Hematopoietic Cell Transplantation


Hematopoietic cell transplantation (HCT) is the IV infusion of hematopoietic stem and progenitor cells designed to establish marrow and immune function in patients with a variety of acquired and inherited malignant and nonmalignant disorders.


Hematopoietic cell transplantation (HCT) is the intravenous infusion of hematopoietic stem and progenitor cells designed to establish marrow and immune function in patients with a variety of acquired and inherited malignant and nonmalignant disorders. These include hematologic malignancies (eg, leukemia, lymphoma, and myeloma), nonmalignant acquired bone marrow disorders (eg, aplastic anemia), and genetic diseases associated with abnormal hematopoiesis and function (thalassemia, sickle cell anemia, and severe combined immunodeficiency). HCT is also used in the support of patients undergoing high-dose chemotherapy for the treatment of certain solid tumors for whom hematologic toxicity would otherwise limit drug administration (germ cell tumors, soft tissue sarcomas, and neuroblastoma).

Hematopoietic Stem Cell Sources

Since the advent of HCT in the 1960s, several different methods of transplantation have evolved. At present, the hematopoietic progenitor cells used for HCT are obtained from either bone marrow or peripheral blood. The decision to use a certain type of HCT is dictated by the patient’s age, disease and condition, and the availability of a donor. In some cases, more than one approach is possible. Table 1 summarizes the characteristics of each stem cell source.

Donor Source

Allogeneic HCT, Match Related

This method involves procurement of bone marrow from a human leukocyte antigen (HLA)-identical sibling of the patient. In some cases, a partially matched sibling or family donor (one antigen mismatch) can be used for HCT.

TABLE 1: Stem cell sources for allogeneic BMT

Allogeneic HCT, Match Unrelated

Given that there are a limited number of alleles of the HLA system, typing of large numbers of individuals has led to the observation that full molecular matches for patients exist in the general population. Tissue typing is performed on the patient’s blood, and a search of the computer files of various international registries is made to determine whether a patient has a match with an unrelated individual.

Haploidentical Transplantation

This technique usually involves the transplant of large numbers of T-cell–depleted stem cells from a donor, usually a sibling or a parent, who is half matched to the patient. Although these are the most difficult transplants to perform successfully, there is great interest in this approach, because most patients will have a donor in their family who is at least a 50% HLA match. Most transplants will engraft, and few patients will have significant graft-vs-host disease (GVHD). However, the relapse rate is high, and the process of immune reconstitution is slow, with patients often having troublesome infections for a long time after transplant. Recently, the Johns Hopkins group developed a method of haploidentical HCT using post-HCT cyclophosphamide as prevention of GVHD, which showed promising results.

Cord Blood Transplantation

The blood in the umbilical cord of newborn babies contains large numbers of stem cells, which have been shown to be capable of long-term engraftment in children and some adults after transplant. Similar to unrelated-donor registries, cord blood banks have been developed to store cord blood cells that can be used for unrelated-donor transplant. Given the immunologic immaturity of cord blood cells, these transplants can be accomplished even when there are disparities (mismatching) in the HLA typing between the donor and recipient. Cord blood transplants are generally used in situations in which the patient does not have a sibling donor and an unrelated adult donor cannot be identified through the international registries.

Autologous HCT

Autologous HCT allows a delivery of myeloablative high-dose chemoradiotherapy, since the infused hematopoietic progenitor cells provide hematopoiesis and immune reconstitution. The source of HCT is usually peripheral blood stem cells in autologous HCT, mobilized with granulocyte colony-stimulating factor (GCSF) sometimes following salvage/priming chemotherapy. The peripheral blood stem cells are harvested and then cryopreserved before administration of chemotherapy and/or high-dose radiation therapy.

Syngeneic Transplantation

In this form of transplantation, marrow or peripheral blood stem cells are procured from an individual who is a genetic identical twin to the patient. This method is essentially the same as autologous HCT, with no concerns about potential tumor contamination within the graft.

Allogeneic Transplantation

HLA Typing

Finding a related donor

As noted previously, matched related allogeneic HCT involves a donor who is an HLA-matched sibling of the recipient. The formula for calculating the chances of a particular person having an HLA-matched sibling is 1 − (0.75)N, where N denotes the number of potential sibling donors. In general, a patient with one sibling has a 25% chance of having a match. The average American family size usually limits the success of finding a family donor to approximately 30% of patients.

HLA typing is performed on blood samples or from buccal smears obtained from the patient and potential donor. Molecular methods are now used for more refined matching of both class I (A, B, C loci) and class II (DR, DQ, DP loci) antigens. A match is noted when the major class I antigens, as well as class II antigens, are the same as those of the donor. Each sibling receives one set of antigens (A, B, C, DR, DQ, DP) from each parent (chromosome 6). Genotypic identity can be confirmed by testing the parents and determining the inheritance of each set of antigens.

Finding an unrelated donor

In cases in which the patient needs an allogeneic transplant and a donor cannot be found within the family, the identification of a matched unrelated donor is accomplished by searching the computer files of the National Marrow Donor Program as well as other, international registries. Through international connections, the National Marrow Donor Program searches more than 18.5 million potential donors. Because there are multiple alleles of any given HLA locus, serologic identity does not necessarily imply genotypic identity, such as is the case among sibling donor-recipient pairs. The development of oligonucleotide probes has greatly increased the precision of HLA typing and has allowed for more specific selection of bone marrow donors by matching molecular alleles of the class I and II antigens.

Advantages and Disadvantages

The major advantages of an allogeneic graft include the absence of malignant cells contaminating the graft; the potential for an immunologic anticancer graft-vs-tumor effect; and the ability to treat malignant and nonmalignant disorders of the bone marrow, including genetic and immunologic diseases.

