Pediatric Chronic Myeloid Leukemia Research Articles

Room To Grow: Bosutinib Approved for Newly Diagnosed or Relapsed/Intolerant Pediatric Chronic Myeloid Leukemia

Room To Grow: Bosutinib Approved for Newly Diagnosed or Relapsed/Intolerant Pediatric Chronic Myeloid Leukemia

The molecular signature of BCR::ABLP210 and BCR::ABLT315I in a Drosophila melanogaster chronic myeloid leukemia model

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder resulting from a balanced translocation leading to BCR::ABL1 oncogene with increased tyrosine kinase activity. Despite the advancements in the development of tyrosine kinase inhibitors (TKIs), the T315I gatekeeper point mutation in the BCR::ABL1 gene remains a challenge. We have previously reported in a Drosophila CML model an increased hemocyte count and disruption in sessile hemocyte patterns upon expression of BCR::ABL1p210 and BCR::ABL1T315I in the hemolymph. In this study, we performed RNA sequencing to determine if there is a distinct gene expression that distinguishes BCR::ABL1p210 and BCR::ABL1T315I. We identified six genes that were consistently upregulated in the fly CML model and validated in adult and pediatric CML patients and in a mouse cell line expressing BCR::ABL1T315I. This study provides a comprehensive analysis of gene signatures in BCR::ABL1p210 and BCR::ABL1T315I, laying the groundwork for targeted investigations into the role of these genes in CML pathogenesis.

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.

Pediatric chronic myeloid leukemia: a case report of a disease with a unique biology

Pediatric chronic myeloid leukemia: a case report of a disease with a unique biology

Tyrosine Kinase Inhibitors in pediatric chronic myeloid leukemia: a focused review of clinical trials.

Tyrosine Kinase Inhibitors (TKIs) is revolutionizing the management of pediatric Chronic Myeloid Leukemia (CML), offering alternatives to Allogeneic Hematopoietic Stem Cell Transplantation (AHSCT). We conducted a comprehensive review of 16 Randomized Controlled Trials (RCTs) encompassing 887 pediatric CML patients treated with TKIs including Imatinib, Dasatinib, and Nilotinib. The median patient age ranged from 6.5 to 14 years, with a median white blood cell count of 234 x 10^9/uL, median hemoglobin level of 9.05 g/dL, and median platelet count of 431.5 x 10^9/µL. Imatinib seems to be predominant first line TKI, with the most extensive safety and efficacy data. BCR::ABL response rates below 10% ranged from 60% to 78%, CCyR at 24 months ranged from 62% to 94%, and PFS showed variability from 56.8% to 100%, albeit with differing analysis timepoints. The Safety profile of TKIs was consistent with the known safety profile in adults. With the availability of three TKIs as first line options, multiple factors should be considered when selecting first line TKI, including drug formulation, administration, comorbidities, and financial issues. Careful monitoring of adverse events, especially in growing children, should be considered in long term follow-up clinical trials.

The Applicability of Tyrosine Kinase Inhibitors in Pediatric Chronic Myeloid Leukemia

