Bethesda Handbook of Clinical Oncology, 2nd Edition

Hematologic Malignancies


Hematopoietic Stem Cell Transplantation

Michael Craig*

Jame Abraham

Richard W. Childs

*Section of Hematology/Oncology, Department of Medicine, West Virginia University, Morgantown, West Virginia

Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia

National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland

Hematopoietic stem cell transplantation (HSCT) remains an effective treatment option for many patients with a wide range of malignant and nonmalignant conditions. In addition to autologous and matched related donor allogeneic transplantations, many patients may be offered unrelated donor, nonmyeloablative, or cord blood transplantation. An estimated 40,000 to 50,000 transplantations were performed worldwide in 2002. Although transplantation may be associated with significant morbidity and mortality, recent advances in supportive care, human leukocyte antigen (HLA) typing, and treatments for graft versus host disease (GVHD) have led to improved outcomes for patients undergoing the procedure. An overview of autologous and allogeneic transplantation is provided in this chapter, along with a discussion of the complications and their management.


Hematopoietic stem cells (HSCs) are immature precursor cells residing within the marrow space that are capable of giving rise to most of the cellular elements within the blood, including lymphoid, erythroid, and myeloid lines. These cells are defined by their ability to rescue lethally irradiated animals from marrow aplasia. In humans, most HSCs express the CD34 antigen and lack lineage-specific markers, although a population of CD34- stem cells has also been described. The number of CD34+ cells that are present in the graft has an impact on transplant outcome; in the allogeneic setting, fewer CD34+ cells are associated with a higher risk of transplant-related mortality and delays in the time to hematopoietic recovery in contrast to more CD34+ cells where transplant-related mortality and the risk of disease relapse is decreased. HSCs can be obtained from peripheral blood, bone marrow, or umbilical cord blood (discussed in subsequent text).

Peripheral Blood Stem Cell Collection

  • Growth factors [granulocyte colony stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF)] are used to “mobilize” or increase the number of HSCs and progenitor cells in the peripheral blood.
  • Cells are collected by apheresis procedure on day 5 or 6.
  • In the autologous transplant setting, chemotherapy may be given (providing an additional antineoplastic effect) before growth factors, with apheresis being performed during hematopoietic recovery.


  • Fewer complications and morbidity are experienced by the donor.
  • Peripheral blood stem cell (PBSC) grafts result in more rapid engraftment than marrow grafts.
  • The minimum goal of PBSC collection is 2 × 106CD34+ cells per kg (range 2.0 to 8.0).
  • More T cells (CD3+) are collected in the allogeneic setting.

Bone Marrow Harvest

  • Traditional source of HSCs; used less often than peripheral blood grafts.
  • Bone marrow is harvested from posterior iliac crests under general anesthesia.
  • A harvest of 15 mL per kg of aspirated marrow is generally considered safe to the donor.
  • The goal cell dose is 2.0 × 108mononuclear cells per kg of recipient weight.
  • Complications to the donor may include pain, neuropathy, and anemia.
  • Severe complications occur in less than 0.5% of procedures.


Many malignant and nonmalignant disorders have been treated successfully with HSCT [the National Marrow Donor Program (NMDP) currently lists more than 70 diseases]. Most transplantations are performed for malignant conditions, including acute myeloid and lymphocytic leukemias, chronic myelogenous leukemia (CML), multiple myeloma, non-Hodgkin lymphoma, and Hodgkin lymphoma. Stem cell disorders (e.g., aplastic anemia and paroxysmal nocturnal hemoglobinuria), inherited immune-system defects (e.g., severe combined immunodeficiency and Wiskott-Aldrich syndrome), erythrocyte disorders (e.g., sickle cell anemia and β-thalassemia), and congenital metabolic diseases have been cured by allogeneic HSCT.


Prior to treatment, a thorough discussion highlighting the transplantation procedure itself as well as risks and benefits associated with the procedure should take place between the physician and the patient.