The disadvantages of an allogeneic transplant include the difficulty in finding an appropriate HLA-matched donor and the development of GVHD after HCT, which contributes to the morbidity and mortality of the procedure.

Reduced-intensity transplant has allowed older patients (up to 75 to 80 years of age) to undergo transplant to treat their disease when clinically indicated.

Autologous Transplantation

TABLE 2: Comparison of allogeneic vs autologous stem cell transplantation

Advantages and Disadvantages

In autologous transplant, the reinfused stem cells come from either the patient’s own bone marrow or peripheral blood. These cells do not cause GVHD, and thus, autologous transplant is associated with less morbidity and mortality than is allogeneic HCT and increases in the number of patients who can undergo the procedure in the upper age limit.

The disadvantages of autologous HCT include the possibility of tumor cell contamination within the graft in many diseases, which can cause relapse; the lack of a significant therapeutic graft-vs-tumor effect; and the limited ability to use autologous stem cells to treat patients not in remission or with inherited nonmalignant lymphohematopoietic diseases. Table 2 summarizes the advantages and disadvantages of these two approaches.

Collection of the Graft

Allogeneic Bone Marrow Cells

Current techniques for harvesting bone marrow involve repeated aspirations from the posterior iliac crests that are designed to obtain adequate numbers of cells that can lead to hematopoiesis. While the donor is under general or spinal anesthesia, 1 to 3 × 108 mononucleated cells/kg of the recipient’s body weight are procured. The procedure has no long-term adverse effects and poses little risk if care is taken to ensure that the donor has no confounding medical conditions. In most cases of ABO incompatibility, the marrow can be treated to remove red blood cells to prevent lysis after infusion.

Autologous Peripheral Stem Cells

Collection of circulating peripheral blood progenitor cells is performed via an apheresis technique. Although this procedure can be accomplished in an individual with a baseline blood count, the number of cells and the efficiency of collection are increased if the cells are procured during white blood cell recovery following chemotherapy or after the administration of hematopoietic growth factors.

The most effective strategy appears to be the collection of cells after the administration of both chemotherapy and growth factors. In most circumstances, adequate numbers of cells can be collected using GCSF (filgrastim) to prime the patient before one to three apheresis procedures. In particular, in patients for whom this is not successful, the use of plerixafor has been effective.

Currently, the adequacy of the number of hematopoietic stem cells is assessed by determining the number of cells that have the CD34 antigen (stem cell) marker. Usually, a minimum of 2 × 106 CD34+ cells/kg of body weight is required to ensure engraftment.

The use of autologous stem cells continues to undergo refinement. Approaches under study include ex vivo expansion to augment the number of progenitor cells as well as techniques that separate hematopoietic cells from any potential contaminating tumor cells. In addition, hematopoietic stem cells are the usual targets of marrow-based gene therapy using viral vectors for transduction of cells before cryopreservation.

Indications for Transplant

The expanded methods of HCT have complicated transplant choices for patients and their physicians. Therefore, the decision requires evaluation of the patient and the disease involved. The most common use of allogeneic HCT has been for the eradication of hematologic malignancies, such as leukemia and non-Hodgkin lymphoma. HCT is associated with significant toxicity and mortality risks (in particular with allogeneic HCT). Thus, the important principle is to consider the prognosis of the patient if HCT is not performed, and assess whether the benefit of HCT (reduction in relapse) significantly outweighs its toxicity and upfront mortality risks.

Acute Myelogenous Leukemia

Patients who are unlikely to be cured with conventional chemotherapy alone should be considered for allogeneic HCT. These include patients who are beyond first complete remission (induction failure or relapse with second or subsequent complete remission). In general, if the possibility of cure for a given patient in first remission is estimated to be 30% to 40% or less, one could justify the use of allogeneic HCT despite its non-relapse mortality rate of 20% to 30%. Thus, high-risk patients (ie, high-risk chromosome abnormalities [ie, −7, −5, complex abnormalities], therapy-related acute myelogenous leukemia (AML), transformed AML from prior myelodysplastic syndrome (MDS), high white blood cell counts at presentation) should be considered for allogeneic HCT. Autologous HCT has not been very successful in these patients. Low-risk patients in first complete remission (ie, good risk cytogenetic abnormalities) are not generally considered for allogeneic HCT. New molecular markers improved the decision-making process for AML patients with normal cytogenetics (intermediate risk). Patients with normal cytogenetics AML with Flt-3 mutation are considered as allogeneic HCT candidates, whereas those without Flt-3 mutation but with NPM-1 mutation are at good risk and not considered for allogeneic HCT. A c-kit mutation also identifies a high-risk group within good-risk cytogenetic abnormalities (core-binding factor AML) of t(8;21) and inv(16). It is increasingly important that these molecular markers be tested at presentation of AML. Autologous HCT can be considered for select cases of intermediate- to low-risk AML in first complete remission, although the role of autologous HCT in the intermediate-risk group is diminishing due to improvements in allogeneic HCTs, which are expanding the pool of potential donors outside the family setting. Autologous HCT is also indicated for patients with acute promyelocytic leukemia in second complete remission if they are in a molecular remission. Otherwise, these patients should be considered for allogeneic transplant.

Acute Lymphoblastic Leukemia

Like for patients with AML, allogeneic HCT is considered as potential curative therapy for patients with acute lymphoblastic leukemia in second complete remission. Patients with acute lymphoblastic leukemia with high-risk features need to be considered for allogeneic HCT in first complete remission. These include Philadelphia chromosome, white blood cell counts greater than 30,000/μL (B lineage) or greater than 50,000/μL (T lineage), hypodiploidy, or mixed lineage leukemia gene rearrangement. Autologous HCT is not considered effective for this disease.

