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Preparative regimens for hematopoietic cell transplantation

Preparative regimens for hematopoietic cell transplantation
Author:
Robert S Negrin, MD
Section Editor:
Nelson J Chao, MD
Deputy Editor:
Alan G Rosmarin, MD
Literature review current through: Jan 2024.
This topic last updated: Sep 11, 2023.

INTRODUCTION — The preparative or conditioning regimen is a critical element in the hematopoietic cell transplantation (HCT) procedure. The purpose of the preparative regimen is twofold:

To provide adequate immunosuppression to prevent rejection of the transplanted graft

To eradicate the disease for which the transplant is being performed

This topic will discuss various myeloablative conditioning (MAC), nonmyeloablative (NMA), and reduced intensity conditioning (RIC) regimens.

Selection of a preparative regimen for a specific disease is discussed in association with that disease.

Choice of a graft source, graft-versus-host disease, and other toxicities and complications of HCT are discussed separately.

(See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells".)

(See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease".)

(See "Treatment of acute graft-versus-host disease".)

(See "Treatment of chronic graft-versus-host disease".)

DEFINITIONS — Preparative regimens for HCT have variable intensity, toxicity, and dependence upon a graft-versus-tumor effect (figure 1). Preparative regimens for HCT have been termed myeloablative, reduced intensity, and nonmyeloablative. While full agreement has not been achieved, generally accepted definitions of these three types of regimens are as follows [1-4]:

Myeloablative – A myeloablative conditioning (MAC) regimen consists of a single agent or combination of agents expected to destroy the hematopoietic cells in the bone marrow and results in profound pancytopenia within one to three weeks from the time of administration. The resulting pancytopenia is long-lasting and usually irreversible unless hematopoiesis is restored by infusion of hematopoietic stem cells. Examples include total body irradiation ≥5 Gy in a single dose or busulfan >8 mg/kg. (See 'Myeloablative regimens' below.)

Nonmyeloablative – A nonmyeloablative (NMA) regimen is one that will cause minimal cytopenia (but significant lymphopenia) by itself and may not require stem cell support. Examples include fludarabine plus cyclophosphamide with or without antithymocyte globulin or total body irradiation ≤2 Gy with or without a purine analog. However, the transplant, when given in this setting, usually becomes myeloablative because the engrafting donor T cells will eventually eliminate host hematopoietic cells, allowing the establishment of donor hematopoiesis. (See 'NMA and RIC regimens' below.)

Reduced intensity – Reduced intensity conditioning (RIC) regimens are an intermediate category of regimens that do not fit the definition of myeloablative or nonmyeloablative. Such regimens cause cytopenias, which may be prolonged and result in significant morbidity and mortality and require hematopoietic stem cell support. Regimens generally considered as reduced intensity include ≤8 mg/kg of busulfan, or ≤140 mg/m2 of melphalan.

Importantly, this nomenclature was designed to reflect the acute regimen related toxicity rather than the overall efficacy of the transplant on the underlying disease state. In addition, these definitions serve only as guidelines, and it is often difficult in practice to know what impact a regimen will have in the absence of transplantation. Multicenter randomized trials are necessary to better compare the efficacy and toxicity of these regimens in particular disease states.

CHOICE OF REGIMEN — There is no optimal preparative regimen for all patients who undergo HCT, and clinical practice varies among institutions. The choice of a preparative regimen should take into account the recipient's comorbidities, underlying condition, disease status, donor, and graft source. Comparisons of preparative regimens are discussed below. (See 'MAC versus RIC regimens' below.)

The following principles should be considered in choosing a preparative regimen:

Recipient comorbidities – A patient's underlying comorbidities often dictate the type of conditioning regimen that may be offered. Patients with substantial comorbidities and older patients are not candidates for myeloablative conditioning regimens but may be candidates for a reduced intensity conditioning (RIC) regimen or a nonmyeloablative (NMA) regimen. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)

Underlying condition – The underlying condition may influence the choice of preparative regimen. For a patient with hematologic malignancy or proliferative condition (eg, thalassemia), eradication of the host's hematopoietic stem cells is an important goal and a myeloablative regimen would be preferred. In contrast, for patients with aplastic anemia or certain immunodeficiency states, eradication is not required, and the preparative regimen is primarily focused on immunosuppression to allow for engraftment and a less intensive regimen may be appropriate.

