Author(s): Mary Craig, MD, Kimberly Hartman, MD, Denesh Ratnasingam, MD
Originally published: August 8, 2017 Last updated: May 16, 2024
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Disease/Disorder

Definition

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.

Lymphoma results from abnormal lymphocytes that impact the lymphatic tissue. Lymphomas result from clonal expansion of abnormal B-cells, T-cells, or natural killer cells. Lymphomas are classified based on morphologic, immunologic, and genetic factors. These are generally classified as Hodgkin (HL) or non-Hodgkin (NHL).

Etiology

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

Hematologic malignancies comprise approximately 40% of all childhood cancers. Leukemia is the most common childhood malignancy (25-30% of all cases) while lymphoma is the third most common childhood malignancy. Acute Lymphatic Leukemia (ALL) is the most common type of leukemia and makes up at least 70% of cases. 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.

Patho-anatomy/physiology

Leukemia refers to the clonal expansion of leukemic cells in the bone marrow. This results from transformation of a progenitor cell that then proliferates indefinitely and spreads throughout the bloodstream. These cells may be of B- or T-cell lineage or early precursor cells. Leukemia is classified based on the abnormal cell type (lymphocyte or myeloid) and chronicity (acute or chronic). 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. Lymphomas typically present as malignant masses in lymphatic tissue. 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 (CIPN) is frequently observed in survivors of ALL due to the neurotoxic effects of some of the commonly used chemotherapeutic agents. CIPN may cause significant pain and sensory impairments as well as peripheral muscle weakness. Severe cases of CIPN may also cause autonomic dysfunction.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

History

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

Physical examination

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 bulk/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.

Functional assessment

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 coordination, 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.

Laboratory studies

Diagnostic and staging assessment may include blood counts including peripheral 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.

Imaging

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

The use of supplemental assessment tools depends on symptoms and type/location of treatments. The Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers can be used as a reference for screening and supplemental testing. 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, involvement by tumor, or use of radiation to the chest/thorax. Electromyography and nerve conduction studies may assist in diagnosis and prognosis of root, plexus, or peripheral nerve involvement. Dual-energy x-ray absorptiometry (DXA or DEXA) may be recommended to evaluate for decreased bone mineral density, particularly those requiring prolonged steroid use. Hearing evaluation is recommended for those receiving ototoxic medications, such as platinum chemotherapy agents. Neuropsychological testing may be warranted in any cancer survivor, but particularly those who received CNS irradiation or intrathecal chemotherapy.

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 updated being the International Pediatric Non-Hodgkin Lymphoma Staging System. Factors that may indicate poorer prognosis include higher stage disease, CNS and bone marrow involvement, high LDH level, poor response to therapy, or certain histological findings.

In HL, disease is staged using the Lugano classification 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.

Environmental

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

Professional issues

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

Pain may occur from sources other than cancer progression. Patients with leukemia may have bone pain and monitoring for pathological fractures is crucial as it impacts how therapy can support the patient with functional goals and leads to discussions around equipment needs. Patients with leukemia are at risk for mucositis whose pain management is unique.

The WHO Guidelines for the Pharmacological and Radiotherapeutic Management of Cancer Pain in Adults and Adolescents use a stepwise approach with non-opioid analgesia medication with or without an adjuvant before considering an opioid medication added for mild to moderate pain and then further adjusted for moderate to severe pain.

Enteral steroids can be used in pediatric cancer pain including visceral, neuropathic, and metastatic bone pain. Multimodal approaches with pain medicine can also include further pain procedures. Some of these procedures can include peripheral nerve blocks, ganglion or plexus blocks, epidural blocks, intrathecal injections/infusion/neurolysis, cordotomy, radiofrequency ablation, cryoablation, and kyphoplasty; however there limited literature evidence on interventional procedures in pediatric patients with leukemia and lymphoma

At different disease stages

The rehabilitation plan may change over the course of care based on the child’s and family’s/caregivers/support system’s needs, tolerance of therapies, and response to treatment. Children with hematologic malignancies may require support and services from multiple members of the rehabilitation team: physical and occupational therapists for gross and fine motor activities and activities of daily living, a speech therapist if fatigue impacts cognition, language processing, and/or swallowing, a nurse on changes in cares, function, and pain assessment, a neuropsychologist if fatigue impacts cognition along with emotional processing, child life specialist for education, emotional processing, and quality of stay, a creative art/music therapist focused on quality of life and emotional processing, and a social worker and case manager for family resources and support during the journey.

