Childhood Chronic Myeloid Leukemia Research Articles

BCR/ABL-Positive Chronic Myeloid Leukemia in Children: Current Treatment Approach.

The purpose of this review is to summarize the most updated treatment recommendations for pediatric CML, and to discuss current areas of investigation. There is new phase 1 data to support the safety of the non-ATP competitive tyrosine kinase inhibitor (TKI) asciminib in the pediatric cohort. Ongoing studies are investigating the role of treatment-free remission in children. Chronic phase CML in children is managed with lifelong TKI therapy; however, evidence of deeper remissions sustained with second-generation TKIs may permit shorter treatment courses. Use of more specific TKIs may mitigate some of the side effects specific to the pediatric cohort. Children with advanced phase CML should achieve a complete hematologic remission with use of a second-generation TKI prior to transplant to achieve the best outcome.

Is the Eutos Long Term Survival (ELTS) Score a Useful Marker to Predict Outcome in Children with Newly Diagnosed Chronic Myeloid Leukemia (CML) in Chronic Phase (CP)? the Experience of the International Registry of Childhood CML

Aims. CML is a very rare disease in children. The present work aims to describe the characteristics of children with CML in chronic phase (CP) and to determine the outcome of this pediatric population. Methods. We retrospectively analyzed children with CML in CP registered in The International Registry of Childhood Chronic Myeloid Leukemia (I-CML-Ped Study; www.clinicaltrials.gov NCT01281735) which represents the largest cohort of children with CML. Results. Between January 2011 and March 2021, 576 CML patients less than 18 years of age at diagnosis were registered. We retrospectively selected 535 (92.8 %) children in CP according to the European leukemia net (ELN) criteria at diagnosis. Boys accounted for 58% of all patients with a boy to girl ratio of 1.25. The median age at diagnosis was 12.4 years (range, 8 months to 18 years). The most common symptoms at presentation were asthenia, weight loss and abdominal pain in 46%, 25% and 23% of the patients, respectively. CML in CP was diagnosed incidentally in 80 (16%) children when a blood assessment was performed for medical reasons. At diagnosis, thrombosis was observed in only one patient whilst 20% of the children presented with bleeding. Bleeding signs were associated with a higher frequency of palpable spleen (p=0.0007), higher leukocyte (p<0.0001) and platelets (p=0.02) counts, and a lower hemoglobin level (p=0.02). Clinical signs of leukostasis were observed in 88 (16.5%) patients. At diagnosis, spleen was palpable in 76% of the patients with a median of 9 cm (range, 1 to 32) below the costal margin. The median leukocyte count was 222 G/L (quartile 95-353). There is no statistical difference between boys and girls in terms of frequency of signs of leukostasis, frequency of splenomegaly, spleen size, median of the leucocyte count and hemoglobin level but the median of the platelet count was significantly higher in girls (p<0.0001). The majority (67%) of the children was allocated to the low-risk group according to the Eutos Long Term Survival (ELTS) score. First line therapy consisted of imatinib in 482 children with a median follow up of 4.6 years (IQR. 2.2-8.4). Among them, 208 (43%) children remained on imatinib with a median follow up of 2.9 years (IQR. 1.5-5.6). The main reason for switching (38.7% of the switches) was failure to achieve hematologic, cytogenetic or molecular response. Among the patients treated with imatinib first line, 15 (3.1%) children died and the probability of overall survival at 36 months was 97.4% (95% CI: 95-99%) (Figure 1). ELTS score was calculated for 406 of these patients: the 3-year survival rate was 98.1.% (95% CI: 96.3-100%), 94.4% (95% CI: 89.1-99.9%) and 95% (95% CI: 88.5-100%) in the low-, intermediate- and high-risk group, respectively (p logrank=0.009). Nineteen of these patients (3.9%) switched from imatinib to another treatment due to progression (accelerated or blastic phase). Progression free survival (PFS) rate at 3-years was 97.1% (95% CI: 94.9-99.2%), 91.7% (95% CI:84.5-98.3%) and 72.0% (95% CI: 59-87.9%) in the ELTS low-, intermediate- and high-risk group, respectively (p logrank<0.001) (Figure 2). Conclusion. The analysis of clinical and biological parameters of the largest cohort of children with CML in CP demonstrated that pediatric CML is characterized by a bulky disease (large splenomegaly, high leucocyte counts). However, these characteristics did not translate in a low rate of response and the outcome was similar to adults. While the ELTS score can identify children with the poorest outcome, a refined prognostic score specific for the pediatric population needs to be established and validated.

Chronic myeloid leukemia in children and young adults: A single centre experience

Chronic myeloid leukemia in children and young adults: A single centre experience

Current childhood chronic myeloid leukemia management under tyrosine kinase inhibitor treatment.

