Determining eligibility for allogeneic hematopoietic cell transplantation

INTRODUCTION — Hematopoietic cell transplantation (HCT) is a general term that encompasses a series of procedures in which the patient is treated with chemotherapy, radiation therapy, or both (referred to as the "preparative/conditioning regimen") followed by the infusion of hematopoietic stem/progenitor cells. Various strategies for HCT have been developed and are applied, dependent on the patient's disease and disease stage, the hematopoietic cell donor, and the source of hematopoietic progenitor cells. The assessment of those parameters, in turn, will affect the selection of the preparative regimen. These factors influence the efficacy of HCT and the short- and long-term toxicities associated with the procedure. (See "Early complications of hematopoietic cell transplantation" and "Survival, quality of life, and late complications after hematopoietic cell transplantation in adults".)

Allogeneic HCT uses hematopoietic progenitor cells collected from a healthy person (not from the patients themselves). Allogeneic HCT is increasingly used to treat a variety of hematologic neoplasms and nonmalignant marrow disorders (acquired and inherited), including inborn errors of metabolism. Eligibility for allogeneic HCT varies across countries and institutions. Ultimately, decisions regarding transplant eligibility should be made on a case-by-case basis dependent on a risk-benefit assessment, and the needs and wishes of the patient. Here we discuss eligibility for allogeneic HCT. Eligibility for autologous HCT, the use of HCT in specific disease settings, and short- and long-term complications of HCT are discussed separately.

●(See "Determining eligibility for autologous hematopoietic cell transplantation".)

●(See "Hematopoietic support after hematopoietic cell transplantation".)

●(See "Early complications of hematopoietic cell transplantation".)

●(See "Survival, quality of life, and late complications after hematopoietic cell transplantation in adults".)

●(See "Long-term care of the adult hematopoietic cell transplantation survivor".)

IMPACT OF UNDERLYING DISEASE

Disease-related indications — Historically, allogeneic HCT was offered to patients with hematologic malignancies who had exhausted other treatment modalities, and eligibility was largely based on whether the patient was in adequate physical condition to tolerate the anticipated toxicity. Currently, a decision to perform allogeneic HCT must include an assessment of the underlying disease state and whether allogeneic HCT is likely to offer results superior to those achieved with nontransplant options. The risks of morbidity and mortality associated with allogeneic HCT must be compared with those of other treatment approaches.

The role of allogeneic HCT in specific diseases is discussed in more detail separately. In general, allogeneic HCT may be considered in the following settings:

●Acute myeloid leukemia (AML) – As post-remission therapy for patients in first or subsequent remission. (See "Acute myeloid leukemia in younger adults: Post-remission therapy", section on 'Myeloablative allogeneic transplantation' and "Treatment of relapsed or refractory acute myeloid leukemia", section on 'Hematopoietic cell transplantation'.)

●Acute lymphoblastic leukemia (ALL) – As post-remission therapy for patients in first or subsequent remission. (See "Post-remission therapy for Philadelphia chromosome negative acute lymphoblastic leukemia in adults", section on 'Allogeneic transplantation' and "Post-remission therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults", section on 'Choices for transplant candidates' and "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Transplantation'.)

●Myelodysplastic syndromes (MDS) – As initial therapy, consolidation therapy, or treatment of relapsed or refractory disease in patients with higher-risk disease. (See "Treatment of high or very high risk myelodysplastic syndromes", section on 'Allogeneic HCT'.)

●Myeloproliferative neoplasms (MPN) – In patients with leukemic transformation, bone marrow failure, or resistance to JAK2 inhibitors or other nontransplant therapy. (See "Myelofibrosis (MF): Management of primary MF and secondary MF", section on 'Transplant-eligible patients'.)

●Chronic lymphocytic leukemia (CLL) – Patients refractory to or relapsing after treatment with fludarabine-containing regimens, resistance to targeted agents such as ofatumumab or ibrutinib, and, occasionally, young patients with high-risk disease at first complete or partial remission. (See "Hematopoietic cell transplantation in chronic lymphocytic leukemia".)

●Chronic myeloid leukemia (CML) – As part of the initial management of patients with accelerated phase disease or blast crisis following induction with a tyrosine kinase inhibitor (TKI), for patients with relapsed disease, disease resistant to multiple TKIs, or in patients intolerant of TKI. (See "Hematopoietic cell transplantation in chronic myeloid leukemia".)

●Peripheral T cell lymphoma (PTCL) – Treatment of chemotherapy-sensitive relapsed disease or as part of the initial management of high-risk disease (eg, adult T cell lymphoma/leukemia). (See "Treatment of relapsed or refractory peripheral T cell lymphoma", section on 'Allogeneic HCT' and "Treatment and prognosis of adult T cell leukemia-lymphoma", section on 'Hematopoietic cell transplantation'.)

●Follicular lymphoma (FL) – Treatment of chemotherapy-sensitive relapsed or refractory disease or disease that has progressed to a clinically aggressive histology (eg, diffuse large B cell lymphoma). (See "Allogeneic hematopoietic cell transplantation in follicular lymphoma", section on 'Preparative regimen' and "Treatment of relapsed or refractory follicular lymphoma", section on 'Autologous transplant for eligible patients'.)

●Diffuse large B cell lymphoma (DLBCL) – Treatment of chemotherapy-sensitive DLBCL that has relapsed following autologous HCT. (See "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically unfit", section on 'Allogeneic hematopoietic cell transplantation'.)

●Nonhematologic malignancies – Treatment of neuroblastoma. (See "Treatment and prognosis of neuroblastoma", section on 'High-risk disease'.)

●Nonmalignant inherited and acquired marrow disorders – Treatment of sickle cell anemia, beta thalassemia major, refractory Diamond-Blackfan anemia, myelodysplastic syndrome, idiopathic severe aplastic anemia, paroxysmal nocturnal hemoglobinuria, pure red cell aplasia, Fanconi anemia, amegakaryocytosis, or congenital thrombocytopenia. (See "Hematopoietic stem cell transplantation for transfusion-dependent thalassemia" and "Hematopoietic stem cell transplantation in sickle cell disease" and "Shwachman-Diamond syndrome" and "Hematopoietic cell transplantation (HCT) for inherited bone marrow failure syndromes (IBMFS)", section on 'Introduction' and "Hematopoietic cell transplantation for acute myeloid leukemia and myelodysplastic syndromes in children and adolescents", section on 'Introduction'.)

