TKI and repeat thereafter periodically.
- •
Echocardiogram and ECG annually.
- •
Inactivated vaccines may be given anytime during TKI treatment, although efficacy is not confirmed.
- •
Live vaccines are not recommended during TKI therapy. May be given after discontinuing TKI for several weeks when the patient is in deep molecular response.
Abbreviations: ECG, electrocardiogram; DEXA, dual-energy X-ray absorptiometry.
Differences in chronic myelogenous leukemia clinical presentation in children and adults
There are some differences in the clinical presentation of CML at diagnosis in children and adults, which suggests different underlying biology. The median baseline white blood cell count (WBC) in adult patients with CML ranges from 80 × 10 9 /L to 150 × 10 9 /L, but is higher in children with CML; WBC was reported to be approximately 250 × 10 9 /L in an international registry of 200 children with CML (median age, 11.6 years; range, 8 months to 18 years). Compared with older adults, adolescents and young adults (16–29 years) also present with higher WBC as well as other aggressive disease features (larger spleen, higher peripheral blast counts, and lower hemoglobin levels), although one study showed similar outcomes. Another study showed less favorable cytogenetic and molecular response rates and a trend for shorter event-free survival in a similar age group (15–29 years) of patients with CML compared with older adults, although overall survival rates were not different. The median size of the spleen is 8 cm below the costal margin (range, 0–25 cm) in children, which is not very different from adults. However, the age-based normal size of the spleen in children is smaller than in adults; therefore, children have proportionally larger spleens. Advanced phases of CML (accelerated phase [AP] or blast crisis [BC]) seem to be diagnosed more frequently in children than in adults. Given the differences in clinical presentation and the wide gap in the prevalence of CML in children and adults, it is possible that different mechanisms account for the pathogenesis in each age group; however, to date there are few data to support this idea.
Issues in pediatric chronic myelogenous leukemia
Lack of Standard Guidelines and Prognostic Scores in Children
There are no standard guidelines in pediatric CML such as those produced by the National Comprehensive Cancer Network (NCCN) and European Leukemia Net (ELN) for adults; thus, many pediatric oncologists follow guidelines that are designed for adult patients. However, there are several issues unique to children with CML that need to be carefully considered.
Various prognostic scores (eg, Sokal, Hasford, and Eutos scores) based on clinical and biological features at diagnosis predict the outcomes of adult patients with CML treated with chemotherapy, interferon, or imatinib, but the validity of these scores has not been established in the pediatric population. For instance, the Sokal score uses age, spleen size, platelet counts, and blast count. Using this score, a 10-year-old with CML would have a lower risk of mortality than a 70-year-old patient if they had the same spleen size and blood cell counts, but in practice this is not always true. Suttorp and colleagues evaluated the 3 scores and a Sokal young score in 90 children with CML (median age, 11.6 years; range, 1–18 years) who were treated with imatinib, and prognostic scores were inconsistent in children and did not predict poor response at 3 months.
More recently, cytogenetic and molecular responses to TKI therapy have been used as prognostic markers. NCCN and ELN guidelines use TKI responses at 3, 6, and 12 months to define treatment failure or to recommend change of treatment. The prognostic value of early TKI response and kinetics of BCR-ABL1 have been also described but they need to be evaluated in pediatric patients with CML.
Cure or Suppression of Disease?
Whether or not CML in children is different from adult disease is debatable, but the host factors are different in these two patient populations and may inform treatment goals. Cure of disease is ideal for any age group, but an acceptable goal of treatment in adults, especially in older patients, may be to maintain CP for a few decades with TKI. If older patients remain BCR-ABL1 –positive by real-time quantitative reverse transcription polymerase chain reaction, but are in CP with TKI, they can expect a good quality of life for many years. In contrast, children have a much longer life expectancy, and there are no data on the long-term efficacy of TKI beyond 15 years. If children with CML continue TKI treatment and remain in CP, they may still develop resistance and progress to AP/BC after decades. Noncompliance with TKI is also more prevalent in adolescents and young adults compared with older adults or younger children, which makes decades-long use of TKI a less attractive option in these patients. Continuing TKI indefinitely can also cause long-term morbidities in children and, over decades, the cost of TKI becomes significant and may also preclude adherence as reported in adults. When pediatric patients with CML enter young adulthood, they face impaired quality-of-life issues related to TKI therapy, which are reported to be significantly worse in the young adult population compared with the older adult population.
One potential solution is to stop TKIs after a period of undetectable BCR-ABL1 . The prospective Stop Imatinib (STIM) study evaluated the feasibility of discontinuing imatinib in patients 18 years of age or older who remained in complete molecular response (CMR) for at least 2 years while on imatinib. Sixty-nine of 100 patients enrolled had median follow-up of 24 months (range, 13–30 months) and 42 of 69 patients (61%) experienced relapse; however, all patients who had molecular relapse responded to reintroduction of imatinib. Despite these studies, there is limited information on the longer-term (beyond 5 years) outcomes of patients with CML in CMR after cessation of imatinib. Although BCR-ABL1 can be persistent without progression of disease for several years, it is also possible that children in CMR may experience molecular relapse after a longer period of time following TKI discontinuation. However, reintroduction of TKI may bring them back to molecular remission. The concept of intermittent TKI dosing to reduce the long-term side effects of TKI and financial burden is intriguing in this regard.
There are several potential therapeutic targets and agents under development that potentially overcome TKI resistance or eradicate CML stem cells, which may achieve cure. These targets and agents include interferon-alfa and components of the JAK/STAT, Hedgehog, and Wnt/β-catenin signaling pathways ; early-phase studies are ongoing. Immunologic approaches like tumor cell–derived peptide vaccination may represent other reasonable strategies to cure CML in the future. New treatment options, particularly those intended to cure, are potentially more beneficial for children than for adults; therefore, it is critical that pediatric studies are pursued as part of the clinical development process.
Hematopoietic Stem Cell Transplant for Children with Chronic Myelogenous Leukemia in First Chronic Phase
HSCT is currently not a first-line treatment of CML in adults; however, whether children with CML should continue on TKI or receive HSCT in the first CP is still a valid question. HSCT is the most established treatment to eliminate leukemic stem cells, although late relapse after HSCT has been reported. HSCT, especially with a myeloablative conditioning regimen, causes significant morbidity, including loss of fertility, but in general, children tolerate HSCT better than adults. The best way to determine the benefit of HSCT for children in first CP is to conduct a prospective randomized trial comparing HSCT and TKI therapy; however, such a trial is not realistic given the small number of pediatric patients with CML.
Data are scarce for the use of HSCT in children with CML in first CP. There are only 3 studies that have reported outcomes of HSCT in this population, including data on more than 100 children ( Table 2 ). Goldman and colleagues reported relapse and late mortality in 2444 patients with CML who received myeloablative HSCT in first CP between 1978 and 1998 and survived in continuous complete remission for 5 years or longer after HSCT. Although the pediatric population was not specifically analyzed in this study, multivariate analysis of a reference group of patients younger than 20 years of age indicated higher disease-free survival than in older patients; relative risk was 1.96 (95% confidence interval [CI], 1.08–3.54); 2.12 (95% CI, 1.2–3.75); 2.92 (95% CI, 1.65–5.15); and 3.93 (95% CI, 2.06–7.51) for patients aged 20 to 29 years ( P = .03); 30 to 39 years ( P = .009); 40 to 49 years ( P <.001); and 50 years or older ( P <.001), respectively.
Full access? Get Clinical Tree
