Patient and Donor Assessments in Preparation for Transplant

Introduction

Hematopoietic cell transplantation (HCT) remains an essential therapeutic intervention for several high-risk hematologic neoplasms. HCT leads to durable responses and remissions for plasma cell neoplasms and indolent lymphomas and can be curative for aggressive lymphomas, acute leukemias, myelodysplastic syndromes, aplastic anemia, and myeloproliferative neoplasms, among other, less frequent indications. However, HCT, particularly allogeneic HCT (allo-HCT), is often associated with several early and late complications after transplant that are greatly related to certain baseline disease and patient characteristics in both autologous HCT (auto-HCT) and allo-HCT. Furthermore, for allo-HCT, source of graft and donor baseline characteristics can partly influence transplant outcomes. Hence the importance of proper evaluation and selection of both patients and donors to optimize transplant outcomes. It is of importance to note the increased number of transplants over the past decade, particularly for older patients, which is likely related to better supportive care therapies and the successes achieved with reduced intensity conditioning both of which increased the pool of transplant for many patients who were otherwise deemed not eligible in the past. On another note, there remains unfortunately no controlled randomized studies to provide evidence-based medicine regarding the appropriate pretransplant evaluation for patients and donors. Hence, recommendations are mostly derived from aggregate data collected from the experience achieved over time by different transplant centers. The pretransplant evaluation process can be complicated, and transplants should only be performed in highly skilled centers, which at minimum meet the Foundation for the Accreditation of Cellular Therapy (FACT) standards. Several disease- (e.g., disease subtype and indication for HCT, disease status, prior treatments), patient- (e.g., age, performance status, medical comorbidities, psychosocial status), and donor-specific factors are to be considered in the evaluation process in preparation for transplant. We briefly summarize in this chapter the essential aspects needed to be evaluated in preparation for a successful HCT, taking into consideration recommendations from large transplant collaborative groups (the American Society of Blood and Marrow Transplantation [ASBMT] and the European Group for Bone Marrow Transplantation ) and our standard practice at The University of Texas MD Anderson Cancer Center. Stem cell collection procedures (apheresis and bone marrow harvests) from patients (for auto-HCT) and healthy donors (for allo-HCT) are not covered in this chapter.

Disease and Patient Assessments

Indications of HCT and Disease Assessments

The indications for HCT continue to evolve over time greatly impacted not only by advances of treatment (e.g., the introduction of tyrosine kinase inhibitors for chronic myeloid leukemia) but also by disease-risk refinements based on the increasingly used next-generation molecular testing, among others. The indications of auto-HCT and allo-HCT are detailed in other disease-specific chapters in this book, but we list here briefly some of these indications, particularly those agreed on by the ASBMT working group ( Table 5.1 ). Multidisciplinary approaches are recommended when deciding on potential candidates for transplant. In addition to disease subtype, response to treatment prior to transplant and certain disease and patient risk factors are known to influence transplant outcomes and hence should be incorporated into the final decision to determine eligibility for HCT. Key information to be collected about the disease include onset of symptoms, confirm ation of diagnosis (review of outside biopsies, imaging, and other pertinent diagnostic tests), current and prior therapies (chemotherapy, targeted therapy, radiotherapy), complications associated with current and past treatments, and disease status (final response, initial remission, relapse). The disease histology and remission status can be pivotal to determine the type of HCT (auto vs. allo) and for timing of transplant.

Table 5.1

Indication for HCT in Adults

Indication and Disease Status	Autologous HCT	Allogeneic HCT
Acute myeloid leukemia
CR1 Favorable	No	No
CR1 Intermediate	No	Yes *
CR1 Adverse	No	Yes
CR2	No	Yes
Acute promyelocytic leukemia
CR1	No	No
CR2, molecular remission	Yes	Yes *
CR2, not in molecular remission	No	Yes
CR3	No	Yes *
Not in remission	No	Yes *
Relapse after autologous transplant	No	Yes *
Acute lymphoblastic leukemia
CR1, standard risk	No	No
CR1, high risk	No	Yes
CR2	No	Yes
CR3	No	Yes *
Chronic myeloid leukemia	No	Yes (TKI resistant or intolerant disease or blastic CML)
Myelodysplastic syndrome	No	Yes (High-risk disease)
Multiple myeloma	Yes	No
Relapsed DLBCL
Chemosensitive	Yes	No
Refractory	No	Yes *
Relapsed follicular lymphoma
Chemosensitive	Yes	No
Refractory	No	Yes *
Mantle cell lymphoma
CR1	Yes	No
>CR1	Yes	Yes
T-cells lymphomas
CR1	Yes	No
>CR1	Yes	Yes
Relapsed Hodgkin lymphoma
Chemosensitive	Yes	No
Refractory	No	Yes *
Severe aplastic anemia	No	Yes

CML , Chronic myelogenous leukemia; CR , complete remission; DLBCL , diffuse large B-cell lymphoma; HCT , hematopoietic cell transplantation; TKI , tyrosine kinase inhibitor

* Standard-of-care, clinical evidence available where large clinical trials and observation studies are not available.

