Pioneering experimentation by Jacobson in the 1940s showed that mice were protected from the deleterious effects of radiation if their spleens were shielded with lead foils [2]. The cellular basis of this protection was proved when infusion from marrow and spleen cells conferred a similar protective effect from radiation. Barnes et al. [3] were the first investigators to report treatment of murine leukemia with high-dose radiation followed by infusion of healthy marrow from littermates. The first group to publish results of long-term survival of patients with acute leukemia was from the Seattle group led by Dr. E.D. Thomas [4]. Patients received total body irradiation (TBI) and cyclophosphamide (Cy)–based conditioning and bone marrow grafts from HLA-matched sibling donors. Only 13 of the initial 100 enrolled patients in this trial eventually survived on long-term follow up, but this initial study gave an indication that this form of therapy could be curative in a proportion of leukemia patients. Similar results published by Blume and Beutler from City of Hope [5] confirmed the initial results from Seattle. Another advance in the field was the introduction of calcineurin inhibitors in combination with methotrexate for prevention of GVHD [6, 7]. This combination was associated with significantly lower risk of Grades II–IV aGVHD and improved disease-free survival. Other advancements in the field have been the development of alternative conditioning regimens to TBI/Cy [8], the introduction of prophylactic ganciclovir for cytomegalovirus (CMV) pulmonary infection [9], and the introduction of allele-level HLA typing as a result of improvement in molecular typing techniques, resulting in better-matched transplants [10]. Introduction of RIC regimens has allowed elderly patients and patients with comorbidities who cannot tolerate fully myeloablative regimens to undergo HSCT from matched sibling and unrelated donors, thus expanding access to this curative modality for a wider patient population [11, 12].

Allogeneic HSCT is often the only potentially curative treatment for hematologic malignancies in an advanced stage or for relapsed disease. For early-stage disease such as acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) in first complete remission (CR1), the risk of relapse can be significantly reduced by allogeneic HSCT, but the medical decision is complex and has to be carefully balanced against the risk of transplant-related mortality. In general, allogeneic HSCT is considered for acute leukemia in CR1 with intermediate-risk or high-risk features, or cases that are beyond CR1. In the United States, AML/ALL and myelodysplastic syndromes (MDS) account for 65 % of patients who undergo allogeneic HSCT based on the most recent data provided by the Center for International Blood and Marrow Transplant Research (CIBMTR) [13]. With the introduction of targeted therapy with tyrosine kinase inhibitors for chronic myeloid leukemia (CML), HSCT is reserved only for patients with refractory disease. Refractory non-Hodgkin’s lymphoma, chronic lymphocytic leukemia (CLL), and nonmalignant diseases such as aplastic anemia, and paroxysmal nocturnal hemoglobinuria (PNH) comprise the remainder of indications for allogeneic HSCT.

The American Society of Blood and Marrow Transplantation (ASBMT) established a multiple-stakeholder taskforce to study role of HSCT in established disease states and identify emerging indications where HSCT may potentially be beneficial. This task force came out with a white paper in 2015 with clearly defined indications across disease states where HSCT has been shown to be of clinical benefit based on available clinical trial data. Published systematic evidence reviews or guidelines were used as the basis for recommendations to categorize indications for HSCT in pediatric and adult populations [13]; this comprehensive review of indications for HSCT based on currently available clinical evidence is highly recommended (Table 1.1) (Fig. 1.2) [14].

Hematopoietic stem cells (HSCs) can be found in a variety of human tissues, but for clinical purposes the most commonly used sources are peripheral blood, bone marrow, and umbilical cord blood. Each source has its unique advantages and drawbacks in clinical settings.

The conditioning regimen used in the allogeneic setting has a dual purpose: The therapeutic component is designed to eliminate tumor cells, and the immunosuppressive component is intended to prevent host immune responses from rejecting the transplanted donor cells. The doses of radiation therapy and chemotherapy employed take advantage of the steep dose-response curve that exists for many malignancies. These doses have been established on the basis of the limitations of other nonhematopoietic organs, such as the liver and lungs. The combined chemotherapy agents employed have a nonoverlapping toxicity profile. Based on their intensity, conditioning regimens are divided into myeloablative (MA) regimens, nonmyeloablative regimens, and reduced-intensity conditioning (RIC) regimens. The type of regimen chosen for any individual patient depends on a variety of factors such as age, performance status, disease status, the risk of relapse, and comorbidities.

GVHD can be broadly divided into acute and chronic, based on clinical manifestations rather than on the temporal relation to the time of transplantation. Acute GVHD includes classic acute GVHD (manifested by maculopapular rash, GI symptoms, or cholestatic hepatitis) and persistent, recurrent, or late-onset acute GVHD (occurring more than 100 days after HSCT). Chronic GVHD (cGVHD) comprises classic chronic GVHD, presenting with clinical manifestations attributable to GVHD alone, and overlap syndrome, which has diagnostic or distinctive cGVHD manifestations together with features typical of acute GVHD [31].