Certain inherited bone marrow failure conditions (eg, Fanconi anemia) are particularly susceptible to the toxicities of chemotherapy and radiation and should receive a lower intensity preparative regimen. (See "Hematopoietic cell transplantation (HCT) for inherited bone marrow failure syndromes (IBMFS)", section on 'Conditioning regimen'.)

Disease status – Myeloablative conditioning (MAC) regimens are preferred for patients with hematologic malignancies that are not in complete remission at the time of transplantation. Total body irradiation may be preferred in some settings due to its potential eradication of tumor cells in sanctuary sites (eg, central nervous system, gonads) that are not sufficiently penetrated by many chemotherapy agents.

Risk of rejection – Graft rejection is more likely when there is increasing human leukocyte antigen (HLA) disparity in major histocompatibility antigens (eg, HLA-mismatch), in recipients who have been exposed to minor histocompatability antigens (eg, multiple prior blood transfusions), following the infusion of grafts with a low stem cell dose, and with T cell depleted grafts. Graft rejection is less likely with increased stem cell dose, use of peripheral blood progenitor cells rather than bone marrow cells, high T cell dose in the graft, and the use of ATG in the preparative regimen. Graft rejection is not generally considered a risk in autologous HCT. (See "Selection of an umbilical cord blood graft for hematopoietic cell transplantation", section on 'Cell dose'.)

Often, MAC regimens are preferred for young patients with a good performance status undergoing allogeneic HCT given the larger experience with these regimens. MAC regimens are also the cornerstone of autologous HCT. RIC or nonmyeloablative regimens may be considered for patients who are not candidates for MAC regimens in whom the underlying disease has been well controlled. A choice between MAC, RIC, and NMA regimens is largely based on institutional preferences, center experience, resources available, and the principles described above.

Prospective randomized trials will be required to compare MAC with NMA regimens for the treatment of a particular disease. In general, MAC regimens are used for autologous HCT and in the allogeneic setting for the treatment of patients not in remission.

MYELOABLATIVE REGIMENS

Examples of MAC regimens — As described above, a myeloablative conditioning (MAC) regimen consists of a single agent or combination of agents expected to destroy the hematopoietic cells in the bone marrow and results in profound pancytopenia within one to three weeks from the time of administration [4]. The resulting pancytopenia is long-lasting, usually irreversible unless hematopoiesis is restored by infusion of hematopoietic stem cells. Commonly employed myeloablative regimens include (table 1) [5]:

Cy/TBI – The Cy/TBI regimen combines cyclophosphamide 120 mg/kg total dose administered over two days with total body irradiation (TBI; 12 to 14 Gy) administered over four days.

Bu4/Cy – The Bu4/Cy regimen combines intravenous busulfan 10 to 12 mg/kg total dose administered over four days with cyclophosphamide 120 mg/kg administered over two days.

Flu/Bu4 – The Flu/Bu4 regimen combines busulfan 16 mg/kg orally or 12.8 mg/kg by vein with fludarabine 120 to 180 mg/m2 administered over four days.

BEAM – The BEAM regimen combines BCNU 300 mg/m2 over one day, etoposide 400 to 800 mg/m2 over four days, cytosine arabinoside 800 to 1600 mg/m2 over four days, and melphalan 140 mg/m2 over one day. BEAM is the most commonly employed myeloablative preparative regimen for patients with non-Hodgkin or Hodgkin lymphoma.

MelphalanMelphalan 200 mg/m2 is commonly employed as the preparative regimen prior to autologous HCT for multiple myeloma. A lower dose 140 mg/m2 is used in older patients (ie, >70 years), those with renal dysfunction, or patients with multiple comorbidities. (See "Multiple myeloma: Use of hematopoietic cell transplantation", section on 'Preparative chemotherapy'.)

CBV – The CBV regimen combines a single dose of carmustine 300 to 500 mg/m2 followed by etoposide 600 to 2400 mg/m2 plus cyclophosphamide 4.8 g/m2 to 7.2 g/m2 over a four-day period. This regimen is commonly used for the treatment of patients with lymphomas.