●Other – Treatment of autoimmune diseases and the treatment of children and adults with inborn errors in metabolism and congenital immune deficiencies. (See "Hematopoietic cell transplantation for severe combined immunodeficiencies" and "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy" and "Mucopolysaccharidoses: Complications" and "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis" and "Severe combined immunodeficiency (SCID) with JAK3 deficiency" and "Chronic granulomatous disease: Treatment and prognosis" and "Krabbe disease" and "NK cell deficiency syndromes: Treatment" and "DiGeorge (22q11.2 deletion) syndrome: Management and prognosis" and "Treatment and prognosis of paroxysmal nocturnal hemoglobinuria" and "Wiskott-Aldrich syndrome".)

Allogeneic HCT is also being studied for a variety of other disorders (eg, multiple myeloma, autoimmune diseases) in the context of clinical trials. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (clinicaltrials.gov).

Recommendations for allogeneic HCT differ between transplant centers, and there are no accepted guidelines or general consensus regarding indications for allogeneic transplantation [1]. For malignant disorders, disease stage at the time of HCT and cytogenetic abnormalities have consistently been identified as the strongest determinants of relapse after allogeneic HCT. These factors are closely linked to the underlying diagnosis and prior treatment. Many pre-HCT factors such as patient age, type of disease, genetic determinants, and most comorbid conditions are not modifiable. However, assuming that a suitable donor is available, clinicians have some control over the timing of allogeneic HCT and thereby the disease stage when allogeneic HCT is carried out.

General issues that complicate recommendations regarding the timing and efficacy of allogeneic HCT include the following:

●Patients who have received extensive cytotoxic therapy before allogeneic HCT are more likely to be in worse physical condition and less likely to tolerate allogeneic HCT. As an example, a patient with refractory disease is likely to have received at least twice the amount of therapy (chemotherapy and/or radiation) before allogeneic HCT than a patient in first remission. Thus, it may be difficult to separate the effect of prior therapy from disease status in such patients.

●There is a general lack of randomized trials comparing allogeneic HCT with nontransplant strategies. Instead, investigators have often relied on a "genetic randomization" in which patients are assigned to treatment with or without allogeneic HCT based on the presence or absence of a human leukocyte antigen (HLA)-matched sibling donor or, more recently, an HLA-matched unrelated donor. Patients without an HLA-matched donor are considered for transplantation from an "alternative" donor (HLA-haploidentical family member or cord blood) or are assigned to treatment with either chemotherapy alone or autologous HCT, depending on the trial design.

●Chemotherapy and radiation therapy programs evolve as new drugs and techniques are developed. Clinicians must determine how to incorporate data regarding new therapies in a setting that has previously shown a benefit from allogeneic HCT. Patients referred for allogeneic HCT may have been exposed to chemotherapeutic or biologic agents whose impact on allogeneic HCT is unknown. Patients who have received these regimens may be more refractory to the effects of allogeneic HCT than patients exposed to different agents in the past.

●A broad spectrum of preparative regimens may be suitable for various disease categories and patient populations (figure 1) [2]. As examples, nonmyeloablative (NMA) conditioning or reduced intensity conditioning (RIC) regimens permit allogeneic HCT in older patients and/or patients with comorbidities. The underlying disease is important when considering NMA/RIC versus high dose (myeloablative) allogeneic HCT, because there appears to be a higher relapse rate with NMA/RIC conditioning in several disease categories [3]. As an example, myeloablative conditioning should be the standard for patients with AML or MDS who can tolerate such a regimen, based on superior clinical outcomes [4-6]. (See "Acute myeloid leukemia in younger adults: Post-remission therapy", section on 'Nonmyeloablative/reduced intensity HCT' and "Treatment of high or very high risk myelodysplastic syndromes".)

●The availability of RIC regimens has also allowed for second transplantations to be carried out after failure of a previous (autologous or allogeneic) transplant after a high dose regimen, a situation where repeat conditioning with high dose therapy may cause prohibitive toxicity [4,7,8].

Ongoing trials are assessing the role of allogeneic HCT in other settings and tumor types. Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).

Disease type and status — The aggressiveness of the underlying disease and the disease status (eg, complete remission [CR], partial remission [PR], measurable residual disease [MRD], previously referred to as minimal residual disease) at the time of transplant have a considerable impact on long-term survival of patients undergoing allogeneic HCT for malignancies. These variables have made the results of studies of transplantation across disease entities difficult to compare.

A disease risk index was created using data from 1539 patients who underwent allogeneic HCT at Dana-Farber Cancer Institute/Brigham and Women's Hospital from 2000 to 2009, and was validated in an independent cohort of 672 patients who underwent transplant at the Fred Hutchinson Cancer Research Center [9]. Sixteen defined underlying diseases were categorized as low risk (eg, AML with favorable cytogenetics, CLL, CML, indolent B cell NHL), high risk (eg, AML or MDS with adverse cytogenetics, extranodal T cell lymphoma), or intermediate risk (all others). Disease stage was categorized as low risk (eg, CR, first PR, untreated disease) or high risk (eg, induction failure, active relapse, accelerated or blast phase CML). These two ratings were then combined to define four risk groups with significantly different estimated rates of overall survival (OS), progression-free survival (PFS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM) at four years.

The disease risk index described above was independently validated by the Center for International Blood and Marrow Transplant Research (CIBMTR) using data from 13,131 patients who underwent HCT between 2008 and 2010, approximately half of whom received a myeloablative preparative regimen [10]. Estimated OS at two years was 64, 51, 34, and 24 percent for those in the low, intermediate, high, and very high risk groups, respectively. Using this large cohort of patients, the CIBMTR was able to further refine the disease index for specific patient populations (table 1).

Risk classification schemes have been developed for diseases such MDS or MPN. The International Prognostic Scoring System (IPSS) in its original or in its revised form (IPSS-R) have significant prognostic relevance in patients with MDS [11,12]. Similarly, various prognostic scores are useful for selecting therapy for primary myelofibrosis [13-17]. (See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults" and "Prognosis of primary myelofibrosis".)

