Rehabilitation Management of Hematologic Malignancies and Bone Marrow Transplant (Adults and Pediatrics)

Disease/Disorder

Definition

Hematologic malignancies refer to cancers of the blood, bone marrow, and lymph nodes. In addition to chemotherapy, bone marrow transplant (also known as a hematopoietic stem cell transplant, or HSCT, and immune effector cell therapies, such as chimeric antigen receptor T-cell (or CAR-T) are commonly used.

Etiology

These cancers develop in blood, bone marrow, and lymph nodes, commonly as a result of a chromosomal translocation. Most malignancies of the hematopoietic and lymphoid tissues fall into distinct categories, defined by morphologic, immunophenotypic, genetic, and clinical features.  Hematologic cancers include leukemias, pre-leukemic conditions (e.g., myelodysplastic syndrome and aplastic anemia), lymphomas, multiple myeloma, and other associated diseases such as Waldenstrom macroglobulinemia and amyloidosis. 

Epidemiology including risk factors and primary prevention

Hematologic malignancies account for 9.4% of the approximately 2,041,910 new cancer cases. New lymphoma cases outnumber leukemia and myeloma cases.¹

Patho-anatomy/physiology

Inappropriate replication of cancerous cells can lead to increased risk of bleeding, blood clots, destruction of bone, and problems related to direct pressure on adjacent viscera, nerves, and blood vessels.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Patients may experience a number of symptoms including fatigue, fever, pruritus, night sweats, weight loss, bone pain, swollen lymph nodes, and bleeding. The initial symptoms often require a work-up including blood work and a bone marrow biopsy that eventually leads to the diagnosis. Abnormalities in blood counts are common and can affect white blood cells, red blood cells, and/or platelet levels.

Treatment usually includes three stages. The first is induction chemotherapy which aims to acutely decrease abnormally high blood counts. The second, or consolidation phase, refers to chemotherapy used to achieve remission of hematologic cancers. The maintenance phase is chemotherapy given after remission to keep the cancer from returning.

Many patients will be offered HSCT which has the potential to cure some malignant disorders but may be associated with life-long morbidity.  Patients may receive their own (autologous)or someone else’s (allogeneic) stem cells. Allogeneic stem cells can be from a matched donor, either related (usually a sibling) or unrelated. Stem cells are harvested either from peripheral or umbilical cord blood.  A conditioning regimen consisting of chemotherapy and monoclonal antibody with or without total body irradiation is utilized to prepare the bone marrow prior to stem cell infusion.

Genetically engineered chimeric antigen receptor T-cell therapy (CAR-T) has been used for refractory hematologic malignancy patients. 

Specific secondary or associated conditions and complications

Patients can present with a number of symptoms or complications that should be addressed by physiatry.