Chronic myeloid leukemia (CML) is very rare during childhood. Tyrosine kinase inhibitors (TKI) provide very good results in terms of survival. The medical records of 15 chronic phase (CP)-CML patients in a university hospital pediatric hematology department between 1997 and 2022 were reviewed retrospectively. Complete hematological response was documented in all patients between 20 and 68 (median 30) days of treatment. Major molecular response was achieved in seven patients within 6months. Median follow-up for the study group was 79 (range 3-330) months and overall survival was 100%. Three patients (2 blastic transformation, 1 therapy resistant) underwent bone marrow transplantation (BMT) and one with blastic transformation is scheduled to undergo BMT. TKI were discontinued in three patients after a median of 86 (range 73-177) months. The complete molecular remission maintenance period before discontinuation of TKI was 81 (range 62-122) months. While no molecular relapse was seen before the last follow-up, the median overall follow-up period was 152 (range 131-300) months. In conclusion, recent advances have led to a very good prognosis for children with CP-CML. With TKI treatment, most patients continue their lives without disease progression. Additionally, in selected patients TKI can be discontinued without molecular relapse.

Prevalence of anemia at diagnosis of pediatric chronic myeloid leukemia and prognostic impact on the disease course.

The clinical presentation of chronic myeloid leukemia (CML) at diagnosis differs in children compared to adults. At younger age, anemia appears to be frequent at diagnosis, but its prevalence and its impact on prognosis are not well known. In the International Registry of Childhood CML, we selected children and adolescents in chronic phase at diagnosis of CML and treated upfront with imatinib. We examined their hemoglobin level at diagnosis according to the WHO grades to assess the prevalence of anemia and its impact on response to tyrosine kinase inhibitors (TKIs). Data on 430 patients were included. Anemia at diagnosis was observed in 350 patients (81%), with a mean hemoglobin level of 96.4g/l (SD 23.6). Among them, 182 patients (52%) presented with moderate anemia and 110 (31%) with severe anemia while 58 (17%) had mild anemia. Compared with mild and no anemia, moderate and severe forms were significantly associated with younger age at diagnosis, asthenia, splenomegaly, and increased leukocyte and basophil counts. Delays in achieving major and deep molecular responses were significantly increased for patients with moderate and severe anemia, and also failure of imatinib treatment was more frequent in these two sub-cohorts. However, hemoglobin level was not significantly associated with survival. Anemia at diagnosis of pediatric CML was frequent and may be considered as a prognostic factor.

Update in Childhood Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) in childhood represents only 3% of newly diagnosed pediatric leukemia. The diagnostic hallmark of CML is the Philadelphia (Ph) chromosome, which derives from the fusion of the ABL1-oncogene located on chromosome 9 to the breakpoint cluster region (BCR) gene on chromosome 22, resulting in a constitutively dysregulated ABL1 tyrosine kinase, either as 210 kDa or 190 kDa. Depending on the localization of the breakpoint site within the major BCR region, the majority of CML patients exhibit transcripts with either the b3a2 or b2a2 junction, or both. Several questions are still open with regard to childhood CML, especially concerning the biologic and clinical features of the disease, and the treatment of choice for pediatric patients with CML. Moreover, over the last few years, several tyrosine kinase inhibitors (TKIs) have been available for children and adolescents with CML, and current clinical practice investigates what the effective and optimal doses of TKIs are in these two categories of patients. The use of TKIs in pediatric patients with CML has also opened up questions on the following items: (1) the long-term effects of these drugs on children; (2) the management of pediatric CML forms resistant or intolerant to TKIs; (3) the monitoring of disease outcomes during treatment; (4) and the right timing to discontinue therapy. Despite the efficacy of TKIs also in the pediatric population, the potential late adverse effects, and the drug resistance, leave open the possibility of allogeneic hematopoietic stem cell transplantation as a treatment option in pediatric CML. Published data and personal experiences regarding these issues will be analyzed and discussed.

Hematopoietic Stem Cell Transplantation for Pediatric Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) accounts for approximately 2 to 3% of all pediatric leukemias. Compared to adults, children tend to present with more aggressive features, such as higher leukocyte counts and massive splenomegaly, and are more likely to be diagnosed with advanced stage disease. Before the advent of tyrosine kinase inhibitors, a couple of decades ago, allogeneic hematopoietic stem cell transplantation (allo-HSCT) was the mainstay of treatment for this disease. This, however, was associated with considerable treatment-related morbidity and mortality. Even so, despite its secondary and somewhat limited indication today, allo-HSCT remains an important alternative and the only curative treatment for CML. In 2020, the Brazilian Group for Pediatric Bone Marrow Transplantation of the Brazilian Society for Blood and Marrow Transplantation and Cellular Therapy (SBTMO) convened a task force to provide evidence-based guidance on the use of allo-HSCT for the appropriate management of childhood CML, the results of which are presented here.

