Risk-based long-term follow-up care for children with acute lymphoblastic leukemia treated on Chinese Children’s Cancer Group ALL-2015 protocol

To the Editor: Long-term follow-up (LTFU) care is crucial for survivors of childhood cancers, as their risks for morbidity and mortality increase as they age.^[1] Risk-based survivorship care, which includes a personalized surveillance plan for potential long-term side effects and interventions to remediate and prevent late effects, is recommended for all childhood cancer survivors at least annually and more frequently as clinically indicated. Health problems related to cancer treatment that persist or develop five or more years after completion of therapy are known as late effects. Key components of LTFU include regular monitoring of organ function (cardiac, pulmonary, renal, hepatic, endocrine, neurocognitive, hearing and vision), screening for subsequent malignancies, psychosocial assessment, and health-promotion counseling. This approach is facilitated by evidence-based clinical practice guidelines. Based on data from the literature linking specific cancer treatments to adverse outcomes, the Children’s Oncology Group^[2] and the International Late Effects of Childhood Cancer Guideline Harmonization Group^[3] provide exposure-based recommendations for screening of long-term side effects in survivors of childhood cancer to support risk-based survivorship care.

The Chinese Children’s Cancer Group ALL-2015 protocol (CCCG-ALL-2015), adapted from St. Jude Children’s Research Hospital Total Therapy Studies 15^[4] and 16 and modified based on a trial at Shanghai Children’s Medical Center for drug tolerance of Chinese patients, utilizes minimal residual disease (MRD) measurements in the context of risk-based therapy and omits prophylactic cranial irradiation.^[5] The CCCG-2015 protocol [Supplementary Figure 1, http://links.lww.com/CM9/C652] reported a 91% overall survival among 7640 children with acute lymphoblastic leukemia (ALL) enrolled on the study, resulting in a substantial survivor population who may benefit from LTFU care.^[5] However, LTFU care has not been fully adopted as the standard of care in China. According to our recent survey evaluating perceived barriers to LTFU care among Chinese pediatric oncologists, only 13.5% of 101 clinicians representing 32 institutions across 22 provinces endorsed having a dedicated follow-up clinic for childhood cancer survivors (CCSs). Approximately 60% (102/164) of caregivers of CCSs reported attending at least one off-therapy clinic appointment within the past two years.^[6] This indicates a need for standardized practices to facilitate the implementation of evidence-based survivorship care. Herein, we propose risk-based LTFU care recommendations to help oncologists and other healthcare providers coordinate survivorship care for ALL patients treated with the CCCG-ALL-2015 protocol (No. ChiCTR-IPR-14005706) and educate survivors about lifestyle factors that can reduce the risks of late effects. Cumulative exposures in the CCCG-ALL-2015 treatment arms are summarized in Supplementary Table 1, http://links.lww.com/CM9/C652.

We describe an initiative that aims to support adherence to recommended risk-based LTFU monitoring by linking the LTFU care plan to protocol-prescribed therapy, ensuring that the care provided is both personalized and aligned with the treatment received. Eligibility criteria for using this LTFU care plan include being ≥5 years from diagnosis and in sustained remission for ≥2 years after completion of therapy. Based on cumulative treatment exposures for children on the clinical trial, potential late effects can be anticipated to inform LTFU surveillance recommendations. These recommendations include a general examination, risk-based assessment of organ health based on specific treatment exposures, evaluation of psychosocial functioning, counseling about healthy lifestyle, delivery of age-appropriate immunizations, and screening for subsequent malignancies. Table 1 outlines specific health risks associated with various therapeutic exposures, such as chemotherapy, radiotherapy, and stem cell transplantation, and recommendations for late effects screening featured in the LTFU care plan.

Table 1.

Late-effects screening recommendation in CCCG-ALL-2015.