  1. Human leukocyte antigen testing (HLA typing) of the patient and a search for a HLA-matched donor (beginning with siblings) is required if an allogeneic transplant is being considered.
  2. Medical history and evaluation
  • Review of original diagnosis and previous treatments, including radiation
  • Concomitant medical problems
  • Current medications and allergies
  • Determination of current disease status (i.e., in remission, relapse, minimal residual disease, etc.)
  • Restaging and confirmation of metastatic spread
  • Transfusion history and complications, as well as ABO typing
  • Psychosocial evaluation and delineation of a caregiver.
  1. Physical examination
  • Thorough physical examination
  • Evaluation of oral cavity and dentition
  • Neurologic evaluation if disease could involve the central nervous system
  • Karnofsky performance status (preferred value >70%).
  1. Organ function analysis
  • Renal function: creatinine clearance >60 mL per minute
  • Hepatic function: alanine aminotransferase (AST) and aspartate aminotransferase (ALT) less than twice the upper level of normal and bilirubin <2



  • Cardiac evaluation [electrocardiogram (ECG) and echocardiography (ECHO) or multiple-gated acquisition imaging (MUGA) with ejection fraction >40%]
  • Chest x-ray and pulmonary function testing including diffusing capacity of lung for carbon monoxide (DLCO) and forced vital capacity (FVC).
  1. Infectious disease evaluation
  • Serology for cytomegalovirus (CMV), human immunodeficiency virus (HIV), and hepatitis
  • Serology for herpes simplex virus (HSV), Epstein–Barr virus (EBV), and varicella
  • Assess for prior history of invasive fungal (aspergillus) infection.
  1. Consideration of referral to reproductive center for sperm banking or in vitrofertilization.


High-dose chemotherapy (HDCT) without stem cell rescue may result in prolonged cytopenias. Autologous stem cells are collected and are reinfused into the patient after the completion of HDCT to reconstitute the hematopoietic system.

  • Autologous transplantation is most effective in chemotherapy-sensitive tumors or as a consolidation therapy for patients in remission.
  • HDCT may also overcome intrinsic tumor resistance to chemotherapy.
  • Most grafts use PBSCs collected by apheresis.
  • The product is frozen viably in dimethyl sulfoxide (DMSO) and thawed just prior to infusion.
  • Reactions during transfusion are rare and may include bronchospasm, flushing, or hypotension secondary to DMSO.
  • Pancytopenia typically persists for 10 to 20 days and is shortened using PBSC and growth factors.
  • Antimicrobials and blood products are typically given to support the patient in the first few weeks following transplantation.
  • Infectious complications may occur as a consequence of the patient being profoundly immunosuppressed.
  • New protocols are currently exploring tandem autologous transplants (two stem cell rescues after HDCT) and autologous followed by nonmyeloablative allogeneic transplantation.
  • Late toxicities include the development of myelodysplasia, especially in regimens with total body irradiation (TBI).



Allogeneic stem cell transplantation has progressed from a treatment of last resort to first-line therapy for some patients. Extensive planning and coordination of care is required for all transplantation candidates, usually involving a network of physicians and support staff. The NMDP is an invaluable resource for physicians and their patients for the purpose of transplantation. The NMDP Web site is All physicians may perform a free initial search for an HLA-matched unrelated donor in the NMDP, which maintains a registry of more than 5 million potential donors.

Graft versus Malignancy

The main therapeutic benefit of allogeneic transplant depends on the potential of the donor's immune system to recognize and eradicate the malignant or abnormal stem cell clone [the so called graft-versus-leukemia (GVL) or graft-versus-tumor (GVT) effect]. This immune effect is evidenced by the lower relapse rate of hematologic malignancies in patients who


undergo allogeneic transplantation than in those who undergo autologous transplantation, as well as by an increased relapse rate in patients receiving a transplant from a syngeneic (identical twin) donor or an allograft that has undergone T-cell depletion. In addition, patients who develop GVHD have a lower risk of relapse than those who do not, and those who relapse after transplantation may be induced into a second remission with a donor lymphocyte infusion (DLI). CML, low-grade lymphoma, and acute myelogenous leukemia (AML) are most susceptible to the GVT effect, whereas acute lymphoblastic leukemia and high-grade lymphomas are relatively resistant to GVT. GVL is predominantly mediated by donor-derived T cells, although new evidence supports a potential contribution from nonspecific cytokines (both host and/or donor derived) and donor-derived natural killer (NK) cells in some settings.

