What are the procedures and considerations involved in performing a bone marrow transplant, including patient evaluation, donor selection, conditioning regimen, stem cell collection, infusion, engraftment monitoring, infection prophylaxis, immunosuppression, and long‑term follow‑up?

Bone Marrow Transplant: Comprehensive Procedural Overview

Bone marrow transplantation (also called hematopoietic cell transplantation or HCT) involves infusing hematopoietic progenitor cells into patients to re-establish normal blood cell production and immune function, typically after high-dose chemotherapy or radiation has destroyed the patient's existing bone marrow. 1

Patient Evaluation and Selection

Initial assessment must determine transplant eligibility based on disease type, disease stage, patient age, performance status, and comorbidities. 1

• The HCT Comorbidity Index (HCT-CI) predicts non-relapse mortality and overall survival, helping identify suitable candidates. 1
• Patients must undergo comprehensive evaluation including complete blood count, bone marrow biopsy with cytogenetics, organ function testing (cardiac, pulmonary, hepatic, renal), and infectious disease screening. 1
• For allogeneic transplant, HLA typing of the patient and potential donors must be completed early in the disease course. 1

Donor Selection and Hierarchy

The donor selection follows a strict priority order: HLA-identical siblings first, then matched unrelated donors (if search time is under 3 months), followed by haploidentical or cord blood donors. 1

• Younger donors are preferred over older HLA-identical siblings when matched unrelated donors are available, as younger donor age correlates with better disease-free survival. 1
• Cytomegalovirus serostatus of donors should be considered when balancing non-relapse mortality versus relapse risk. 1
• For matched sibling and unrelated donor transplants, peripheral blood is the recommended stem cell source due to faster engraftment, reduced graft failure, and lower transplant-related mortality compared to bone marrow. 1
• Bone marrow grafts remain indicated for specific conditions like severe aplastic anemia. 1, 2

Stem Cell Collection

Peripheral blood stem cells are mobilized using granulocyte-colony stimulating factor (G-CSF) and collected via apheresis, targeting approximately 3 × 10⁸ nucleated cells per kilogram for bone marrow or higher CD34+ cell doses for peripheral blood. 1, 3

• For autologous transplant, cells are harvested from the patient before conditioning and cryopreserved. 1
• For allogeneic transplant, donor cells are typically collected fresh on the day of infusion or shortly before. 3

Conditioning Regimen

Conditioning chemotherapy and/or radiation is administered before stem cell infusion to eradicate malignant cells and create immunosuppression for donor cell engraftment. 1

Myeloablative Conditioning (MAC)

• Recommended for fit patients aged ≤55 years with HCT-CI score <2. 1
• Common regimens include fludarabine/busulfan (Flu/Bu4), which has less toxicity than busulfan/cyclophosphamide (Bu/Cy). 1
• Total body irradiation (TBI)-based regimens should be considered for patients with CNS disease or myeloid sarcoma. 1

Reduced Intensity Conditioning (RIC)

• Indicated for patients >55 years or those with significant comorbidities (HCT-CI ≥2). 1
• RIC regimens rely more heavily on graft-versus-leukemia effect rather than direct cytotoxic tumor eradication. 1
• For patients with chronic myelomonocytic leukemia, myeloablative conditioning should be preferred when patients are fit enough, as relapse rates approach 27-52% with reduced intensity approaches. 1

Critical Timing Consideration

• All infectious complications from prior chemotherapy must be under adequate control before proceeding with conditioning. 1

Stem Cell Infusion

The actual transplant involves intravenous infusion of collected stem cells, similar to a blood transfusion, typically occurring 1-2 days after completion of conditioning. 1, 3

• The infusion itself is relatively straightforward and takes 15 minutes to several hours depending on cell volume. 3
• Patients may experience minor reactions including fever, chills, or allergic symptoms during infusion. 3

Engraftment Monitoring

Engraftment—when donor cells begin producing new blood cells—typically occurs 14-21 days post-infusion. 3

• Daily monitoring includes complete blood counts to track absolute neutrophil count (ANC) recovery, with engraftment defined as ANC >500/μL for three consecutive days. 3
• Platelet recovery typically lags behind neutrophil recovery by several days to weeks. 3
• Chimerism testing (analyzing the proportion of donor versus recipient cells) is performed at regular intervals to confirm donor cell engraftment and detect early relapse. 1

