Blood malignancies are a group of cancers that originate from hematopoietic stem cells and are generally divided into leukemia and lymphoma. Leukemia is a progressive malignancy of the blood and bone marrow due to abnormal production of immature leukocytes. Generally, leukemias are classified as acute or chronic and by type of white blood cell involved (lymphoblastic or myeloid).
Lymphoma results from abnormal lymphocytes that impact the lymphatic tissue. Lymphomas may be classified as Hodgkin (HL) or non-Hodgkin (NHL), with the latter further classified based on cell of origin.
For both leukemia and lymphoma, the etiology is unknown in the vast majority of cases. Although inherited and environmental (non-inherited) factors may be involved, less than 5% of childhood blood malignancies have an identifiable genetic association, such as Down syndrome, Li-Fraumeni, Bloom syndrome, or ataxia-telangiectasia.
Epidemiology including risk factors and primary prevention
Leukemia is the most common childhood malignancy (25-30% of all cases) while NHL is third (6-8%). Leukemia diagnosis peaks between ages 2 and 5 years, with ALL having a slight predominance in Caucasians, boys, and developed nations. Lymphoma is more common in males (2.5:1) and peaks in adolescence (ages 15-19 years).
Risk factors for leukemia may include smoking, ionizing radiation, chemicals (e.g. benzene), drugs (e.g. alkylating agents), and Down syndrome. Radiation also increases the risk for lymphoma as does immunodeficiency. There is some evidence linking infectious agents, such as Epstein-Barr virus, to blood malignancies. Avoiding exposure to these agents may help reduce the risk of malignancy.
Leukemia results from transformation of a progenitor cell that then proliferates indefinitely. These cells may be of B- or T-cell lineage or early precursor cells. Leukemia is classified based on the abnormal cell type. Molecular studies are now able to identify certain chromosomal abnormalities that can be used for targeting therapies as well as for determining prognosis.
Similarly, lymphoma results from clonal expansion of abnormal B-, T-, and/or NK-cells. Lymphomas are classified based on morphologic, immunologic, and genetic features. Location for childhood NHL depends on subtype but is most commonly the abdomen (35%), mediastinum (25%), or head/neck (13%) whereas HL commonly involves the mediastinum (60%) or is systemic (30%). Central nervous system involvement may be seen in Burkitt and lymphoblastic lymphoma subtypes and late in Hodgkin lymphoma.
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
Disease progression can vary significantly based on the type of malignancy, cytogenetics of the specific malignant cells, and stage of disease at time of diagnosis. Untreated, blood malignancies lead to a progressive increase in abnormal blood cells, which impairs production of normal blood cells and ultimately leads to severe immunocompromise and death. Phases of disease are defined based on the type of malignancy, but broadly include treatment, remission, and relapse.
Presenting signs and symptoms of leukemia include easy bruising, bone pain, limp, fevers, neutropenia, fatigue, pallor, petechiae, bleeding, dyspnea, headache, dizziness, blurred vision, lymphadenopathy, or hepatosplenomegaly.
Presenting signs and symptoms of lymphoma vary depending on primary tumor site but include abdominal pain, nausea, vomiting, intussusception, facial mass, lymphadenopathy, dyspnea, edema, headache, or altered mental status.