Characteristics, Treatment and Outcome of 15 to 18 Years-Old Adolescents with Chronic Myeloid Leukemia (CML): The Experience of the International Registry of Childhood CML (I-CML-Ped Study)

Introduction: CML is a rare disease in children and adolescents, accounting for 2-3% of leukemia cases in this population. Pediatric CML is more frequent in the 2 nd decade of life but data on adolescents are limited. Only response to treatment has been analyzed in few studies and seems to be poorer in this age cohort. The International Registry of Childhood Chronic Myeloid Leukemia gave us the opportunity to analyze the characteristics and outcome in a large cohort of adolescents.Aims and objectives: To report on clinical features and response to treatment in adolescents (15-18 years of age at diagnosis) with CML in chronic phase (CML-CP).Material and methods: The International Registry of Childhood CML (I-CML-Ped Study, registered at www.clinicaltrials.gov NCT01281735) enrolled patients less than 18 years of age at diagnosis of CML in all phases according to the criteria of the European Leukemia Net (ELN). Data from this registry collected from Jan 2011 - Mar 2021 into the I-CML-Ped Study (Poitiers, France) were retrospectively analyzed.Results: Out of 614 patients (pts) registered in the I-CML-Ped Study, we identified 144 (23.4%) adolescents (15-18 years of age at diagnosis) with sufficient available data. Among them, according to the ELN criteria, 132 (92%), 7 (5%), and 5 (3%) pts presented with CML-CP, accelerated phase (AP), and blastic phase (BP), respectively. The median age of the cohort comprising 132 adolescents with CML-CP was 16.2 years [range, 15-18]. Ratio male/female was 1.75. Splenomegaly was reported in 66% of the pts with a median spleen size of 11.5 cm below the costal margin [range, 1-32]. Hepatomegaly was reported in 31% of the pts with a median liver size of 2.5 cm below the costal margin [range, 1-19]. Pain, asthenia and weight loss were the most frequent symptoms at diagnosis in 35%, 33%, and 20% of pts, respectively. The performance status according to the OMS and Karnofsky scores were 0 and 100% in 81% and 57% of the pts, respectively. At diagnosis, median leukocyte count was 181 G/L [range, 7-820]; median platelet count was 516 G/L [range, 102-2619], and median hemoglobin level was 10.45 g/dL [range, 4-17]. BCR-ABL1 transcript type b3a2 was present in 53% of the assessable pts. Additional chromosomal abnormalities and variants were found in 5% of the pts. 9% and 40% of pts were considered at high-risk according to the ELTS score and to the Sokal score (for pts less than 45 years), respectively. The majority of pts (97%) were treated with imatinib as first line treatment. After 12 months of treatment, in pts with data available, rate of complete cytogenetic response (CCyR) was 74/109 (68%) pts with imatinib first line. Overall, rate of CCyR was 101/109 (93%) pts with imatinib first line [88/109 (81%) pts receiving imatinib only, 13/109 (12%) pts after switching to another TKI, 8/109 (7%) pts did not achieve CCyR]. Median time to achieve CCyR was 8.2 months [range, 2.7-106.7]. The cumulative rate of MMR at month 12 was 40/111 (36%) pts. Overall rate of MMR was 91/111 (82%) pts [72/111 (65%) pts with first line imatinib only; 19/111 (17%) pts with another TKI]. Median time to achieve first MMR was 14.5 months [range, 0.9-63.1]. Out of all patients on first line imatinib, 11/123 (9%) pts progressed: 3/11 pts progressed to AP and 8/11 pts to BP. Further progress to BP was observed in 2 of the 3 pts with AP. BP phenotype was myeloid in 5/10 pts, lymphoid in 3/10 pts and bilineage in 1/10 pts (no data for 1/10 pts). With imatinib first line, deaths occurred in 5/123 (4%) pts, among them 4/5 due to complications associated with hematopoietic stem cell transplantation. With a median follow up of 37 months [range, 0.9-231], the overall survival rate was 89.2% [83.6%; 94.7%] for pts treated with imatinib first line (N = 123).Conclusion: Our results are in line with publications describing adolescents and young adults (AYAs) as a risk population for a poorer treatment outcome: when comparing AYAs (15-29 yrs) to adults (>30 yrs), CCyR and MMR were inferior in AYAs (cumulative CCyR 84% vs 93%, cumulative MMR 75% vs 86%, respectively) [Pemmaraju N et al., Haematologica 2012] and rates of progression to AP and BP were 8.7% in AYAs (16-29 yrs) but only 5.3% and 6.1% in adults (45-59 yrs and >60 yrs, respectively) [Kalmanti L et al. , Ann Hematol. 2013]. Additional research is required in adolescents with CML to shed light on the cause(s) for the observed differences and to further improve the outcome. DisclosuresNo relevant conflicts of interest to declare.