Myelodysplastic Syndrome

Allogeneic HCT is the only potentially curative option for MDS. However, the natural course and prognosis of MDS varies widely and the optimal timing of HCT is difficult to determine, particularly with recent availability of hypomethylating agents. The decision needs to consider several factors, such as patient age; comorbid conditions; International Prognostic Scoring System (IPSS) or World Health Organization Classification-Based Prognostic Scoring System score; psychosocial status, including the availability of a caregiver; and the availability of a donor. Allogeneic HCT is generally considered for MDS patients with high risk or intermediate-2 risk by IPSS. Patients with therapy-related MDS or severe cytopenia should also be considered for allogeneic HCT even if their risk category is in intermediate-1.

Chronic Myelogenous Leukemia

Over the past decade, the indications for HCT in chronic myelogenous leukemia (CML) have dramatically changed as a result of the development of tyrosine kinase inhibitors (TKIs). Three TKIs (imatinib, dasatinib, nilotinib) are currently available. Allogeneic HCT is considered for patients with a history of blast crisis (second or subsequent chronic phase) after blast crisis. It is considered as salvage therapy for patients with accelerated phase and chronic phase after failing to achieve hematologic/cytogenetic response to TKIs. Autologous HCT is generally not indicated for CML.

Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia is associated with a wide range of prognoses and disease courses and many therapeutic agents. Allogeneic HCT can be considered for select patients in whom one or more standard courses of treatment, including fludarabine/rituximab-containing regimens with high-risk features (ie, short duration of response, ZAP70+, CD38+, chromosome 17p deletion), have failed. Autologous HCT is generally not considered for chronic lymphocytic leukemia because the results from earlier studies have been disappointing.

Myelofibrosis/Myeloproliferative Disorders

Allogeneic HCT is the only potentially curative therapy for myelofibrosis/myeloproliferative disorders. But because of the heterogeneity in their prognosis and natural course, selection of high-risk patients is important. There have been efforts in developing prognostic scores for these patients. Those who are transfusion-dependent or have increased blasts in bone marrow/peripheral blood are considered eligible for allogeneic HCT.

Non-Hodgkin Lymphoma

Autologous HCT is the treatment of choice for patients with relapsed/refractory diffuse large B-cell non-Hodgkin lymphoma (NHL) that responded to salvage therapy, including those patients with lymphoma in the setting of human immunodeficiency virus (HIV) infection. With the improved outcomes with first-line regimens incorporating rituximab, autologous HCT as consolidation for first complete remission patients with diffuse large B-cell NHL has not been clearly proved beneficial by randomized trials. Autologous HCT is not recommended for patients who have had multiple relapses.

Autologous HCT is considered for patients with mantle cell lymphoma who are in first complete remission. Patients who fail to achieve remission or who have relapsed disease can be cured by an allogeneic approach because the graft-vs-lymphoma effect is strong against mantle cell lymphoma. Autologous HCT has been shown to prolong overall and progression-free survival for relapsed/refractory follicular NHL, although it is not considered curative.

Allogeneic HCT can be considered for patients with relapsed/induction failure intermediate- or high-grade NHL who could not proceed with auto-HCT because of bone marrow involvement of lymphoma or failure to collect a sufficient number of CD34+ hematopoietic progenitor cells. NHL patients who relapsed after prior autologous HCT can be considered for allogeneic HCT using reduced-intensity conditioning. NHL patients in whom secondary MDS developed are clearly candidates for allogeneic HCT. Select patients with relapsed low-grade NHL can also be considered for allogeneic HCT (ie, multiple relapse, first relapse with high-risk features, and relapse after autologous HCT).

Hodgkin Lymphoma

Studies by the British National Lymphoma Investigation and the German Hodgkin Study)/European Group for Bone and Marrow Transplantation demonstrated improved progression-free/event-free survival (but not overall survival) with autologous HCT compared with conventional chemotherapy in relapsed or refractory Hodgkin lymphoma. Reduced-intensity allogeneic HCT can be considered for Hodgkin lymphoma patients who relapsed after autologous HCT.

Multiple Myeloma

Autologous HCT is associated with high response rates and remains the standard of care for patients with multiple myeloma after initial induction therapy. Its benefit over conventional cytotoxic chemotherapy has been clearly demonstrated in multiple randomized studies (ie, IFM 90, MRC VII). While most of these studies enrolled patients younger than 65 years, recent studies suggest benefits for older eligible patients. Tandem autologous HCT has been associated with improved event-free survival (and overall survival in IMF 94 study). However, the added benefit was not seen in a subset of patients with a complete remission or very good partial response. A delayed second autologous HCT can be beneficial for select myeloma patients who relapsed after the first HCT.

It should also be noted that these randomized studies were designed before the availability of thalidomide, revlimid, and bortezomib. Therefore, the role of autologous HCT may evolve and be refined in the future. Autologous HCT is not considered curative for multiple myeloma, and recent efforts include post-HCT maintenance therapy to delay future recurrences. An approach of combined auto-HCT followed by non-myeloablative HCT showed a promising result in phase II studies, yet the results from phase III trials showed mixed data without clear advantage in this approach. Thus, upfront allogeneic HCT is only recommended in the context of clinical trials.

Solid Tumors

In general, only autologous transplant is used for some solid tumors, such as germ cell tumors, soft tissue sarcomas, and neuroblastoma. Allogeneic transplant studies in patients with renal cell cancer suggest that a graft-vs-tumor effect can be elicited against this tumor, but the results are inconsistent.