Specific secondary or associated conditions and complications
Secondary conditions in leukemia may be based on extramedullary disease and in lymphoma, based on primary tumor site. Involvement of the CNS may include spinal cord compression, intracerebral mass, or cranial nerve palsies. Complications are also related to tumor location as well as treatment, such as neurotoxicity with vincristine, cardiac toxicity with anthracyclines, and pulmonary toxicity with cyclophosphamide. Chemotherapy-induced peripheral neuropathy is frequently observed in survivors of ALL due to the neurotoxic effects of some of the commonly used chemotherapeutic agents. This may then lead to peripheral muscle weakness. 1 Complications from radiation are based on location but can include cognitive/CNS deficits, infertility, lymphedema, skin lesions, pain, and secondary cancers. Complications related to hematopoietic stem cell transplantation and bone marrow transplantation may include musculoskeletal pain, muscle weakness, decreased cardiopulmonary capacity, and metabolic disease. The use of vincristine is contraindicated in patients with Charcot-Marie-Tooth disease 1a and possibly other forms of Charcot-Marie-Tooth disease as it may result in acute deterioration and a potentially life threating or severely disabling neuropathy.2
Essentials of Assessment
A comprehensive cancer-related history should include cancer specific type, stage and current/previous treatments (surgical, chemotherapy, radiation, and transplant). When possible, obtain the dose of chemotherapy agents and dose and field of radiation. A developmental history as appropriate for the child’s age should be obtained, including assessment of milestones and school performance. A thorough review of systems should include common cancer-related symptoms such as fatigue, pain, edema, mood disturbance, and functional impairments. Screening for an underlying hereditary neuropathy should be carried out as certain forms of chemotherapy could be contraindicated if such disease exists.2
A comprehensive, age-appropriate neurologic exam should include assessment of mental status, cranial nerves, strength, sensation, tone, and movement patterns. Musculoskeletal exam should include range of motion, muscle atrophy, joint assessments, balance, and gait mechanics. It is important to perform a general evaluation of lymphoid tissue, cardiopulmonary systems, abdomen, and skin. Particular attention should be focused on radiation fields as well as the trunk and extremities for edema/lymphedema.
Children with blood malignancies have more difficulties with gross motor skills, such as strength, balance, agility, and speed, and fine motor skills, such as dexterity and speed, compared to age-matched peers.3-5 Children may also have decreased exercise capacity and reduced cardiopulmonary reserve. These effects can be seen during and after treatment. In addition, neurocognitive deficits are prevalent (26%).6 A general functional assessment should be obtained with focus on these areas.
Diagnostic and staging assessment may include blood counts including blood smear, bone marrow aspirate, serum chemistries including electrolytes and immunoglobulin levels, CSF cell counts and chemistries, and coagulation profile. Molecular, genetic, and pathology studies are typically obtained by the oncologist. Assessment of infectious titers assists with vaccination planning and avoiding exposure. Surveillance bloodwork should be obtained per the oncologist or as symptoms dictate. Neutropenia, anemia, thrombocytopenia, and electrolyte disturbances can impact a child’s function and may alter therapeutic interventions. In the setting of fever and neutropenia, prompt cultures (blood, urine, possibly CSF) are critical to determine source of infection and treatment plan.
Diagnostic imaging is guided by presenting symptoms and type of malignancy. Imaging is needed for disease staging and generally includes chest x-ray for mediastinal masses, CT scan of chest/abdomen/pelvis, PET scan, and brain/spine MRI if concern for CNS involvement. Surveillance imaging may help guide treatment decisions. Additional imaging in the subacute/chronic setting is based on symptoms.
Supplemental assessment tools
Cardiac function (EKG and echocardiogram) should be assessed if cardiotoxic medications are planned or there is mediastinal involvement. Pulmonary function tests should be ordered if there is anticipated respiratory toxicity or involvement by tumor. Electromyography and nerve conduction studies may assist in diagnosis and prognosis of root, plexus, or peripheral nerve involvement.
Early predictions of outcomes
Prognosis depends on type of malignancy and staging. In ALL, several risk factors are used in prognosis, including: age (better if 1-9 years old), WBC count (worse if >50,000/mm3), immunophenotype (better if early pre-B cell, worse if mature T-cell), DNA index, cytogenetics, or early response to induction therapy.
In NHL, there are several classification systems, with the most common being the St. Jude staging system. Factors that may indicate poorer prognosis include higher stage disease, CNS and bone marrow involvement, high LDL, poor response to therapy, or certain histological findings.
In HL, disease is staged using the Ann Arbor criteria and prognosis is generally worse with: higher staging, bulky disease, “B” symptoms (e.g. unexplained weight loss > 10% over 6 months, unexplained recurrent fever > 38oC, or drenching night sweats), or male gender.