A number of variations on these myeloablative regimens have been employed at centers throughout the world. They were developed by escalating the dose of either radiation or a particular drug to the maximally tolerated dose. Drugs with non-overlapping toxicities were employed in an effort to avoid synergistic injury to a particular organ (table 2). (See 'Definitions' above.)

MAC toxicity — All MAC regimens have side effects that can be life-threatening. In addition to myelotoxicity, common toxicities include:

Mucositis (see "Early complications of hematopoietic cell transplantation", section on 'Oral mucositis' and "Oral toxicity associated with systemic anticancer therapy")

Nausea and vomiting (see "Prevention of chemotherapy-induced nausea and vomiting in adults")

Alopecia (see "Alopecia related to systemic cancer therapy")

Diarrhea (see "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation")

Rash

Peripheral neuropathies (see "Overview of neurologic complications of conventional non-platinum cancer chemotherapy" and "Overview of neurologic complications of platinum-based chemotherapy")

Infertility, which can be devastating to young patients, is almost universal when using myeloablative regimens. This can be addressed with sperm cryopreservation for male patients, assuming they have adequate sperm number and function. Embryo or oocyte cryopreservation in female patients can also be attempted, with generally less success. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

Pulmonary and hepatic toxicity are also relatively common. As an example, busulfan, which is a component of many preparative regimens, can produce both interstitial lung disease and hepatic sinusoidal obstructive syndrome [6,7]. As a result, it is imperative that patients be screened for comorbidities prior to initiating the preparative regimen to avoid unnecessary risk. Monitoring of busulfan pharmacokinetics, a common practice, can also reduce the risk of these complications. (See "Busulfan-induced pulmonary injury" and "Determining eligibility for allogeneic hematopoietic cell transplantation" and "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults".)

Radiation-containing regimens — Total body irradiation (TBI) has been the mainstay of preparative regimens since the inception of HCT, based upon early studies in the dog and other animal models. Initial preparative regimens included TBI administered as a single dose using opposing Cobalt-60 sources [8]. At present, TBI-based regimens typically fractionate the radiation and administer the total dose over several days, typically four, which helps decrease toxicity and increase tolerability (table 1) [9]. Partial lung shielding is included in an effort to reduce the potential for irreversible lung injury.

The maximally tolerated dose of TBI is approximately 15 Gy. Higher doses produce excessive nonhematologic toxicity, primarily to the lungs, but also to other organs including the heart. Two randomized trials evaluated the efficacy of different doses of TBI (12 and 16 Gy) plus cyclophosphamide, prior to allogeneic HCT in patients with acute myeloid leukemia in first remission and chronic myeloid leukemia in the chronic phase [10,11]. Decreased relapse rates were observed with the higher TBI dose (eg, 12 versus 35 percent at three years in patients with acute myeloid leukemia), but overall survival was similar due primarily to increased transplant-related mortality at the higher doses (eg, 32 versus 12 percent at three years) [10]. This observation has provided one of the major rationales for developing radiolabeled monoclonal antibodies as part of the preparative regimen. (See 'Radiolabeled Mabs' below.)

In the initial regimens, TBI was combined with cyclophosphamide (Cy) and this Cy/TBI combination is still widely used. In Cy/TBI, cyclophosphamide is usually given at a dose of 60 mg/kg of adjusted ideal body weight on each of two successive days [12-14]. Attempts at further intensification, either by increasing the TBI dose or adding other agents have been unsuccessful at improving overall survival largely due to an increase in non-relapse mortality. TBI has also been combined with other chemotherapy agents. As examples:

Etoposide (VP16) has been given with fractionated TBI at a maximally tolerated dose of 60 mg/kg [15], with excellent results having been obtained in large numbers of patients [16,17]. In addition, VP 16 has been combined with cyclophosphamide and TBI (TBI/CY/VP16) in both the autologous and allogeneic setting, in an attempt to reduce relapse rates in patients with high risk or advanced stage hematologic malignancies [18-20].

High dose cytarabine (cytosine arabinoside, usually at a dose of 3 g every 12 hours for six days) also has been given with TBI, with and without cyclophosphamide, in patients with acute leukemia [21,22]. The rationale for this approach is to reduce the likelihood of relapse via the antileukemic activity of cytarabine. However, the possible superiority of using cytarabine rather than cyclophosphamide remains unproven [23].