Infection Prophylaxis

Comprehensive antimicrobial prophylaxis is mandatory during the neutropenic period and beyond due to profound immunosuppression. 1

• Antibacterial prophylaxis with fluoroquinolones is standard during neutropenia. 1
• Antifungal prophylaxis with azoles (fluconazole or broader-spectrum agents like voriconazole or posaconazole) prevents invasive fungal infections. 1
• Antiviral prophylaxis with acyclovir or valacyclovir prevents herpes simplex and varicella-zoster reactivation. 1
• Pneumocystis jirovecii prophylaxis with trimethoprim-sulfamethoxazole is required for at least 6 months post-transplant, longer if chronic GVHD develops. 1
• Cytomegalovirus monitoring with preemptive therapy (letermovir prophylaxis or weekly PCR monitoring with treatment if positive) is essential for at-risk patients. 1

Immunosuppression for GVHD Prevention

For allogeneic transplant, immunosuppressive medications prevent graft-versus-host disease, where donor immune cells attack recipient tissues. 1

• Standard GVHD prophylaxis combines a calcineurin inhibitor (cyclosporine or tacrolimus) with methotrexate or mycophenolate mofetil. 1, 3
• Post-transplant cyclophosphamide is increasingly used for haploidentical transplants and shows comparable outcomes to traditional prophylaxis. 1
• Immunosuppression is typically tapered starting 3-6 months post-transplant if no GVHD develops. 3

Acute GVHD Management

• Acute GVHD (occurring within 100 days) affects skin, liver, and gastrointestinal tract and is treated with high-dose corticosteroids as first-line therapy. 3
• Steroid-refractory GVHD requires second-line agents including antithymocyte globulin or newer targeted therapies. 3

Chronic GVHD Management

• Chronic GVHD (occurring after 100 days) can affect multiple organ systems and requires prolonged immunosuppression, often for years. 3

Supportive Care During Engraftment

Intensive supportive measures are critical during the 2-4 week neutropenic period. 1

• Red blood cell transfusions maintain hemoglobin >7-8 g/dL. 1
• Platelet transfusions maintain counts >10,000/μL (or >50,000/μL if bleeding or procedures planned). 1
• Nutritional support via parenteral nutrition may be necessary due to severe mucositis. 3
• Growth factors (G-CSF) may be used to accelerate neutrophil recovery, though their routine use remains controversial. 1

Long-Term Follow-Up

Lifelong monitoring is required due to risks of late complications including relapse, chronic GVHD, infections, organ dysfunction, secondary malignancies, and endocrine disorders. 4, 3

Relapse Surveillance

• Regular bone marrow examinations and disease-specific monitoring (every 3 months initially, then less frequently) detect early relapse. 1
• Minimal residual disease monitoring using flow cytometry or molecular techniques identifies impending relapse before morphologic recurrence. 1

Late Complications Screening

• Annual screening includes pulmonary function tests (restrictive/obstructive lung disease), ophthalmologic exams (cataracts), endocrine evaluation (thyroid dysfunction, growth hormone deficiency, gonadal failure), and bone density assessment (osteoporosis). 4, 3
• Lifelong cancer surveillance is mandatory due to 2-6 fold increased risk of secondary malignancies. 4

Immunization Schedule

• Patients require re-immunization starting 6-12 months post-transplant, as transplant eliminates prior vaccine immunity. 1
• Live vaccines are contraindicated until at least 24 months post-transplant and only if no active GVHD or immunosuppression. 1

Critical Pitfalls to Avoid

• Never delay transplant evaluation in eligible patients—up to one-third of patients fail to reach transplant after the decision is made due to disease progression or complications. 1
• Do not proceed with conditioning if active infections are not controlled—this dramatically increases transplant-related mortality. 1
• Avoid using cord blood as first choice when other donor options exist—outcomes are generally inferior except in specific circumstances. 1
• Never discontinue antimicrobial prophylaxis prematurely—infections remain the leading cause of non-relapse mortality. 1