INTRODUCTION The advent of tyrosine kinase inhibitors (TKIs) has shifted the treatment paradigm of adult CML, limiting SCT to a last-resort option for TKI-ineligible or resistant cases. However, determination of the optimal dosing and duration, potential long-term side effects, and the viability of therapy discontinuation remain under-explored aspects of TKIs in pediatric CML. Emerging data supports administering novel TKIs as initial or second-line treatments in pediatric CML amid variable results. This review discusses the RCTs conducted on pediatric patients with CML who received TKIs, aiding in better understanding of the effectiveness and safety of TKIs in the pediatric CML population. METHODS We searched Medline, OVID, and Web of Science for all RCTs reporting the efficacy and safety of TKI in pediatric CML (< 18 years). We compiled the individual efficacy and safety data into distinct tables, emphasizing demographics, treatment modalities, and outcomes pertaining to both the safety and efficacy of TKI. RESULTS This review analyzed 17 Randomized Controlled Trials (RCTs) with 887 pediatric CML patients. Median age was 11.3 years (range 6.5-14 years). Efficacy studies had 718 patients, safety studies had 851.. The median white blood cell count was 234 x10 9/uL [range 19 to 378; reported in 9 RCTs], median hemoglobin level was 9 g/dL [range 5.6 to 10.8; from 7 RCTs], and the median platelet count was 431.5 x10 9/µL, [range 31 to 594; from 6 RCTs]. TKIs were first-line treatment in 65% of the studies, Imatinib being the commonest (61% of studies). Dasatinib and Nilotinib were used in 17% and 11% of studies, respectively, while 6% received a combination of imatinib and chemotherapy. Efficacy reporting in the RCTs was a major concern that challenged the accumulation of results (Table 1). BCR-ABL response of <10% ranged from 60 % to 78%, and the complete cytogenetic response (CCYR) at 24 months ranged from 62% to 94%. Progression free survival (PFS) ranged from 56.8% to 100%; however, the timepoint for PFS analysis was not standardized among studies (36 to 48 months). Safety data from 16 studies (851 patients) included anemia (n=228), thrombocytopenia (n=161), neutropenia (n=257), hepatotoxicity (n=98), and cutaneous side-effects (n=156). Cardiovascular complications with second generation TKIs included QTc prolongation with Nilotinib (n= 11) and heart failure with Dasatinib (n=4). Nausea/vomiting were reported in 119 patients on imatinib, vs. 64 and 37 patients on Dasatinib and Nilotinib, respectively. Diarrhea occurred in 40 patients on Imatinib ,and 20 and 2 patients in Dasatinib and Nilotinib cohorts, respectively. Other AEs included impaired bone growth (70 on Imatinib and 10 on Dasatinib), headache (44 on Imatinib, 38 on Nilotinib and 13 in Dasatinib), musculoskeletal pain (161 on Imatinib, 31 on Dasatinib and 8 on Nilotinib). Treatment AEs leading to drug discontinuation were reported in 22 patients (6 studies), however the exact AE leading to drug discontinuation were not reported. CONCLUSION There remains a limited experience in treating pediatric CML with TKIs. Hence, evidence from prospective clinical trials and real-life clinical practice are required to establish appropriate guidelines for the standard therapeutic management in this population. Imatinib has the most extensice efficacy and toxicity data in pediatric patients. The Safety profile of TKIs was consistent with the known safety profile in adults. With the availability of three TKIs as first line options, multiple factors should be considered when selecting first line TKI, including drug formulation, administration, comorbidities, and financial issues. Careful monitoring of adverse events, especially in growing children should be considered in long term follow-up clinical trials.

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 (CML) in children and adolescents-Clinicopathological findings.

Barely two per million Belgian children/adolescents are diagnosed with chronic myeloid leukemia (CML) annually. In this retrospective study, we aimed to investigate the diagnostic features, clinical and laboratory characteristics, and treatment outcome of this rare entity. Medical records of all pediatric CML patients (age ≤ 17 years) diagnosed at the University Hospitals Leuven between 1986 and 2021 were reviewed. Fourteen patients (median age at diagnosis 12.5 years) were included, all presenting in chronic phase. Five patients were diagnosed before 2003; main therapy included hydroxyurea (n = 5/5), interferon-alfa (n = 3/5) and allogeneic hematopoietic stem cell transplantation (allo-Tx) (n = 3/5). Complete hematologic response (CHR), complete cytogenetic response (CCyR) and major molecular response (MMR) was reached in resp. 4/5, 4/5 and in 2/3 of evaluable patients. Three patients progressed to accelerated/blast phase (median time 19 months) and 1/5 is alive and disease-free at last follow-up. Nine patients were diagnosed after 2003 and were treated with first generation (1°G) tyrosine kinase inhibitors (TKI): 3/9 subsequently underwent an allo-Tx, 4/9 were switched to 2°G TKI, one patient was additionally switched to 3°G TKI. CHR, CCyR and MMR was reached in 9/9, 9/9 and 8/9 of these patients. No progression to accelerated/blast phase was observed and none of these patients deceased. At last follow-up, 7/9 patients were in MMR or disease free, the two remaining patients did not reach or lost MMR, both related to compliance issues. Our study confirmed that TKI significantly improved the prognosis of pediatric CML. However, drug compliance poses a considerable challenge.

