Phases of Transplant
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).
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.
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.
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.
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.
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.
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 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.