Health risks	Therapeutic exposures	Medical history/examination/consultation	Screening
General	Any chemotherapy	Physical examination: Measure height and weight for body mass index calculation, and blood pressure; Educate about potential late effects and purpose of LTFU; Counsel on healthy protective behaviors; Nutrition/physical activity consultation as indicated; Psychosocial consultation as indicated; School/vocational consultation as indicated; Fertility consultation as requested; Recommend age-appropriate immunizations	Physical examination: Measure height and weight for body mass index calculation, and blood pressure; Educate about potential late effects and purpose of LTFU; Counsel on healthy protective behaviors; Nutrition/physical activity consultation as indicated; Psychosocial consultation as indicated; School/vocational consultation as indicated; Fertility consultation as requested; Recommend age-appropriate immunizations
Cardiac toxicity	Daunorubicin	History: Shortness of breath, dyspnea, chest pain, palpitations; Physical: Blood pressure; cardiac exam	EKG: Baseline at entry into LTFU, repeat as clinically indicated; Echo: No screening with doxorubicin equivalent dose <100 mg/m2[5,7]
Bladder toxicity	Cyclophosphamide	History: Hematuria, urinary urgency/frequency, urinary incontinence/retention, dysuria nocturia, abnormal urinary stream	Urinalysis, yearly
Liver function	Methotrexate (IV, IM, and PO), high dose methotrexate, mercaptopurine	History: Jaundice, ascites, spleen/liver enlargement; Physical: Abdominal exam	ALT, AST, bilirubin: Baseline at entry into LTFU, repeat as clinically indicated
Delayed puberty/infertility	Cyclophosphamide, TBI, HSCT	History: Onset and tempo of puberty; Physical: Tanner staging and growth until sexually mature	Estradiol, Testosterone, AMH, LH/FSH as clinically indicated; Endocrine referral: No signs of puberty by age 14 for boys/13 for girls
Thyroid dysfunction	TKI, TBI	History: Fatigue, cold intolerance, constipation, depressed mood; Physical: Thyroid exam	TSH, Free T4: As clinically indicated, yearly
Metabolic syndrome	TBI	Physical: Height, weight, body mass index	Fasting blood glucose, hemoglobin A1c and lipids : As clinically indicated, every 2 years
Dental abnormalities	Any chemotherapy	Physical: Oral exam, dental exam, and cleaning	Evaluation by dentist: Every 6 months
Cataracts	Dexamethasone, prednisone, TBI	History: Visual changes; Physical: Visual acuity, funduscopic exam	Evaluation by ophthalmologist or optometrist, yearly
Bone mineral density deficit	Dexamethasone, prednisone	History: Atraumatic/fragility fractures	DXA: Baseline at entry into LTFU, repeat as clinically indicated; Bone health specialist referral: If Z-score >2 SD below the mean; If Z-score >1 and <2 SD below the mean, evaluation for hormonal deficiencies (e.g., GH deficiency) and consultation with a bone health specialist
Osteonecrosis	Dexamethasone, prednisone	History: Joint pain; Physical: Musculoskeletal exam	MRI as clinically indicated
Peripheral sensory or motor neuropathy	Vincristine	History: Weakness, foot drop, paresthesias, dysesthesias; Physical: Neurologic exam	Neurologic exam, yearly, until 2–3 years after therapy, monitor yearly if symptoms persist; Physical therapy referral: Patients with symptomatic neuropathy
Neurocognitive deficits	HD/IT; methotrexate, cytarabine chemotherapy; CNS radiation	History: Educational and/or vocational progress	Neuropsychological evaluation: Baseline at entry into LTFU, repeat as clinically indicated
Hypogammaglobulinemia	HSCT with any history of chronic GVHD	History: Recurrent unusual infections	Quantitative immunoglobulins: Baseline at entry into LTFU, repeat as clinically indicated
Subsequent hematological malignancies	Daunorubicin; cyclophosphamide	History: Fatigue, bleeding, easy bruising; Physical: Dermatologic exam (pallor, petechiae, purpura)	CBC with differential and platelets as clinically indicated
Subsequent solid neoplasms (skin, thyroid, CNS, etc.)	HSCT, TBI	History: Skin lesions, changing moles; thyroid nodules; headaches, vomiting, cognitive/motor-sensory, deficits, seizures; Physical: Skin exam; thyroid exam; neurologic exam	Imaging and other diagnostic tests as clinically indicated

ALT: Alanine aminotransferase; AMH: Anti-Mullerian hormone; AST: Aspartate aminotransferase; CBC: Complete blood count; CCCG-ALL-2015: Chinese Children’s Cancer Group ALL-2015 protocol; CNS: Central nervous system; DXA: Dualenergy X-ray absorptiometry; EKG: Electrocardiogram; FSH: Follicle-stimulating hormone; GH: Growth hormone; GVHD: Chronic graft versus host disease; HDMTX: High-dose methotrexate; HSCT: Hematopoietic stem cell transplantation; IM: Intramuscular injection; IT: Intrathecal therapy; IV: Intravenous injection; LH: Luteinizing hormone; LTFU: Long-term follow-up; MRI: Magnetic resonance imaging; PO: Per os; SD: Standard deviation; TBI: Total body irradiation; TKI: Tyrosine kinase inhibitor; TSH: Thyroid stimulating hormone.

Merging care plans with frontline trials creates a comprehensive, risk-based roadmap for LTFU that is accessible to both healthcare providers and patients’ families. This initiative supports adherence to LTFU monitoring by linking the care plan to the treatment protocol. A structured, protocol-specific LTFU care plan raises awareness of potential late effects and equips clinicians and families with tools to manage these risks effectively. We have a large cohort of 7640 childhood ALL patients uniformly treated under the CCCG-ALL-2015 study,^[5,7] who may benefit from the implementation of this strategy. Adherence to guideline-recommended surveillance of LTFU remains suboptimal in many settings. We believe that this LTFU care plan will support healthcare providers in their daily practice and improve the quality of LTFU care in China. Providing clear and accessible information about potential late effects and recommended follow-up care through a personalized survivorship care plan can empower families to take an active role in managing the patient’s long-term health, potentially improving adherence to surveillance. Promotion of the services and benefits of LTFU care by treating oncologists remains critical to survivor engagement and attendance.

Integrating LTFU care plans with frontline trials is essential to the collection of valuable data on long-term outcomes, which can be used to refine and improve future care plans. This continuous feedback loop leads to more effective strategies for managing late effects and informs care of newly diagnosed children with cancer. The CCCG-ALL-2015 trial demonstrated that pulse therapy with vincristine and dexamethasone may be omitted after one year of treatment without compromising event-free survival.^[8] Based on these findings, we modified our 2020 study with the aim of reducing the long-term side effects caused by these medications. This LTFU care plan will facilitate surveillance to determine if this strategy successfully mitigates toxicity.

Funding

This study was supported by the Global Scholars Grant Program at St Jude Children’s Research Hospital, Department of Global Pediatric Medicine, USA, the VIVA China Children’s Cancer Foundation, and American Lebanese Syrian Associated Charities (ALSAC).

Conflicts of interest

None.

Supplementary Material

cm9-139-2517-s001.pdf ^{(216.9KB, pdf)}