Hematologic malignancies refer to cancers of the blood, bone marrow, and lymph nodes. Bone marrow transplant (often referred to as hematopoietic stem cell transplant) is a treatment often used to treat hematologic malignancies. It consists of an infusion of bone marrow stem cells to replace cancerous cells.
These cancers develop in blood, bone marrow, and lymph nodes. Most malignancies of the hematopoietic and lymphoid tissues fall into distinct diagnostic categories that are defined by morphologic, immunophenotypic, genetic, and clinical features. Chromosomal translocations often are the root cause of the cancers. Hematologic cancers include leukemias, pre-leukemic conditions (e.g., myelodysplastic syndrome and aplastic anemia), lymphomas, multiple myeloma, and other associated diseases such as Waldenstrom macrogloblinemia and amyloidosis.
Epidemiology including risk factors and primary prevention
Hematologic malignancies account for 10.4% of the approximately 1,900,000 new cancer cases. New lymphoma cases outnumber leukemia cases.
Inappropriate replication of cancerous cells leads to increased viscosity of the blood, increased susceptibility to infections, and cytopenias of other cells lines.
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, pruritis, 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 cell blood counts are common and can affect white blood cells, red blood cells, and/or platelet levels.
Patients are initially treated with three stages of chemotherapy. 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 the hematologic cancer. The maintenance phase is chemotherapy given after remission to keep the cancer from returning.
Many patients will be offered hematopoietic stem cell transplants (SCT). SCT has the potential to cure some malignant disorders but may be associated with life-long morbidity. Donors for the stem cells can be autologous (from the patient) or allogeneic (from someone else). Allogeneic stem cells can be from a matched unrelated donor or a matched related donor (usually a sibling). Stem cells can be harvested peripherally or from umbilical cords. A conditioning regimen consisting of chemotherapy, monoclonal antibody or total body irradiation are utilized to prepare the bone marrow prior to stem cell infusion.
Genetically engineered chimeric antigen receptor T-cell (CAR-T) have 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., pacilitaxel), vincristine, and bortezomib in particular are associated with CIPN. The CIPN can result in pain, weakness, and numbness, all of which can affect function. Patients with a 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 IIB 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.1,2,3,4 Gastrointestinal and oral mucosal GVHD may further reduce oral intake and exacerbate malnutrition.
- Cognitive dysfunction can be the result of a number of causes related to the malignancy and its treatment, or due to the presence of CNS lesions or leptomeningeal disease. Other causes include cerebrovascular accidents, both hemorrhagic from thrombocytopenia and ischemic from hypercoagulability.5
- Graft Versus Host Disease (GVHD) is a common occurrence after a hematopoietic stem cell transplant. Symptoms vary on the site of the GVHD. Acute GVHD typically occurs during the first 100 days after transplantation and may affect the dermal and gastrointestinal symptoms. Gastrointestinal GVHD can cause significant abdominal pain, nausea, diarrhea, and weakness. Chronic GVHD may be potentially most devastating in terms of function and quality of life. Chronic GVHD can affect many systems including the skin/fascia, oral, ocular, dental, cardiac, and pulmonary systems. Fascial cGVHD, for example, can cause edema, fibrosis, and joint contracture. Appropriate positioning, range of motion exercises, edema management, and splinting may be of some utility.
- Cytokine Release Syndrome (CRS) can be associated with CAR-T cell treatment and affect a number of organ systems including pulmonary, renal, liver and cardiac effects. Generalized 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 therapy patients 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 and may require ICU and mechanical ventilation.
- Edema. Patients can suffer from edema due to capillary leak syndrome (after SCT), malnutrition/hypoproteinemia, venous thrombosis, and lymphedema. This can have both pain and functional implications. The use of lymphedema treatment, such as complex decongestive therapy, (whether or not the etiology is truly lymphatic dysfunction) may be of benefit. Intravenous infusion of albumin and diuretics are also used. Monitoring of cardiac and renal status is recommended.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.7 A history of radiation treatment, use of anti-estrogen medications and certain cytotoxic chemotherapies have also been implicated.8
- Osteoporosis – patients are at increased risk of osteoporosis due to hormonal and inflammatory changes. Up to 50% of post-SCT patients have osteoporosis.9
Several issues need to be taken into account when treating this patient population:
- 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 also 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.
- 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
Essentials of Assessment
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 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 active range of motion in multiple joints and also serve to monitor response to treatment.
An evaluation of transfers, stairs, gait, and endurance is needed.
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 test, iron panel, urinalysis (UA) test, thyroid panel, and hormones, including testosterone (in males). In leukemia patients, a peripheral blast percentage may indicate disease status.
Imaging studies may be helpful in detection of 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 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 the 6-minute walk test, time up-and-go test, hand grip strength, and wrist actigraphy.11
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.12,13 These indices are unvalidated.
Functional assessments should take into account 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 daily transfusions which can take hours.
Social role and social support system
An evaluation of the social support network should take into account transportation, monetary resources, and available family members. Stem cell transplant patients often must stay close to the hospital with a family member for several months 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.11
Physiatrists may provide a great deal of hope to 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 one guideline, individuals with chronic graft-versus-host disease with sclerodermoid disease should be referred for rehabilitation management.14
At different disease stages
Dietz divided cancer rehabilitation into four stages.15
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 type 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 type/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 type 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, care of the 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.16
Survivorship care is an area of intense growth for cancer rehabilitation.17 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.
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.18
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.19 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.20
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 requires 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 physical impairments.21 (Firestein H, Journal of Acute Care Physical Therapy, 2022).
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 prior to SCT or in combination with post-transplant interventions. These interventions generally include low-to-moderate aerobic exercise, resistance training, and nutritional interventions. The available evidence thus far suggests that prehabilitation in this setting is feasible and may offer favorable improvements in fitness and quality of life.22 However, more research is needed.