PRETRANSPLANT ASSESSMENT — To best determine the likelihood that a patient with an indication for allogeneic HCT is an appropriate candidate for the procedure, a pretransplant assessment must establish the extent of disease and provide information about the individual's comorbidities that are likely to impact outcomes. This assessment varies somewhat by institution.

History and physical examination — It is our practice to perform the following pretransplant assessment:

●Detailed history – While all elements of the patient's history are pertinent, issues particularly relevant to potential complications include: performance status (table 2), psychological history, prior therapies, transfusion history, drug allergies (especially to antibiotics), and a detailed infection history (especially a history of aspergillus infection or tuberculosis). (See "Evaluation for infection before hematopoietic cell transplantation", section on 'Recipient'.)

●Physical examination with particular attention to the oral cavity (a potential source of infection) and central nervous system. A dental examination and dental radiographs allow for the maximization of dental status prior to transplant.

Laboratory studies — Laboratory studies include human leukocyte antigen (HLA) testing, complete blood count with differential, chemistries with liver and renal function and electrolytes, and an assessment of prior exposure to various infectious agents (table 3). (See "Evaluation for infection before hematopoietic cell transplantation".)

●A chest radiograph, an electrocardiogram, and a study of cardiac function (eg, ejection fraction measured by echocardiogram or MUGA). (See "Tests to evaluate left ventricular systolic function".)

●Pulmonary function test, including diffusing capacity of the lungs for carbon monoxide (DLCO). (See "Overview of pulmonary function testing in adults".)

●Disease-specific restaging studies – This assessment usually includes a computed tomography (CT) scan or combined positron emission tomography (PET)/CT scan for patients with lymphoma. Patients with leukemia or lymphoma should undergo a bone marrow biopsy to assess for involvement and a lumbar puncture with cytologic examination in order to evaluate for meningeal involvement. Patients with meningeal involvement usually require intrathecal chemotherapy and/or cranial radiation prior to transplantation. Similarly, parenchymal involvement of the central nervous system may increase the risk of cerebral bleeding during the transplantation procedure. (See "Monitoring of the patient with classic Hodgkin lymphoma during and after treatment", section on 'After treatment' and "Pretreatment evaluation and staging of non-Hodgkin lymphomas" and "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Introduction'.)

Further studies may be required depending on clinical findings.

HCT consultation — Patients with a disease-related indication for allogeneic HCT should be offered the opportunity to discuss the procedure with a transplantation physician.

PRETRANSPLANT COUNSELING — We suggest the following:

End-of-life and advance care planning — Advance care planning (ACP; eg, living will, power of attorney for health care, life-support instructions) should be completed while the patient is competent, to ensure that care is consistent with the patient's wishes. (See "Advance care planning and advance directives".)

This issue was explored in all patients at least 19 years of age who underwent their first HCT for a hematologic malignancy between the years 2001 and 2003 at a single medical center. The following observations were made [18]:

●Of the 343 patients in this study, 172 (50 percent) did not have ACP, as defined above.

●Of those with ACP, 22, 68, and 10 percent completed ACP before cancer diagnosis, after cancer diagnosis but before HCT, or following HCT, respectively.

●Of interest, patients without ACP before HCT had a significantly greater risk of death compared with patients with ACP (hazard ratio 2.1; 95% CI 1.3-3.3). Stated otherwise, in this exploratory study the patients least likely to have planned for poor outcomes were the ones most likely to face them.

Fertility preservation — Children, men, and women with childbearing potential should receive counseling about the potential effect of treatment on their fertility and options for fertility-preserving measures. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

Patient expectations — Despite the improvements noted above, informed consent guidelines mandate that patients have an accurate understanding of the risks of HCT. A single institution study of patients undergoing HCT indicated that patients and their physicians had the most concordant and accurate pre-transplant expectations of post-transplant survival when outcomes were most likely to be favorable [19]. Thus, for autologous transplants, in which the actual treatment-related mortality at one year was 10 percent, patient and physician estimates were 12 and 10 percent, respectively.

This was not true when one year treatment-related mortality was significantly higher. As an example, in patients with intermediate or advanced disease receiving a transplant from an unrelated donor (actual one-year mortality 44 to 67 percent), physician expectations were appropriately modified (estimated mortality of 38 to 55 percent), while those of patients were overly optimistic (15 to 19 percent) [19].

IMPACT OF INDIVIDUAL FACTORS — A decision to proceed with allogeneic HCT must take into consideration multiple factors regarding the patient's physical condition. Some studies have evaluated the impact of individual parameters (eg, age, performance status, cardiopulmonary function), while others have created scoring systems to evaluate the effects of multiple parameters. These are described in the following sections. None of these factors represents an absolute contraindication to allogeneic HCT. Instead, they must be carefully weighed within the context of the clinical scenario. (See 'Determining eligibility' below.)

Age — The incorporation of age cutoffs into eligibility criteria for allogeneic HCT is controversial. Historically, myeloablative allogeneic HCT was limited to patients ≤55 years of age due to the expected toxicity associated with the procedure. The development of transplantation conditioning regimens of lower intensity (ie, nonmyeloablative, reduced intensity) has allowed allogeneic HCT to be carried out with less toxicity than observed in the past and has permitted transplantation of patients who hitherto had not been considered candidates. While lower intensity regimens appear to be associated with less toxicity, they are associated with a greater risk of relapse [20]. Many centers continue to use an age cutoff of 55 years for myeloablative allogeneic HCT, but allow for lower intensity allogeneic HCT in physically fit patients up to age 75 years.

The median age of transplanted patients has increased continuously over decades, with reports including patients up to age 75 years. The Center for International Blood and Marrow Transplantation Research (CIBMTR) database shows a median patient age of 25, 39, and 46 years in the 1980s, in the 1990s, and in the first decade of this century, respectively [21]. Transplants performed between 2002 and 2009 included a substantial percentage of patients >50 years (44 percent) and >60 years (20 percent).