Chronic Myeloid Leukemia in Children and Adolescents (A bout 2 cases)

Pediatric chronic myelogenous leukemia is a rare entity (2 to 5% of childhood leukemia) classified as myeloproliferative neoplasia characterized by the presence of the BCR-ABL fusion gene, the oncogenic product of the translocation (9; 22), responsible for the disease by its deregulated tyrosine kinase activity. Pediatric chronic myelogenous leukemia evolves spontaneously in three phases: chronic, accelerated and blast, during which the malignant clone gradually loses its capacity for differentiation. The diagnosis is based on the clinic mainly by the presence of a marked splenomegaly, the blood count by a hyperleukocytosis generally greater than 250,000 / mm³, myelogram which shows granular hyperplasia associated with no blast infiltration and morphologically define the stage of the disease, cytogenetics and molecular biology which confirms the diagnosis by the detection of the Philadelphia chromosome and more specifically the molecular abnormality BCR-ABL1. Imatinib is the treatment of choice for curative purposes used in our hospital structure, but regular monitoring of residual molecular disease and the absence of cytogenetic evolution are essential to understand resistance to TKIs (the inhibitor of tyrosine activity kinase) and detect disease progression. We report two observations of pediatric chronic myeloid leukemia, describing the different diagnostic aspects and which were in agreement with clinical and biological data in the literature.

Chronic Myeloid Leukemia in Children: Immune Function and Vaccinations.

Children with CML need TKI treatment for many years, and the lack of knowledge about immune dysfunction with TKI has hindered routine immunizations. This review attempts to provide an overview of the effects of TKIs licensed for children (e.g., imatinib, dasatinib, and nilotinib) on immune function, as well as its implications on immunizations. We discuss surveillance strategies (e.g., immunoglobulin blood serum levels and hepatitis B reactivation) and immunizations. All inactivated vaccines (e.g., influenza, pneumococcal, and streptococcal) can be given during the treatment of CML in the chronic phase, although their efficacy may be lower. As shown in single cases of children and adults with CML, live vaccines (e.g., varicella, measles, mumps, rubella, and yellow fever) may be administered under defined circumstances with great precautions. We also highlight important aspects of COVID-19 in this patient population (e.g., the outcome of COVID-19 infection in adults with CML and in children with varying hemato-oncological diseases) and discuss the highly dynamic field of presently available different vaccination options. In conclusion, TKI treatment for CML causes humoral and cellular immune dysfunction, which is mild in most patients, and thus infectious complications are rare. Routine immunizations are important for health maintenance of children, but vaccinations for children with CML on TKI therapy should be carefully considered.

CML-111: Outcomes of Allogeneic Hematopoietic Cell Transplantation for Childhood Chronic Myeloid Leukemia: A Single Center Experience

Context: Despite the apparent efficacy and favorable toxicity profile of TKIs, allogeneic HSCT remains the only curative treatment for CML, especially in younger patients, but transplant-related mortality should be considered. Objective: This study objective was to analyze the outcome of allogeneic HSCT in children with CML treated in a single center. Design/Setting: This is a retrospective study included children and adolescent patients (below 18 years of age) with confirmed CML who received an allogeneic HSCT at the stem cell transplantation unit of Children Cancer Hospital Egypt (CCHE 57357) between August 2007 and December 2017 with follow-up until June 2018. Patients or Other Participants: Out of 121 patients with newly diagnosed CML, 43 (35.5%) had available matched related donors and underwent HSCT, while 78 (64.5%) were maintained on TKI therapy. The median age at diagnosis was 12 years (range: 4.42 to 17.38 years), and the median time to transplant from diagnosis was 13 months. Intervention: All patients received Myeloablative conditioning chemotherapy containing BU/CY (busulfan in 16–20 mg/kg, and cyclophosphamide 4×50 mg/kg), with cyclosporine/short courses of MTX as GVHD prophylaxis. Patients with blastic crises received TKI therapy for one-year post HSCT. Main Outcomes Measures: Event-free survival, progression-free, and overall survival were measured. Incidence of GVHD and transplant-related mortality were also reported. Results: At initial diagnosis, there were 39 patients in chronic phase and 4 had blastic crises. Bone marrow harvest was the stem cell source in 32 patients, while 11 cases received mobilized peripheral blood stem cells with an average stem cell dose of 4.45×106/kg. The probabilities of overall survival and event-free survival at 5 years were 97.4% and 79.8%, respectively. TRM at 100 days and at 1-year post-transplant were 0%. The incidence of chronic GVHD was significantly higher in peripheral blood than bone marrow stem cell source (P=0.004). Conclusions: Considering the excellent survival rates and very low TRM, HSCT is still a valid option for pediatric patients with newly diagnosed CML, best using a bone marrow stem cell source to avoid a significant risk of cGVHD and its related complications.

Discontinuation of Imatinib in Children with Chronic Myeloid Leukemia: A Study from the International Registry of Childhood CML.

