A total of 156 patients (age range 1.3-18.0 years, median 13.2 years; 91 (58.3%) male) with newly diagnosed CML (N = 146 chronic phase (CML-CP), N = 3 accelerated phase (CML-AP), N = 7 blastic phase ...(CML-BP)) received imatinib up-front (300, 400, 500 mg/m
, respectively) within a prospective phase III trial. Therapy response, progression-free survival, causes of treatment failure, and side effects were analyzed in 148 children and adolescents with complete data. Event-free survival rate by 18 months for patients in CML-CP (median follow-up time 25 months, range: 1-120) was 97% (95% CI, 94.2-99.9%). According to the 2006 ELN-criteria complete hematologic response by month 3, complete cytogenetic response (CCyR) by month 12, and major molecular response (MMR) by month 18 were achieved in 98, 63, and 59% of the patients, respectively. By month 36, 86% of the patients achieved CCyR and 74% achieved MMR. Thirty-eight patients (27%) experienced imatinib failure because of unsatisfactory response or intolerance (N = 9). In all, 28/148 patients (19%) underwent stem cell transplantation (SCT). In the SCT sub-cohort 2/23 patients diagnosed in CML-CP, 0/1 in CML-AP, and 2/4 in CML-BP, respectively, died of relapse (N = 3) or SCT-related complications (N = 2). This large pediatric trial extends and confirms data from smaller series that first-line imatinib in children is highly effective.
Objectives: A decade after being licensed for treatment of CML in minors, the TKI imatinib (IMA) is well known for it’s inhibitory “off-target” effects on activity and proliferative capacity of ...osteoclasts and osteoblasts resulting in impaired bone remodeling (Vandyke K et al 2010 Blood 115:766; Tauer JT et al Blood 2011:118). This causes longitudinal growth retardation in not outgrown individuals (Millot F et al 2009 Blood 114:863; Shima H et al 2011 Pediatrics 159:676; Bansal D et al 2012 Ped Blood Cancer 59:481) which can be aggravated by a disrupted growth hormone:IGF-I axis as a possible additional off-target effect exerted by TKI treatment (Ulmer A et al 2013 Klin Padiatr 225:120; Bansal D et al 2012 Ped Blood Cancer 59:481). Starting a pediatric trial in the year 2006 which recruits approx. 15 pediatric patients (pts) with CML annually, we investigated to what extend growth is impaired depending on sex, age, and pubertal stage at start of IMA treatment in a pediatric cohort.
Methods: 102 pts (54 male / 48 female; median age 12 years, range: 1-18 years) at diagnosis of CML receiving IMA as upfront treatment were enrolled retrospectively in this analysis from centers in Germany and participating countries during 02/2006 to 06/2014. Height standard deviation scores (SDS) were derived from WHO-AnthroPlus, version 1.04 software, a global growth-monitoring tool providing normal range values for the age cohorts from birth till 19 years. 81 out of 102 pts fulfilled the criteria for continuous assessment of growth scheduled at three months intervals during IMA exposure. 21 pts were analyzed at intervals ≠ 3 month. Pts excluded comprised individuals shifted to a 2nd generation TKI, or cumulative interruptions of drug intake exceeding 4 weeks, or pts undergoing stem cell transplantation.
Results: The mean and median duration of IMA exposure was 12 months and 9 months, respectively (range: 0–98 month). 27/102 pts (13 male, 14 female) were prepubertal (age: <10 years) at initiation of IMA treatment while 46/102 pts were pubertal (age: 10-14 years; 23 male, 23 female), and 29/102 pts were in postpubertal stage (age: >14 years; 18 male, 11 female). In comparison to mean SDS at diagnosis a mean decrease in height of 0.48 SDS per year was observed in the total cohort during the first three years of treatment, being more pronounced in prepubertal pts. In pts diagnosed shortly before or at puberty a mean reduction of 0.75 SDS per year during the first three years were observed. Older teenagers revealed no change in body height z-score during TKI treatment compared to height z-score at diagnosis.
Discussion: Growth retardation is a significant adverse effect of IMA in children with CML affecting predominantly prepubertal children. Possible medical interventions still need to be investigated.
Acknowledgment: Supported by grant DFG SU122-3/1 to MS.
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No relevant conflicts of interest to declare.
Imatinib (IM) front-line treatment impressively improved survival of children with chronic myeloid leukemia (CML). In contrast to adult CML, specific scoring systems predicting the treatment response ...in individual pediatric patients (pts) are still lacking. Here we analyzed a cohort of pediatric pts with CML applying the established prognostic scores for adults in a comparative fashion. We question the value of four scoring systems (Sokal-, Sokal young-, Hasford-, Eutos-Score) especially with regard to grouping individual children differently or homogeneously into a defined risk category. In addition, we analyzed which scoring system would classify most specifically the prognosis of pediatric CML with regard to early molecular response (MR) on IM.