The patient's goal of care and/or eligibility for allogeneic HCT may change with age. In younger patients, decisions regarding HCT are primarily governed by disease risk and donor availability, and allogeneic HCT aims to add many more years of life. In older patients, the importance of quality of life (QOL) may increase, while comorbid conditions and the suitability of conditioning regimens play a central role in the decision process [22]. In either case, QOL can be significantly impaired by transplantation-related complications, in particular graft-versus-host disease (GVHD) and its treatment. (See "Survival, quality of life, and late complications after hematopoietic cell transplantation in adults", section on 'Quality of life'.)

The following is a description of studies that have investigated the impact of recipient age on outcomes after HCT:

●A retrospective study from the European Bone Marrow Transplantation (EBMT) group analyzed the impact of age on the outcomes of 1333 older adults (age 50 to 74 years) who underwent myeloablative (38 percent) or reduced intensity allogeneic HCT from human leukocyte antigen (HLA)-identical siblings (61 percent) or unrelated donors for the treatment of myelodysplastic syndromes (MDS) or secondary acute myeloid leukemia (AML) [23]. Estimated four-year survival for all patients was 31 percent. There was no significant association between age and relapse or nonrelapse mortality (NRM). Relapse was significantly more likely in patients with advanced disease and those who underwent reduced-intensity conditioning. In contrast, NRM was greater in those with advanced stage disease, the use of unrelated donors, and reduced-intensity conditioning regimen. In the absence of more details regarding comorbidities, it is unknown how much selection bias influences whether patients go on to receive a transplant and what conditioning regimen is chosen.

●In another analysis from the CIBMTR, 1080 older adults (>40 years) underwent reduced intensity conditioning followed by allogeneic HCT for MDS or AML in first remission from 1995 to 2005 [24]. Among those with AML, estimated two-year survival was 44, 50, 34, and 36 percent among those ages 40 to 54, 55 to 59, 60 to 64, or older than 64 years, respectively. Two-year overall survival was correlated with pre-HCT performance status. Chronologic age did not impact rates of NRM, relapse, or GVHD.

●An analysis of 372 patients aged 60 to 75 years enrolled in prospective clinical trials of nonmyeloablative allogeneic HCT reported five-year cumulative incidences of NRM and relapse of 27 and 41 percent, respectively, and overall and progression-free survival rates of 35 and 32 percent, respectively [25]. There was no statistically significant difference in these outcomes when stratified by age. Greater age was associated with increased bacterial infections and hospitalizations. The incidence of chronic GVHD and the rate of resolution were similar to that seen in younger patients treated with HCT. Two-thirds of survivors had resolution of their GVHD and returned to near-normal physical function.

Chronologic age alone should not be the sole criterion used to determine eligibility for allogeneic HCT but, in the context of comorbid conditions, may impact the choice of conditioning regimen. Although it is difficult to agree on parameters to define biologic age, age must be taken into consideration in the decision process. Even in the absence of clinically apparent comorbidities, changes in organ function with age may modify drug metabolism or excretion and contribute to differences in outcome compared with younger patients. As an example, increasing age is associated with decreased glomerular filtration rate and is a risk factor for the development of chronic kidney disease after allogeneic HCT [26-28]. Similarly, increasing age is associated with decreased forced expiration volume at one second, which might interfere with airway clearance and infection prevention after HCT. Therefore, it is important to consider age as a predictor of how well (or poorly) a patient is expected to tolerate not only the transplantation regimen but also the management after HCT, in particular GVHD and its treatment. In a study performed by CIBMTR, 1106 patients age >70 years underwent allogeneic HCT. When analyzed in cohorts based on date of transplant, the overall and progression-free survival improved over time with two-year overall survival 39 percent and progression-free survival of 32 percent in patients transplant in 2008 to 2013. Multivariate analysis from that cohort revealed higher mortality was associated with the use of an umbilical cord blood graft, higher HCT-CI score, and myeloablative conditioning. HCT can be considered for selected patients with hematologic malignancies >70 years of age [29].

Comorbidities — Screening for pulmonary, cardiac, liver, and kidney dysfunction is performed in an attempt to identify patients at increased risk for complications and to help guide therapy. Patients with organ dysfunction prior to allogeneic HCT are expected to have more complications with the procedure. In addition, knowledge of underlying organ dysfunction can guide therapy decisions to minimize further toxicity. As examples:

●Pulmonary disease – Historically, a corrected diffusing capacity of the lungs for carbon monoxide (DLCO) of ≥60 percent has been required for allogeneic HCT eligibility. However, a subset of patients with DLCO <60 percent can be transplanted successfully [30]. Patients with known pulmonary dysfunction should avoid conditioning regimens that are known to decrease diffusion capacity (eg, BCNU-based regimens or busulfan plus total body irradiation). This is particularly important for patients with autoimmune diseases involving the lungs who are considering HCT. (See "Pulmonary toxicity associated with antineoplastic therapy: Cytotoxic agents".)

●Cardiac disease – While life-threatening cardiac complications are uncommon following allogeneic HCT, the transplant procedure is associated with subacute cardiac injury even in patients with normal cardiac function pretransplant. This cardiac injury is assumed to be of greater impact in patients with less cardiac reserve. Cardiac risk factors should be minimized in all patients prior to transplant (eg, smoking, obesity, hyperlipidemia, hypertension, hyperglycemia). The degree of cardiac dysfunction allowed depends largely on the underlying disease and conditioning regimen. In general, patients with a left ventricular ejection fraction (LVEF) <40 percent or uncontrolled coronary artery disease or uncontrolled arrhythmias are not considered candidates for allogeneic HCT. A reduced ejection fraction and a history of congestive heart failure have a strong association with cardiotoxicity following transplant.

●Liver dysfunction – A substantial percentage of patients with hematologic malignancies have abnormalities on liver function tests. Causes include those seen in patients without malignancy (eg, hepatitis, alcohol abuse, hepatic steatosis) and iron overload due to a large number of previous transfusions. Patients with abnormal liver function tests should undergo a detailed workup for etiology, ideally in consultation with a hepatologist. There is an increased risk of developing hepatic sinusoidal obstructive syndrome (SOS; veno-occlusive disease) post-HCT in patients with increased transaminases, a prior history of SOS, and a history of exposure to gemtuzumab ozogamicin. (See "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults".)