Simple SummaryAbout 50% of adults with chronic myeloid leukemia (CML) in sustained deep molecular response (DMR) to tyrosine kinase inhibitors (TKI) could discontinue the treatment permanently without molecular relapse. Recommendations regarding discontinuation apply only for adults because childhood CML is a very rare disease and represents a separate entity. The aim of our retrospective study was to assess within the International Registry of Childhood CML, the rate of children remaining in molecular response after discontinuation of imatinib in a context of DMR defined as BCR-ABL1/ABL1 < 0.01% (MR4) for at least two years. Eighteen patients less than 18 years old at diagnosis of CML exhibiting a sustained DMR followed by imatinib discontinuation were identified. After discontinuation, the molecular free remission rate was 61%, 56% and 56% at 6, 12 and 36 months, respectively. Our findings represent the basis of recommendation regarding discontinuation for physicians involved in the pediatric CML field.Within the International Registry of Childhood Chronic Myeloid Leukemia (CML), we identified 18 patients less than 18 years old at diagnosis of CML who were in the chronic phase and exhibiting a sustained deep molecular response (DMR) to imatinib defined as BCR-ABL1/ABL1 < 0.01% (MR4) for at least two years followed by discontinuation of imatinib. Before discontinuation, the median duration of imatinib was 73.2 months (range, 32–109) and the median duration of MR4 was 46.2 months (range, 23.9–98.6). Seven patients experienced loss of major molecular response (MMR) 4.1 months (range, 1.9–6.4) after stopping and so restarted imatinib. The median molecular follow-up after discontinuation was 51 months (range, 6–100) for the nine patients without molecular relapse. The molecular free remission rate was 61% (95% CI, 38–83%), 56% (95% CI, 33–79%) and 56% (95% CI, 33–79%) at 6, 12 and 36 months, respectively. Six of the seven children who experienced molecular relapse after discontinuation regained DMR (median, 4.7 months; range, 2.5–18) after restarting imatinib. No withdrawal syndrome was observed. In univariate analysis, age, sex, Sokal and ELTS scores, imatinib treatment and DMR durations before discontinuation had no influence on treatment free remission. These data suggest that imatinib can be safely discontinued in children with sustained MR4 for at least two years.

Long-Term Outcome in Children and Adolescents with Chronic Myeloid Leukemia in Chronic Phase Treated with High-Dose Imatinib— the Italian Experience

The availability of imatinib (IM) and thereafter of second-generation tyrosine kinase inhibitors (TKI2) has extended therapeutic options for childhood chronic myeloid leukemia (CML) with a favorable influence on disease outcome and overall prognosis. The aim of this report was to evaluate the response to therapy and long-term outcome of children and adolescents with CML in chronic phase (CP) treated with high-dose imatinib (IM).CP-CML patients (pts) aged <18 years (yrs) at diagnosis treated with IM at a dosage of 340 mg/m2/day and with a follow-up ≥24 months were considered. Treatment response was evaluate every 3 months by cytogenetics on bone marrow (BM) and/or by quantitative RT-PCR on peripheral blood and/or on BM. A complete cytogenetic response (CCyR) is defined as the absence of Ph+ cells. The terms MR3, MR4, MR4.5 and MR5 are used to indicate BCR-ABL1 IS ≤0.1%, BCR-ABL1 IS ≤0.01%, BCR-ABL1 IS ≤0.0032%, BCR-ABL1 IS ≤0.001%, respectively (Cross et al, 2012). No response, toxicity and loss of response leading to a treatment change were considered as failures.Between March 2001 and June 2015, 58 pts with a diagnosis of CP-CML (males/females 1.6; median age 114/12 years) were treated with IM at dose of 340 mg/m2/day in 14 Italian pediatric centers. Sixteen (27.5%) had an HLA-matched sibling. Thirty-eight pts (65.5%) received IM for a period >24 months. After 3 months of IM treatment, 83% and 56% of ptsshowed BCR-ABL1 IS ≤10% and ≤1%, respectively. BCR-ABL1 transcript levels ≤0.1% were found in 61% and 69% of pts at 12 and 18 months. At 24 months, 66% and 54% of pts showed BCR-ABL1 levels ≤0.1% and ≤0.01%, respectively. Overall, 91%, 85%, 56% and 39% of pts achieved CCyR, MR3, MR4, MR4.5 and MR5 after a median time of 6.1, 12.5, 16.4 and 19 months, respectively. BCR-ABL1 IS ≤10% and ≤1% after 3 months of treatment did not impact on the overall CCyR, MR3, MR4-MR4.5 and MR5. Treatment with IM was stopped in 29/58 pts (50%) after a median time of 16.7 months (range: 1.4-157) because of failure (58.5%), toxicity or intolerance (14%) and allogeneic hematopoietic stem cell transplant (HSCT) (27.5%). Eighteen pts (62%) received one or more TKI2, 3 pts (10%) α-interferon (IFN), 1 pt conventional chemotherapy (3.5%) and 16 pts (55%) underwent a HSCT (Table 1). Transplants were performed after a median of 12 months: 10 from an identical sibling, 5 from a matched unrelated donor and 1 from an umbilical cord blood. Three early transplanted pts had disease recurrence after 24, 36 and 83 months, respectively; they were rescued with IM ± conventional chemotherapy ± 2nd HSCT (2 pts) or dasatinib (1 pt). Among 29 pts who continued IM, 15 (52%) (1 in MR3, 6 in MR4-MR4.5 and 8 in MR5) started intermittent treatment (IM for 3 weeks a month); thereafter, 5 pts resumed continuous IM and 1 patient shifted to dasatinib because of response loss; 3 adolescents with long-lasting BCR-ABL1 IS <0.0032% discontinued treatment. The overall failure-free survival (FFS) at 60 and 120 months was 72.3% (95% CI, 64.1-81.6) and 58.4% (95% CI, 49.8-68.5); transcript levels <10% and <1% BCR-ABL1 ISat 3 months favorably influenced the FFS (Figs 1 and 2). After a median follow-up of 87 months (range: 24-196), 6 pts (10%) are lost to follow-up, 5 (8.5%) have been referred to a Center for adults, 14 (24%) are treatment-free in MR4-MR5(3 pts after 78, 78 and 98 months from IM discontinuation, respectively, and 1 after 20 months from nilotinib discontinuation), 22 (38%) are on IM treatment (1 for a blast crisis after HSCT) and 11 (19%) are receiving a TKI2 ± IFN. All patients are alive, 1 with active disease after transplantation. Two females (1 transplanted and 1 in TKI2) had two pregnancies each (3 healthy children and 1 spontaneous abortion).In conclusion, this larger cohort of pts with a longer follow-up confirmed our previous results on the high response rates in children and adolescents treated with high-dose IM and the prognostic impact of the transcript levels after 3 months of treatment on the disease outcome. Unfortunately, failures occurred late during treatment with IM. Over time, the efficacy of IM and the availability of TKI2 also in childhood CML has limited the use of HSCT leading to avoid transplants even in children with an identical sibling. Both transplant and TKI did not prevent pregnancies. Although the stop of treatment is not recommended outside of clinical trials, IM or TKI2 can be safely discontinued in some children and adolescents with a durable deep molecular response. [Display omitted] DisclosuresSaglio:Ariad: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Foa:Roche: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Sandoz: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau.

