Bone Marrow Transplantation The 5 Minute Pediatric Consult


	Bone Marrow Transplantation

Ann Marie Leahey

Database
Common Questions and Answers
Bibliography

DATABASE

DEFINITION

Treatment with marrow-ablative chemoradiotherapy followed by an infusion of marrow from:

The patient (autologous)
An identical twin (syngeneic)
A histocompatible donor (allogeneic)

INDICATIONS

Accepted indications if a human leukocyte antigen (HLA) identical sibling is available:
- Acute lymphoblastic leukemia (ALL) in second complete remission (CR) and in certain patients in first CR (Philadelphia chromosome positive ALL)
- Acute myelogenous leukemia in first CR
- Chédiak-Higashi and other severe neutrophil defects
- Chronic myelogenous leukemia (CML)
- Diamond-Blackfan anemia (resistant to medical therapy)
- Fanconi anemia
- Juvenile myelomonocytic leukemia (formerly called JCML)
- Myelodysplasia
- Myelofibrosis
- Osteopetrosis
- Severe aplastic anemia
- Severe combined immunodeficiency and other congenital immunodeficiencies
- Thalassemia major (treatment of choice in Italy)
- Wiskott-Aldrich syndrome

Autologous transplantation is an accepted treatment for lymphoma in second CR and for unfavorable neuroblastoma in CR or very good partial response.

Under investigation:
- Autologous bone marrow transplantation (BMT) is also under investigation for treatment of relapse in Wilms tumor, germ-cell tumors, and selected brain tumors and sarcomas.
- Sickle cell disease: A national trial is studying BMT in patients who have developed significant sequelae, such as stroke. European investigators have successfully performed BMT on asymptomatic patients, but the risk:benefit ratio is unknown.
- Mucopolysaccharidoses, lipidoses, and mucolipidoses
BMT can lead to restoration of enzymatic activity in white cells and removal of accumulated substrate in affected tissues. In some diseases, such as adrenoleukodystrophy (childhood onset), it has been successful. In others, such Krabbe disease (infantile form), it has been a failure. Of concern is that improvement in organ function has not always led to improvement in intellectual function.

DONOR SELECTION (IN ORDER OF PREFERENCE)

Identical twin: The increased risk of relapse of leukemia is offset by decreased treatment-related mortality.
HLA identical sibling
Other family members
- Rarely (i.e., in 5% of families), a nonsibling relative who is phenotypically mismatched for one antigen—will be found. Such transplantations have comparable results to HLA-identical sibling BMT.
Haploidentical transplantations have been performed but require depletion of T cells from the graft to avoid fatal graft-versus-host disease (GVHD). They are associated with a lower survival than conventional BMT.
Unrelated donors
- The National Marrow Donor Program (NMDP) presently has over 2 million volunteers registered and maintains a cooperative search agreement with European registries. Over 60% of preliminary searches yield at least one potential donor, although this percentage is lower for minority patients.
Autologous
- Gene-marking studies have shown that infused marrow containing tumor can contribute to relapse. Better methods of purging marrow are needed.

PREPARATIVE REGIMENS

The purpose of the preparative regimen is twofold:
- To eradicate malignancy and/or ablate the patient’s bone marrow
- To suppress the patient’s immune system so that it will accept a foreign bone marrow
Agents used primarily for immunosuppression:
- Cyclophosphamide
- Antithymocyte globulin (ATG)
Agents used primarily for antineoplastic effects or bone marrow ablation:
- Busulfan
- Cytarabine (ARA-C)
- Etoposide (VP-16)
- Carmustine (BCNU)
- Carboplatin
- Melphalan
Agents used for both purposes:
- Total-body irradiation (TBI)
- Thiotepa

Note: Few randomized trials have compared one regimen to another. Choice depends on the disease being treated, the type of donor available, and previous treatment received.

STEM-CELL COLLECTION METHODS

Conventional marrow harvesting from the iliac crests under general anesthesia
Peripheral blood stem-cell (PBSC) collections via apheresis
- Hematopoietic stem cells normally circulate in the peripheral blood in small numbers but can be mobilized by chemotherapy and/or growth factors. Previously used for autografts, successful allogeneic transplantations have now been performed with PBSCs.
Umbilical cord blood
- A rich source of hematopoietic stem cells; even 45 mL of cord blood is sufficient to reconstitute the hematopoietic system of a child.