●Renal dysfunction – The impact of renal dysfunction on transplant eligibility largely depends on the planned preparative regimen and underlying disease. Adequate renal function is important due to the potential for exposure to many nephrotoxic agents (eg, cyclosporine, tacrolimus, aminoglycosides and amphotericin) following transplant. Patients with renal failure must be approached with caution since many of the clinical trials evaluating conditioning regimens have mainly studied patients with serum creatinine <2.0 mg/dL (177 micromol/L) or creatinine clearance >50 to 60.

Infectious disease status — Screening for infectious diseases before allogeneic HCT is designed to prevent post-transplant infections by defining specific infection control policies and antimicrobial prophylaxis and therapy, which will be necessary after transplantation. This is discussed in more detail separately. (See "Evaluation for infection before hematopoietic cell transplantation".)

Seropositivity for human immunodeficiency virus (HIV), hepatitis B, or hepatitis C does not exclude patients from undergoing allogeneic HCT but does affect transplant care. Patients with these infections need further evaluation regarding the status of the infection, ideally in consultation with an infectious disease expert. Patients with hepatitis B or hepatitis C are at increased risk of viral reactivation after transplant, even if the infection appears to be resolved. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy" and "HIV-related lymphomas: Treatment of systemic lymphoma", section on 'Allogeneic HCT'.)

Weight and nutritional status — Obesity, unless extreme, should not a priori exclude patients from undergoing allogeneic HCT, although body weight is a relevant factor. However, patient weight may affect drug delivery and dosage considerations. Patients with obesity, anorexia, cachexia, or malnutrition should be evaluated by a dietician to optimize their nutritional status before and during the transplant procedure.

Several analyses examined the impact of patient weight on transplantation outcome with mixed results [31-33]. When compared with patients closer to ideal body weight, patients who are severely underweight or patients with obesity appear to have inferior outcomes following allogeneic HCT [33-36]. Inferior outcome in underweight patients may be related to aggressive pre-HCT therapy, resulting in a negative nitrogen balance and wasting. Inferior outcomes in overweight patients may be related to general deconditioning and reduced activity; physical constraints regarding the care of patients with obesity who are too ill to care for themselves; and an increased incidence of infections. In addition, inferior outcomes may reflect differences in the volume of distribution of drugs and the impact of weight on pharmacokinetics [37].

RISK ASSESSMENT SCORING SYSTEMS — Several composite scoring systems are available for estimating mortality risk in patients considering allogeneic HCT. The most commonly used assessments are the European Group for Blood and Marrow Transplantation (EBMT) risk assessment score for allogeneic transplantation [38] and the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) [39,40].

A potentially important issue is that mortality rates after allogeneic HCT have decreased since these tools were created. A retrospective single-center study of 1418 patients who underwent allogeneic HCT from 1993 through 1997 and 1148 patients who were transplanted from 2003 through 2007 reported a significant decrease in nonrelapse mortality (odds ratio [OR] 0.48, 95% CI 0.40-0.57) and overall mortality (OR 0.59, 95% CI 0.52-0.67) in the patients in the latter group [41]. Similar results were reported in a study of 5972 patients younger than age 50 years undergoing myeloablative conditioning and allogeneic HCT for acute myeloid leukemia (AML) in first or second complete remission (CR) [42]. This benefit probably reflects shifts in conditioning regimens, preferred stem cell source, graft-versus-host disease (GVHD) prophylaxis, and other supportive measures.

There are few studies comparing these risk scores. An analysis involving data on 286 patients transplanted at a French center found the comorbidity indices to have little discriminating power but acknowledged that many children did not have pulmonary function tests available [43].

While future studies will be needed to validate these scoring systems and other available comorbidity scores [39,40,44,45], including the Karnofsky performance status [46], all can serve to help patients better appreciate their mortality risk after allogeneic HCT.

EBMT score — The EBMT devised a risk score based on five separate characteristics, which predicted treatment-related mortality and five-year overall survival (OS) following allogeneic HCT for patients with chronic myeloid leukemia (CML) (table 4) [38]. (See "Hematopoietic cell transplantation in chronic myeloid leukemia", section on 'Prognostic factors'.)

This risk score was subsequently validated in the following clinical settings:

●CML, using separate data from the International Bone Marrow Transplant Registry [47]

●Acute leukemia (both AML and ALL), which correlated with 100-day mortality, two-year OS, leukemia-free survival, and nonrelapse related mortality, using data from the Italian national transplantation network (GITMO) [48]

●Various hematologic disorders (ie, CML, AML, acute lymphoblastic leukemia [ALL], myelodysplastic syndromes [MDS], myeloma, non-Hodgkin lymphoma, aplastic anemia), which predicted survival, treatment-related mortality, and death from relapse [49]

HCT-CI score — The Charlson Comorbidity Index (CCI) is commonly used to predict the impact of comorbidities on mortality from various medical conditions including solid malignancies. However, many of the comorbidities assessed in the original CCI are exclusion criteria for allogeneic HCT [44]. As such, a modified HCT-specific comorbidity index (HCT-CI) was created for this patient population (table 5) [39,40,50]. The HCT-CI score could be calculated using an online calculator at www.hctci.org.

The HCT-CI score weighs 17 possible comorbidities for a score ranging from 0 to 29. In a validation cohort of 346 patients undergoing allogeneic HCT, rates of two-year nonrelapse mortality for patients with scores of 0, 1, 2, 3, and 4 or more were 14, 22, 19, 41, and 40 percent, respectively [39]. Further study has identified an increased HCT-CI score as a potential risk factor for severe (grade 3/4) acute GVHD [51]. The HCT-CI has also been used to predict nonrelapse mortality and OS in pediatric patients undergoing a first allogeneic HCT [52]. The HCT-CI strictly considers only pre-HCT patient characteristics, in particular cardiovascular, gastrointestinal, hepatic, and renal dysfunction, along with antecedent solid cancer. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease", section on 'Risk factors'.)

Increasing HCT-CI scores are associated with increased mortality and lower survival rates. Patients with scores of ≥3 generally had significantly inferior survival, often half the probability of patients without comorbidities. As an example, a score of 3 could result from a combination of atrial fibrillation with diabetes mellitus and a body mass index of more than 35, or an active infection in a patient with moderate renal disease or a prior diagnosis of breast cancer.