Advanced Phases at Diagnosis of Childhood Chronic Myeloid Leukemia : The Experience of the International Registry for Chronic Myeloid Leukemia (CML) in Children and Adolescents (I-CML-Ped Study)

Introduction. Chronic myeloid leukemia (CML) is a very rare disease in children and adolescents. The international registry of CML in children and adolescents (I-CML-Ped Study) established in the year 2011 has proven very beneficial to better describe this disease in pediatric cohorts.Aims: To describe the characteristics and the outcome of the pediatric population with advanced phases of CML at initial diagnosis.Patients and Methods: Patients enrolled in the international registry for CML in children and adolescents (I-CML-Ped Study) were the subjects of the study .Disease phases were defined according to the ELN criteria. Characteristics and outcome were determined in children in accelerated (AP) and blastic phase (BP). No recommendations were given regarding the treatment of the patients. Overall survival (OS) was estimated from diagnosis by the Kaplan and Meier method.Results. 479 children and adolescents less than 18 years old with CML were enrolled in the I-CML-Ped study between January 2011 and April 2017. Among them, 37 patients (7.7%) presented at initial diagnosis with CML in advanced phase according to the ELN criteria: 20 children (13 boys and 7 girls, median age 12.6 years - range 3 to 18 years) and 17 children (11 boys and 6 girls, median age 11 years - range 5 to 17 years) were diagnosed in AP and in BP, respectively. Among the 17 patients diagnosed in BP, 12 (70%) had lymphoid and 2 myeloid phenotype (not specified: 2 patients with extramedullary disease as unique criteria of BP). According to the Sokal score for patients less than 45 years, 73% and 82% of the patients in AP and BP at diagnosis were high risk patients, respectively. For the 17 children in BP, treatment consisted of tyrosine kinase inhibitors (TKI) (n=3) or a combination of chemotherapy and TKI successively and/or simultaneously (n=14); 11 of them were transplanted (sibling donor: n=2; unrelated donor n=8; unknown: n=1) with a median time after diagnosis of 7 months (range, 4.5 to 10 months). For the 20 children in AP, treatment consisted of TKI (n=17) or a combination of chemotherapy and TKI successively and/or simultaneously (n=3); 6 of them were transplanted (sibling donor: n=5; unrelated donor n=1) with a median time after diagnosis of 8 months (range, 4 to 21.5 months). With a median time from diagnosis of 3.5 years (range 8 months to 13.5 years), 13 out of 17 patients in BP at initial diagnosis are alive in at least major molecular response (MMR) (11 patients) or without MMR (2 patients) including 5 patients who were not transplanted; death occurred in 3 transplanted patients (relapses: 2 patients; chronic graft versus host disease: 1 patient) and in one patient with progression of the disease. Nineteen out of 20 patients in AP at initial diagnosis are alive (one patient died after progression) in at least MMR (15 patients) or without MMR (2 patients) or unknown status (2 patients). The 5 years OS rates were 94% (95% confidence interval (CI): 66%-99%) and 74% (95% CI: 44%-89%) for patients diagnosed in AP or BP, respectively.Conclusion: The data indicates that the frequency of advanced phases at diagnosis of CML is similar in children and in adults but with a predominance of lymphoid phenotype in children in blastic phase compared to adult population. Hematopoietic stem cell transplantation remains a curative treatment of children in blastic phase at diagnosis.Acknowledgment: The I-CML Ped study is supported by an unrestricted grant from Novartis Pharmaceutical Company DisclosuresNo relevant conflicts of interest to declare.