Given the heterogeneity in transplant outcomes by disease subtype, disease risk index (DRI) ( Table 5.2 ) was developed and is considered a useful tool to predict outcomes based on the disease subtype and disease status at HCT. DRI separates patients into four risk groups with significantly different overall survival and progression free survival. The respective 4-year OS rates for patients with low-risk, intermediate-risk, high-risk, and very high-risk DRI are 64%, 46%, 26%, and 6%. DRI does not, however, account for important patient-specific factors. Furthermore, minimal residual disease (MRD) status is emerging as one of the strong prognostic factors for transplant outcomes. Hence, in addition to disease-specific studies to assess disease status, assessment of MRD should be considered before HCT.

Table 5.2

Disease Risk Index

Risk	Disease	Stage
Low	AML with favorable cytogenetic, CLL, CML, indolent B-cell NHL	CR1, CR ≥ 2, PR1, untreated, CML CP, PR ≥ 2 (if RIC)
Intermediate	AML with intermediate cytogenetic, MDS with intermediate cytogenetic, myeloproliferative neoplasms, MM, HL, DLBCL/transformed indolent B-NHL, MCL, T-cell lymphoma nodal	-
High	AML with adverse cytogenetic, MDS with adverse cytogenetic, T-cell lymphoma extranodal	PR ≥ 2 (if MAC), induction failure, active relapse, CML AP or BP

AML , Acute myeloid leukemia; AP , accelerated phase; BP , blastic phase; CLL , chronic lymphocytic leukemia; CML , Chronic myelogenous leukemia; CP , chronic phase; CR , complete remission; DLBCL , diffuse large B-cell lymphoma; HL , Hodgkin lymphoma; MAC , myeloablative conditioning; MDS , myelodysplastic syndrome; MM , multiple myeloma; NHL , non-Hodgkin lymphoma; OS , overall survival; PR , partial remission; RIC , reduced-intensity conditioning

Initial Visit and Patient Evaluation

Patients are typically referred for consideration of transplant after they already have an established diagnosis by the referring provider and, frequently, have received or will be receiving upfront or salvage treatments for the underlying malignancy. Hence, the patient’s first visit to the transplant center is of critical importance for both the transplant providers and the patients. For the transplant consultants, it is during this visit that they have to decide on the indication of transplant and make a decision for next steps in the evaluation process based on a comprehensive medical history and examination. For patients, most of them are not familiar with the transplant process and would expect to be counseled in details about the rationale/indications of transplant, the logistics of donor search to identify suitable donors (allo-HCT), and the logistics and potential complications associated with conditioning chemotherapy and stem cell infusion. This initial visit to transplant centers will require much preparation, which starts before the patient is seen, to include coordinating care with the referring provider and obtaining all pertinent medical records and tests if any were done at another institution. Furthermore, transplant centers should have written and/or electronic educational materials regarding the transplant process that involves patients and their caregivers, and this important information should be provided to patients either prior (preferred) or on the day of the initial visit.

A comprehensive medical history and physical examination are essential during this initial visit. Key aspects from the medical history, which could impact transplant eligibility and/or intensity of conditioning therapy, include patient age, functional status, constitutional symptoms, disease-specific factors (such as treatments received, complications associated with prior treatments, transfusion history, disease status), medications and allergies, past medical history (cardiac, pulmonary, inflammatory diseases, infections), and family and social history (including family members who can be potential donors, smoking, alcohol, illicit drugs). It is as important to obtain a psychosocial history and refer the patient for a comprehensive psychosocial evaluation after that initial visit. Based on this initial visit, transplant consultants should be able to determine whether transplant is indicated, the type of transplant (auto vs. allo), and the preliminary patient candidacy for transplant. It is noteworthy that only a few absolute contraindications can determine patient's final eligibility during this visit (such as pregnancy, advanced liver cirrhosis), but most others can be difficult to determine during the initial visit. If a decision is made to proceed with HCT, human leukocyte antigen (HLA) typing (for allo-HCT) from the patient should be sent during this initial visit so a formal donor search can be initiated while a comprehensive system-based patient assessment approach is started in preparation for transplant. Below, we outline a systematic-based approach for the essential components required during the evaluation process to determine patients' eligibility for transplant. Table 5.3 summarizes initial sreening procedures to be performed for potential HCT candidates.