There are several environmental factors that have been associated with higher risk of blood malignancy (see “Epidemiology including risk factors” above). Environmental assessment should also include the child’s home and school setup, including stairs, bathroom arrangement, classroom arrangement, and distance between classes.
Social role and social support system
Neurocognitive and functional deficits can impact school and vocational endeavors. Close monitoring is required to ensure the appropriate resources are in place to improve school performance and community integration. Parental stress is a strong predictor of a patient’s poor functional outcome and therefore this stress should be monitored.6
Children with cancer present unique challenges. Physiatrists must consider the impact of diagnosis and treatments on the child and family and balance rehabilitation with other medical needs. Physiatrists must also anticipate changes in functional goals in the setting of relapse or palliative management and modify the rehabilitation program to suit each individual patient.
Pain Management Approach
Available or current treatment guidelines
There are no standardized pediatric-specific rehabilitation guidelines for blood malignancies. Small longitudinal studies have shown a decrease in motor performance over the course of cancer treatment in children with ALL.3,7 Several studies have demonstrated safety and feasibility of inpatient, outpatient, and home exercise programs. Small studies demonstrate benefits on body mechanics, flexibility, cardiorespiratory fitness, strength, and health-related quality of life (QOL) in patients with ALL.8-11 Programs during inpatient acute care have been found to be safe, however have significant variability in design. It is recommended that such programs include direct supervision, combination training, individualized and potentially group sessions, with sessions 3-5 times per week.12,13 There are many limitations to these data, including small sample size, lack of randomization, and varied outcomes measures. Therefore, currently there is minimal evidence to support any specific intervention and further research is needed.11
Cancer-related pain is a common complaint in children receiving cancer treatments. The rehabilitation team may play an important role in the management of pain through an integrative approach with rehabilitation therapists and pharmacologic prescriptions. Therapists may utilize strategies such as assistive devices for mobility related pain, desensitization techniques for neuropathy related pain, or diet modifications in children with mucositis. 1
Fatigue is one of the most significant cancer related complaints in children and adolescents with cancer. Some studies on fatigue management have recommended physical activity, relaxation, and mindfulness as primary strategies to mitigate symptoms. Cognitive intervention is a secondary recommendation if the first are not effective or feasible.14
At different disease stages
The rehabilitation plan may change over the course of care based on the child’s and family’s needs, tolerance of therapies, and response to treatment. Children with hematologic malignancies typically require an occupational therapist and a physiotherapist as part of the rehabilitation team.
Pretreatment: Therapies should focus on establishing a strong baseline for strength and endurance prior to receiving treatment.9 Building rapport and trust is important during this phase as the child and family are grieving the new diagnosis and potential impact on their lives.
Induction: Therapy is likely inpatient during this phase. Children undergoing cancer treatments are typically less active, and side effects such as nausea and fatigue are likely to impact function and participation during this phase. Continued encouragement and use of appropriate medications can assist in maintaining strength and endurance. Monitor for peripheral neuropathy and maintain close communication with the oncology team to limit side effects.
Maintenance: Therapy may be inpatient, outpatient, or home-based. A home exercise program can assist in maintaining function while away from the treatment center and minimize time in a medical facility.8,10 Equipment and bracing should be utilized as needed to maintain and improve function. Physical activity is important, as children with cancer are at an increased risk for sedentary lifestyle, which may exacerbate complications related to the disease and associated treatments.
Remission/survivorship: The mainstay of therapy is a home exercise program. Though chemotherapy has subsided in this phase, children may continue to experience diminished exercise tolerance. Small physical therapy-based exercise programs for ALL survivors have demonstrated small improvements in ankle range of motion, better motor proficiency, and improved physical activity levels.15 The Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers acts as a resource for information on physical activity and diet as well as monitoring for and management of side effects, such as chronic pain and peripheral neuropathy. Therapy should be modified to meet the individual child’s needs.