Fractionated TBI has been relatively difficult to standardize in multi-institutional trials, due to differences in dose rates, shielding, and center-specific techniques. Dose rates differ by machine and lower total doses must be given when using machines with a high dose rate in order to limit toxicity. Fractionation reduces the incidence and severity of acute and late complications. Lower total doses may decrease toxicity but increase the risk of graft failure and disease recurrence. In contrast, higher doses decrease graft rejection and disease relapse but increase treatment-related morbidity and mortality.

The major limitations of fractionated TBI include mucositis, lung toxicity, infertility, and the relatively sophisticated instrumentation required to effectively administer this treatment. However, keratinocyte growth factor (palifermin) has been successful in reducing the risk of mucositis following radiation-containing regimens. (See "Early complications of hematopoietic cell transplantation", section on 'Oral mucositis'.)

Long-term complications following TBI used as part of a HCT preparative regimen are common. In one study of 186 adults surviving at least one year following TBI and HCT, who were followed for a median time of four years (range one to 11 years), the most commonly seen complications included [24]:

Asymptomatic alterations in pulmonary function – 19 percent [25]

Cataracts – 15 percent; surgery was necessary in 57 percent

Sicca syndrome – 13 percent

Hypothyroidism – 6.5 percent; one-half required medical treatment

Thyroiditis – 3 percent

Many centers are transitioning away from the use of radiation-based regimens in preference for chemotherapy-based regimens.

Chemotherapy without RT — A number of regimens have been developed in which TBI is replaced with additional chemotherapeutic agents [26]. These approaches were primarily developed for autologous transplantation but have also been used widely in the allogeneic setting. The primary advantage of regimens that lack TBI is reduced toxicity. In addition, the cost is lower, the regimen is easier to administer and schedule, and radiation can still be given to sites of disease following the transplant [27].

Drug combinations have been selected based upon the biologic activity of the particular drug, the ability to escalate the dose of the drug, and non-overlapping toxicities when delivering the drugs at maximally tolerated dosages. The most widely used non-radiation-containing regimen is the combination of busulfan and cyclophosphamide (Bu/Cy) [6,28-34]. BCNU (carmustine), etoposide, cytosine arabinoside and melphalan (BEAM) or BCNU, etoposide and cyclophosphamide are widely used preparative regimens for patients with non-Hodgkin or Hodgkin lymphoma [35]. High dose melphalan is commonly employed as a myeloablative preparative regimen prior to autologous HCT for multiple myeloma. Different doses and schedules of these drugs have been employed at various transplant centers, making it difficult to compare results with this regimen from one study to the next [11,36-40]. (See 'Examples of MAC regimens' above.)

Initial Bu/Cy regimens used high dose oral busulfan, which had to be administered prior to emetogenic agents, had variable pharmacokinetics, and was associated with high rates of hepatic sinusoidal obstructive syndrome and seizures [41]. Modern Bu/Cy regimens use an intravenous formulation of busulfan, which has less pharmacokinetic variability and is associated with fewer toxicities (less emetogenic, less liver toxicity) [42]. The administration of adjusted dose IV busulfan, where the dose of busulfan is adjusted based upon pharmacologic evaluation, with cyclophosphamide has resulted in excellent outcomes with improved tolerability [43]. Prophylactic anticonvulsant therapy should be initiated prior to the administration of busulfan.

A significant problem with carmustine (BCNU)-containing regimens has been the relatively high incidence of pulmonary toxicity, particularly in patients who have received prior radiotherapy to the chest [44,45]. This condition typically responds to corticosteroids (approximate prednisone dose 1 mg/kg) especially in early disease. An approach to minimizing lung toxicity is the combination of busulfan, melphalan, and thiotepa, followed by autologous peripheral blood progenitor cells in patients with aggressive or relapsed lymphoma [46]. Among the 40 patients treated with this regimen, interstitial pneumonitis developed in only one patient who had received prior lung radiotherapy. (See "Nitrosourea-induced pulmonary injury".)

The preferred preparative regimen may also vary with the nature of the underlying disease. Among patients with aplastic anemia, for example, it is desirable to increase the degree of immunosuppression (to prevent rejection of the graft) while avoiding excessive myelotoxicity. This has been successfully achieved with the combination of cyclophosphamide and antithymocyte globulin [47]. (See 'Choice of regimen' above and "Hematopoietic cell transplantation for aplastic anemia in adults".)