Tyrosine Kinase Inhibitors and Beyond for Chronic Myeloid Leukemia in Children.

Chronic myeloid leukemia (CML) is rare in children but presents a unique challenge as recent drug innovations have turned CML into a chronic disease with implications for treatment into adulthood. With the approval of newer-generation tyrosine kinase inhibitors (TKIs) in addition to imatinib, providers have more options for the treatment of chronic-phase CML (CML-CP) in children. The second-generation TKIs approved for use in children, nilotinib and dasatinib, have higher response rates than first-generation imatinib; however, overall survival rates appear to be the same. Even more options may soon become available with ongoing investigations into the use of bosutinib and ponatinib and other new agents in children. Possible long-term side effects of TKIs, including growth failure, should be carefully acknowledged by the treating provider. Although these known associations may not preclude treatment, providers should be aware of them to guide their management of pediatric patients with CML being treated long term with TKI therapy. Treatment-free remission is a desired goal for pediatric patients and providers alike, but current recommendations are for attempts at achieving this to be restricted to clinical study settings.

Discontinuation of Imatinib in Children with Chronic Myeloid Leukemia: An International Registry of Childhood Chronic Myeloid Leukemia (I-CML-Ped) Study

Background: Imatinib, a tyrosine kinase inhibitor (TKI) is currently proposed as first line therapy in children with chronic myeloid leukemia (CML) in chronic phase (CP). Studies in adults with CML demonstrated that 40 to 50% of patients with prolonged deep molecular response under TKI could discontinue TKI permanently without molecular relapse. However, data regarding TKI discontinuation in children with CML are limited. Methods: Using the ELN criteria we identified in the International Registry of Childhood Chronic Myeloid Leukemia 18 patients less than 18 years of age at diagnosis with CML in CP exhibiting under imatinib treatment sustained deep molecular response &amp;gt;MR4.0 (DMR) for ≥ 2 years and then discontinued the TKI. We retrospectively analyzed outcome of these patients and treatment-free remission rate (TFR) at various time points. Treatment with imatinib was resumed in case of molecular relapse defined as loss of major molecular response (MMR). Results: There were 11 boys and 7 girls. From diagnosis in CP until TKI discontinuation the 18 children showed no progression, resistance, warning or suboptimal response or switch to another TKI before discontinuation. Median age at diagnosis of CML was 11.9 years (range, 2.3 to 15.8 years) and median age at discontinuation of TKI was 16 years (range, 9 to 24 years). Median overall follow-up from diagnosis of CML was 107 months (range, 67-209 months). DMR was achieved after a median time of 12 months (range, 3 - 50 months) on imatinib. Before discontinuation median treatment duration of imatinib was 73.25 months (range, 32 to 109 months) and median duration of MR4.0 was 46.2 months (range, 23.9 to 98.6 months). Seven patients experienced molecular relapse 4.1 months (range, 1.9-6.4 months) after stopping and restarted imatinib. Two patient resumed imatinib 3.6 and 3.4 months after discontinuation because of increased in transcript level (from 0.001% to 0.01 and 0.012, respectively) but without loss of MMR. The median molecular follow up after discontinuation was 116 months (range, 71 to 209 months) for the patients without molecular relapse. The proportion of patients maintaining molecular free remission was 61% (95% CI, 38%-83%), 56% (95% CI, 33%-79%) and 56% (95% CI, 33%-79%) at 6, 12, and 36 months, respectively (Figure 1). Six of the 7 children who experienced molecular relapse after discontinuation again achieved MR4.0 at median of 4.7 months (range, 2.5-18 months) after restart of imatinib; the remaining patient achieved MMR but not DMR and was switched to Dasatinib. No withdrawal syndrome was observed in this cohort of 18 patients. In univariate analysis, age, sex, Sokal and ELTS scores, imatinib treatment duration before discontinuation and duration of DMR until imatinib discontinuation had no influence on treatment free remission. Conclusion: These data indicate that imatinib could be safely discontinued in children younger than 18 years of age at diagnosis of CML with sustained MR4.0 for at least 2 years under imatinib. Larger studies of TKI discontinuation in children with CML are needed in order to identify factors predicting treatment free remission. Disclosures Dalle: Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medac: Consultancy, Honoraria; Orchard: Consultancy, Honoraria; Bellicum: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria; AbbVie Pharmacyclics: Membership on an entity's Board of Directors or advisory committees.

