Second solid tumors: screening and management guidelines in long-term survivors after allogeneic stem cell transplantation

With greater numbers of patients surviving long-term after allogeneic stem cell transplantation (SCT), second malignancies have increasingly been recognized. Secondary solid tumors, the most prevalent second malignancies after allogeneic SCT, are reviewed with particular emphasis on recent developments in the pathogenesis, early diagnosis, and treatment of these transplant-related complications.     

Secondary malignancies after hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) offers patients with malignant and nonmalignant diseases the oportunity to pursue life-prolonging therapy. The number of survivors after successful HSCT is continually increasing. However, HSCT can induce tissue and organ damage that occurs not only "on treatment" , but long after completing therapy. Secondary malignancies belong to serious late complications after HSCT. A significant association of certain risk factors with increased likelihood of secondary malignancies after HSCT has been published over the last ten years. Better knowledge of pathogenesis of these complications, their early identification and treatment may contribute to better health outcomes of allogeneic and autologous hematopoietic stem cell transplantation recipients. We review here the incidence and risk factors of secondary malignancies after hematopoietic stem cell transplantation.     

Minor histocompatibility antigens as targets of graft-versus-leukemia reactions

The main advantage of allogeneic stem cell transplantation over autologous stem cell transplantation for hematologic malignancies is the ability to perform cellular immunotherapy using donor-derived immune effector cells after transplantation. In HLA-matched allogeneic stem cell transplantation, the beneficial graft-versus-leukemia effect of donor lymphocytes appears to be caused mainly by alloreactive T cells that are capable of recognizing minor histocompatibility antigens on the malignant cell population from the patient. The tissue distribution of minor histocompatibility antigens probably determines the clinical result of T-cell responses against these antigens. Whereas T cells recognizing broadly expressed antigens cause not only graft-versus-leukemia but also graft-versus-host disease, T cells recognizing minor histocompatibility antigens specifically expressed on hematopoietic cells may mainly eliminate hematopoietic cells from the recipient, including the malignant cells, without affecting donor hematopoiesis or normal nonhematopoietic tissues. Graft-versus-host disease may still occur because of the induction of inflammatory responses against hematopoietic cells in the tissues. Vaccination of patients after transplantation or vaccination of stem cell donors before transplantation using minor histocompatibility antigen-specific peptides, production of minor histocompatibility antigen-specific T cells, and redirection of T-cell specificity by gene transfer of T-cell receptors may be strategies to eradicate specifically the malignant cells after allogeneic stem cell transplantation.     

Treatment of lymphoid malignancies with non-myeloablative stem cell transplantation

The traditional approach to allogeneic hematopoietic stem cell transplantation involves the administration of myeloablative preparative regimens. This form of conditioning is associated with a relatively high incidence of regimen-related toxicity. As a result, candidates for allogeneic stem cell transplantation may be excluded owing to advanced age or co-morbid medical illness. Recently, so-called "non-myeloablative" regimens have been introduced, where less intense conditioning therapy is used in an attempt to reduce regimen-related toxicity. In addition, non-myeloablative transplantation takes advantage of the graft-versus-tumour effect that is characteristic of allogeneic stem cell transplantation. We review the background, available clinical data, and future directions in non-myeloablative stem cell transplantation, and focus on its potential use in the treatment of lymphoid malignancies.     

Treatment of Lymphoid Malignancies with Non-myeloablative Stem Cell Transplantation

The traditional approach to allogeneic hematopoietic stem cell transplantation involves the administration of myeloablative preparative regimens. This form of conditioning is associated with a relatively high incidence of regimen-related toxicity. As a result, candidates for allogeneic stem cell transplantation may be excluded owing to advanced age or co-morbid medical illness. Recently, so-called "non-myeloablative" regimens have been introduced, where less intense conditioning therapy is used in an attempt to reduce regimen-related toxicity. In addition, non-myeloablative transplantation takes advantage of the graft-versus-tumour effect that is characteristic of allogeneic stem cell transplantation. We review the background, available clinical data, and future directions in non-myeloablative stem cell transplantation, and focus on its potential use in the treatment of lymphoid malignancies.     