TABLE 3: Disease sensitivity to a graft-vs-malignancy effect

The worldwide study of nonmyeloablative or reduced-intensity transplantation approaches has facilitated transplant for many patients who otherwise would not have been candidates because of concomitant medical problems or older age. The results indicate that slower-growing malignancies are the most responsive. Thus, patients with low-grade lymphoma, AML, myeloma, myelodysplasia, and CML are probably good candidates for this type of allogeneic transplant, whereas those with advanced disease (eg, leukemia in relapse, high-grade lymphoma) benefit less, because the allogeneic antitumor effect requires time to develop and achieve remission of the disease. Table 3 shows the relative sensitivity of different hematologic malignancies to a graft-vs-malignancy effect that could be mediated by a nonmyeloablative transplant.

Benign Hematologic or Congenital Disorders

In general, for disorders that require replacement of an abnormally functioning hematopoietic system, such as thalassemia and aplastic anemia, an allogeneic transplant is performed. For young patients with severe aplastic anemia (SAA) who have a matched sibling donor, an allogeneic BMT is the standard therapy. Those who are considered at high risk for BMT (elderly, with comorbidity) are treated with immunosuppressive therapy (IST) using antithymocytoglobulin/cyclosporine. SAA patients with no sibling donors are also initially treated with IST while unrelated donors are searched; BMT is considered if there is no response to IST.

Congenital immune deficiency can be corrected by allogeneic HCT. As genetic therapy for hematopoietic stem cells becomes more of a reality, patients with these diseases may also be candidates for autologous transplant after gene modification (adenosinedeaminase deficiency, chronic granulomatous disease).

HIV infection and HIV-associated malignancies

NHL is an acquired immune deficiency syndrome (AIDS)-defining malignancy and Hodgkin lymphoma is among the most common non–AIDS-defining malignancies. The incidence of NHL and Hodgkin lymphoma is markedly increased in patients with HIV infection compared with the general population. HIV-associated lymphomas frequently show poor prognostic features, such as an advanced stage, extranodal disease, “B” symptoms, and intermediate or high International Prognostic Index. The advent of highly active antiretroviral therapy (HAART) dramatically changed the natural history of HIV infection and related malignancies by reducing the incidence of opportunistic infections and improving the underlying immune deficiency. Autologous HCT has been successfully used for the treatment of patients with relapsed or refractory HIV-associated lymphoma receiving HAART in both prospective and retrospective studies. Consideration of HCT for treatment of malignancy is only appropriate in patients for whom it is anticipated that the HIV-1 itself can be controlled.

Small numbers of allogeneic HCTs have been performed, and in the era of effective HAART, they have yielded encouraging results. Outcomes for a very small number of patients appear similar to what might be expected in the general population. Among the recipients of allotransplant was a patient in Berlin with AML who received a graft from a donor who was homozygous for a polymorphism that confers resistance to HIV-1 infection; HAART was discontinued, and 3.5 years later it appears that the patient was cured of AML and of HIV-1 infection. This polymorphism involves CCR5, an HIV co-receptor. Homozygosity for CCR5Δ32 confers profound resistance against HIV infection, and heterozygous mutation that induces a decrease in CCR5 surface expression is associated with lower plasma viral load and delayed progression to AIDS. Basic and clinical studies are under way in evaluating various approaches of genetic engineering of mature T cells or hematopoietic stem cells with autologous HCT used to treat the underlying HIV-associated malignancy.

Timing of Transplant

The Goldie-Coldman model proposes that the probability that a tumor contains treatment-resistant cells is a function of its size and inherent mutation rate. This finding suggests that the likelihood of cure is greatest when a marrow transplant is performed early in the natural history of an inherently chemosensitive tumor. Studies to date indicate that patients who undergo transplant late in their disease course have inferior disease-free survival compared with those who undergo transplant early.

Phases of Transplant

Preparative Phase

In the first phase of marrow transplant, the preparative phase, patients receive high-dose chemotherapy and/or radiation therapy (sometimes referred to as a conditioning regimen).

Allogeneic transplantation

The conditioning regimen used in the allogeneic setting has both a therapeutic component designed to eliminate tumor cells and an immunosuppressive component to prevent host immune responses from rejecting the transplanted donor graft. The doses of radiation therapy and chemotherapy employed take advantage of the steep dose-response curve that exists for many malignancies. These doses have been established on the basis of the limitations of other nonhematopoietic organs, such as the liver and lungs.

Although busulfan-based regimens are most commonly used worldwide for allogeneic transplant, the oral administration of busulfan leads to unpredictable absorption, which has been correlated with relapse (low absorption) and increased toxicity (increased absorption). Studies with an intravenous formulation of the drug have shown much more predictable pharmacokinetics, less toxicity, and good survival when used in the transplant regimen.

Typically, preparative regimens for full allogeneic BMT consist of total body irradiation and/or chemotherapeutic agents (cyclophosphamide, busulfan, and etoposide). The most commonly used regimens are (1) total body irradiation (1,200 to 1,400 cGy administered in multiple fractions over a period of days) and cyclophosphamide (60 mg/kg for 2 days); (2) fractionated total body irradiation and etoposide (60 mg/kg); and (3) busulfan (16 mg/kg over 4 days) and cyclophosphamide (60 mg/kg for 2 days).