A total of 90 pts (male/female: 57/33; median age: 11.6 yrs, range: 1-18) with CML-CP enrolled in the prospective trial CML-PAED-II were included in this analysis. Registry data were collected on standardized forms filled in by the treating physicians. On this basis the Eutos-, Sokal- and Hasford-Scores were calculated using internet resources of the ELN (www.leukemia-net.org/content/leukemias/cml/cml_score), whereas the Sokal young Score (Sy) – a score described specifically for adolescents and younger adults (Sokal JE, Blood 1985;66:1352) – was manually calculated. Pts were grouped using the original three risk categories (low=LR, intermediate=IR, high=HR) or two categories, respectively, for the Eutos-Score (LR or HR). Evaluation of therapeutic response was performed by assessing the MR by measurement of the transcript ratio BCR-ABL1/ABL1 in blood specimen sent to the central reference laboratory at month 3 after start of IM treatment. Measurements were expressed according to the International Scale.
By Sokal-Score 59/90 pts were classified as LR, 20/90 pts as IR and 11/90 pts as HR. By Hasford Score 57/90 pts were classified as LR, 25/90 pts as IR, and 8/90 pts as HR. By Eutos Score 73/90 pts were classified as LR and 17/90 pts as HR. As the hematocrit value was not collected systematically at diagnosis, this necessary parameter for calculating the Sy-Score was applicable only in 46/90 pts and thus 44/46 pts were classified as LR, 2/46 as IR, and 0/46 as HR. Comparing results of individual pts only 25/46 pts (54%) were categorized homogeneously as LR by applying all 4 scoring systems, while 54/90 pts (60%) were classified as LR if Sy-Score was excluded. Thus, the remaining 21/46 pts (46%) were grouped heterogeneously by applying each of the 4 prognostic scores, and correspondingly 33/90 pts (37%) were classified heterogeneously within different risk categories by the Eutos, Hasford and Sokal Score. Only 3 pts were categorized homogenously as HR by each of the Sokal, Hasford, and Eutos Score and by applying all 4 scoring systems no patient was concordantly classified as HR. When comparing only the Sokal-Score to the Sy-Score, discordant results were obtained in 19/46 (41%) pts.
BCR-ABL1/ABL1 transcript ratio could be analyzed quantitatively in 72/90 pts at month 3 after treatment initiation. In this cohort we identified 46/72 good responders (ratio BCR-ABL1/ABL1 <10%) and 26/72 poor responders (ratio >10%). Although the Eutos-score performed best in in a logistic regression analysis with an Odds Ratio OR=3.02 to predict an unfavorable course of IM-treated CML in the HR group, the discrimination did not reach statistical significance (p=0.08). However, by reducing the cut-off point for the Eutos Score from 87 to 64 an OR=4.8 with p=0.004 was achieved, thus indicating that a refined risk categorization appears beneficial.
Comparing risk categorization by all four scores in individual pediatric pts, results may vary considerably. Keeping in mind that the number of pts analyzed is still small, especially applying the Sy-Score seems not to provide benefit in this cohort with a median age of only 11 years. Contrasting results in adults, in this pediatric cohort the Sokal- and Hasford-Scores did not predict a poor IM treatment response at month 3 while the Eutos Score achieved borderline significance. Thus, there is an urgent need for the development of a more specific pediatric risk score.
No relevant conflicts of interest to declare.
Purpose
Results of the prospective trial “CML-PAED-II” assessing treatment efficacy and side effects in children and adolescents with newly diagnosed chronic myeloid leukemia (CML) are reported.
...Patients and Methods
156 patients (age range 1.3-18.0 years, 91 male) with newly diagnosed CML (N= 146 chronic phase (CML-CP), N= 3 accelerated phase (CML-AP), N= 7 blastic phase (CML-BP)) received imatinib upfront (300 mg/m², 400 mg/m², 500 mg/m², respectively). Therapy response, progression-free survival, causes of treatment failure and proportion of patients undergoing stem cell transplantation were analyzed in 148 patients with complete data.
Results
Event-free survival rate at 18 months for pediatric patients diagnosed in CML-CP (median follow-up time 25 months, range: 0.1-120) was 97% (95% CI, 94.2%-99.9%). According to the 2006 ELN-criteria complete hematologic response at month 3, complete cytogenetic response (CCyR) at month 12, and molecular response (MR3.0) at month 18 were achieved in 98%, in 63%, and 59% of the patients, respectively. At month 36 on continuous first line imatinib or 2nd generation tyrosine kinase inhibitor treatment, 86% of the patients achieved CCyR and 74% achieved MR3.0.