Ponatinib in childhood Philadelphia chromosome–positive leukaemias: an international registry of childhood chronic myeloid leukaemia study

BackgroundPonatinib is effective in adults with Philadelphia chromosome–positive (Ph+) leukaemias, but scant data are available regarding the use of this tyrosine kinase inhibitor in children. AimsThe aim of this study isto describe the tolerance and efficacy of compassionate use of ponatinib in a paediatric cohort of patients with Ph+ leukaemias. MethodsData from 11 children with chronic myeloid leukaemia (CML) registered to the international registry of childhood chronic myeloid leukaemia and from 3 children with Ph+ acute lymphoblastic leukaemia (Ph+ ALL) treated with ponatinib were collected retrospectively. ResultsIn 11 girls and 3 boys (median age 14 years), ponatinib was used as a second- to eighth-line treatment. Ponatinib was administered as single therapy (9 patients) or in combination with chemotherapy (8 patients). The status of the disease when ponatinib was started was as follows: CML in advanced phases (n = 8), CML in chronic phase without achievement of molecular response (n = 2) or presence of T315I mutation (n = 1) and Ph + ALL in molecular (n = 1) or marrow (n = 2) relapses. The median dose administered was 21.4 mg/m2 and median duration of ponatinib was 2.5 months. Ponatinib alone or in combination with chemotherapy administered on 16 occasions led to achievement of major molecular response in 50% of cases. Ponatinib was used as a bridge to transplant in 4 cases. Among the 9 patients treated with ponatinib alone, toxicity grade III–IV (2 patients) was exclusively haematologic. No vascular events related to ponatinib were observed. ConclusionPonatinib may be a reasonable additional treatment option for children with Ph+ leukaemias who have failed several lines of therapy.

[Research status of and treatment progress in chronic myeloid leukemia in children].

慢性粒细胞白血病（CML）在儿童中相对罕见，其临床表现、免疫表型及遗传学特征与成年患者存在差异。CML患儿处于特殊的成长时期，可能接受长达数十年的酪氨酸抑制剂（TKI）治疗，不良反应发生率可能高于成年患者。与成年CML患者相比，首诊CML患儿的TKI药物选择仍需要探讨，造血干细胞移植的地位存在争议。本文对儿童CML的研究现状、TKI时代患儿用药、疗效监测及移植时机选择进行综述。.

Chronic Myeloid Leukemia in Children: Challenges and Opportunities : Based on 7th Dr. I. C. Verma Excellence Award for Young Pediatricians Delivered as Oration on 29th Sept. 2019.

Treatment with tyrosine kinase inhibitors (TKI) is an effective therapy for children and adolescents with chronic phase of chronic myeloid leukemia (CML). For the majority of patients with CML in low- and middle-income countries (LMIC), imatinib is the TKI of choice for reasons of cost, availability, and experience. Children are exposed to therapy for a greater proportion of their lifetime as compared to adults. The adverse effects of prolonged administration of TKI is a subject of ongoing research, as more experience is collected. Therapy with TKI is currently considered to be life-long. Trials on stopping treatment are ongoing to explore if it may be feasible in selected patients, as reported in adults. Growth-failure is a concerning adverse effect. Currently, it seems unclear if the final height attained is within the expected range of the mid-parenteral height and growth standards. Whether the children will achieve a normal height at the end of their growth potential or remain below the predicted range is critical to decide if therapeutic interventions (E.g., growth hormone therapy, or interruption in TKI) should be considered during the period of growth potential. Research on CML in children is at a relatively slow pace, largely due to the rarity of the disease. This provides a unique opportunity for research in population-dense LMICs, as several tertiary centers tend to have a sizable cohort of children and adolescents with CML on follow-up. This narrative summarises the challenges and opportunities in dealing with CML in children, particularly in reference to a center in LMIC.

Outcomes of allogenic hematopoietic cell transplantation for childhood chronic myeloid leukemia: Single‐center experience

Despite the apparent efficacy and favorable toxicity profile of TKIs, allogeneic SCT remains the only curative treatment for CML especially in younger patients, but TRM should be considered. We evaluated the clinical outcomes of pediatric CML patients who had SCT in our center. This retrospective study included children with CML, who received an allogeneic SCT at Children Cancer Hospital Egypt, 57357, from 2007 to 2017. All patients received myeloablative conditioning chemotherapy containing busulfan/cyclophosphamide followed by stem cell infusion from MRD. From 121 patients diagnosed with CML, 43 had available MRD and subjected to HSCT while 78 patients continued TKI therapy. The median time to transplant from diagnosis was 13months. At initial diagnosis, there were 39 patients in CP and 4 had blastic crises. Bone marrow harvest was the stem cell source in 32 patients, while 11 cases received mobilized peripheral blood stem cells with average stem cell dose of 4.45×106 /kg. The probabilities of overall survival and event-free survival at 5years were 97.4% and 79.8%, respectively. TRM at 100days and TRM at 1-year post-transplant were 0%. The incidence of chronic GVHD was significantly higher in peripheral blood than bone marrow stem cell source (P=.004). Considering the excellent survival rates and very low TRM, HSCT is still a valid option for pediatric patients with newly diagnosed CML with best using marrow stem cell source to avoid a significant risk of cGVHD and its related complications.