Reduced-intensity allogeneic transplantation

This approach uses lower doses of chemotherapy, with or without total body irradiation and immunosuppression, to facilitate engraftment of donor stem cells. Donor stem cells obtained from either the peripheral blood or marrow are then infused into the patient, leading to hematopoietic engraftment. The major therapeutic effect that results from this type of transplant is a graft-vs-tumor effect, because the nonmyeloablative regimen has limited long-term antitumor effect. Some disorders, such as CML, AML, and low-grade lymphoma, are particularly sensitive to this approach.

Reduced-intensity transplant is used primarily for patients who are older or who have comorbid conditions that might increase the risk of a fully ablative transplant. The most common regimens use fludarabine combined with either melphalan or busulfan or with a single fraction of total body irradiation, followed by infusion of either donor bone marrow or peripheral blood–derived stem cells. All patients still require post-transplant immunosuppression similar to all other patients undergoing non–T-cell–depleted transplants. For patients receiving either a matched sibling or fully matched unrelated transplant, the engraftment of donor cells after reduced-intensity transplant is usually 100% by day 30 to 60 after transplant, and the immunosuppressive medications are tapered over a few months. Although the chemotherapy does have antitumor activity in this type of transplant, the major factor in eliminating the malignancy is the donor immune system, and it is, as in the fully ablative transplant setting, influenced by the presence or absence of GVHD.

TABLE 4: Acute and long-term toxicities of common preparative agents used for HCT

Autologous transplantation

For patients who undergo autologous transplant, stem cells are reinfused following high-dose therapy to reestablish hematopoiesis as rapidly as possible. The regimens used for autologous BMT depend on the disease being treated. High-dose melphalan (200 mg/m2) is the most commonly used regimen for myeloma, and BEAM (BCNU [carmustine], etoposide, cytarabine [Ara-C], and melphalan) or CBV (cyclophosphamide, BCNU [carmustine], and etoposide) are the two most commonly used regimens for lymphoma. Recent trials have incorporated radioimmunotherapy into the high-dose chemotherapy regimens in the treatment of B-cell lymphoma (131I-tositumomab, 90Y-ibritumomab), with early promising data. However, a multicenter phase III trial in the United States failed to show an advantage of BEAM plus 131I-tositumomab, compared with rituximab plus BEAM. An international phase III trial of BEAM with or without 90Y-ibritumomabis underway (ClinicalTrials.gov identifier: NCT02366663).

Toxicities of preparative regimens

The acute toxicities of irradiation and chemotherapy include nausea and vomiting, which can be managed by prophylactic use of antiemetics, particularly serotonin antagonists. Busulfan can cause seizures; prophylactic phenytoin is effective in preventing this complication. Both cyclophosphamide and etoposide require forced hydration to reduce toxicities. Table 4 lists the acute and long-term toxicities of the major agents used in HCT preparative regimens.

Transplant Phase

After completion of the preparative regimen, there is a day or more wait before reinfusion of marrow or peripheral blood stem cells. This delay allows for elimination of any active drug metabolites so that the reinfused cells are not injured by any remaining drug.

Minimal toxicities are associated with the infusion. They include headache, nausea, and dizziness. This dizziness is related less to the infusion and more to the cryoprotectant dimethyl sulfoxide used to store cells from most patients who undergo autologous transplant.

Supportive Care Phase

Following administration of the preparative regimen and during and after marrow transplant, all patients require strict attention to infectious disease–related complications secondary to neutropenia. The duration of neutropenia following transplant increases the risk of complicating infections. Patients who undergo full allogeneic transplant usually require more stringent isolation, whereas patients who undergo autologous transplant need less rigorous protection. With the availability of more effective antiemetics (eg, ondansetron, granisetron), portions of the transplant can now be performed in the outpatient setting.

Following allogeneic transplant, various complications may develop that require treatment. For some complications, prophylactic measures can be instituted to prevent their occurrence.

Neutropenic sepsis

Fever, often with positive blood cultures, will develop in nearly all patients who have undergone transplant within 7 days of becoming neutropenic. Sepsis usually is caused by enteric bacteria or bacteria found on the skin, and antibiotic choices are based on initial assessment and the results of blood cultures. The antibiotics chosen are continued until the neutrophil count begins to rise (> 500 μL).

Prevention of fungal infections. For patients who are expected to have prolonged neutropenia, various methods of antifungal prophylaxis are used, including oral fluconazole (200 mg bid) or voriconazole (200 mg IV or PO bid). The use of liposomal amphotericin B or caspofungin/micafungin formulations has improved the safety and lowered the toxicity of antifungal therapy and is particularly worthwhile in patients with renal compromise.

Mucositis, nausea, and anorexia

Regimen-related toxicity often results in severe oral mucositis, nausea, and anorexia. Patients often require supplemental parenteral nutrition to maintain adequate caloric intake during this period. Because of the mucositis, enteral feedings are usually not employed, and total parenteral nutrition is maintained until patients are able to eat. Studies are exploring novel agents that could prevent severe mucositis or accelerate healing with recombinant keratinocyte growth factor (palifermin), which has been shown to decrease this complication following total body irradiation–based autologous transplant regimens.

Oral herpes simplex virus reactivation

Nearly all patients who are seropositive for herpes simplex virus will have a reactivation of the virus, which can accentuate the pain and oral discomfort following BMT. To prevent this problem, most transplant programs use acyclovir at a dose of 250 mg/m2 tid during the neutropenic phase.

TABLE 5: Clinical classification of acute GVHD according to organ injury


All patients will require both red blood cells and platelets in proportion to the duration of the pancytopenia. Platelet levels are kept over 10,000/μL to 20,000/μL because of complicating bleeding from mucositis, although in some instances, a lower threshold is feasible. Patients no longer receive granulocyte transfusions unless they have uncontrolled sepsis with positive blood cultures. For patients who are negative for cytomegalovirus (CMV) and who have a CMV-negative donor, CMV-negative cell support is generally provided (see “CMV infection” section).