Allogeneic hematopoietic stem cell transplantation: current issues and future prospects

Major developments have occurred in the field of hematopoietic stem cell transplantation since the first successful transplants from HLA-identical siblings in the late 60's. The formally experimental procedure has become established therapy for a number of congenital or acquired disorders of the hematopoietic system and for chemotherapy-sensitive malignancies. Reduced transplant-related mortality has led to a widening of indications. The present review summarizes current issues and future prospects in allogeneic stem cell transplantation. These issues and prospects will include; stem cell sources, alternative donors, graft-versus-host disease, indications and long-term survival following allogeneic stem cell transplantation.     

Infectious risks and outcomes after stem cell transplantation: are nonmyeloablative transplants changing the picture?

PURPOSE OF REVIEW: Opportunistic infections contribute to morbidity and mortality after myeloablative allogeneic stem cell transplantation. The development of nonmyeloablative or toxicity-reduced conditioning regimens for allogeneic hematopoietic stem cell transplantation might change this picture significantly. These regimens are in general highly immunosuppressive, but effects on myelopoiesis and mucosal toxicities are usually reduced compared with myeloablative hematopoietic stem cell transplantation conditioning regimens. This review summarizes the infectious risks associated with each type of hematopoietic stem cell transplantation conditioning regimen, and presents the results of early clinical studies. RECENT FINDINGS: Although the data are preliminary, the results of recent studies suggest that nonmyeloablative conditioning regimens may decrease the risks of bacterial infections associated with mucosal damage and persistent neutropenia; however, risks for late viral and fungal infections persist during severe graft versus host disease. Results of several case reports and series emphasize that therapeutic outcomes of infections may be improved in patients who receive nonmyeloablative conditioning regimens. SUMMARY: Infectious risks and outcomes after hematopoietic stem cell transplantation appear to be in evolution given the introduction of alternative, nonmyeloablative conditioning regimens. Although infections remain a prominent cause of transplant-related mortality, the timing and types of infections may differ. Further studies are necessary to define appropriate preventative strategies, and to determine whether patients with ongoing infections might benefit from nonmyeloablative hematopoietic stem cell transplantation.     

Prospective study of hepatitis B virus reactivation in patients with hematological malignancies

Background and aim. The best strategy for managing patients with resolved hepatitis B virus infection (HBsAg negative, anti-HBc antibodies positive with or without anti-HBs antibodies) and hematological malignancies under immunosuppressive therapies has not been defined. The aim of this study was to prospectively analyze the risk of hepatitis B virus reactivation in these patients.Material and methods. Twenty-three patients (20 positive for anti-HBs) were enrolled. Eleven patients underwent hematopoietic stem cell transplantation (autologous in 7 cases, allogeneic in 4 cases) while the remaining 12 were treated with immunosuppressive regimens (including rituximab in 9 cases).Results. During the study no patient presented acute hepatitis. However, three anti-HBc/anti-HBs positive patients who were treated with allogeneic hematopoietic stem cell transplantation demonstrated hepatitis B virus reactivation within 12 months from transplant. No one of the remaining patients showed hepatitis B virus reverse seroconversion.Conclusions. Allogeneic hematopoietic stem cell transplantation is a high risk condition for late hepatitis B virus reactivation in patients with resolved infection. Reverse seroconversion seems to be a rare event in anti-HBc/anti-HBs positive patients submitted to autologous hematopoietic stem cell transplantation or systemic chemotherapy with or without rituximab.     

Critical review on non-myeloablative stem cell transplantation (NST)

Allogeneic stem cell transplantation is an established treatment modality for a variety of hematologic malignancies. Unfortunately, it carries a high risk of complications and toxicities related to the intensive preparative regimen which is traditionally used for pre-transplant myeloablation and the graft versus host disease, which may be life threatening. Thus allogeneic stem cell transplantation has been used only for younger patients with a good performance status, excluding many other potential candidates due to advanced age or comorbid conditions. Using reduced intensity preparative regimens for allogeneic stem cell transplantation (non-myeloablative stem cell transplantation (NST)) researchers attempted to overcome these barriers in patients' selection and tried to make hematopoietic stem cell (HSC) transplantation a safer procedure. The well-described graft versus malignancy effect would be the most curative element in this treatment. After more than 5 years of cumulative clinical experience, we know that NST is a feasible treatment option for patients with suboptimal performance status and is mostly effective in slow proliferating malignancies, which gives time for a graft versus malignancy effect to take place. Additionally achievement of stable donor cell engraftment with NSTs provides a platform for adoptive immune cell treatments and is promising for extended indications of stem cell transplantation in the future.     