Table 5.3

Screening Procedures to Be Performed in HCT Patients

Disease status evaluation, bone marrow aspiration, bone marrow biopsy and MRD status

HLA typing

ABO and Rh blood group antibody screening

CBC, coagulation tests

Blood chemistry: bun, creatinine, electrolyte, liver function test, blood sugar

Infectious screening: see Table 5.5

Chest x-ray, pulmonary function test (include FEV ₁ and DLco)

Electrocardiogram, MUGA scan or echocardiogram for evaluate cardiac function

Nutritional assessment

Dental evaluation, gynecologic evaluation and psychologic/psychiatric evaluation

CBC , Complete blood count; DLco , carbon monoxide diffusing capacity; FEV ₁ , forced expiratory volume in 1 second; HCT , hematopoietic cell transplantation; HLA , human leukocyte antigen; MRD , minimal residual disease; MUGA , multigated acquisition

Patient Age

Age is known for its prognostic role on transplant outcomes, and it has been incorporated into HCT comorbidity index (HCT-CI). There remains no agreed-on upper cut off age where patients are considered ineligible for transplant, but rather age combined with other risk factors (particularly functional status and medical comorbidities) that determine transplant eligibility. Furthermore, disease and transplant type can be important factors. For instance, an increasing number of myeloma patients who are above age 75 years are receiving auto-HCT without detrimental toxicities. For allo-HCT, an increasing number of older patients are being transplanted in more recent years given the advances in supportive care and the adoption of reduced-intensity conditioning regimens. Several groups reported improved transplant outcomes for older patients by using reduced-intensity regimens, likely related to decreased non-relapse mortality (NRM).

Performance Status

Performance status is long known for its role in predicting outcomes in cancer patients, including those who undergo HCT. Two commonly used methods to assess functional status are the Karnofsky performance status (KPS) and the Eastern Cooperative Oncology Group (ECOG) performance status. KPS is a more detailed and practical tool to evaluate functional status and is frequently used in the transplant field. Table 5.4 provides KPS scale and ECOG. Although final eligibility for HCT is not solely determined by KPS score (unless severely compromised with KPS <50), it is frequently used to decide on the intensity of conditioning regimen. For instance, patients with KPS <70 to 80 are usually considered for reduced-intensity regimens.

Table 5.4

Provides Karnofsky Performance Status (KPS) Scale and ECOG

Karnofsky			ECOG
Score	Specific Criteria	Condition	Score	Condition
100	Normal, no complaints, no evidence of disease	Able to carry on normal activity; no special care needed	0	Fully active, able to carry on all predisease performance without restriction
90	Able to carry on normal activity, minor signs or symptoms of disease		0
80	Normal activity with effort, some signs or symptoms of disease		1	Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
70	Care for self, unable to carry on normal activity or to do work	Unable to work, able to live at home and care for most personal needs, varying amount of assistance needed	1
60	Requires occasional assistance from others but able to care for most needs		2	Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
50	Requires considerable assistance from others and frequent medical care		2
40	Disabled, requires special care and assistance	Unable to care for self, requires institutional or hospital care or equivalent, disease may be rapidly progressing	3	Capable of only limited self-care, confined to bed or chair more than 50% of walking hours
30	Severely disabled, hospitalization indicated, but death not imminent		3
20	Very sick, hospitalization necessary, active supportive treatment necessary		4	Completely disabled. Cannot carry on any selfcare. Totally confined to a bed or chair
10	Moribund		4
0	Dead		5	Dead

ECOG , Eastern Cooperative Oncology Group.

Cardiac Evaluation

Assessing cardiac function is essential to all transplant patients. Testing should follow local institutional guidelines, but at a minimum, an electrocardiogram and echocardiography should be obtained to assess for cardiac arrhythmias, ischemic changes, ejection fraction, and cardiac valves. Additional testing, including a cardiac stress test, may be needed according to patient risk factors and results of initial cardiac testing. Baseline ejection fraction of ≥ 45% to 50% is considered reasonable for the HCT candidacy. Patients who have preexisting cardiac conditions are at higher risk for posttransplant complications regardless of their ejection fraction, hence the importance of patient counseling about their increased risk of complications and also the importance of optimizing cardiac status before transplant.

Pulmonary Evaluation

A baseline lung function test is one of the powerful predictors for posttransplant complications and NRM. Various factors may increase the risk of lung toxicity, including conditioning regimen (total body irradiation [TBI], busulfan, carmustine), infections, and noninfectious complications (diffuse alveolar hemorrhage, idiopathic pneumonia syndrome, graft-versus-host disease [GVHD]). Abnormal pulmonary function tests (PFTs), specifically reduced forced expiratory volume in 1 second (FEV ₁ ) and carbon monoxide diffusing capacity (DLco), are associated with increased NRM. Patients with FEV ₁ and/or DLco (adjusted for hemoglobin) <40% to 50% of predicted are generally considered ineligible for HCT. As with age and other medical comorbidities, a composite score of multiple factors rather than one single factor can determine final transplant eligibility.