All blood products are irradiated to prevent engraftment of lymphoid cells and are often filtered to remove leukocytes in order to reduce CMV infection or alloimmunization and febrile reactions. Most patients receive single-donor platelet pheresis products, which may need to be HLA-matched if patients show evidence of refractoriness to the transfusion (ie, if platelet levels fail to rise after transfusion).

Sinusoidal Obstruction Syndrome

In the first few weeks after BMT, sinusoidal obstruction syndrome (veno-occlusive disease), characterized by hepatomegaly, jaundice, and fluid retention, develops in 5% to 10% of patients. It is caused by damaged endothelial cells, sinusoids, and hepatocytes and is related to the intensity of the cytoreductive therapeutic regimen.

The diagnosis of sinusoidal obstruction syndrome is usually made on clinical grounds, based on the occurrence (usually within 8 to 10 days after starting the cytoreductive regimen) of the triad of hepatomegaly, weight gain, and jaundice. Patients also exhibit renal sodium retention, and the prognosis is related to the degree of liver and kidney dysfunction and the level of bilirubin. The use of regimens that contain busulfan has been associated with the highest incidence of veno-occlusive disease, which has decreased with targeted oral or intravenous busulfan dosing. The use of ursodiol appears to have reduced the incidence of liver toxicity after high-dose preparative regimens.


Once veno-occlusive disease has occurred, treatment is primarily supportive, consisting of careful management of fluid overload, kidney dysfunction, and other attendant complications. On the basis of early phase II studies, defibrotide is now being tested in phase III trials as an agent that can help reverse the syndrome.

Acute GVHD

GVHD is a clinical syndrome that results from the infusion of immunocompetent lymphocytes accompanying the hematopoietic stem cell graft that are capable of recognizing minor histocompatibility antigens (in the setting of HLA match) in the host and initiating an immunologic reaction. This syndrome may arise after allogeneic transplant or rarely after transfusion of cellular blood products in patients who are immunodeficient and share HLA loci that allow engraftment of transfused cells. For unknown reasons, the primary organs affected by acute GVHD are the skin, liver, and gastrointestinal tract.

The syndrome usually occurs within 15 to 60 days after transplant and can vary in severity. Table 5 shows a commonly used grading system for GVHD. This system has both therapeutic and prognostic importance.

Prophylaxis. All patients who undergo non–T-cell–depleted transplant require some form of GVHD prophylaxis. The most common regimens involve a combination of methotrexate (MTX) and a calcineurin inhibitor (cyclosporine or tacrolimus). In reduced-intensity HCT, mycophenolate mofetil (MMF) plus a calcineurin inhibitor has also been used. The combination of tacrolimus and sirolimus has been studied and appears to be an effective approach for the prevention of GVHD. These medications, in the absence of GVHD, are tapered over 6 to 12 months after BMT. The regimens of sirolimus and tacrolimus are tapered in a similar manner. Adverse effects of tacrolimus and cyclosporine include renal toxicity, hypertension, magnesium wasting, seizures, and microangiopathy. Sirolimus, an oral agent, can cause hemolytic uremic syndrome in association with tacrolimus and requires careful dose and drug level monitoring. It can also raise blood triglyceride levels. Newer approaches to prevent GVHD include an addition of maraviroc (a CCR5 antagonist), vorinostat (a histone deacetylase inhibitor), or bortezomib (a proteasome inhibitor) to calcineurin inhibitor/MMF or MTX. Post-transplant cyclophosphamide also showed promising results in matched donor transplants as well as haploidentical donor transplants.

Treatment. Despite prophylaxis, many allogeneic transplant recipients still develop some degree of GVHD and require increasing doses of prednisone (1 to 2 mg/kg/d). There is no single standard therapy for patients who do not respond to corticosteroids. Antithymocyte globulin (10 mg/kg/d for 5 to 10 days) has been used in this setting. More recent options include anti-CD25 monoclonal antibodies (basiliximab, daclizumab, pentostatin, anti-TNF agents (etanercept, infliximab) and MMF. There have been extensive efforts to improve upfront therapy beyond steroids. However, in a multicenter randomized trial comparing prednisone alone vs prednisone plus MMF for patient with newly diagnosed acute GVHD, the addition of MMF did not show a benefit in this setting.

Chronic GVHD

Chronic GVHD may occur within 3 to 6 months in patients who have undergone allogeneic HCT. It is often preceded by acute GVHD that may or may not have resolved. Although chronic GVHD is also related to infusion of T cells with the graft, it resembles other autoimmune connective-tissue diseases, such as scleroderma, Sjögren syndrome, biliary cirrhosis, and bronchiolitis obliterans. Patients with chronic GVHD often have accompanying cytopenias and immune deficiency as well as abnormalities of the oral mucosa, conjunctiva, and gastrointestinal tract. Patients who come off immunosuppression at 6 months need close monitoring for the development of chronic GVHD for 3 further months.

Treatment. Chronic GVHD is generally treated with prolonged courses of corticosteroids, cyclosporine/tacrolimus, and other modalities, such as psoralen-ultraviolet A light for skin and oral GVHD. Other immunsuppressive agents such as MMF, sirolimus, and pentostatin have been used. Use of extracorporeal photopheresis has been associated with varying response rates. There has been increasing recognition of the pathogenic role of B cells in chronic GVHD (eg, as Cutler et al have described). In fact, rituximab has been used successfully in this setting, for therapeutic and prophylactic purposes. There are also promising results from phase I/II studies using low-dose IL-2, which increases the number of regulatory T cells (Treg) in vivo (as discussed by Koreth et al). Similar to the prognosis for acute GVHD, the outlook for patients with chronic GVHD is related to the extent of organ compromise and response to treatment.