Continuous therapy response references for BCR::ABL1 monitoring in pediatric chronic myeloid leukemia

Response to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML) is monitored by quantification of BCR::ABL1 transcript levels. Milestones for assessing optimal treatment response have been defined in adult CML patients and are applied to children and adolescents although it is questionable whether transferability to pediatric patients is appropriate regarding genetic and clinical differences. Therefore, we analyzed the molecular response kinetics to TKI therapy in 129 pediatric CML patients and investigated whether response assessment based on continuous references can support an early individual therapy adjustment. We applied a moving quantiles approach to establish a high-resolution response target curve and contrasted the median responses in all patients with the median of the ideal target curve obtained from a subgroup of optimal responders. The high-resolution response target curve of the optimal responder group presents a valuable tool for continuous therapy monitoring of individual pediatric CML patients in addition to the fixed milestones. By further comparing BCR::ABL1 transcript levels with BCR::ABL1 fusion gene copy numbers, it is also possible to model the differential dynamics of BCR::ABL1 expression and cell number under therapy. The developed methodology can be transferred to other biomarkers for continuous therapy monitoring.

Front-Line Tyrosine Kinase Inhibitors in Pediatric Chronic Myeloid Leukemia: A Study on Efficacy and Safety.

We conducted a retrospective study on 51 pediatric patients with newly diagnosed chronic myeloid leukemia chronic phase or accelerated phase. The patients were classified into the IMA group (N = 33), treated with imatinib, and the DSA group (N = 18), treated with dasatinib, as front-line tyrosine kinase inhibitors (TKIs). At 12 months, the rates of complete cytogenetic response were similar between the IMA group (92.3%) and DSA group (100%) (p = 0.305). However, the rate of early molecular response was higher in the DSA group than in the IMA group (100.0% vs. 80.0%, p = 0.043). By 12 and 24 months, the DSA group showed faster and higher cumulative rates of both major (DSA group: 72.2% and 100%, respectively; IMA group: 41.2% and 68.7%, respectively; p = 0.002) and deep molecular responses (DSA group: 26.0% and 43.6%, respectively; IMA group: 13.8% and 17.5%, respectively; p = 0.004). Both TKIs were well tolerated. Although the height standard deviation scores decreased in both groups, the height decline was greater in the DSA group between one and two years from the start of TKI therapy. In this study, dasatinib achieved faster and higher molecular responses with an acceptable safety profile. Further follow-up is necessary to assess the long-term outcomes of TKI treatment in children.

Priapism at Diagnosis of Pediatric Chronic Myeloid Leukemia: Data Derived from a Large Cohort of Children and Teenagers and a Narrative Review on Priapism Management.