Comparison of RT with chemotherapy — It is difficult to compare the relative efficacy of the large number of different myeloablative preparative regimens that have been developed, since there are few direct comparisons in randomized clinical trials. In addition, it is likely that patient selection has a large impact on the results obtained, making it difficult to assess the impact of any given preparative regimen from the large number of phase II trials reported in the literature. An instructive example was reported in a retrospective cohort study which compared a radiation-containing preparative regimen (TBI/cyclophosphamide/etoposide) with a chemotherapy-only regimen (BEAM) in patients with non-Hodgkin lymphoma undergoing autologous peripheral blood stem cell transplantation [48]. The TBI-containing regimen resulted in relapse-free and overall survivals similar to that after BEAM. Further analysis indicated that transplantation before the year 2000, rather than the conditioning regimen, was a more important predictive factor for long-term outcome.

Despite these difficulties, a number of retrospective and randomized trials, including one meta-analysis, have compared Bu/Cy with Cy/TBI [6,29,49,50]:

The International Bone Marrow Transplant Registry retrospectively compared outcomes following allogeneic HCT in 381 human leukocyte antigen (HLA)-matched sibling transplants receiving Bu/Cy with 200 transplants using Cy/TBI for acute myeloid leukemia in first remission [50]. The incidence of hepatic sinusoidal obstructive syndrome (SOS, previously called hepatic veno-occlusive disease [VOD]), was higher with Bu/Cy than with Cy/TBI (13 versus 6 percent) and the relapse risk was higher with Bu/Cy (relative risk 1.7, 95% CI 1.05-2.81). Nevertheless, there were no differences in treatment-related mortality, risk for acute or chronic graft-versus-host disease, leukemia-free survival, or overall survival between the two treatments.

A meta-analysis of five prospective randomized studies comparing Bu/Cy with Cy/TBI came to similar conclusions [49], with an increased risk of hepatic SOS in the Bu/Cy group (odds ratio 2.5, 95% CI 1.2-5.2) but no significant differences in acute or chronic GVHD, interstitial pneumonitis, disease-free survival, or overall survival.

These studies did not include dose adjustment of busulfan based on pharmacokinetics, which may have an impact on regimen-related complications, such as hepatic SOS. Given these results, many groups have utilized Bu/Cy preparation for patients with myeloid diseases rather than TBI-based regimens. (See "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults", section on 'Modifiable risk factors'.)

NMA AND RIC REGIMENS

General principles — Among patients with leukemia treated with allogeneic HCT, an important contributing factor is a graft-versus-tumor (GVT) effect mediated by donor immunocompetent cells [51]. The importance of GVT is illustrated by the different outcomes with grafts from identical twin and nonidentical donors. Patients who have an identical twin donor do not develop either graft-versus-host disease (GVHD) or GVT and are therefore at higher risk of relapse of the underlying malignant disease than similar patients transplanted with human leukocyte antigen (HLA)-matched but nonidentical sibling donors (who develop both GVHD and GVT). (See "Biology of the graft-versus-tumor effect following hematopoietic cell transplantation".)

The GVT effect requires the engraftment of donor type immunocompetent cells, which does not necessarily require a high dose myeloablative preparative regimen. As a result, the possibility of achieving donor-specific engraftment using nonmyeloablative (NMA) or reduced intensity conditioning (RIC) regimens has been extensively explored [2,52-56]. This approach, which relies more on donor cellular immune effects and less on the cytotoxic effects of the preparative regimen to control the underlying disease [51,57-59], permits transplantation in older, as well as high-risk, heavily pretreated patients of any age, with an attendant decrease in regimen-related toxicity and treatment-related mortality [60-68]. (See 'Definitions' above.)

In many instances, cancer cells cannot be eradicated entirely by high dose chemotherapy alone (eg, multiple myeloma), or patients with these disorders are too ill because of age and/or co-morbidities to tolerate myeloablative chemotherapy followed by transplantation [61,69,70]. Many of the observed long-term tumor responses have been brought about by immunologic antitumor effects (ie, the GVT effect) generated by the allograft (eg, donor lymphocyte infusion in CML relapsing after allogeneic HCT) [51,71].