GVHD and relapse. Although, in general, GVHD has contributed to significant morbidity and mortality in patients who have undergone allogeneic BMT, it is also associated with reduced relapse rates, primarily in patients with hematologic malignancies, highlighting that the alloreactivity of the graft contributes to the cure of the disease.

Late effects of transplant

Late infections after BMT are caused by impaired cellular and humoral immunity. The most common late pathogens include Pneumocystis jiroveci, varicella-zoster virus, and encapsulated bacteria.

P jiroveci prophylaxis. All patients who undergo allogeneic transplant require prophylaxis against P jiroveci infection. This can be accomplished with one double-strength trimethoprim/sulfamethoxazole tablet twice a week once hematopoiesis has been restored. Alternatively, atovaquone (750 mg bid) has been used. It should be used when patients remain on immunosuppression.

Herpes zoster. Approximately 40% of patients will develop herpes zoster (either dermatomal or disseminated), which is often treated with oral or intravenous acyclovir. A patient may complain of severe localized pain for several days before the rash develops. The use of valacyclovir for 1 year after BMT can reduce or delay the risk of reactivation of herpes zoster after both autologous and allogeneic BMT. In some patients, herpes zoster may still develop after discontinuation of preventive antiviral therapy.

Bacterial prophylaxis. Many patients with chronic GVHD develop an accompanying severe immunodeficiency syndrome that leaves them susceptible to infection with encapsulated bacteria, primarily in the sinuses and lungs. In some cases, prolonged prophylaxis with trimethoprim/sulfamethoxazole or penicillin, as well as immunoglobulin replacement, is necessary.

Fungal prophylaxis. Late infection with either Candida or Aspergillus is a risk for patients with chronic GVHD, especially those receiving corticosteroids long-term. These patients require preventive measures such as oral fluconazole, voriconazole, or posaconazole.

CMV infection (early/late)

Historically, CMV interstitial pneumonia had been responsible for approximately 15% to 20% of patient deaths following allogeneic BMT until development of CMV monitoring and effective anti-CMV drugs (pre-emptive therapy). CMV pneumonia occurs 7 to 10 weeks after BMT and is due to reactivation of latent CMV or is acquired from donor marrow or transfusions. Active CMV infection, GVHD, and the inability to develop a virus-specific immune response that limits viral infection are risk factors for CMV pneumonia.

Diagnosis. Infection is diagnosed by the combination of an abnormal chest radiograph, hypoxemia, and the detection of CMV in bronchoalveolar lavage or lung biopsy specimens, as well as by the absence of other pathogens.

Treatment. The only consistent treatment has been the combination of ganciclovir, 5 mg/kg bid for 3 weeks, and IV immunoglobulin, given every other day. Although the reason for the synergy between these agents is unclear, neither one alone is effective in reversing pneumonia once it has developed.

Prevention in CMV-seronegative patients. The most successful means of preventing CMV infection in CMV-seronegative patients who have a seronegative donor is to limit their exposure to the virus. CMV status should be determined in all patients before BMT to plan for post-transplant transfusion strategies. The presence of leukocytes in blood products increases the transmission of CMV. Thus, the use of leukocyte-reduced or CMV-seronegative blood products in CMV-seronegative recipients decreases the incidence of primary CMV infection.

Prevention in CMV-seropositive patients. The most effective strategy for preventing reactivation of CMV infection in patients who are CMV-seropositive is the preemptive use of ganciclovir at the first sign of CMV reactivation after transplant (as indicated by blood culture, shell viral culture, or antigen or polymerase chain reaction detection of the virus). The duration of preemptive therapy is somewhat controversial for CMV, but it is usually for at least 2 weeks after the CMV polymerase chain reaction assay becomes negative.

Ganciclovir has been the most effective agent because it significantly reduces both viral reactivation and associated disease. Ganciclovir is associated with many adverse effects, including neutropenia and elevated creatinine levels, and thus exposes a large number of patients to potential toxicity. For those patients with ganciclovir-induced cytopenia or resistant virus, foscarnet is used with careful attention to renal function.

Monitoring of all patients for CMV infection after completion of antiviral therapy is necessary, because some patients, particularly those with GVHD or those who have undergone cord blood or T-cell–depleted transplant, are at risk for late or recurrence of infection because of an inadequate immune response against CMV. Currently, newer antiviral drugs such as maribavir, letermovir, and brincidofovir are being tested in clinical trials, and appear to have good antiviral activity with less toxicity. In addition, there have been efforts to develop effective CMV vaccines, and a few such vaccine candidates are being evaluated in clinical trials.

Immunizations. All patients who have undergone allogeneic transplant should undergo re-immunization at 1 year after transplant unless they are still receiving intensive immunosuppression, as summarized in the Centers for Disease Control and Prevention guidelines for transplant patients, including annual influenza vaccine.

Management of Relapse

Despite the intensity of the preparative regimen, some patients relapse after receiving an allogeneic BMT. For patients with CML, withdrawal of immunosuppression to allow for an augmented graft-vs-tumor effect sometimes leads to remission. Other patients with CML may respond to post-transplant interferon or reintroduction of drugs such as imatinib or dasatinib, or nilotinib, which appears to be a useful approach. Intriguingly, infusion of donor lymphoid cells (DLI) into patients with CML is an effective means of inducing hematologic and cytogenetic responses in those who have relapsed after transplant; this approach has led to complete and durable remissions.