Pediatric chronic myeloid leukemia (CML) is a very rare malignancy (age-related incidence 0.1/100,000) typically presenting with leucocyte counts >100,000/µL. However, clinical signs of leukostasis are observed at diagnosis in only approximately 10% of all cases and among these, priapism is infrequent. Here, we analyze data from pediatric CML registries on the occurrence of priapism heralding diagnosis of CML in 16/491 (3.2%) boys (median age 13.5 years, range 4-18) with pediatric CML. In the cohort investigated, duration of priapism resulting in a diagnosis of CML was not reported in 5 patients, and in the remaining 11 patients, occurred as stuttering priapism over 3 months (n = 1), over 6 weeks (n = 1), over 1-2 weeks (n = 2), over several days (n = 2), or 24 h (n = 1), while the remaining 4 boys reported continuous erection lasting over 11-12 h. All patients exhibited splenomegaly and massive leukocytosis (median WBC 470,000/µL, range 236,700-899,000). Interventions to treat priapism were unknown in 5 patients, and in the remaining cohort, comprised intravenous fluids ± heparin (n = 2), penile puncture (n = 5) ± injection of sympathomimetics (n = 4) ± intracavernous shunt operation (n = 1) paralleled by leukocyte-reductive measures. Management without penile puncture by leukapheresis or exchange transfusion was performed in 3 boys. In total, 7 out 15 (47%) long-term survivors (median age 20 years, range 19-25) responded to a questionnaire. All had maintained full erectile function; however, 5/7 had presented with stuttering priapism while in the remaining 2 patients priapism had lasted <12 h until intervention. At its extreme, low-flow priapism lasting for longer than 24 h may result in partial or total impotence by erectile dysfunction. This physical disability can exert a large psychological impact on patients' lives. In a narrative review fashion, we analyzed the literature on priapism in boys with CML which is by categorization stuttering or persisting as mostly painful, ischemic (low-flow) priapism. Details on the pathophysiology are discussed on the background of the different blood rheology of hyperleukocytosis in acute and chronic leukemias. In addition to the data collected, instructive case vignettes demonstrate the diagnostic and treatment approaches and the outcome of boys presenting with priapism. An algorithm for management of priapism in a stepwise fashion is presented. All approaches must be performed in parallel with cytoreductive treatment of leukostasis in CML which comprises leukapheresis and exchange transfusions ± cytotoxic chemotherapy.

Effect of Imatinib Mesylate on Growth in Pediatric Chronic Myeloid Leukemia: A Systematic Review and Meta-analysis.

The outcomes of pediatric chronic myeloid leukemia (CML) have improved with the use of imatinib mesylate (IM). Multiple reports of growth deceleration with IM have raised concerns, necessitating careful monitoring and evaluation in children with CML. We systematically searched the databases of PubMed, EMBASE, Scopus, CENTRAL, and conferences-abstracts, reporting the effect of IM on growth among children with CML, and published in the English language from inception till March 2022. For observational studies, the modified Newcastle Ottawa Scale was used to assess the risk of bias. Pooled estimates were derived using a random-effects meta-analysis, and heterogeneity was assessed using Cochrane Q statistic test of heterogeneity and I2 statistic. Of the 757 studies identified through electronic search, 15 (n=265) were included in the final analysis. Six studies (n=178) were included in the meta-analysis of the primary outcome. There was a significant deleterious effect of IM on height-standardized mean difference (SMD): -0.52 (95% CI: -0.76; -0.28) ( I2 =13%). The adverse effect of IM on height was significant among studies with a follow-up period <3 years [SMD: -0.66 (95% CI: -0.93, -0.40), I2 =0%, P =0.59] but not in studies with follow-up period ≥3 years [SMD: -0.26 (95% CI: -0.63, 0.11), I2 =0, P =0.44], indicating that the effect of IM on height is a short-term effect. The effect of IM on height was not dependent upon pubertal status at the initiation of therapy. Prospective studies with adequate sample size are required to confirm the findings of the effect of IM on height in children with CML.

Treatment free remission in pediatric chronic myeloid leukemia

BackgroundThe aim was to evaluate the impact of discontinuation of imatinib in children in chronic phase of chronic myeloid leukemia (CML) and assess treatment free remission (TFR). Patients and methods: We performed a retrospective study in children diagnosed with CML chronic phase up to 18 years of age, who were on imatinib for 5 years and had consistent BCR:ABL1 negative/undetectable transcripts through RT-PCR. Complete blood counts were monitored monthly and BCR:ABL1 transcripts by RT-PCR monitored 3 months. Results: Among the 14 patients who continued to remain PCR negative, we attempted discontinuing imatinib in eleven children as per the above-mentioned criteria. Eight (72%) continued to be in remission and did not require imatinib to be restarted. Among the remaining three patients, one child was noted to have increasing basophilia in the differential counts and was hence restarted on imatinib. Two other patients demonstrated recurrence of BCR:ABL1 transcript copy numbers six months after stopping TKI, following which imatinib was restarted. All three patients had documented major molecular response within three months of therapy. The median duration of TFR was 18 months in our cohort (range: 3 months–5 years). Among patients who continued to be off imatinib, TKI withdrawal symptoms were documented in 4 (36%) patients. Conclusions: Treatment free remission was achieved in 8/11 (72%) children after discontinuation of imatinib, and re-introduction of imatinib resulted in major molecular response in those with recurrence. Monitoring of BCR:ABL1 transcripts through RT PCR is essential.

