Syed Ali Abutalib

Prevention and Treatment of Relapse After HLA-Haploidentical Hematopoietic Cell Transplantation

Recent advances in HLA-haploidentical hematopoietic cell transplantation have been associated with significant reduction in treatment-related mortality; however, disease relapse remains the most common cause of treatment failure as with any other type of allogeneic transplant. While, in general, etiology of relapses after haploidentical transplantation may overlap with other types of allogeneic transplants, unique relapse mechanism with loss of heterozygosity (LOH) is only observed after haploidentical transplantation. Haploidentical transplants may offer augmented graft-versus-tumor (GvT) effect owing to its unique treatment platform, HLA disparity, and in certain situations enhanced natural killer (NK) cell alloreactivity. Preemptive infusions of modified donor lymphocytes, NK cells, or chimeric antigen receptor (CAR) T-cells after haploidentical transplantation are interesting areas of ongoing research to prevent and treat relapses and will also be the focus of this review chapter.

Special care of blood and marrow hematopoietic cell transplant recipient

Hematopoietic cell transplantation (HCT) has evolved into one of the most effective therapeutic modalities for the treatment of neoplastic, immunologic, and genetic disorders in pediatric and adult populations. Careful preclinical scientific studies in the late 1940s and 1950s set the stage for the triumph of clinical HCT. Essentially all eligible patients now have the possibility of undergoing either an autologous or an allogeneic HCT, the latter using a related, histocompatible or partially mismatched donor; matched unrelated adult donor; an umbilical cord blood graft; or a haploidentical donor graft. Regimen intensity now can be adjusted per patient tolerance, e.g., myeloablative conditioning; reduced-intensity conditioning; and nonmyeloablative conditioning. The median age of recipients steadily has increased as well. The necessary vigorous supportive care with blood component transfusions, broad-spectrum antibiotics, and immunosuppressives to prevent or treat graft-versus-host (GvHD) have resulted in cure or significant prolongation of survival in thousands of subjects affected by hematologic malignancies, immunologic disorders, or in-born errors.

Allogeneic Hematopoietic Cell Transplant in β-Thalassemia Major

β-Thalassemia major (BTM) occurs globally and represents a major growing health problem in many countries (Weatherall et al. 2010). BTM involves deficient or absent synthesis of the β-globin chains that constitute hemoglobin molecules and results in chronic hemolytic anemia. Subjects with BTM must adhere to continuous red blood cell replacement program to sustain life but unfortunately therapy comes with undesirable and sometimes life-threatening complications (Fung et al. 2006; Rahav et al. 2006). Without regular transfusions, BTM patients develop tremendous skeleton deformities, hepatomegaly, and splenomegaly from chronic hemolysis with expansion of the hematopoietic system, and as the disease advances, extramedullary hematopoiesis ensues (Sabloff et al. 2011; Angelucci et al. 2010). In addition, the patients usually incur cardiopulmonary problems from chronic anemia and iron overload. The only curative outlet from BTM is via deployment of allo-HCT preferably from HLA-matched sibling donor (MSD) early in the course of the disease. The pre-HCT chronic iron overload (plus its sequelae) and viral infection(s) must be medically managed even after successful allo-HCT in patient now referred to as “ex-thalassemics.” The basic concept behind allo-HCT is to substitute carefully selected HLA-MSD’s CD34+ hematopoietic cells with recipient “thalassemic clone” hematopoietic cells with a goal to achieve effective and sustainable hematopoiesis translated into transfusion independence. Evaluation prior to allo-HCT in younger children ( 17 years of age) patients with BTM usually have organ damage due to higher degree of iron overload with increase incidence of graft rejection compared to younger children (Lucarelli G et al. 1999). Usually, BTM patients older than 17 years of age fall into “high-risk” category and are best served with more complex allo-HCT program, somewhat analogous to the transplant programs employed for younger children with Pesaro class 3 risk group (Lucarelli et al. 1992), although with less intensive conditioning regimen to minimize treatment-related mortality (TRM). It is prudent to acknowledge that in the current era and in the middle-high-income countries, morbidity and mortality of allo-HCT are challenged by the accomplishment of better survival rates with nontransplant approaches but these approaches offer no chance of a cure and in many cases persistence of lifelong complications. The discussion for and against allo-HCT should be carefully conducted in centers with expertise handling patients with BTM.

Looking Toward the Future: Novel Strategies Based on Molecular Pathogenesis of Acute Lymphoblastic Leukemia

There has been exponential growth in our understanding of the pathobiology of acute lymphoblastic leukemia (ALL) leading to the discovery of new prognostic markers and potential new treatment strategies. The inferior treatment outcome observed in adults with ALL in comparison with children with ALL means that new therapeutic approaches are required, preferably based on novel molecular insights. In this concluding article, the important themes that have been discussed in earlier articles are reviewed. Looking toward the future, the authors highlight several of the new therapeutic agents and discuss some of the recently described molecular genetic aberrations that might serve as therapeutic targets for future drug development.