Refining hematopoietic cell transplant: A concise review

Authors

  • Ashley Rosko,

    1. Department of Medicine and the Case Comprehensive Cancer Center, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio 44106
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  • Hillard M. Lazarus

    Corresponding author
    1. Department of Medicine and the Case Comprehensive Cancer Center, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio 44106
    • University Hospitals Case Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA
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As a result of clinical and translational successes, the field of hematopoietic cell transplantation (HCT) is vast and ever-growing. The authors Spitzer et al. (1), a seasoned and talented group of investigators with a long and productive experience within this subspecialty of hematologic malignancies, succinctly review many important advances. They discuss various patient-, disease-, and treatment-related factors for HCT as a treatment strategy in acute myeloid leukemia (AML). Initially, they provide the reader with a historic perspective for prognostic risk stratification, specifically in terms of cytogenetic and molecular abnormalities of the malignant cells that define tumor behavior. This major scientific advance was not a routine part of clinical practice until about two decades ago, at a time when all patients received essentially the same therapy. Cytogenetic assessment of the AML cells at presentation is imperative for determining prognosis and for postremission therapy planning. A number of studies, including those from Cancer and Leukemia Group B (CALGB), have shown 5 year overall survival rates in younger AML patients of 55% for favorable, 24% for intermediate, and 5% for poor-risk cytogenetics (2). As a result of improvements in technique and interpretation of such cytogenetic findings, including use of FISH, clinicians now are able to recognize and plan treatments according to genetic heterogeneity of AML. More recently, the recognition and implementation of the even more sensitive molecular markers enable clinicians to target patients who would benefit from more intensive chemotherapy strategies. For example, Patel et al. (3) for the Eastern Cooperative Oncology Group (ECOG) have shown that DNMT3A and NPM1 mutations and myeloid-lymphoid leukemia (MLL) translocations predict an improved patient outcome with the use of high-dose daunorubicin-containing therapy (as opposed to standard-dose induction chemotherapy). Formerly, many patients with higher risk disease potentially could be undertreated while others with a better prognosis could be given more intense and often more toxic therapy. This risk-adaptive approach helps practitioners identify and treat those patients with more unfavorable genetic risk profiles and then direct this group to HCT while reserving this potentially curative, but greater-risk HCT therapy in better prognosis patients at a later time in the disease course, that is, after relapse. These companion translational studies explain the results of the ECOG-led, practice-changing high-dose daunorubicin (90 mg/m2/day for 3 days) plus conventional dose cytarabine versus standard-dose daunorubicin (45 mg/m2/day for 3 days) plus conventional dose cytarabine phase III trial. This approach demonstrated a statistically significant improved median overall survival (24 vs. 16 months) for AML patients 60 years of age and younger who received the more-intense induction dosing (4).

In their review, Spitzer et al. (1) also discuss novel and potentially more effective therapies that extend beyond standard chemotherapy. One class of agents is the proteasome inhibitors which target the ubiquitin enzyme complex that plays a critical role in the degradation of many proteins involved in cell cycle regulation and apoptosis. Other classes of drugs that target regulatory pathways fundamental to cancer cell survival include the hypomethylating agents and histone deacetylating drugs. These agents modify and regulate epigenetic, chromatin, and gene expression via methylation of DNA and histone accessibility (5). This class of drugs increasingly plays an important role in helping get more patients to HCT as well as improving patient outcomes when administered after HCT.

Spitzer et al. (1) also inform the reader that the HCT modality has become much more available to patients due to significant advances in understanding the principles important in conditioning, that is, the HCT preparative regimens. Transplant eligibility now includes an older patient population due to the availability of more tolerable HCT chemoradiation therapy conditioning regimens. This approach is divided into three intensity categories: myeloablative, reduced-intensity, and nonmyeloablative conditioning. The definition of these categories is based on the anticipated duration of cytopenias and on the requirement for hematopoietic progenitor cell support (6). The myeloablative (or more traditional) conditioning approach has been associated with a lower relapse rate after HCT but higher treatment-related mortality and is poorly tolerated by older patients and those with preexisting comorbid illnesses. The two less intense conditioning regimens possess somewhat less toxicity and can be applied to subjects who formerly would be excluded from receiving a conventional HCT, for example, the more elderly and those who have conditions such as visceral organ dysfunction. These lesser-intensity approaches, however, are plagued by higher relapse rates and greater engraftment failure rates than the myeloablative conditioning approach. At present, it is not clear which regimen intensity is optimal and on-going phase III studies are in progress to answer this important question.

Formerly, HCT was reserved for those subjects who had histocompatible siblings, whose malignancy was in remission and who were younger in age. HCT has become more available, in part, due to the wider availability of alternate donor graft sources such as matched unrelated adult donors; umbilical cord blood (UCB) grafts; and haploidentical donor grafts. More than 18 million volunteer adult donors or UCB units are available worldwide. HCT outcomes with alternative donor graft sources have improved considerably and in some situations appear to approach those results obtained with histocompatible sibling donor grafts. In part, these findings reflect the use of sophisticated high resolution HLA typing performed on recipients and unrelated donors (7). In general, increasing genetic disparity between patient and donor is associated with a greater risk of graft-versus-host disease (GVHD), a higher transplant-related mortality, and lower overall survival in HCT. UCB grafts, on the other hand, use immunologically naïve cells that have never been exposed to pathogens and are more immunologically tolerant. Use of these cells is associated with less GVHD. Further, the required degree of matching is less and more HCT procedures can be undertaken in those of diverse ethnic or racial backgrounds. Due to many fewer cells present in the UCB product, however, such transplants are associated with prolonged time to marrow recovery and more failed engraftments. Further, use of this graft source precludes the possibility of using a donor lymphocyte infusion, that is, collection and infusion of donor effector (predominately T) cells that can mount a graft-versus-tumor effect (8). Efforts to improve hematopoietic engraftment after UCB HCT include the use of double UCB grafts and ex vivo expansion of UCB units (9). Finally, Spitzer et al. (1) discuss some of their sentinel experiences at the Massachusetts General Hospital and the Dana-Farber Cancer Institute with HLA mismatched/haploidentical allografts. This approach recently has been used more frequently as an alternative cell source for patients who have no other available grafts (10). Haploidentical grafts often are obtained from a parent or child and are readily available, but their use may be complicated by a high risk of graft failure, relapse, and opportunistic infections.

Other obstacles to successful HCT include the persistence of acute and chronic GVHD despite use of potent immunosuppressive agents for prophylaxis and for therapy. GVHD remains a two-edge sword as the allogeneic effect of the donor graft is associated with reduced relapse rates; however, GVHD and the requirement for immunosuppressive therapy may lead to high rates of visceral organ injury, opportunistic infection, engraftment failure, and significant patient morbidity and mortality. Reducing relapses after transplant continues to be an unfulfilled target. Newer strategies include various sophisticated techniques that readily can detect minimal residual disease in acute leukemia patients thought to be in complete (clinical) remission. Such patients then can receive either additional therapy or proceed sooner to HCT.

The field of HCT continues to expand and has been incorporated into many facets of standard patient care. Spitzer et al. (1) eloquently have identified the successes as well as the key challenges and contemporary solutions to this life-saving art applied.

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