Pediatric and adolescent chronic myeloid leukemia: A follow-up study in Western India.

Chronic myeloid leukemia (CML) is relatively rare in pediatric and adolescent age groups. The purpose of this study was to evaluate the clinical, hematopathological, and biochemical parameters of CML in pediatric and adolescent age groups, along with an assessment of the treatment response with first-line tyrosine kinase inhibitors (TKI) and its correlation with the prognostic scoring systems of adults. A retrospective study of 44 Breakpoint Cluster Region-Abelson leukemia virus (BCR-ABL1)-positive pediatric and adolescent CML cases registered at our hospital was done. The clinical and laboratory parameters were evaluated using hospital software. The treatment response was monitored and scoring was performed using mathematical calculations. The mean age was 11.6 (±4.7) years. The median hemoglobin was 8.4 g/dL and 63.6% of the cases showed white blood cell (WBC) counts >250,000/μL. The average follow-up was 21 months. A total of 97.7 and 78.1% cases achieved complete hematological response (CHR) and molecular response, respectively, during the treatment course. The maximum number of patients had low Sokal and European treatment and Outcomes Study (EUTOS) scores. Seventy-five per cent of the cases achieved CHR at 3 months, while 73.6 and 78.6% CML-Chronic phase (CP) cases with low Sokal and EUTOS scores achieved CHR at 3 months, respectively. This study revealed that the CML cases in pediatric and adolescent age groups are normally present with higher WBC counts at the time of diagnosis. The association of the prognostic scoring system with treatment response was statistically insignificant. However, a larger cohort study is needed to determine the treatment response of TKI in children and adolescent CML and its correlation with the prognostic scoring systems.

Pediatric chronic myeloid leukemia (CML) presenting with ocular manifestations: A case report

A 14-year-old male child presented to the ophthalmologist with complaints of floaters and headache. Ophthalmic examination revealed dilated and tortuous retinal veins, perivascular infiltrates scattered throughout the fundus, and multiple white centered hemorrhages (leukemic infiltrates). A provisional diagnosis of leukemia or lymphoma was made. The diagnosis was confirmed by further systemic workup and complete blood count. A final diagnosis of CML in chronic phase was made after bone marrow aspiration, biopsy, and presence of BCR-ABL translocation. This case report highlights the role of an ophthalmologist in diagnosing and prognosticating a rare entity of pediatric CML with ocular manifestation as its presenting symptoms.

Pediatric chronic myeloid leukemia in myeloid blast crisis

Chronic myeloid leukemia (CML) accounts for 2-3% of childhood leukemias. About 5% of cases present in a blastic phase of CML which clinically and morphologically mimics more common acute leukemias of childhood. We report a case of a 3-year-old male who presented with gradual onset swelling of the abdomen and extremities along with generalized weakness. Examination revealed massive splenomegaly, pallor, and pedal edema. Initial workup showed anemia, thrombocytopenia, and leukocytosis (120,000/uL) with a blast percentage of 35%. Blasts were positive for CD13, CD33, CD117, CD34 and HLA-DR, and stained negative for Myeloperoxidase and Periodic Acid Schiff. Fluorescence in situ hybridization was positive for b3a2/e14a2 junction BCR-ABL1 transcript and negative for RUNX1-RUNX1T1/t(8;21), clinching the diagnosis of CML in myeloid blast crisis. The patient expired within 17 days of diagnosis and initiation of therapy.