Sources of Donor Hematopoietic Progenitor Cells

Matched Related Donor

  • The probability of HLA-identity between siblings is 25%.
  • In the United States, approximately 30% of patients will have an HLA-matched sibling.
  • The risk of GVHD increases as the HLA disparity between the patient and donor increases; therefore, most transplant centers prefer a 6/6 or 5/6 HLA match.

Syngeneic Donor

  • Rarely, an identical twin can serve as the donor.
  • Because GVHD does not occur, posttransplantation immunosuppression is not required (although the risk of disease relapse is higher in this setting).

Matched Unrelated Donor

  • Search through the NMDP for appropriate HLA match.
  • Time from identifying a preliminary donor to collecting the allograft is typically 3 to 4 months.
  • Seventy percent of whites will have an HLA-matched donor.
  • It is more difficult to find matched donors for certain minority groups.
  • Thirty percent of searches through the NMDP result in a transplant.
  • The risk of GVHD and graft failure increases with increasing HLA mismatches.

Umbilical Cord Transplantation

  • Umbilical cords are obtained from umbilical vessels at delivery and are cryopreserved; a registry records the HLA type of the donor.
  • Lymphocytes from cord grafts are immunologically immature, which appears to decrease the risk of GVHD that is associated with using an HLA-mismatched graft.
  • Low stem cell numbers in the graft lead to increased risk of graft failure and a prolonged interval to hematopoietic recovery.

Haploidentical Donor

  • Parent or sibling may serve as donor, with HLA match restricted to three loci.
  • Large numbers of CD34+cells increase the chances of engraftment.
  • T-cell depletion of the allograft is required to reduce the risk of lethal GVHD.
  • The process requires prolonged immunosuppression, which increases the risk of infection.



Donor Evaluation

Careful donor selection and evaluation is an integral part of the pretransplantation workup. The donor must be healthy and able to withstand the apheresis procedure or a bone marrow harvest.

  1. Donor HLA typing
  2. ABO typing
  3. History-relevant information of the donor
  • Any previous malignancy within 5 years except nonmelanoma skin cancer (absolute exclusion criteria)
  • Cardiac or coronary artery disease
  • Complications to anesthesia
  • History of lung disease
  • Back or spine disorders
  • Medications
  1. Infection exposure
  • HIV, human T-lymphotropic virus (HTLV), hepatitis, CMV, HSV, and EBV.
  1. Pregnancy.

Human Leukocyte Antigen Typing

The HLA system is a series of cell surface proteins, which play an important role in immune function. The system is intimately involved in cell-to-cell interactions and recognition. The genes encoding the HLA system are located on chromosome 6 and are codominantly expressed. A striking feature of the HLA system is its enormous diversity. HLA class I molecules include HLA-A, HLA-B, and HLA-C loci. HLA class II molecules are made up of more than 15 antigens, with HLA-DR having the greatest impact on transplantation outcome. Further complexity of the HLA system was revealed with the advent of molecular-based HLA typing, showing that HLA antigens previously identified by serologic testing were actually diverse when classified by DNA analysis. Current recommendations include matching of the donor and recipient at the allele level for HLA-A, HLA-B, and HLA-DRB1 loci.