Palliative: Therapy may be in the home or a hospice center. The focus may shift to quality of life. Goals for therapy need to be individualized to meet the needs of the child and family. An important role of the physiatrist is to provide home equipment recommendations to facilitate care, comfort, and mobility to maximize life experiences.
Coordination of care
It is important to work closely with the hematologist/oncologist, radiation oncologist, surgeon, therapists, psychologist, and social worker to set appropriate expectations, plan therapy interventions, and communicate updated oncologic treatment plans that may impact rehabilitation medicine plan. Involvement of the palliative care team would likely help guide treatment decisions for patients with relapsed disease or undergoing palliative treatment.
Patient & family education
It is important to provide education to both patients and family members on common cancer- and treatment-related side effects and their effects on function. Involving parents is particularly important because systematic review reports suggest that increasing parental involvement in exercise interventions is associated with a more positive outcome.
Emerging/ Unique Interventions
Measurement of patient outcomes
A majority of inpatient programs utilize the Pediatric Functional Independence Measure (WeeFIM) to assess treatment outcomes. This measure has not been validated specifically in children with cancer, but can provide a reference to measure change over time. Health-related quality of life scales, such as the Pediatric Cancer Quality of Life (PCQL), evaluate function, mood, socialization, and community integration.16 The pediatric fatigue items on the patient-reported outcomes measurement information system (PROMIS) may be used to evaluate fatigue management. 14
Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
There are many side effects from cancer treatment, such as nausea, vomiting, and fatigue, that can limit participation in therapies. Establishing a routine of therapies and exercise prior to cancer treatment may help mitigate potential negative impact on the rehabilitation medicine program from such side effects.
Cutting Edge/ Emerging and Unique Concepts and Practice
Experimental treatment approaches, such as using monoclonal antibodies directed against leukemia-specific antigens, may improve patient function by eliminating or reducing exposure to toxic chemotherapeutic agents. Exercise is being investigated in adults as a cancer “drug” that may enhance the outcomes of current treatment regimens.
Gaps in the Evidence- Based Knowledge
Improvements in health-related quality of life (HRQoL) and physical activity have been demonstrated in pediatric patients with leukemia or lymphoma after undergoing a four-week inpatient rehabilitation program. 17 Several studies have demonstrated the efficacy of exercise programs on prevention of long-term side effects of cancers and cancer-related treatments in children with malignancies. Larger, randomized, controlled trials and longitudinal studies are needed to develop appropriate protocols and clinical practice guidelines for this group of patients.
- Tanner L, Keppner K, Lesmeister D, Lyons K, Rock K, Sparrow J. Cancer rehabilitation in the pediatric and adolescent/young adult population. Sem Oncol Nurs. 2020;36(1):150984. doi:10.1016/j.soncn.2019.150984
- Hildebrandt G, Holler E, Woenkhaus M, et al. Acute deterioration of Charcot-Marie-Tooth disease IA (CMTIA) following 2 mg of vincristine chemotherapy. Ann Oncol. 2000;11(6):743-747. doi:10.1023/a:1008369315240
- Green JL, Knight SJ, McCarthy M, De Luca CR. Motor functioning during and following treatment with chemotherapy for pediatric acute lymphoblastic leukemia. Pediatr Blood Cancer. 2013;60:1261-1266.
- Hockenberry M, Krull K, Moore K, Gregurich MA, Casey ME, Kaemingk K. Longitudinal evaluation of fine motor skills in children with leukemia. J Pediatr Hematol Oncol. 2007;29:535-539.
- Wright MJ, Halton JM, Martin RF, Barr RD. Long-term gross motor performance following treatment for acute lymphoblastic leukemia. Med Pediatr Oncol. 1998;31:86-90.
- Hile S, Erickson SJ, Agee, B, Annett RD. Parental stress predicts functional outcome in pediatric cancer survivors. Psycho-Oncology. 2014;3:1157-1164.
