Horn of plenty: Value of the international registry for pediatric chronic myeloid leukemia

Abstract

Chronic myeloid leukemia (CML) in minors is a rare disease which can be effectively treated by tyrosine kinase inhibitors (TKIs) since the year 2000. A majority of pediatricians will encounter one or two CML patients in the course of their careers and will typically have to rely on written information along with their own intuition to provide care. Knowledge of response to TKIs and of age-specific side effects has an impact on the design of pediatric CML trials in many ways aiming to contribute toward greater predictability of clinical improvements. Information from a registry on a rare disease like CML offers the enormous benefit of enabling treating physicians to interact and share their collective experience. The International Registry on Pediatric CML (IR-PCML) was founded at Poitiers/France almost 10 years ago. Since then, the number of collaboration centers and in parallel of registered patients continuously increased (> 550 patients as of December 2019). Ideally, from a given treatment center in a country data are transferred to a national coordinator who interacts with the IR-PCML. In the sense of quality assurance, the registry can offer dissemination of knowledge on state-of-the-art diagnostics (including reference appraisal), optimal treatment approaches, and follow-up procedures within a network that is exerting its strength via participation. With continuous growth during the recent years, very rare subgroups of patients could be identified ( e.g ., CML diagnosed at age < 3 years, children presenting with specific problems at diagnosis or during course of treatment) which had not been described before. Publications coming from the IR-PCML disseminated this useful information derived from patients who robustly participate and share information about their disease, among themselves and with their caregivers and clinicians. Patient input driving the collection of data on this rare leukemia is the basis for the considerable success of bringing new therapeutics into clinical use.

Definition, Epidemiology, Pathophysiology, and Essential Criteria for Diagnosis of Pediatric Chronic Myeloid Leukemia

“…More than 90% of all pediatric patients with CML are diagnosed in CML-CP. The proportion of children in advanced phases (CML-AP and CML-BP) represents only 7.5% of all patients according to the International Registry for Childhood CML [ 4 , 74 ]. Because of leukemic infiltrates the spleen is enlarged in 70% to 80% and the liver in 50% to 60% of pediatric patients in CML-CP [ 69 , 70 , 75 ].…”

“…Assessment of the following criteria is desirable when CML BCR-ABL1 is diagnosed: (a) for optimal monitoring of treatment response in individual patients: gender, age, height, bodyweight in correlation to the TKI dose administered [ 108 ], identification of mutations in the BCR-ABL1 kinase domain in patients with CML-AP and CML-BP, identification of the BCR-ABL1 breakpoint on a genomic (DNA) level [ 63 , 66 , 109 , 110 , 111 , 112 ], (b) to compare data on pediatric CML BCR-ABL1 internationally: a threphine biopsy (degree of fibrosis, nests of blasts), due to the rarity of pediatric CML all patients should be enrolled in trials and enrolled into the international pediatric CML registry [ 4 ], for comparison of BCR-ABL1 mRNA levels when assessing the treatment response, data derived from individual laboratories must be aligned to a reference method (International Standard, IS) applying laboratory-specific conversion factors [ 113 , 114 ], (c) to improve the scientific understanding of the disease: identification of genes and their products influencing TKI blood serum concentration and metabolism [ 108 , 115 ], assessment of acquired von Willebrand disease in cases with elevated platelets [ 73 , 81 ], vaccination status at diagnosis and maintenance of immunity under TKI treatment [ 116 , 117 , 118 ], identification of somatic or germline mutations and epigenetic modification in addition to BCR-ABL1 [ 55 , 57 , 66 , 112 , 119 , 120 , 121 , 122 ]. …”

“…Before the introduction of tyrosine kinase inhibitors (TKI) for the treatment of CML, stem cell transplantation was the recommended therapeutic approach for young patients and data on pediatric CML were deposited at the EBMT and IBMTR registries [ 1 , 2 , 3 ]. Given the enormous improvement of therapeutic success achieved by TKIs, the interest in the long-term outcome of this novel treatment especially in pediatric patients resulted in foundation of the International Registry on Pediatric CML (IR-PCML) at Poitiers/France in the year 2010 [ 4 ]. Since then, the number of collaboration centers and in parallel of registered patients continuously has increased.…”

Features and outcome of chronic myeloid leukemia at very young age: Data from the International Pediatric Chronic Myeloid Leukemia Registry

“…The constant growth of an international collaboration for collection of data on pediatric CML resulted in the establishment of the international Pediatric CML Registry (I-CML-Ped Study, Chair: F. Millot, Poitiers, France) 10 years ago. 8,9 The accumulated unique and valuable data from almost 500 patients younger than 18 years now allow an analysis of very rare subcohorts. 10,11 Therefore, in this study, we aimed to determine in children under the age of 3 years (a) the main presenting features of CML, (b) their clinical and biological characteristics, and (c) treatment outcome in the tyrosine kinase inhibitor (TKI) era.…”

“…However, there has been no separate data analysis on children diagnosed in the first years of life. The constant growth of an international collaboration for collection of data on pediatric CML resulted in the establishment of the international Pediatric CML Registry (I‐CML‐Ped Study, Chair: F. Millot, Poitiers, France) 10 years ago 8,9 . The accumulated unique and valuable data from almost 500 patients younger than 18 years now allow an analysis of very rare subcohorts 10,11 .…”