Hematopoietic Stem Cell Transplantation

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Hematopoietic stem cell transplantation (HSCT) has become an accepted therapeutic modality for a wide variety of diseases and is increasingly utilized for the treatment of malignant and nonmalignant disorders. Tables 25-1 and 25-2 list the indications for allogeneic and autologous stem cell transplantation, respectively. Preparation for HSCT involves delivery of high-dose chemotherapy with or without radiation to ablate normal (and abnormal) hematopoiesis and provide sufficient immunosuppression to allow donor cell engraftment.

The rationale for high-dose chemotherapy involves the theory of the steep dose-response curve for many chemotherapeutic agents. Most drugs exhibit a loglinear relationship between tumor cell kill and dose over a certain range, followed by flattening of the curve in the upper dose ranges. For this reason, small changes in dose can produce significant changes in response for chemotherapeutic agents whose major dose-limiting toxicity is myelosuppression. Hematopoietic growth factor support offers the potential to maximize the dose-response effort of high-dose therapy. A 3- to 10-fold increase in drug dose may result in a multiple log increase in tumor cell killing. Multidrug therapy, compared to a single agent, is necessary to overcome tumor heterogeneity and drug resistance.

The most common form of stem cell transplantation to treat leukemia is allogeneic, using a human leukocyte antigen (HLA)-matched histocompatible donor, usually a sibling. Solid tumors have been treated with high-dose chemotherapy followed by autologous bone marrow transplantation (purged or unpurged marrow, depending on whether the bone marrow is actually or potentially invaded with malignant cells) or peripheral blood stem cell transplantation (PBSCT) with concomitant use of hematopoietic growth factors, for example, granulocyte colony-stimulating factor (G-CSF), or granulocyte macrophage colony-stimulating factor (GM-CSF) (see Chapter 26), to reduce the effects of neutropenia caused by escalating doses of chemotherapy.* Exogenous erythropoietin is beneficial in correcting the anemia that may occur for up to 1 year post-allogeneic stem cell transplantation.

Table 25-3 lists the different sources of hematopoietic stem cells for transplantation. Tables 25-4 and 25-5 list the advantages and disadvantages of allogeneic and autologous HSCT, respectively.

*G-CSF and GM-CSF stimulate the production, maturation, and function of the myeloid and monocytic cell lineages.

Table 25-1. Indications for Allogeneic Hematopoietic Stem Cell Transplantation

Malignant disorders Leukemias

1. Acute lymphoblastic leukemia (ALL) in first remission with high risk for relapse (e.g., failure to enter complete remission, Philadelphia chromosome-positive ALL) or in second remission

2. Acute nonlymphoblastic leukemia (AML, ANLL) (after first remission)"

3. Chronic myelogenous leukemia—Ph+

a. Stable phase b. Accelerated phase

4. Juvenile chronic myeloid leukemia (JCML)

5. Juvenile myelomonocytic leukemia (JMML)

Lymphomas (second or subsequent complete remission or partial remission)

1. Hodgkin

2. Non-Hodgkin Myelodysplasia Myelofibrosis

Familial hemophagocytic lymphohistiocytosis

Nonmalignant disorders Congenital

1. Immunodeficiency syndromes a. Severe combined immunodeficiency syndrome (SCID)

b. Congenital agammaglobulinemia (Bruton disease)

c. DiGeorge syndrome d. Wiskott-Aldrich syndrome e. Chronic mucocutaneous candidiasis f. Other immune-mediated disorders such as X-linked lymphoproliferative syndromes, ALPS (Chapter 13)

2. Hematologic disorders a. Hemoglobinopathies:

Sickle cell anemia (selected cases) Thalassemia b. Fanconi anemia (progressive)

c. Shwachman-Diamond syndrome d. Kostmann agranulocytosis6

e. Diamond-Blackfan anemia f. Dyskeratosis congenita g. Thrombocytopenia absent radii syndrome (TAR)

h. Chronic granulomatous disease i. Chédiak-Higashi syndrome j. CD11/19 deficiency (leukocyte adhesion deficiency) k. Neutrophil actin defects

3. Storage diseases (Gaucher disease)c

4. Lysosomal diseases

5. Mucolipidosis

6. Mucopolysaccharidoses

7. Infantile osteopetrosis Acquired

1. Severe aplastic anemia

2. Paroxysmal nocturnal hemoglobinuria

"After initial remission in AML, investigators differ regarding the optimum treatment strategy. Comparison of HSCT for HLA-matched sibling donors with patients without such donors who receive chemotherapy demonstrates a significantly better disease-free survival for HSCT (50-57%) compared with those receiving chemotherapy (36-37%). Beyond first remission, HSCT from unrelated donor or mismatched family member is recommended.

6G-CSF may be successful in treatment and avoiding HSCT. cEnzyme replacement may avoid HSCT.

Hematopoietic Stem Cell Transplantation 671

Table 25-2. Indications for Autologous Hematopoietic Stem Cell Transplantation

Hematologic malignancies

1. Non-Hodgkin lymphoma

2. Hodgkin disease

3. AMLa (investigational)

4. CMLa (investigational)

Solid tumors

1. Neuroblastoma stage IV

2. Ewing sarcoma, primitive neuroectodermal tumor6

3. Rhabdomyosarcoma6

4. Germ cell tumor6

5. Brain tumor

6. Testicular cancer6

7. Wilms' tumor6

"When HLA-compatible donor is not available.

•"Metastatic disease at presentation but achieved partial remission with conventional chemotherapy or relapsed but has chemosensitive disease.

Table 25-3. Sources of Hematopoietic Stem Cells for Transplantation

1. Allogeneic bone marrow or peripheral blood stem cell (PBSC) using HLA-matched sibling.

2. Allogeneic bone marrow or PBSC using HLA-DR-matched family members other than sibling donors.

3. Syngeneic bone marrow or PBSC (an identical twin).

4. Allogeneic bone marrow or PBSC using HLA-matched unrelated donors.

5. Autologous bone marrow: Patient's own marrow is cryopreserved and reinfused after patient has received aggressive chemotherapy and/or radiation therapy to treat the underlying malignancy in vivo purging or ex vivo purging.a

6. Peripheral blood stem cells. The number of circulating stem cells can be increased by the use of recombinant growth factors, which can increase stem cell numbers by 100-fold prior to apheresis. This induces a more rapid hematopoietic recovery after transplantation.6

7. Umbilical cord blood stem cells (always allogeneic). Ex vivo expansion of cells in culture to increase the number of CD34+ cells available for transplant has been employed experimentally.

8. Fetal liver stem cells administered to patients in utero (26- to 30-week gestation) with severe immunodeficiency and inborn errors of metabolism.

aEx vivo purging for removing malignant cells from peripheral blood stem cells or marrow relies on physical

(density or velocity sedimentation, filtration), pharmacologic (e.g., 4-hydroperoxycyclophosphamide [4HC]), or immunologic (monoclonal antibodies, magnetic immunobeads) principles.

6This is a useful method in patients who have received previous pelvic radiation therapy or because of tumor in the marrow. G-CSF 10 |g/kg/day or GM-CSF 500 mg/m2 for 5-7 days can be used to mobilize progenitor cells.

Blood progenitor cells can be collected for 2-5 days beginning on day 4 or 5 after initiation of growth factor.

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