TOXICITIES

Chemoradiotherapy
- Universal: nausea/vomiting/diarrhea, alopecia, pancytopenia
- Possible and agent-specific:
  - TBI: skin erythema, parotitis
  - Cyclophosphamide: hemorrhagic cystitis, SIADH, cardiomyopathy
  - ATG: allergy, serum sickness
  - Busulfan: seizures, pulmonary fibrosis, bronzing of the skin
  - ARA-C: fever, neurologic symptoms, acute respiratory distress syndrome (ARDS)
  - VP-16: allergic reactions
  - BCNU: pulmonary fibrosis
Graft failure
- Can occur early (failure to engraft) or even after successful engraftment
- Rare in HLA-identical sibling transplantations
- Risk increases with unrelated donors (6%) or T-cell depletion (approximately 14% but depends on the degree of T-cell depletion)
- Usually fatal
Graft-versus-host disease (see chapter on GVHD)
Infection: the major cause of nonrelapse mortality
- In the first month posttransplantation, bacterial and fungal infections predominate.
- In the second and third months, viral infections predominate, which include cytomegalovirus (CMV), adenovirus, herpesvirus, and polyomaviruses.
- After 3 months: herpes zoster and bacterial infections in patients with chronic GVHD

Note: After T-depleted transplantations, the risk of fatal Epstein-Barr virus infection is significant.

Hepatic veno-occlusive disease
- Clinical criteria met when two of the following are present:
  - Hepatomegaly and/or right upper quadrant pain
  - Hyperbilirubinemia (>2.0 mg/dL)
  - Greater than 5% weight gain and/or ascites
  - Incidence of approximately 25% (range, 1%–54%) and mortality of 30% (range, 3%–67%) have been reported.
- Therapy is largely supportive. Some striking reports of improvement after treatment with recombinant tissue plasminogen activator and, more recently, defibrotide have been published.
Interstitial pneumonitis
- Typically appears 40 to 80 days post-BMT as rapid-onset tachypnea associated with bilateral interstitial infiltrates
- Common etiologies include:
  - CMV
  - Pneumocystis carinii
  - Idiopathic: when no bacterial, viral, fungal, or protozoan cause is identified. Radiation to the lungs probably plays a role in the development of “idiopathic” pneumonitis.

LATE COMPLICATIONS

Endocrine
- Hypothyroidism: seen in approximately 20% of patients after TBI; rare after chemotherapy alone
- Growth hormone deficiency: seen in over half of patients receiving TBI
- Primary gonadal failure and absence of development of secondary sexual characteristics are common, especially if the recipient was prepubertal at the time of transplantation or received TBI.
Infertility: Sterility is expected after TBI; fertility may be preserved after cyclophosphamide alone.
Opthalmologic: Cataracts are seen in 40% of patients after TBI and in 20% after chemotherapy alone. A higher incidence is seen in those who also receive steroids.
Dental: Poor calcification of teeth and root blunting have been seen. The defects are more severe in children younger than age 7 at transplantation.
Renal
- Radiation nephritis
- Hemolytic uremic syndrome and thrombocytopenic purpura occur, especially during treatment with cyclosporine
Secondary malignancies: Fifteen-year cumulative incidence rates are 6% and 20% after regimens with and without TBI, respectively.
Intellectual function: Few prospective studies published

COMMON QUESTIONS AND ANSWERS

Q: When should I immunize a patient after transplantation?
A: At 1 year post-BMT, patients free of chronic GVHD should begin a primary immunization schedule with DPT/Salk/HiB/hepatitis B. MMR is usually given at 2 years post-BMT.

Q: If my patient relapses after BMT, can a second BMT be done?
A: Previously, there were few therapeutic options for patients who relapsed less than 1 year post-BMT. Remissions after an infusion of buffy coat (containing T cells) from the patient’s donor can been achieved. Although the majority of successful infusions have been in patients with CML, success has also been seen in acute leukemia. Chronic GVHD will often result.

BIBLIOGRAPHY

Armitage JO. Bone marrow transplantation. N Engl J Med 1994;330:827–838.

Kernan KA, Bartsch G, Ash RC, et al. Analysis of 462 transplantations from unrelated donors facilitated by the National Marrow Donor Program. N Engl J Med 1993;328:593–602.

Sanders JE. Bone marrow transplantation in pediatric oncology. In: Pizzo PA, Poplack DG, eds. Principles and practice of pediatric oncology, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 1997:357–373.

Vannatta K, Zeller M, Noll RB, Koontz K. Social functioning of children surviving bone marrow transplantation. J Pediatr Psychol 1998;23(3):169–178.

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