• Chemotherapy Induced Peripheral Neuropathy (CIPN) is associated with the use of chemotherapy agents. Platinum agents (e.g., cisplatin), taxanes (e.g., paclitaxel), vincristine, and bortezomib in particular are associated with CIPN. CIPN can result in pain, weakness, and numbness, all of which can affect function. Patients with preexisting neuropathy may be more at risk for developing symptoms.
• Steroid Myopathy is commonly associated with prolonged use of steroids. Steroids are often used in SCT patients to prevent or limit graft versus host disease (GvHD) and are often part of chemotherapy protocols. Patients present with predominantly Type IIX muscle fiber atrophy and proximal greater than distal weakness. This may result in difficulty with sit-to-stand transfers and ascending/descending stairs.
• Deconditioning/Asthenia is due to the inflammatory and hormonal effects of the cancer and its treatment, medical complications, prolonged immobility, and inadequate nutrition. Fatigue is commonly associated with this.² Gastrointestinal and oral mucosal GvHD may further reduce oral intake and exacerbate malnutrition.
• Cognitive dysfunction and focal neurologic deficits can result from the disease itself, including leptomeningeal spread, and treatment, including toxic/metabolic effects and complications of radiation therapy. Other causes include cerebrovascular accidents, both hemorrhagic from thrombocytopenia and ischemic from hypercoagulability.
• Graft Versus Host Disease (GvHD) is a common occurrence after an allogeneic HSCT with incidence and severity influenced by the degree of donor-recipient match. Recipients of HLA- mismatched grafts have a higher incidence of grades II-IV acute GvHD compared to matched donor recipients. For example, large registry data show cumulative incidence of acute GvHD of approximately 39% in matched sibling donor transplants versus 59% in unrelated donor transplants.³ In chronic GvHD, HLA disparity also increases risk, but the effect is less pronounced than for acute GvHD. Symptoms vary depending on the organ system involved. Acute GvHD typically occurs during the first 100 days after transplantation and typically affects skin and gastrointestinal (GI) tract, leading to symptoms such as rash, abdominal pain, nausea, diarrhea, and weakness. Chronic GvHD (cGvHD), which can persist for months to years, is often more debilitating and has a greater impact on function and quality of life. It can affect many systems including the skin, fascia, oral cavity, ocular, dental, cardiac, and pulmonary systems. Fascial cGvHD, for example, can cause edema, fibrosis, and progressive joint contracture. Neuromuscular complications of cGvHD are increasingly recognized and include polyneuropathy, inflammatory myopathy, and myasthenia gravis. Neuropathy after HSCT is distinct from CIPN. Determining timeline of neuropathic symptoms is essential as neuromuscular complications typically present more than 100 days after HSCT. In a retrospective review of patients with immune-mediated neuromuscular complications of graft-versus-host disease (GVHD), myositis emerged as the most common manifestation, characterized by axial and proximal weakness.⁴ Coordinated care between the treating oncologist and physiatrist is vital for successful treatment as immunomodulatory therapy must be carefully integrated with rehabilitation strategies such as positioning, splinting, stretching, resistance training, and aerobic conditioning for effective restorative care.
• Cytokine Release Syndrome (CRS) can be associated with CAR-T cell treatment and affects a number of systems including pulmonary, renal, hepatobiliary and cardiac. Symptoms including fatigue, chills, and fever are common. Neurologic symptoms include confusion, dizziness, decreased coordination and tremors.
• Immune effector cell-associated neurotoxicity syndrome (ICANS) can occur in 20-70% of CAR-T cell recipients about 3-10 days after administration. It can be associated with a number of neurologic symptoms including cognitive changes, hallucinations, aphasia, apraxia and seizures. ICANS can be potentially life threatening, requiring intensive care, including organ system support, such as mechanical ventilation and systemic anti-cytokine therapy, such as tocilizumab.
• Edema – Patients can suffer from edema due to capillary leak syndrome (after HSCT), malnutrition/hypoproteinemia, venous thrombosis, and lymphedema. Increased limb volume can result in decreased function due to pain, reduced range of motion, and additional weight. Both medical (diuresis and intravenous albumin infusions) and physical (complex decongestive therapy) treatments may be necessary.  Monitoring cardiac and renal function is recommended.⁵
• Pathologic fractures – Osteolytic lesions primarily from multiple myeloma, osteoporosis from HSCT, and concurrent steroid use in treatment regimens can increase the risk of pathologic fractures. These can involve both the axial and appendicular skeleton, with vertebral compression fractures and long bone fractures being common. Vertebral fractures may lead to pain, reduced mobility, height loss, or spinal instability, while limb fractures can significantly impair function and delay cancer treatment. Patients can present with prodromal pain or remain asymptomatic until the time of fracture. Early recognition of impending fracture is vital not only for possible early surgical intervention/prophylactic treatment, but also for potential radiation therapy for local tumor control and pain relief.⁶
• Avascular necrosis – typically affects major joints including the femoral heads, knees, and shoulders. Chronic use of steroids, older age, female sex, diabetes, tobacco use, lupus, renal transplant, sickle cell anemia, alcoholism, and hematologic malignancy are risk factors.  A history of radiation treatment, use of anti-estrogen medications and certain cytotoxic chemotherapies have also been implicated.⁷
• Osteoporosis – patients are at increased risk of osteoporosis due to hormonal and inflammatory changes. Up to 50% of post-SCT patients have osteoporosis.⁸
• Leukopenia and neutropenia can be of concern. Patients may be at high risk for infection and could benefit from reverse isolation and refraining from group therapy sessions. Clinicians also need to be sensitive to these concerns from a psychosocial perspective. As exemplified during the COVID-19 pandemic, these legitimate anxieties may take a significant emotional toll, as it may impede efforts in community integration and social activities. There is evidence showing that exercise stimulates neutrophils and hematopoietic progenitors suggesting a role for exercise in treatment regimens.⁹
• Anemia and thrombocytopenia can affect energy levels and ability to participate in therapy. Falls in these patients can be particularly severe due to their bleeding risk. Nevertheless, a recent narrative review concluded that exercise is likely safe and feasible with platelet counts >20,000/µL, although these patients should be closely monitored for any signs of bleeding.¹⁰