Stages of Transplant

Conditioning (“The Preparative Regimen”)

  • The goals of the conditioning regimen include immunosuppression of the recipient to prevent graft rejection and to eradicate residual disease or abnormal cell populations.
  • Conditioning strategies can be categorized as myeloablative (conventional conditioning) or nonmyeloablative (see section on nonmyeloablative transplants) strategies. Several myeloablative conditioning regimens are currently being used, with the most common regimens incorporating high-dose cyclophosphamide combined with either TBI or busulfan. The choice of a particular conditioning regimen is guided by factors such as the sensitivity of the malignancy to drugs in the regimen, the toxicities inherent to individual conditioning agents, and the age and performance status of the patient.
  • Initial side effects of the transplantation procedure that are related to the preparative regimen include mucositis, nausea, diarrhea, alopecia, pancytopenia, and seizures (with busulfan).
  • Late effects of transplant conditioning include lung toxicity, growth retardation, and second malignancy.

Transplantation Phase

  • The transplantation phase usually starts 24 hours after completing the preparative regimen.
  • Infusion of donor product is usually well tolerated by the recipient.
  • The day of transplantation is traditionally referred to as “Day 0.”




  • Engraftment is defined as time to develop a sustained absolute granulocyte count of >500 cells per µL
  • Platelet recovery usually lags behind granulocyte recovery.
  • Duration of conditioning-induced cytopenias depends on the CD34+cell count in the graft, use of growth factors, and agents used for GVHD prophylaxis.

Supportive Care Phase

  • Hematologic support is provided with blood products.
  • Infection prophylaxis and treatment form a part of this phase.
  • GVHD and other transplantation-related complications occur in this phase.


Infection remains a major cause of morbidity for patients undergoing HSC transplantation. Figure 30.1 displays an overview of potential pathogens. Indwelling catheters are a common source of infections, and sepsis may occur during the neutropenia phase of the transplantation. Current approaches to minimize the risk of life-threatening infections include the use of prophylactic antimicrobial, antifungal, and antiviral agents, as well as aggressive screening for common transplantation-associated infections.


FIG. 30.1. Phases of opportunistic infections among allogenic HSCT recipients. *without standard prophylaxis; Δprimarily among persons who are seropositive before transplant. (From Centers for Disease Control and Prevention. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients: recommendations of CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation. MMWR Morb Mortal Wkly Rep 200;49(No. RR-10):[1–60], with permission.)

Neutropenic Fever

See Chapter 36 for overview of management of neutropenic fever.

Cytomegalovirus Infection

  • Cytomegalovirus infection is a major cause of morbidity and mortality, especially pneumonia.
  • In addition to pneumonia, symptoms may include fever, hepatitis, enteritis, and marrow suppression.
  • CMV infection most commonly occurs as a result of the reactivation of a prior infection in the patient or because of the transfer of an infection from the donor (rare).
  • The infection usually occurs after engraftment and may coincide with GVHD or with the use of immunosuppressive agents used to treat GVHD. The window of risk for viral reactivation is greatest from the day of engraftment to 100 days after transplantation.
  • Screening for viral reactivation is performed weekly after transplantation by measuring the CMV antigen levels or by polymerase chain reaction (PCR).
  • Initial treatment is with intravenous ganciclovir ± intravenous immunoglobulin treatment.
  • Foscarnet is an alternative treatment (especially in patients with cytopenias).

Invasive Fungal Infection

  • Invasive fungal infection is another cause of significant morbidity, with presentation of pneumonia, sinusitis, cellulitis, or blood infection.
  • Common agents are Aspergillus, Fusarium, Zygomycetes, as well as Candidaspecies.
  • Expanded selection of antifungal agents may improve outcome.
  • Candidafungal prophylaxis with fluconazole is used by many centers.

Hematologic Support

  • Hematologic support is provided by replacement of blood and platelet products as needed.
  • All blood products should be irradiated prior to infusion.
  • Leukocyte reduction filters are indicated to reduce CMV transmission and to reduce febrile reactions.





Venoocclusive Disease

Hepatic venoocclusive disease (VOD) is characterized by jaundice, tender hepatomegaly, and unexplained weight gain or ascites. VOD remains extremely difficult to treat, with the risk for this complication increasing with the use of busulfan-containing preparative regimens. Treatment typically involves supportive care measures focused on maintaining renal function, the coagulation system, and fluid balance. Monitoring busulfan drug levels with appropriate dose adjusting appears to decrease the incidence of this complication. Defibrotide, an investigational agent, has recently been used with success to treat severe VOD.