●In an analysis of results in patients with chronic myelomonocytic leukemia (CMML), a score of 3 or higher reduced the probability of long-term survival from 54 to less than 20 percent [53].

●In another study, 391 patients with AML and 186 patients with MDS underwent nonmyeloablative (NMA, 125 patients) or myeloablative conditioning (MA, 452 patients) followed by allogeneic HCT [54]. Patients receiving NMA conditioning were older and were more likely to have high HCT-CI scores, to receive an unrelated transplant, and to have been heavily pretreated. There were higher relapse rates following NMA conditioning. Estimated rates of two-year survival varied by HCT-CI score, disease risk, and conditioning regimen as follows:

•HCT-CI scores of zero to 2 undergoing NMA conditioning with low or high risk disease – 70 and 57 percent, respectively

•HCT-CI scores of zero to 2 undergoing MA conditioning with low or high risk disease – 78 and 50 percent, respectively

•HCT-CI scores of 3 undergoing NMA conditioning with low or high risk disease – 41 and 29 percent, respectively

•HCT-CI scores of 3 undergoing MA condition with low or high risk disease – 45 and 25 percent, respectively

●In an analysis of 372 patients age 60 to 75 years enrolled on prospective clinical trials of NMA allogeneic HCT, HCT-CI predicted survival [25].

●The HCT-CI was validated in a prospective, multicenter study of 1937 patients receiving HCT in Italy from 2008 to 2011 [55]. Estimated two-year nonrelapse mortality rates were 14.7, 21.3, and 27.3 percent for patients with HCT-CI scores of 0, 1 to 2, and ≥3, respectively. Corresponding rates of OS at two years were 56.4, 54.5, and 41.3 percent, respectively.

These are important observations that show that the patient's condition, including comorbidities and performance status, which presumably reflects biologic age, is of equal importance to disease status when assessing a patient's suitability for HCT [56].

HCT-CI/age composite score — The HCT-CI/age composite score incorporates patient age and comorbidities to better predict nonrelapse mortality and OS in patients undergoing allogeneic HCT. To calculate the HCT-CI/age composite score, an additional point is added to the HCT-CI score for patient age 40 years or older. The HCT-CI/age total score could be calculated using an online calculator at www.hctci.org. An HCT-CI/age composite score <3 is associated with estimated survival rates at two years of more than 60 percent [57].

This composite score provides an estimate of the impact of both comorbidities and chronologic age that can be considered along with features of their primary disease when determining eligibility for allogeneic HCT. Importantly, age >40 years has a similar weight as a single underlying comorbidity (eg, diabetes requiring pharmacologic intervention). As such, decisions regarding eligibility for allogeneic HCT cannot be made on chronologic age alone. Older patients, including those >60 years, may well be able to tolerate myeloablative conditioning and allogeneic HCT. In contrast, unacceptably high rates of nonrelapse mortality are seen in patients with significant pretransplant comorbidities, including those younger ≤40 years. (See 'Determining eligibility' below.)

Estimating mortality risk — A number of risk scores are available for estimating mortality risk in patients considering allogeneic HCT. Of these, the three most commonly used assessments are the EBMT risk assessment score for allogeneic transplantation [38], the Pretransplant Assessment of Mortality (PAM) score [58], and the HCT-CI [39,40].

A potentially important issue is that mortality rates after allogeneic HCT have decreased since these tools were created [41,42,59]. A retrospective single center study of 1418 patients who underwent allogeneic HCT from 1993 through 1997 and 1148 patients who were transplanted from 2003 through 2007 reported a significant decrease in nonrelapse mortality (odds ratio [OR] 0.48, 95% CI 0.40-0.57) and overall mortality (OR 0.59, 95% CI 0.52-0.67) in the patients in the latter group [41]. Similar results were reported in a study of 5972 patients younger than age 50 years undergoing myeloablative conditioning and allogeneic HCT for AML in first or second complete remission (CR) [42]. This benefit probably reflects shifts in conditioning regimens, preferred stem cell source, GVHD prophylaxis, and other supportive measures.

The EBMT devised a risk score based on five separate characteristics, which predicted treatment-related mortality and five-year OS following allogeneic HCT for patients with CML (table 4) [38]. This risk score was later validated for CML using separate data from the International Bone Marrow Transplant Registry [47] and subsequently for predicting survival, treatment-related mortality, and death from relapse for those transplanted for hematologic disease in general (ie, CML, AML, ALL, MDS, multiple myeloma [MM], non-Hodgkin lymphoma [NHL], aplastic anemia [AA]) [49]. (See "Hematopoietic cell transplantation in chronic myeloid leukemia", section on 'Prognostic factors'.)

Investigators at Seattle constructed a PAM score incorporating the following eight pretransplant clinical variables (factors associated with a significantly increased risk of death at two years are shown in parentheses) [58]:

●Patient age (>50 years)

●Donor type (unrelated or mismatched related)

●Disease risk (all conditions with the exception of CML in chronic phase, refractory anemia, AA, Blackfan-Diamond syndrome)

●Conditioning regimen (all regimens except nonmyeloablative)

●Serum creatinine (>1.2 mg/dL or >106 micromol/L)

●Serum alanine aminotransferase level (>49 U/L)

●Forced expiratory volume in one second (FEV1; ≤80 percent of normal)

●Carbon monoxide diffusing capacity (<70 percent of normal)

By applying weighting factors derived from a multivariate analysis, they obtained a score ranging from 8 to 50, which was found to predict two-year mortality in early and late validation groups as well as three separate groups of patients with CML, AML, or MDS. As an example, the estimated two-year mortality for patients with CML and the following risk scores were:

●Score 9 to 16 – 14 percent two-year mortality; HR 1.0

●Score 17 to 23 – 32 percent mortality; HR 2.5, 95% CI 1.8-3.6

●Score 24 to 30 – 60 percent mortality; HR 5.8, 95% CI 4.1-8.3

●Score 30 to 44 – 83 percent mortality; HR 12.0, 95% CI 7.6-19

The CCI is commonly used to predict the impact of comorbidities on mortality from various medical conditions including solid malignancies. However, many of the comorbidities assessed in the original CCI are exclusion criteria for allogeneic HCT [44]. As such, a modified HCT-CI was created for this patient population (table 5) [39,40]. This index weighs 17 possible comorbidities for a score ranging from 0 to 29. In a validation cohort of 346 patients undergoing allogeneic HCT, rates of two-year nonrelapse mortality for patients with scores of 0, 1, 2, 3, and 4 or more were 14, 22, 19, 41, and 40 percent, respectively [39]. The HCT-CI has also been used to predict nonrelapse mortality and OS in pediatric patients undergoing a first allogeneic HCT [52].