- Hamari L, Lähteenmäki PM, Pukkila H, et al. Motor performance in children diagnosed with cancer: A longitudinal observational study. Children. 2020;7(8):98. doi:10.3390/children7080098
- Esbenshade AJ, Friedman DL, Smith WA, et al. Feasibility and initial effectiveness of home exercise during maintenance therapy for childhood acute lymphoblastic leukemia. Pediatr Phys Ther. 2014;26(3):301-307.
- Gohar SF, Comito M, Price J, Marchese V. Feasibility and parent satisfaction of a physical therapy intervention program for children with acute lymphoblastic leukemia in the first six months of medical treatment. Pediatr Blood Cancer. 2011;56:799-804.
- Moyer-Mileur LJ, Ransdell L, Bruggers CS. Fitness of children with standard-risk acute lympohoblastic leukemia during maintenance therapy: response to a home-based exercise and nutrition program. J Pediatr Hematol Oncol. 2009;31(4):259-266.
- Braam KI, vander Torre P, Takken T, Veening MA, van Dulmen-den Broeder E, Kaspers GJL. Physical exercise training interventions for children and young adults during and after treatment for childhood cancer. Cochrane Database of Syst Rev. 2016:3.
- Rustler V, Hagerty M, Daeggelmann J, et al. Exercise interventions for patients with pediatric cancer during inpatient acute care: A systematic review of literature. Pediatr Blood Cancer. 2017;64:e26567. Doi:10.1002/pbc.26567.
- Zucchetti G, Rossi F, Vina CC et al. Exercise program for children and adolescents with leukemia and lymphoma during treatment: A comprehensive review. Pediatr Blood Cancer. 2018;65:e26924. Doi:10.1002/pbc.26924.
- Robinson PD, Oberoi S, Tomlinson D, et al. Management of fatigue in children and adolescents with cancer and in paediatric recipients of haemopoietic stem-cell transplants: a clinical practice guideline. Lancet Child Adolesc Health. 2018;2(5):371-378. doi:10.1016/s2352-4642(18)30059-2
- Tanner LR, Hooke MC. Improving body function and minimizing activity limitations in pediatric leukemia survivors: The lasting impact of the Stoplight Program. Pediatr Blood Cancer. 2019;66:e27596. Doi: 10.1002/pbc.27596.
- Varni JW, Katz ER, Seid M, Quiggins DJ, Friedman-Bender A. The pediatric cancer quality of life inventory-32 (PCQL-32): I. Reliability and validity. Cancer. 1998;82(6):1184-1196.
- Müller, C., Krauth, K.A., Gerß, J. et al. Physical activity and health-related quality of life in pediatric cancer patients following a 4-week inpatient rehabilitation program. Support Care Cancer. 2016;24:3793–3802. doi.org/10.1007/s00520-016-3198-y
Coombs A, Schilperoort H, Sargent B. The effect of exercise and motor interventions on physical activity and motor outcomes during and after medical intervention for children and adolescents with acute lymphoblastic leukemia: A systematic review. Crit Rev Oncol. 2020;152:103004. doi:10.1016/j.critrevonc.2020.103004
Lanzkowsky P, ed. Manual of pediatric hematology and oncology. 5th ed. Oxford, UK: Elsevier; 2011.
Lemay V, Caru M, Samoilenko M, et al. Physical activity and sedentary behaviors in childhood acute lymphoblastic leukemia survivors. J Pediatr Hematol Oncol. 2019;42(1):53-60. doi:10.1097/mph.0000000000001594
Stubblefield MD, O’Dell MW. Cancer rehabilitation. New York, NY: Demos Medical Publishing; 2009.
Original Version of the Topic
Kimberly Hartman, MD and Michael Fediw, MD. Rehabilitation in Blood Malignancies Including Leukemia and Lymphoma. 8/8/2017
Kimberly Hartman, MD, MHPE
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Mary Craig, MD
Nothing to Disclose