Pulmonary Toxicity

  • Bacterial, viral, or fungal organisms may cause pneumonia.
  • Diffuse alveolar hemorrhage (usually conditioning related) may respond to high-dose steroids.
  • Interstitial pneumonitis with fever, diffuse infiltrates, and hypoxia may occur in 10% to 20% of patients; although commonly idiopathic, CMV needs to be excluded as the cause in all the cases.
  • The need for ventilator support is associated with poor outcome.

Graft Versus Host Disease

GVHD remains a main toxic effect associated with allogeneic transplantation. This clinical condition results when donor-derived T cells recognize and react against normal recipient tissues. Acute GVHD occurs most commonly within the first 100 days of the transplantation, whereas chronic GVHD occurs most commonly more than 100 days after transplantation. Up to 50% of matched sibling allogeneic transplants are complicated by acute GVHD. Current approaches to lessen the risk include the use of prophylactic pharmacologic agents and T-cell depletion of the graft. The clinical presentation of GVHD may be variable but the most commonly affected organs are skin, liver, and the gastrointestinal system. The staging system for GVHD is presented in Table 30.1. Risk factors for acute GVHD are shown in Table 30.2.

TABLE 30.1. Staging System for Graft versus Host Disease (GVHD)

Level of injury


Liver (bilirubin)


GI, gastrointestinal.


Maculopapular rash <25% of body surface

2–3 mg/dL

500–1,000 mL liquid stool/d


Maculopapular rash 25%–50% of body surface

3–6 mg/dL

1,000–1,500 mL liquid stool/d


Generalized erythroderma

6–16 mg/dL

>1,500 mL liquid stool/d


Generalized erythroderma with bullae or desquamation

>15 mg/dL

Severe abdominal pain with or without ileus

Level of injury

Clinical grade



GI tract


1 or 2








2 or 3

2 or 3

2 or 3





TABLE 30.2. Risk factors for Acute Graft versus Host Disease (GVHD)

HLA, human leukocyte antigen; CMV, cytomegalovirus.

Level of HLA mismatch

Infection (e.g., CMV, varicella, etc.)

Use of unrelated donors

Older patients

Donor with a prior history of pregnancy

Sex-mismatched transplant (female allografts into male recipients)

Intensive conditioning regimens



Prevention of Acute Graft Versus Host Disease

  • T-cell depletion of the allograft or combinations of cyclosporine, methotrexate, tacrolimus, prednisone, or mycophenolate mofetil prevent acute GVHD.
  • A common regimen for sibling donor transplants is cyclosporine, PO or i.v., and methotrexate i.v. on days 1, 3, 6, and 11.
  • Cyclosporine dose 5 mg/kg/day, divided in two doses; the goal is to maintain blood levels of cyclosporine at 150 to 300 ng per mL.
  • Tacrolimus dose 0.05 to 0.1 mg/kg/day, divided in two doses; the goal is to maintain levels at 5 to 15 ng per mL.
  • Many medications may interact with immunosuppressant drugs.
  • Donor T-cell depletion prior to transplant decreases risk of GVHD but may increase the risk of relapse.
  • T-cell depletion may be accomplished by various methods, such as CD34+selection of the graft or the use monoclonal antibodies directed against T-cell antigens.

Treatment of Acute Graft versus Host Disease

  • Initially, methylprednisolone should be given at a dose of 1 to 2 mg/kg/day.
  • For those patients who do not respond or for those who have a partial response, additional agents can be added with variable success (see Table 30.3); clinical trials should be considered.

TABLE 30.3. Treatments that May be Useful for Acute Graft versus Host Disease (GVHD) Treatment






Muromonab-CD3 (OKT3)


Antithymocyte globulin

Chronic Graft versus Host Disease

  • Chronic GVHD typically occurs after 100 days from transplantation.
  • Prior history of acute GVHD and the use of PBSC allografts are risk factors.