While future studies will be needed to validate these scoring systems and other available comorbidity scores [39,40,44], including the Karnofsky performance status (table 6) [46], all can serve to help patients better appreciate their mortality risk after allogeneic HCT. (See "Comprehensive geriatric assessment for patients with cancer", section on 'Comorbidity'.)

DONOR AVAILABILITY — The selection of a donor is a critical element contributing to the success of allogeneic HCT. There are several possible sources for these cells:

●An identical twin (syngeneic, human leukocyte antigen [HLA] identical)

●A sibling, relative, or unrelated donor (who can be HLA identical, haploidentical, or mismatched)

●Umbilical cord blood (which can be HLA identical, haploidentical, or mismatched)

General issues involved in donor selection for HCT and the decision as to which donor source to utilize depends to a large degree on the clinical situation and the approaches employed at the individual transplant center. This is discussed in more detail separately. (See "Donor selection for hematopoietic cell transplantation" and "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells".)

RACE, SOCIAL, AND ECONOMIC ISSUES — The final decision to perform an allogeneic HCT must take into account the psychosocial and financial support structure available to the patient. A plan must be in place to care for the patient's usual responsibilities and dependents during the prolonged hospital stay.

The patient's living situation must be taken into consideration. Patients are immunocompromised following allogeneic HCT and are therefore at increased risk for infectious complications, especially if exposed to large crowds. As such, patients who are homeless are unlikely to be able to get the needed care post-transplant. Similarly, transportation costs may become significant for patients who do not live near the transplant center. Some centers require that the patient have available or hire a full-time caregiver during the peritransplant period, and this may be cost prohibitive. (See "Overview of infections following hematopoietic cell transplantation".)

Low socioeconomic status has a negative impact on the success of HCT, based on a retrospective analysis [60]. Low socioeconomic status is correlated with a lower likelihood of health insurance, which may be associated with poor health maintenance, and the need to delay HCT. Postponement or delayed referral may be associated with more advanced disease, although such an explanation was not supported by one analysis [61]. Although many patients have health insurance that would cover allogeneic HCT, even patients with insurance coverage often have a lifetime maximum coverage on insurance contracts, and the cost for allogeneic HCT and subsequent medical care may exceed that maximum [62]. As a result, patients may incur major out-of-pocket expenses, thereby exhausting their savings, or even being forced to sell their home. Expenses are due not only to direct medical costs, but also the need for the patient's partner or other family members or caregivers, serving as caregivers, to take a leave from work, thus incurring a loss of income and the frequent need to rent an apartment close to the medical center to allow for appropriate treatment of the patient. Therefore, caregivers must weigh this investment against the probability of long-term success.

There are disparities in the use of allogeneic HCT among patients of different races and ethnicities [63], and parameters may differ between countries. Studies investigating this association are complicated by the understanding that race is a complex social, cultural, and political construct, rather than a biologic concept. A retrospective analysis, summarizing data from four states, showed that Black American patients were less likely than White American patients to undergo HCT for leukemia or lymphoma [64]. Results of subsequent studies have been mixed, with some confirming this difference and others not showing a difference [65,66]. Factors that may contribute to this include health insurance coverage, educational status, and health literacy.

Retrospective studies have suggested that Black patients may have inferior survival rates following allogeneic HCT [60,61,67]. Examples include:

●An analysis of 2221 allogeneic HCT recipients reported that Black Americans had a significantly higher mortality rate compared with White American patients (HR = 1.65) [61]. Black patients had more severe acute GVHD and higher nonrelapse mortality following related and unrelated allogeneic HCT. A matched cohort analysis showed no correlation of higher mortality with socioeconomic status, suggesting that differences may be the result of currently unidentified genetic polymorphisms.

●In an analysis of 6207 patients undergoing unrelated allogeneic HCT, Black Americans (but not Hispanic Americans or Asian/Pacific Islanders) had inferior overall survival (relative risk [RR] = 1.47) when compared with White patients [60]. In addition, nonrelapse mortality was higher in Black patients (RR = 1.56) and Hispanic patients (RR = 1.30). Across all racial groups, patients in the lowest quartile of median income had worse overall survival (RR = 1.15) and higher risk of nonrelapse mortality (RR = 1.21) than patients with higher incomes. This suggested that inferior transplantation outcome in Black patients is not fully explained by socioeconomic status; other factors, such as genetic polymorphisms and health behavior, may contribute.

Other potential explanations for apparent differences in outcome according to race include a higher rate of comorbid conditions (eg, hypertension and kidney disease, which are prevalent in the Black population) and difficulty in interpreting skin findings (eg, cutaneous GVHD) in patients with dark skin complexion. Studies are needed to address these factors.

DETERMINING ELIGIBILITY — Eligibility for allogeneic HCT varies across countries and institutions and there are few strict rules about who is and who is not an appropriate candidate. Instead, clinical judgment should be used for the majority of patients as to whether the long-term and short-term risks with the transplant outweigh the benefits. Risk factors include and are based on performance status, comorbidity, age, compliance, extent and status of disease, as well as the sensitivity of the tumor to standard therapy. We are currently not able to predict who will develop chronic graft-versus-host disease (GVHD) or other complications, but we must inform patients of those possibilities and their effects on quality of life; risk-averse patients may not want to proceed. All of these factors should be considered when determining appropriateness of allogeneic HCT for an individual. The final decision on transplant eligibility should be made based on a risk-benefit assessment, and the needs and wishes of the patient.

The following general principles apply (table 7) [68]:

●General features associated with superior outcomes following allogeneic HCT include: younger age, disease that is in remission or responsive to therapy with a low risk of disease relapse after HCT, the absence of active infections or other comorbid conditions, the presence of a human leukocyte antigen (HLA)-matched donor, and a good socioeconomic support system.