66% of the patients experienced at least one side effect. Imatinib-related anemia was the most frequent toxicity observed if all grades were considered (N=98; 66%) while neutropenia was the most frequently reported grade 3/4 hematologic adverse effect (N=22; 15%). Among non-hematologic toxicities, all grades of gastrointestinal toxicity were observed most frequently (N=57, 38%), however, it occurred at lower grades 1/2 in all but one patient. Higher grade 3/4 musculoskeletal pain was also frequent (N=53, 36%). Twenty-seven patients (18%) had to discontinue treatment temporarily while nine patients permanently terminated imatinib due to non-tolerable side effects (neutropenia N= 4, muscle cramps N= 3, skin N= 1, liver N= 1).
Thirty-eight patients (27%) experienced imatinib failure because of unsatisfactory response (N= 27) or intolerance (N= 9). 28/148 patients (19%) underwent stem cell transplantation (SCT). In the SCT sub-cohort 2/23 patients diagnosed in CML-CP, 0/1 in CML-AP, and 2/4 in CML-BP, respectively, died of relapse (N=3) or SCT-related complications (N=2).
Conclusion
This large pediatric trial provides evidence confirming that first line imatinib in children is highly effective. Observed adverse effects are acceptable and mainly comprise hematological side effects. Long term outcome and effects of a potentially life-long TKI treatment have to be registered in cooperation with adult hematologists in extended surveillance follow-up studies.
Suttorp:Novartis: Research Funding. Schrappe:JAZZ Pharma: Consultancy, Research Funding; Baxalta: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; SigmaTau: Consultancy, Research Funding; Medac: Consultancy, Research Funding. Thiede:Novartis: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Roche: Consultancy; Agendix: Employment.
Summary
Early recognition of children with chronic phase chronic myeloid leukaemia (CML‐CP) at risk for developing a lymphoid blast crisis (LyBC) is desirable, because therapy options in CML‐LyBC are ...limited. We used Multiplex Ligation‐dependent Probe Amplification to determine whether B‐cell lymphoid leukaemia‐specific copy number alterations (CNAs) (e.g. IKZF1, PAX5, CDKN2A deletions) could be detected in CML‐CP and may be used to predict disease progression to LyBC. CNAs were detected in all patients with CML‐LyBC, but in none of the 77 patients with CML‐CP. Based on this study we conclude that CNAs remain a hallmark of disease progression.
Chronic myeloid leukemia (CML) is a rare malignancy in children and is mostly diagnosed in the chronic phase (CP). In adults, the five-year overall survival rate is 89% for patients on Imatinib and ...disease progression occurs in 1-3% per year (Druker 2006). Once a blast crisis (BC) has occurred, treatment options are limited with a median survival of only a few months (Cortes 2008). Therefore, early recognition of patients at risk for developing a BC is desirable. Besides the translocation t(9;22)(q34;q11), IKZF1, PAX5, and CDKN2A deletions have been reported in CML lymphoid blast crisis (LyBC) of both adult and pediatric patients (Mullighan 2008, Alpár 2012).
The aim of this study was to investigate the presence of IKZF1 deletions and other copy number alterations (CNAs) by MLPA analysis in a large cohort of pediatric CML patients at time of diagnosis in order to determine whether CNAs commonly found in pediatric ALL might predict disease progression and / or treatment response.
Between October 1991 and October 2012 a total of 86 children with newly diagnosed CML were included. The median follow up was 31 months.
Among the 86 patients, 82 patients were diagnosed in CP, 2 patients in accelerated phase (AP), and 2 patients in LyBC. Six patients experienced progression to a BC respectively a myeloid blast crisis (MyBC) (N=2) and LyBC (N=4).
At time of diagnosis, an IKZF1 deletion was detected in one patient diagnosed with CML-AP (Table A, patient no 58). IKZF1 and EBF1 deletions were detected in one patient diagnosed with CML-LyBC (Table A, patient no 22). No CNAs were detected in the 82 patients diagnosed with CML-CP. Display omitted
At time of disease progression, new CNAs were detected at time of the LyBC (Table A, patient no 62, 64, and 67). Due to the absence of material no CNAs could be detected in both patients experiencing a MyBC.
In conclusion, we were able to detect CNAs in progressive CML disease (CML-AP and CML-LyBC) and not in the samples at the time of chronic phase in this large pediatric cohort of CML patients. Therefore, the investigated CNAs could not be used to predict disease progression at time of diagnosis. The CNAs detected in patients with progressive CML were similar to specific CNAs detected in pediatric B-cell precursor ALL, indicating a similar disease development (Kuiper 2010).
Additionally, our results are in accordance with existing literature, suggesting that mechanisms of disease progression in pediatric and adult CML might be similar (Brazma, 2007).
No relevant conflicts of interest to declare.
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