Adapted from Mina et al.¹¹

Essentials of Assessment

History

History should include prior and ongoing cancer treatments, symptoms, complications, and specific impairments. A thorough symptom assessment, including fatigue, pain, and cachexia should be performed. Medications should be reviewed for chemotherapy agents, steroids, or antimicrobial agents.

Physical examination

Physical examination should include evaluating the lungs, mouth, and skin for signs of infection. Pneumonia, oral candidiasis, and herpes oral lesions are commonly found due to their immunosuppression. A detailed neurologic examination should include evaluation of strength, sensation (including proprioception), and cognition.

A musculoskeletal examination may reveal abnormalities that are common in these patients. Muscle atrophy and edema are common. Range of motion should be evaluated in patients with fascial and musculoskeletal GvHD. The Photographic Range of Motion (P-ROM) scale can be used to rapidly assess upper and lower limb mobility to monitor treatment response. The P-ROM scale and the NIH joint/fascial score are validated measures that assess the joint and fascial manifestations of GvHD.¹²

Adapted from Vukic et al.¹²

Functional assessment

An evaluation of transfers, stairs, gait, balance, coordination and endurance is needed.

Laboratory studies

Laboratory studies should include frequent cell blood counts in patients with pancytopenia. Nutrition and fatigue laboratory studies may be useful, including prealbumin, C-reactive protein, and albumin. A fatigue panel may be useful, consisting of a comprehensive metabolic panel, complete blood count (CBC), vitamin D, iron panel, urinalysis, thyroid panel, erythrocyte sedimentation rate, and hormones, including testosterone (in males). In leukemia patients, a peripheral blast percentage may indicate disease status.

Imaging

Imaging studies may be helpful in detecting infections, especially in immunocompromised patients. Central nervous system imaging is indicated in patients suffering from new neurologic symptoms to rule out metastasis. Patients may be at an increased risk of fracture and avascular necrosis due to chronic steroid use. X-rays or more sophisticated imaging modalities such as CT, MRI, or PET may be needed in patients with new pain.  Bone scans, which are often used in the cancer setting to detect fractures or bone metastasis, may be falsely negative in the setting of purely lytic lesions, such as often occurs with multiple myeloma. 

Supplemental assessment tools

Both subjective and objective assessments are valuable for comprehensive evaluation of this population.  Subjective assessments may include quality of life tools such as the PROMIS measures or Functional Assessment of Cancer Therapy – Bone Marrow (FACT-BMT). Objective assessments may include gait speed, 2- or 6-minute walk test, 30 second sit-to-stand, Timed Up-And-Go test, hand grip dynamometry (HGD), and wrist actigraphy. Gait speed and HGD have been shown to predict mortality, hospitalization and survival, underscoring the need to obtain these metrics consistently.¹³

Early predictions of outcomes

For inpatient rehabilitation, the Return to Primary Bone Marrow Transplant index and the Return to Primary Leukemia Index may be useful in predicting which patients are likely to suffer from medical complications while on inpatient rehabilitation.¹⁴ These indices are unvalidated. Prior to HSCT, comprehensive geriatric assessment, frailty assessment, and Brief GAH (Geriatric Assessment in Hematology) scale can be used to identify vulnerabilities in older adult patients that can put them at risk for poor oucomes.¹⁵

Environmental

Functional assessments should consider the patient’s home setting. Stairs can be particularly difficult for patients with steroid myopathy, and their medical outpatient follow-up appointments can also make for long, exhausting days. Patients may require daily blood checks and transfusions which can take hours.

Social role and social support system

An evaluation of the social support network should consider transportation, monetary and human resources. HSCT recipients often must stay close to the hospital with a caregiver for the first 100 days post-transplant.  When appropriate, a return-to-work assessment should include an evaluation of the medical condition, functional capacity, psychosocial barriers, and job evaluation with the goal of optimize social reintegration.¹⁶

Professional issues

Physiatrists may provide a great deal of hope for cancer patients, even those with a limited prognosis. Rehabilitation is a phase of treatment where patients can recognize demonstrable gains despite difficult circumstances. Providing realistic support and encouragement can assist patients in persevering through their therapies.