Some patients with AML have responded to either DLI or the combination of chemotherapy and donor stem cells. Hypomethylating agents (5-azacitidine, decitabine) have been studied as treatment of prevention of post-HCT AML relapses. Patients with acute lymphoblastic leukemia have had the lowest response rate to DLI. However, novel immunotherapeutic approaches using bi-specific T-cell engagers (BiTE) or CD19-specific chimeric antigen receptor (CD19 CAR) T cells showed highly promising results even in the cases of post-HCT relapses.

Patients with relapsed lymphoma or leukemia after autologous HCT and patients in whom myelodysplasia develops after autologous HCT (therapy-related MDS) can sometimes be successfully treated with reduced-intensity allogeneic transplant to restore normal hematopoiesis and cure the MDS.

Second Malignancy After HCT

Patients who undergo transplant are at risk for developing a second cancer. For those who undergo autologous transplant, particularly for treatment of lymphoma and Hodgkin lymphoma, the most common cancer is myelodysplasia/AML, which occurs in up to 10% of patients, usually within 3 to 7 years after transplant.

Risk factors for the development of myelodysplasia/AML after transplant include the number of prior chemotherapy and radiation therapy treatments; specific drugs, such as alkylating agents or topoisomerase inhibitors; difficulty in mobilizing stem cells; persistent cytopenias after transplant; and use of total body irradiation in the transplant preparative regimen. All patients should undergo cytogenetic screening of the marrow before stem cell collection and should be followed up for this complication after recovery from transplant.

Patients who undergo either autologous or allogeneic transplant are also at risk for the development of solid tumors up to 20 years after transplant. The risk is greater in patients who receive an allogeneic transplant. The most common tumors are related to the skin, but both common (breast, lung, and colon) and less common (sarcoma) tumors have been seen. As part of their long-term follow-up, all patients require screening for this complication to diagnose the cancer in its earliest stage.

Additional Long-Term Effects

Chronic GVHD

Given the increasing numbers of patients who are long-term survivors of allogeneic transplant, both primary care physicians and medical oncologists are seeing patients with chronic GVHD as part of their practice. Thus, recognition of the manifestations of chronic GVHD and its complications are an important component of long-term care, as well as close coordination with the transplant unit for their management. Chronic GVHD may evolve from acute GVHD that develops early after transplant, but it may also occur after resolution of acute GVHD or it may occur without prior acute GVHD, often after a patient has returned to his or her primary care physician.

Common manifestations include lichenoid changes of the skin and mucous membrane, vitiligo, periorbital hyperpigmentation, odynophagia, nail dysplasia, keratoconjunctivitis, xerostomia, alopecia and, most important, susceptibility to infection. Hence, there is the need for prevention strategies as well as immunizations as previously mentioned. In women, vaginal strictures and dyspareunia can be the presenting features, and some patients may present with polyserositis, bronchiolitis obliterans, and malabsorption. All of these problems warrant discussion with a transplant team, and all patients who undergo transplant should have early and consistent oral care, with involvement of a dentist, to prevent caries.

Most patients with chronic GVHD require therapy with corticosteroids, often in association with tacrolimus or other medications. Thus, the sequelae of long-term corticosteroid use, including diabetes, lipid abnormalities, increase in blood pressure, skin changes, muscle atrophy, gastritis, pancreatitis, and psychological effects, are important components of care. Unlike acute GVHD, organ injury due to chronic GVHD may be very slow to resolve, necessitating long courses of treatment. In addition, tapering of immunosuppression may result in a flare requiring another course of treatment, so that the ultimate management and resolution of GVHD may occur over a period of years. The most important aspect of care is preventing infection. Patients with chronic GVHD are especially susceptible to reactivation of CMV, herpes simplex virus, and varicella-zoster virus infection; recurrent sinusitis or bronchitis; and Pneumocystis infection, and they require ongoing prevention therapy, as previously described. Although all patients should undergo re-vaccination, patients with chronic GVHD may not respond as well, and particular attention must be paid to these infections. Live vaccines, such as measles, mumps, and rubella, are not administered until 2 years after HCT in the absence of chronic GVHD and immunosuppressive therapy. Family members should receive routine vaccines, including influenza vaccine, and patients should avoid contact with children who received oral polio virus vaccine for about a month after vaccination.

Endocrine dysfunction

Hypothyroidism is common after HCT, occurring in about a quarter of patients, particularly after total body irradiation. Thyroid adenomas and carcinomas may occur at rates higher than expected. In general, adrenal and pituitary function are not affected, although patients who receive corticosteroids long-term may have secondary hypoadrenalism and may require testing or even replacement therapy in the setting of decreased adrenal reserve.

Gonadal dysfunction is very common after transplant, especially if the patient received high-dose chemotherapy and radiation. Most men have relatively normal testosterone and luteinizing hormone levels, but when these levels are low, they should have replacement therapy, usually through the use of an androgen patch or testosterone injections. Women typically are anovulatory and have high levels of follicle-stimulating hormone and luteinizing hormone, and young women should receive replacement therapy. Infertility is not a universal consequence of transplant.

Increasingly, osteoporosis is a recognized problem in patients who have undergone HCT, and it often is a process begun even before transplant, likely due to the direct effect of hematologic cancers as well as their treatment. Thus, all patients require periodic bone density evaluations and adequate attention to both vitamin D and calcium replacement or, in some cases, the use of a bisphosphonate.

Avascular necrosis may occur in up to 5% of patients and is usually related to the use of corticosteroids and radiation. The hips are most commonly affected, but ankles and shoulders have also been involved and successful joint replacement has been performed.

Suggested Reading

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On HIV and HCT

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