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/caregiver/support system are grieving the new diagnosis and potential impact on their lives. Discussing the role of physiatry and how besides function, our collaboration with other disciplines around pain, nausea, fatigue, and our potential use of equipment and orthotics can help the patient achieve their goals.

Induction: Therapy is likely inpatient or outpatient during this phase depending on the clinical institution. 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. Clinically, electrolyte abnormalities and cell count changes can also impact fatigue and deconditioning. Continued encouragement, scheduled exercise and activity, 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 a 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 and patient/family/caregiver/support system focused goals. 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. The physiatrist can work collaboratively with hematology/oncology and palliative care on medication recommendations to optimize quality of life and energy conservation directed to tasks that are meaningful for the patient and their family.

Coordination of care

It is important to work closely with the hematologist/oncologist, radiation oncologist, surgeon, therapists, psychologist, child life specialist, nutritionist/dietician, social worker, and case manager 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 throughout their cancer journey, with relapsed disease, and/or undergoing palliative treatment.

Patient & family education

It is important to provide education to both patients and family members/caregivers/support systems on common cancer- and treatment-related side effects and their effects on function. Involving them is particularly important because systematic review reports suggest that increasing caregiver involvement in exercise interventions is associated with a more positive outcome. While family/caregiver/support system education can occur during clinical interactions in person, providing them resources to continue education at their pace improves inclusivity and allows them to process the clinical care and emotions surrounding that. Use of the interdisciplinary rehabilitation team including child life and intra-disciplinary team with partnership with palliative medicine result in collaborative discussions, sustained support, and opportunities to use tools like the Courageous Parents Network.

Emerging/unique interventions

Impairment-based measurement

It is important to utilize validated tools to measure physical and functional performance of children and adolescents during and after cancer treatments. A variety of assessments are currently being used to understand impact of disease and treatment on cardiorespiratory fitness, muscle strength, flexibility, mobility, gait, balance, speed, and motor performance. According to a 2022 systematic review, the most common method used to assess cardiorespiratory fitness in pediatric patient with malignancies is the 6-minute walk test. The most utilized method to assess motor performance in test batteries is the Bruininks-Oseretsky Test short form. To assess grip strength, a grip strength test and or isokinetic dynamometry are commonly used. To measure running speed, a shuttle run is most frequently used. To assess balance, a sensory organization test on dynamic posturography system is performed. Flexibility is often measured using goniometry. Functional mobility is assessed using the timed up and go test. There is a high level of variation among assessment tools used to measure outcomes.

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. Utilization of other scoring systems for measurements of function need to be evaluated in patients with leukemia and lymphoma. Larger, randomized, controlled trials and longitudinal studies are needed to develop appropriate protocols and clinical practice guidelines around rehabilitation and pain management for this patient population.

References

  1. 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
  2. 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
  3. 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.
  4. 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.
  5. 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.
  6. Hile S, Erickson SJ, Agee, B, Annett RD. Parental stress predicts functional outcome in pediatric cancer survivors. Psycho-Oncology. 2014;3:1157-1164.
  7. 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
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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
  15. 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.
  16. 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.
  17. 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

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Original Version of the Topic

Kimberly Hartman, MD, Michael Fediw, MD. Rehabilitation in Blood Malignancies Including Leukemia and Lymphoma. 8/8/2017

Previous Revision(s) of the Topic

Kimberly Hartman, MD, Mary Craig, MD. Rehabilitation in Blood Malignancies Including Leukemia and Lymphoma. 8/8/2017

Author Disclosure

Mary Craig, MD
Nothing to Disclose

Kimberly Hartman, MD
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Denesh Ratnasingam, MD
Nothing to Disclose