  • Chronic GVHD presents with variable organ involvement and symptoms, including clinical presentations that may resemble autoimmune disorders (i.e., lichenoid skin changes, sicca syndrome, scleroderma-like skin changes, chronic hepatitis, and bronchiolitis obliterans).
  • Chronic GVHD is often accompanied by cytopenias and immunodeficiency.
  • Treatment involves prolonged courses of steroids and other immunosuppressive agents as well as prophylactic antibiotics (e.g., penicillin). Some trials have shown a benefit from thalidomide, mycophenolate mofetil, photopheresis, and Psoralen-UV-A (PUVA) (for chronic skin GVHD).

Relapse after Transplant

Relapse of malignant disease after allogeneic transplant is an ominous event. Most relapses occur within 2 years of transplantation. Immunosuppression is typically withdrawn to enhance a GVT effect, and in some cases, a DLI is given (lymphocytes from the original stem cell donor). This frequently results in GVHD, which may also be associated with a GVT response. The most favorable responses to DLI have been seen in patients with CML, especially those in the molecular or chronic phase of relapse.

Nonmyeloablative Transplantation

Nonmyeloablative transplantation (NST) relies principally on the graft versus malignancy effect. Instead of intense myeloablative preparative regimens, this technique incorporates immunosuppression to allow for engraftment of donor cells. The most common preparative regimen consists of fludarabine combined with an alkylating agent or low-dose TBI. Nonmyeloablative transplants may be performed in older adults (i.e., older than 60 years) because regimen-related toxicities are less in this case. A mixture of donor and recipient hematopoietic cells is present just after transplant (called mixed chimerism). As immune suppression is removed, the surviving recipient cells are gradually eradicated by the donor immune system, ultimately resulting in full donor engraftment. GVT effects have been observed to occur in CML, AML, chronic lymphocytic leukemia (CLL), lymphoma, multiple myeloma, as well as in select metastatic solid tumors.

A number of small studies have recently reported that GVT effects may be observed in patients with cytokine-refractory metastatic renal cell carcinoma. Disease regression is usually delayed, occurring 4 to 6 months after transplantation following the withdrawal of immunosuppression and occurring frequently in association with either acute or chronic GVHD. Clinical trials investigating GVT effects in renal cell carcinoma and a variety of other metastatic solid tumors are ongoing.


HSC transplantation has dramatically improved over the last several decades into an effective therapeutic treatment for a variety of malignant and nonmalignant conditions. The number of patients who benefit from this procedure will likely increase as future transplantation strategies continue to evolve that limit complications while maximizing beneficial donor immune-mediated graft-versus-malignancy effects.


American Society of Blood and Marrow Transplantation. Web site 2004.

Barrett AJ, Rezvani K, Solomon S, et al. New developments in allotransplant immunology. In: Broudy V, Prchal J, Tricot G, eds.Hematology 2003: the American Society of Hematology education program book. Washington, DC: American Society of Hematology, 2003:350–371.

Bensinger W, Martin P, Storer B, et al. Transplantation of bone marrow as compared to peripheral-blood cells from HLA-identical relatives in patients with hematological cancers. N Engl J Med 2001;344:175–181.



Centers for Disease Control and Prevention. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients: recommendations of the CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation. MMWR Morb Mortal Wkly Rep 2000;49(No. RR-10):1–125.

Champlin R, Khouri I, Kornblau S, et al. Allogeneic hematopoietic stem cell transplantation as adoptive immunotherapy: induction of graft-versus-malignancy as primary therapy. Hematol Oncol Clin North Am 1999;13:1041–1057.

Childs R, Chernoff A, Contentin N, et al. Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med 2000;343:750–758.

Hurley C, Lowe L, Logan B, et al. National Marrow Donor Program HLA-matching guidelines for unrelated marrow transplants. Biol Blood Marrow Transplant 2003;9:610–615.

International Bone Marrow Transplant Registry. Web site 2004.

National Marrow Donor Program. Web site 2004

If you find an error or have any questions, please email us at Thank you!