Importantly, not all diseases are equally susceptible to GVT effects. Follicular lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, and chronic myeloid leukemia appear particularly responsive, whereas acute lymphoblastic leukemia and Hodgkin lymphoma are relatively resistant. The biological explanation for these observations remains elusive. As an example, in one analysis of 834 patients who had undergone allogeneic HCT, the overall relapse rate per patient year was 0.36. Patients with chronic lymphocytic leukemia, multiple myeloma in remission, low grade or mantle cell lymphoma, and high grade non-Hodgkin lymphoma had the lowest rates (0 to 0.24), whereas those with advanced myeloid and lymphoid malignancies had rates of more than 0.52 [72].

Additional studies need to determine the relative role of this transplant approach, including such variables as the age and overall comorbidity status of the recipient, presence or absence of complete or partial remission at the time of HCT and clinical aggressiveness of the underlying disorder, the degree of HLA matching of the donor, and the agents and doses used in the reduced intensity conditioning regimens and GVHD prophylaxis [72-77]. However, these approaches have been tolerated reasonably well even in older patients who have significant medical comorbidities, allowing for many more patients to be treated with transplantation. This is important because many of the diseases for which allogeneic HCT has been successful typically occur in patients in their fifth to seventh decades of life.

Examples of NMA/RIC regimens — Specifics regarding the definitions of RIC and NMA preparative regimens are the subject of ongoing debate (table 1). In general, RIC regimens have toxicity profiles that are significantly lower than myeloablative conditioning (MAC) regimens and higher than NMA regimens.

Commonly employed NMA regimens include [5]:

Flu/TBI – The Flu/TBI regimen combines fludarabine 90 mg/m2 total dose administered over three days with low dose total body irradiation (TBI, 2 Gy) administered on the day of graft infusion.

TLI/ATG – The TLI/ATG regimen combines total lymphoid irradiation (TLI, 8 to 12 cGy) administered over 11 days with anti-thymocyte globulin (ATG; 1.25 mg/kg) administered over five days. In this approach, TLI and ATG appear to alter the host immune profile to favor regulatory natural killer T cells that suppress GVHD but retain graft antitumor activity [78]. Initial studies of this approach appeared promising, with an apparent reduction in acute GVHD risk with retention of GVT effects and very low transplant related mortality [79,80].

In one of the few randomized studies, compared with Flu/TBI, TLI/ATG resulted in a lower risk of non-relapse mortality and a higher risk of relapse with similar rates of overall survival (OS) and event-free survival (EFS) [81].

Commonly employed RIC regimens include [5]:

Flu/Mel – The Flu/Mel regimen combines fludarabine (125 to 150 mg/m2 total dose) administered over five days with melphalan (140 mg/m2) administered over two days.

Flu/Bu2 – The Flu/Bu2 regimen combines fludarabine (150 to 160 mg/m2) total dose administered over four to five days with oral busulfan (8 to 10 mg/kg) administered over two to three days.

Flu/Cy – The Flu/Cy regimen combines fludarabine (150 to 180 mg/m2) total dose administered over five to six days with cyclophosphamide (120 to 140 mg/kg) administered over two days.

Flu/Bu/TT – This regimen combines fludarabine 150 mg/m2 total dose administered over three days with busulfan (8 mg/kg) administered over three days and thiotepa (5 to 10 mg/m2) over one or two days, respectively.

Flu/Treo – This regimen combines fludarabine (150 mg/m2) total dose over five days with treosulfan (10 g/m2 daily two-hour infusion for three days) [82]. Treosulfan is approved for use in Canada and Europe, but not in the United States.

All of these regimens have shown promise and are being used by different centers. All have merit and appear to be reasonably well tolerated in older individuals and in patients with significant co-morbid medical conditions, including patients who have undergone prior autologous transplantation.

MAC versus RIC regimens — It is difficult to directly compare efficacy and toxicity of MAC versus NMA/RIC or between various preparative regimens since there are few randomized clinical trials or other well-controlled studies. Patient selection has an important impact on outcomes and studies vary with regard to patient populations, underlying disease, remission status, and graft source. In general, compared with NMA/RIC regimens, MAC is associated with superior relapse-free survival (RFS), but increased treatment-related mortality (TRM); the effects offset one another, so overall survival (OS) is comparable with the two approaches.