- Dimeo FC. Effects of exercise on cancer-related fatigue. Cancer. 2001;92(6 Suppl): 1689-1693.
- Persoon S, Kersten MJ, van der Weiden K, et al. Effects of exercise in patients treated with stem cell transplantation for a hematologic malignancy: A systematic review and meta-analysis. Cancer Treat Rev. Cancer Treat Rev. 2013 Oct;39(6):682-90.
- Siefert ML (2010) Fatigue, pain, and functional status during outpatient chemotherapy. Oncol Nurs Forum. 2010;37(2):E114-E123.
- Bertheussen GF, Kaasa S, Hokstad A, et al. Feasibility and changes in symptoms and functioning following inpatient cancer rehabilitation. Acta Oncol. 2012 Nov;51(8):1070-80.
- Moleski M. Neuropsychological, neuroanatomical, and neurophysiological consequences of CNS chemotherapy for acute lymphoblastic leukemia. Arch Clin Neuropsychol. 2000;15(7):606-630.
- Kerchner K, Fleischer A, Yosipovitch G. Lower extremity lymphedema update: pathophysiology, diagnosis, and treatment guidelines. J Am Acad Dermatol. 2008 Aug;59(2):324-31.
- Seamon J, Keller T, Saleh J, Cui Q. The pathogenesis of nontraumatic osteonecrosis. Arthritis. 2012;2012:601763.
- Shim K, MacKenzie MJ, Winquist E.Chemotherapy-associated osteonecrosis in cancer patients with solid tumours: a systematic review. Drug Saf. 2008;31(5):359-71.
- McClune BL, Polgreen LE, Burmeister LA, Blaes AH, Mulrooney DA, Burns LJ, Majhail NS. Screening, prevention and management of osteoporosis and bone loss in adult and pediatric hematopoietic cell transplant recipients. Bone Marrow Transplant. 2011 Jan;46(1):1-9.
- Morishita S, Nakano J, Fu JB, Tsuji T. Physical exercise is safe and feasible in thrombocytopenic patients with hematologic malignancies: a narrative review. Hematology. 2020 Dec;25(1):95-100.
- Mohammed J, Smith SR, Burns L, Basak G, Aljurf M, Savani BN, Schoemans H, Peric Z, Chaudhri NA, Chigbo N, Alfred A, Bakhsh H, Salooja N, Chris Chim A, Hashmi SK. Role of physical therapy before and after hematopoietic stem cell transplantation: White paper report. Biol Blood Marrow Transplant. 2019 Jun;25(6):e191-e198.
- Fu JB, Lee J, Smith DW, Guo Y, Bruera E. Return to primary service among bone marrow transplant rehabilitation inpatients: An index for predicting outcomes. Arch Phys Med Rehabil. 94(2):356-61, 2/2013.
- Fu JB, Lee J, Smith DW, Bruera E. Frequency and reasons for return to acute care in patients with leukemia undergoing inpatient rehabilitation: A preliminary report. Am J Phys Med Rehabil. 92(3):215-22, 3/2013.
- Dignan FL, Clark A, Amrolia P, Cornish J, Jackson G, Mahendra P, Scarisbrick JJ, Taylor PC, Hadzic N, Shaw BE, Potter MN. Diagnosis and management of acute graft-versus-host disease. Br J Haematol. 2012 Jul;158(1):30-45.
- Dietz JH. Adaptive rehabilitation of the cancer patient. Curr Probl Cancer. 1980 Nov;5(5):1-56.
- Sabers SR, Kokal JE, Girardi JC, et al. Evaluation of consultation-based rehabilitation for hospitalized cancer patients with functional impairment. Mayo Clin Proc. 1999;74(9):855-861.
- Gamble GL, Gerber LH, Spill GR, Paul KL. The future of cancer rehabilitation: emerging subspecialty. Am J Phys Med Rehabil. 2011;90(5, Suppl 1):S76-87.
- Mohananey D, Sarau A, Kumar R, Lewandowski D, Abreu-Sosa SM, Nathan S, Okwuosa TM. Role of physical activity and cardiac rehabilitation in patients undergoing hematopoietic stem cell transplantation. JACC CardioOncol. 2021 Mar 16;3(1).
- El-Jawahri A, Nelson AM, Gray TF, Lee SJ, LeBlanc TW. Palliative and end-of-life care for patients with hematologic malignancies. J Clin Oncol. 2020 Mar 20;38(9):944-953.
- Stout NL, Santa Mina D, Lyons KD, Robb K, Silver JK. A systematic review of rehabilitation and exercise recommendations in oncology guidelines. CA Cancer J Clin. 2021 Mar;71(2):149-175.
- Firestein H. The role of physical therapy following CAR T-Cell therapy: A case report. J Acute Care Phys Ther. 2021 Sept; ePub doi: 10.1097/JAT.0000000000000183.
- Santa Mina D, van Rooijen SJ, Minnella EM, Alibhai SMH, Brahmbhatt P, Dalton SO, Gillis C, Grocott MPW, Howell D, Randall IM, Sabiston CM, Silver JK, Slooter G, West M, Jack S, Carli F. Multiphasic prehabilitation across the cancer continuum: A narrative review and conceptual framework. Front Oncol. 2021 Jan 11;10:598425.
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
Nothing to Disclose
Jack B. Fu, MD
Japanese Society of Physical Therapy, Honorarium, Author paper; Japanese Cancer Rehabilitation Conference, Honorarium, Symposium lecture; MS/Foundation, Other Remuneration, Grant Evaluation; HRH Princes Chulabhorn, Honorarium, Symposium lecture; Miwa Shoten Ltd, Honoarium, Book chapter author