●General features associated with increased risk of morbidity and mortality following allogeneic HCT include: older age, relapsed or refractory disease or disease with a high risk of relapse after HCT, a history of aggressive chemotherapy, and comorbidities.

Eligibility criteria for allogeneic HCT are not absolute and vary by center. In general, patients are eligible for allogeneic HCT if they meet these criteria (table 8):

●A disease-related indication – An underlying hematologic disease at a stage likely to benefit from allogeneic HCT. (See 'Disease-related indications' above.)

●Functional capacity – An ECOG (Eastern Cooperative Oncology Group) performance status ≤2 or Karnofsky performance status ≥70 (table 2) for a myeloablative HCT or ≥50 for a nonmyeloablative HCT.

●Renal function – Serum creatinine <2 mg/dL (177 micromol/L) or creatinine clearance >50. Transplantation of patients with greater renal impairment differs by center. (See 'Comorbidities' above.)

●Cardiac reserve – Left ventricular ejection fraction (LVEF) >35 percent.

●Pulmonary function – A corrected diffusing capacity of the lungs for carbon monoxide (DLCO) >35 percent.

●Liver function – Patients with frank cirrhosis of the liver are excluded from allogeneic HCT because of excessive mortality and morbidity.

●Support structure – Adequate psychosocial and financial support. (See 'Race, social, and economic issues' above.)

●Other factors – While no specific age cutoff is universally used, many centers limit myeloablative allogeneic HCT to patients <55 years of age, and reduced intensity allogeneic HCT to patients <75 years of age. Patients must be informed of the potential short- and long-term complications (eg, GVHD) and be willing to accept these risks.

Patients with high HCT-CI/age scores (eg, ≥3) might benefit more from nonmyeloablative/reduced intensity conditioning regimens conditional on the status of their primary cancer. Patients with low HCT-CI/age scores (eg, ≤2) may tolerate high dose conditioning even if >60 years of age, particularly if they have high risk primary cancer that may respond to increasing dose intensity. (See 'HCT-CI/age composite score' above.)

Pretransplantation, transplantation-associated, and post-transplantation risk factors cannot be separated completely, as pretransplantation conditions will affect selection of the transplantation protocol, and both may modify post-transplantation events, such as the risk and severity of GVHD and infections.

The morbidity and mortality associated with allogeneic HCT has decreased over the past several decades [41,42]. This is in part related to efforts directed at optimizing patient selection, graft selection, conditioning regimens, and supportive care. We can expect the field to continue to evolve, hopefully eliminating some of the problems that currently exist. Two major obstacles that remain are relapse and GVHD [69,70]; because of the GVHD-associated graft-versus-tumor (GVT) effect, these problems are closely interrelated. As the intensity of transplantation conditioning is reduced, we rely increasingly on donor cell-mediated GVT effects to prevent relapse. As an example, the relationship between GVHD and GVT was investigated in an analysis of 1092 patients receiving a uniform conditioning regimen consisting of fludarabine and low dose total body irradiation [71]. Most relapses occurred early after HCT while patients were on immunosuppression for prevention of acute GVHD. Chronic GVHD, but not acute GVHD, was associated with increased GVT effects. (See "Biology of the graft-versus-tumor effect following hematopoietic cell transplantation".)

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 regimen. Many older adults are not candidates for reduced intensity conditioning. However, allogeneic HCT may be considered for older adults who are biologically younger than their chronologic age if the following are met: they have no significant comorbidities; they have stable social and economic support; their disease is considered "responsive" to treatment; and the patient fully understands the potential complications and long-term sequelae that may ensue [72].

Even younger patients and patients without significant comorbidities, whose disease has been refractory to various chemotherapeutic regimens, are not good candidates for current transplantation strategies except, possibly, as part of clinical trials that address refractory disease with disease-specific approaches. In such settings, it is not known whether allogeneic HCT offers a significant advantage over nontransplantation therapy.

Patients must have a suitable donor, a good social support system, and a secure financial net. They must be well informed, not only about the transplantation process but also about expected or potential post-HCT events, including GVHD and delayed effects, which may become manifest only years after HCT. Treatment with glucocorticoids in particular can have severe side effects in older persons.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

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.)

●Basics topics (see "Patient education: Allogeneic bone marrow transplant (The Basics)")

SUMMARY

●Allogeneic hematopoietic cell transplantation (HCT) can be used to treat patients with a variety of neoplasms, nonmalignant marrow disorders, autoimmune disorders, and inborn errors of metabolism. There is no consensus regarding indications for allogeneic HCT and criteria vary among transplant centers. Patients with a potential disease-related indication for allogeneic HCT should be offered the opportunity to discuss the procedure with a transplantation physician. (See 'Disease-related indications' above.)

●Pretransplant assessment must establish the extent of disease and provide information about comorbidities that are likely to have an impact on transplant-related complications.

Comorbid conditions may affect the choice of conditioning regimen. Importantly, the choice of conditioning regimen is linked to expected toxicities and potential efficacy compared with nontransplant therapies. (See 'Pretransplant assessment' above.)

●HCT consultation – Patients with a disease-related indication for allogeneic HCT should be offered the opportunity to discuss the procedure with a transplantation physician. (See 'HCT consultation' above.)

●Counseling – Patients should have an accurate understanding of the risks and benefits of HCT compared with those of other treatments.

•Advance care planning (eg, living will, power of attorney for health care, life-support instructions) should be completed prior to HCT, to ensure that care is consistent with the patient's wishes. (See 'End-of-life and advance care planning' above.)

•Fertility preservation should be discussed, when appropriate. (See 'Fertility preservation' above.)

●Risk assessment scoring – Patients must have adequate functional capacity, cardiopulmonary, liver and kidney function, limited comorbidities, and adequate psychosocial and financial support (table 7). (See 'Risk assessment scoring systems' above.)

●Impact of individual factors on transplant risk – Factors that impact the efficacy and toxicity of allogeneic HCT include the patient's performance status, comorbidity, age, compliance, extent and status of disease, as well as the sensitivity of the tumor to alternative therapies (table 8). The final decision on transplant eligibility should be made based on a risk-benefit assessment, and the needs and wishes of the patient. (See 'Determining eligibility' above.)