Examples of informative studies include:

A multicenter phase 3 trial that included 272 patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) reported fewer relapses after MAC than after RIC, but there was no difference in survival [83]. Compared with RIC, MAC was associated with superior RFS (68 versus 47 percent, respectively), but a higher rate of TRM (16 versus 4 percent); as a result, there was no difference in OS at 18 months. A subsequent analysis of this trial reported that the benefits of MAC were related to improved outcomes among patients who had measurable residual disease (MRD) prior to transplantation [84]. Further details of this trial are presented separately. (See "Acute myeloid leukemia in younger adults: Post-remission therapy", section on 'NMA/RIC versus MAC regimens'.)

A prospective age-adapted strategy for adults with AML showed no difference in OS between MAC and RIC [85].

Retrospective studies with AML or MDS suggested that RIC is associated with increased rates of relapse and less TRM [86-94]. As a result, both approaches achieved similar OS, even though patients who received RIC were generally older and less fit.

Comparison of different RIC regimens — Comparisons of different reduced intensity regimens are based on uncontrolled retrospective studies, as there are no randomized or well-controlled prospective trials [95].

Minimal intensity (antibody) conditioning — Some patients, such as those with severe organ toxicity and/or DNA/telomere repair defects, may be unable to tolerate MAC or even NMA regimens and may be candidates for minimal intensity conditioning. (See "Hematopoietic cell transplantation for severe combined immunodeficiencies".)

This concept was tested in a phase I/II study of 16 high-risk patients who underwent allogeneic HCT for primary combined immunodeficiency. The conditioning regimen included the use of two rat anti-CD45 antibodies, an anti-CD52 antibody (alemtuzumab), fludarabine, and low-dose cyclophosphamide. Results included [96]:

Rates of clinically significant acute and chronic GVHD were 36 and 31 percent, respectively. No grade 4 toxicities were seen.

15 of 16 patients engrafted, of whom 11 achieved full or high-level mixed chimerism in both lymphoid and myeloid lineages.

At a median follow-up of 40 months post-HCT, 13 of the 16 patients (81 percent) were alive and cured of their underlying disease.

Radiolabeled Mabs — Monoclonal antibodies (Mab) conjugated with high energy emitting radioisotopes have been used to increase the radiation dose to tumor cells in bone marrow and reduce doses to other organs, such as the liver, lungs, and kidneys. This approach has not been widely adopted for conditioning regimens.

There remains concern that high doses of radioactivity in the marrow space may injure or kill stromal cells. In addition, the delivery of such high doses of some radioisotopes requires sophisticated expertise, equipment, and shielding of the patient to avoid risk to health care workers.

Anti-CD20 radioimmunoconjugates — Anti-CD20 radioimmunoconjugates have been used to treat patients with B cell non-Hodgkin lymphoma (NHL). As an example, ibritumomab tiuxetan is a murine anti-CD20 monoclonal antibody conjugated to yttrium-90.

Addition of anti-CD20 radioimmunoconjugates to standard preparative regimens for autologous transplantation in patients with B cell NHL provided encouraging preliminary results and tolerable toxicity profiles [97-100]. A randomized trial reported similar progression-free survival and OS for BEAM plus anti-CD20 radioimmunoconjugates versus BEAM alone [101].

Anti-CD45 antibody — A monoclonal antibody directed against CD45, which is highly expressed on hematopoietic cells, allows targeting of radioisotopes to the marrow space [102,103]. In one report, compared with registry data using Bu/Cy alone, addition of this monoclonal antibody to Bu/Cy was associated with a more favorable outcome [104]. The difficulty of administering I-131 has limited use.

Anti-CD66 antibody — CD66 is highly expressed on normal myeloid cells from the promyelocyte to the mature granulocyte. In one report, 30 pediatric and adolescent patients undergoing allogeneic HCT for malignant (16 patients) or nonmalignant (14 patients) disorders underwent conditioning with yttrium-90 conjugated CD66 monoclonal antibody in combination with an RIC or MAC regimen [105]. The combination of antibody plus RIC resulted in consistent myeloablation and stable complete donor chimerism in the setting of nonmalignant hematologic disease.