Recent progress in the management of pediatric chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a rare myeloproliferative disease in children. The primary cause of CML is the chimeric BCR::ABL1 gene in hematopoietic stem cells, which leads to leukocytosis, platelet proliferation, and splenomegaly. Lately, tyrosine kinase inhibitors (TKIs) have replaced hematopoietic cell transplantation, which was previously considered the only curative therapy, as the first-line treatment for chronic-phase CML. However, the clinical efficacy of TKIs, including those effective in adult CML, has not been well-investigated in pediatric CML. This review describes the recommended TKI-based management strategies for pediatric CML according to the literature and guidelines. Furthermore, we discuss the prospects for TKI discontinuation to avoid important adverse events, such as growth impairment, in children.

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.

Patient-reported long-term outcome following allogeneic hematopoietic stem cell transplantation in pediatric chronic myeloid leukemia.

BackgroundPediatric CML is very rare. Before the introduction of tyrosine kinase inhibitors (TKIs), allogeneic hematopoietic stem cell transplantation (HSCT) from a donor -if available- was the standard cure attempt. Data on the long-term outcome and health-related quality of life (HRQOL) in former pediatric CML patients undergoing HSCT are lacking.Study questionWe investigated long-term survivors’ self-reporting to a questionnaire sent out to patients formerly enrolled in pediatric CML-HSCT trials.MethodsIndividuals with CML transplanted at age <18 years were identified from the German Childhood Cancer Registry database. Long-term survivors received a questionnaire based on the SF-36 and FACT-BMT asking them to self-report HRQOL issues. (Ethical vote #541_20 B, Medical Faculty, University of Erlangen-Nürnberg).Results111/171 (64.9%) individuals survived HSCT long-term and 86/111 (77.5%) fulfilled all inclusion criteria and received the questionnaire. 37/86 (43%) participants (24 female, 13 male, median age at HSCT 12 years [range 2-18], median age at the time of the survey 29 years [range 18-43]) responded after a median follow-up period of 19 years (range 4-27) after HSCT. 10/37 (27%) participants underwent no regular medical follow-up examinations. Self-reported symptoms like chronic graft-versus-host disease (cGvHD)-associated organ impairments and conditioning regimen consequences could causatively not sharply be separated in each case. Complains comprised hypothyroidism (N=11, 30%), infertility (N=9, 24%), lung problems, dry eyes (each N=7, 19%), skin alterations (N=6, 17%), hair problems (N=4, 11%), and sexual dysfunction (N=3, 9%). 10 (27%) participants experienced 13 CML relapses after a median interval from HSCT of 31 months (range 2-93). Only one patient underwent 2nd SCT after failure of relapse treatment with TKIs. Six secondary malignancies (dysplastic melanocytic nevus and ALL, basal cell carcinoma (N=2), rhabdomyosarcoma, and thyroid carcinoma developed in 5 (13%) participants. As assessed by the SF-36 questionnaire, impaired physical health was mainly associated with cGvHD. The mental component summary score showed that also participants without cGvHD scored significantly lower than the general population. When assessed by the FACT-BMT, participants with cGvHD scored significantly lower while participants without cGvHD scored even 5 points higher than the data from controls. 18 (49%) participants considered the sequelae of HSCT an obstacle to education. Out of the total cohort, N=20 (54%), N=7 (19%), N=5 (14%), and N=4 (11%) participants worked full time, part-time, were unemployed, or had not yet finalized their education, respectively. 20 (54%) participants lived as singles, 8 (22%) lived in a partnership, 6 (16%) were married, and 3 (8%) had been divorced. Four (11%) participants reported a total number of 7 children.ConclusionThis first assessment of HRQOL in former pediatric patients with CML surviving HSCT for more than two decades demonstrates self-reported satisfactory well-being only in the absence of cGvHD. Research-based on self-reported outcomes sheds light on former patients’ perspectives and provides an additional layer of valuable knowledge for pediatric and adult hematologists. Regular follow-up examinations are mandatory helping to avoid that late secondary neoplasias, CML-relapse, and disorders forming the broad range of possible long-term consequences of HSCT are not detected too late.