Rehabilitation Management and Treatments

Available or current treatment guidelines

According to current guidelines, individuals with  cGvHD involving skin, fascia and muscle should be referred for rehabilitation management.¹⁷

At different disease stages

Dietz divided cancer rehabilitation into four stages.¹⁸

The first is the preventive stage. Similar approaches have been coined “buffering” or “prehabilitation.” This stage of cancer rehabilitation occurs before the onset of major treatment. In the case of hematologic patients, rehabilitation before chemotherapy or a stem cell transplant would be an example.

The second stage of cancer rehabilitation is restorative. This occurs after a recent cancer treatment to restore function. Most rehabilitation in an inpatient setting is of this category.

The third stage of cancer rehabilitation is supportive rehabilitation. This occurs during cancer treatment. Cancer rehabilitation for long-term cancer survivors would be of this nature.

The fourth stage is palliative. This is done near the end of life. An example would be preparing a patient for discharge home after no further cancer treatment is available. Rehabilitation goals are typically more modest, and given the reduced life expectancy, emphasis is on returning the patient home as soon as possible and easing the burden of care on family/support systems.

Coordination of care

Coordinating care with the patient’s oncologist, other physicians, and supportive care clinicians is necessary during and after cancer treatment. For example, pancytopenia and other medical complications such as infections need to be addressed.

Physiatry led consult-based rehabilitation has been utilized at a number of institutions to provide more intensive rehabilitation while patients remain on the acute care oncology service.¹⁹

Survivorship care is an area of intense growth for cancer rehabilitation. Coordinating care with other specialties to address the symptoms and comorbidities of these patients is important.

Patient & family education

Patients and families should be educated about their cancer and its potential effects on energy, endurance, strength, and bleeding, among others. Precautions should be taken with respect to anemia, thrombocytopenia, neutropenia, and hypovolemia.

Emerging/unique interventions

As survival after SCT has improved, cardiovascular disease and associated risk factors have gained importance.  Cardiac rehabilitation and structured exercise programs are an emerging intervention for SCT survivors to optimize long-term outcomes.²⁰ 

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Patients with hematologic malignancies may struggle with late effects, post-treatment complications, and post-traumatic stress symptoms that can significantly diminish their quality of life.  A growing body of evidence is demonstrating that rehabilitation services are a recognized and important component of oncology care and that improving guideline concordant rehabilitative care could have a substantial impact on function and quality of life among cancer survivors.²¹

Cutting Edge/Emerging and Unique Concepts and Practice

More recently, chimeric antigen receptor (CAR) T-cell therapy is available for certain hematologic malignancies. CAR-T cell therapy can lead to significant functional impairments that also require rehabilitation.  As more patients receive CAR T-cell therapy to treat malignancies, the rehabilitation community will need further education and training on interventions to address emerging impairments, such as parkinsonism.²²

Gaps in the Evidence-Based Knowledge

Prehabilitation prior to SCT has received increasing attention over the last decade.  While rehabilitation interventions delivered after SCT to remediate deconditioning and dysfunction have been better studied, an emerging body of research is examining prehabilitation alone or in combination with post-transplant interventions.  These include low-to-moderate intensity aerobic exercise, resistance training, and nutritional interventions.  The available evidence thus far suggests that prehabilitation is feasible and may offer favorable improvements in fitness and quality of life.²³ However, more research is needed.

References

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Original Version of the Topic

Jack B. Fu, MD, Arash Asher, MD. Rehabilitation management of hematologic malignancies and bone marrow transplant (adults and pediatrics). 7/17/2013

Previous Revision(s) of the Topic

Jack B. Fu, MD, Arash Asher, MD. Rehabilitation management of hematologic malignancies and bone marrow transplant (adults and pediatrics). 4/4/2017

Arash Asher, MD, Jack B. Fu, MD. Rehabilitation Management of Hematologic Malignancies and Bone Marrow Transplant (Adults and Pediatrics). 6/16/2022

Author Disclosure

Marc Christopher Ramos Emos, MD
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Grigory Syrkin, MD
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