Chimerism — Chimerism refers to the coexistence of donor and host cells in the bone marrow. Chimerism is more common following nonmyeloablative or reduced intensity conditioning and following umbilical cord blood transplantation. For many genetic disorders, a state of mixed donor-host chimerism is sufficient to relieve the patient of disease-related manifestations (eg, beta thalassemia major). (See "Thalassemia: Management after hematopoietic cell transplantation".)

In the light of reduced intensity of conditioning regimens, and with the induction of partial donor chimerism, donor leukocyte infusions [106] or other immunotherapeutic interventions could be applied in an effort to balance the interactions between the following competing issues (see "Immunotherapy for the prevention and treatment of relapse following allogeneic hematopoietic cell transplantation") [79,107-115]:

Maximizing the graft-versus-tumor effect

Minimizing acute and chronic GVHD

Minimizing graft rejection

Minimizing opportunistic infections (eg, CMV infection) through rapid immune reconstitution [116]

This approach relies heavily on the serial assessment of chimerism, using techniques such as fluorescence in situ hybridization (FISH) or analysis of a variable number of tandem repeats (VNTR) between donor and recipient [117-121]. In the setting of a sex-mismatched transplant, FISH for the X and Y chromosomes in interphase nuclei is a highly accurate technique for identifying chimerism.

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)")

SUMMARY

Description – The preparative (conditioning) regimen is a critical element in the hematopoietic cell transplant (HCT) procedure. The purpose of the preparative regimen is twofold:

To provide adequate immunosuppression to prevent rejection of the transplanted graft

To treat the disease for which the transplant is being performed

Categories – Preparative regimens for HCT differ regarding agents (eg, chemotherapy, immunotherapy, radiation therapy), intensity, and degree of myeloablation. Generally accepted definitions follow (table 1):

Myeloablative conditioning – A myeloablative conditioning (MAC) regimen consists of a single agent or combination of agents expected to destroy the hematopoietic cells in the bone marrow and produce profound pancytopenia. The resulting pancytopenia is long-lasting and usually irreversible unless hematopoiesis is restored by infusion of hematopoietic stem cells. Examples include total body irradiation ≥5 Gy or busulfan >8 mg/kg orally. (See 'Myeloablative regimens' above.)

Nonmyeloablative conditioning – A nonmyeloablative (NMA) conditioning regimen is one that will cause minimal cytopenia (but significant lymphopenia) by itself and does not require stem cell support. Examples include fludarabine plus cyclophosphamide with or without antithymocyte globulin or total body irradiation ≤2 Gy with or without a purine analog. However, the transplant, when given in this setting usually results in full donor engraftment because the engrafting donor T cells will eventually eliminate host hematopoietic cells, allowing the establishment of donor hematopoiesis. (See 'NMA and RIC regimens' above.)

Reduced intensity conditioning – Reduced intensity conditioning (RIC) regimens are an intermediate category of regimens that do not fit the definition of MAC or NMA. Such regimens cause cytopenias, which may be prolonged and result in significant morbidity and mortality and require stem cell support. Regimens generally considered as reduced intensity include ≤8 mg/kg of oral busulfan, or ≤140 mg/m2 of melphalan.

Choice of MAC regimen – Selection of a regimen is generally informed by institutional and physician preference and experience. Few randomized trials directly compare the efficacy of one MAC preparative regimen with another for particular diseases. (See 'Choice of regimen' above.)

MAC versus RIC/NMA regimens – MAC regimens are generally associated with lower rates of relapse but higher rates of treatment mortality and morbidity; as a result, most studies suggest comparable overall survival with MAC versus RIC/NMA regimens. (See 'MAC versus RIC regimens' above.)

Adverse effects – All preparative regimens have short-term and long-term adverse effects, in addition to myelotoxicity. Other common toxicities include mucositis, nausea and vomiting, alopecia, diarrhea, rash, peripheral neuropathy, infertility, interstitial lung disease, and sinusoidal obstructive syndrome. Long-term complications following total body irradiation also include asymptomatic alterations in pulmonary function, cataracts, sicca syndrome, and thyroid dysfunction. (See 'MAC toxicity' above.)

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Topic 3557 Version 34.0

References

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