Hepatic

Checking baseline liver function using liver function tests (LFTs) is indicated for all patients. Additional hepatobiliary testing can be performed if baseline LFTs are abnormal and/or patient has a history suggestive for an underlying liver disease. Patients with cirrhosis are not eligible for transplant given the risk of fulminant hepatic failure. Increased serum aspartate aminotransferase (AST) before transplantation have 3 to 10 times higher risk of developing hepatic sinusoidal obstruction syndrome (SOS). Patients with elevated LFTs >3 to 5 above upper normal are excluded from clinical trials. Obtaining a detailed history of prior treatments is essential, as certain treatments are known to be associated with increased risk of SOS (such as gemtuzumab ozogamicin and inotuzumab ozogamicin), and hence additional preventive measures should be considered for these high-risk patients. Conditioning regimen with certain alkylating agents (busulfan, cytarabine, cyclophosphamide) can be also associated with increased risk of SOS.

Renal Function Evaluation

Renal function test should be obtained before undergoing HCT. Suitable values of proper eligibility criteria are serum creatinine of ≤1.5 mg/dL and a creatinine clearance over 50 to 60 mL/min. However, with the use of reduced-intensity and nonmyeloablative conditioning, creatinine clearance down to 40 mL/min may be permitted. One exception includes patients with plasma cell neoplasms with advanced and end-stage renal disease where auto-HCT with reduced-dose melphalan can be performed relatively safely.

Infections

Infection after transplant is one of the leading causes of NRM, hence the need for an extensive infectious evaluation before transplant, not only to assess transplant eligibility but also to identify high-risk patients who may benefit from antimicrobial prophylaxis. History taking (including travel history) and physical examination should be performed for presence of active infection, vaccination history, prior infections, and infectious complications during previous cancer treatments. Regardless, all patients should be tested for past infections/exposures (as some of these can potentially reactivate after transplant) and to rule out, on rare occasions, an ongoing subclinical infection. Screening should at a minimum include cytomegalovirus (CMV), hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), syphilis, Epstein Barr virus (EBV), herpes simplex virus (HSV), varicella zoster virus (VZV), toxoplasma, human T lymphotropic virus (HTLV)-I/II, and Chagas disease ( Table 5.5 ).

Table 5.5

Infectious Screening in Donor and Patient Before Undergoing HCT

Tests	Donor	Patient
CMV IgG	+	+
Hepatitis B: HBsAg, anti-HBsAg, anti-HBc, Viral load *	+	+
Anti-HCV	+	+
VZV IgG	+	+
HSV IgG	–	+
EBV IgG	+	+
Anti-HIV	+	+
HTLV-1, -2 antibodies	+	+
RPR or VDRL or a TPHA antibody test	+	+
Toxoplasma gondii IgG	+	+
West Nile virus antibodies	+/–	–
Trypanosoma cruzi serology	+	+/–
SARS-CoV-2 PCR on nasopharyngeal swab specimen	+	+

CMV , Cytomegalovirus; EBV , Epstein Barr virus; HCT , hematopoietic cell transplantation; HBsAg , hepatitis B surface antigen; HCV , hepatitis C virus; HIV , human immunodeficiency virus; HSV , herpes simplex virus; HTLV , human T-lymphotropic virus; Ig , immunoglobulin; PCR ; polymerase chain reaction; RPR , rapid plasma reagin; SARS-CoV-2 , severe acute respiratory syndrome coronavirus 2; TPHA , treponema pallidum hemagglutination; VDRL , venereal disease research laboratory test; VZV , varicella zoster virus.

* All patients who are anti-HBc positive but negative for HBsAg and anti-HBs and all donors who are either anti-HBc positive or HBsAg positive should perform viral load testing for hepatitis B virus.

Cytomegalovirus

Presence of CMV disease before undergoing HCT is correlated with a high risk of early CMV disease and death after transplantation. A seronegative patient should have a seronegative donor because of decreasing risk of CMV reactivation after transplant. In a seropositive recipients, seropositive donors might be preferable given the potential protective effect of passive immunity.

Hepatitis B virus

Hepatitis B screening includes checking for hepatitis B surface antigen (HBsAg), and testing for anti-HBsAg and anti-HBc antibodies. Additional testing to include HBV viral load and evaluation for liver disease is to be considered based on initial screening test results. Donors who are either anti-HBc positive or HBsAg positive should also be tested for viral load. Antiviral prophylaxis is generally recommended for patients who are anti-HBc positive; new agents (entecavir or tenofovir) are preferred over lamivudine. Infected donors should be avoided, but if a recipient receives a graft from an infected donor, HBV immunoglobulins should be also considered in additiont to antiviral prophylaxis.

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