Allogeneic hematopoietic stem cell transplantation

More than 30 years have passed since the first clinical application of allogeneic bone marrow transplantation to treat hematological diseases. In recent years, the availability of peripheral blood and cord blood as additional sources of stem cells other than bone marrow has expanded the applicability of hematopoietic stem cell transplantation. In addition to differences in stem cell content, immune cells in the grafts from the three sources are different in quality and quantity. As a consequence, transplants from different sources have different kinetics of hematological recovery. Stem cell sources also influence risks for developing graft-versus-host disease. In this paper, we review recently reported results of thus diversified allogeneic hematopoietic, stem cell transplantation.     

Allogeneic hematopoietic stem cell transplantation: complications and results

Acute complications such as veno-occlusive disease of the liver, acute and chronic graft-vs-host disease (GVHD), and infectious conditions remain major obstacles for the success of allogeneic hematopoietic stem cell transplantation (HSCT). Progress in allogeneic HSCT depends on several factors, including the adequate prevention and management of associated complications, advances in the conventional management of diseases currently treated with allogeneic HSCT, expansion of the donor pool, selective control of GVHD, development of more effective preparative regimens to eradicate the neoplastic cell population, characterization of a new generation of hematopoietic growth factors and cytokines, and development of newer techniques for ex vivo manipulation of stem cells. Hematopoietic growth factor-mobilized donor progenitor cells collected from peripheral blood have been shown to be associated with rapid hematopoietic engraftment without an increase in the incidence of acute GVHD compared with allogeneic bone marrow transplantation. Implementation of this approach will enhance donor acceptance, eliminate the risk of general anesthesia, decrease cost, and reduce the risk of infectious complications by reducing the duration of neutropenia. Nonmyeloablative allogeneic stem cell transplantation represents a novel treatment approach that may lead to reduced toxic effects and extended use of this treatment in older patients and in those with malignant and nonmalignant disorders. However, GVHD and disease recurrence remain a challenge. Promising results have been reported in patients with refractory hematologic malignancies and in metastatic renal cell cancer. Because late complications are commonly encountered in patients receiving allogeneic HSCT, lifelong observation is needed.     

Review of “Minitransplantation”: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Nonmyeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation (HSCT) have been developed over the past few years as important alternatives to conventional myeloablative conditioning regimens for older or medically unfit patients with hematologic malignancies, as well as for patients with certain nonmalignant hematologic diseases or renal cell cancer. This review summarizes the biological background, current clinical applications, and indications for this novel treatment approach for treating hematologic malignancies. Historically, allogeneic HSCT has been based on the use of cytotoxic and myeloablative chemotherapy and radiotherapy conditioning regimens that are intended both to eradicate malignancy and to eliminate host hematopoiesis and immune cells. Such a regimen was followed by the infusion of histocompatible donor marrow or peripheral blood stem cells to rescue hematopoiesis. For older patients or for those who had previously been treated with intensive chemotherapy or radiotherapy, the toxicity of myeloablative conditioning was prohibitive. Although most hematologic malignancies occur in older patients, these patients had not been previously eligible for the potentially curative therapy offered by allogeneic HSCT. Based in large part on preclinical studies with the dog model of HSCT and on an improved understanding of the mechanisms for controlling immune modulation, successful development of nonmyeloablative conditioning regimens for clinical use has occurred. Clear evidence of a therapeutic graft-versus-tumor effect mediated by allogeneic T-cells prompted an exploration for HSCT regimens that rely solely on nonmyeloablative immunosuppression to facilitate allogeneic engraftment. In lieu of intensive chemoradiotherapy before transplantation, engrafted donor T-cells are used to accomplish the task of eradicating the host's malignant cells. We review the updated results of an ongoing multicenter study to investigate the safety and efficacy of nonmyeloablative HSCT using a regimen of 2 Gy total body irradiation in patients with advanced hematologic malignancies who were ineligible for conventional myeloablative conditioning. In addition, we review the results of reduced-intensity HSCT trials from other transplantation centers.     

Role of autologous stem cell transplantation in chronic lymphocytic leukemia

Autologous hematopoietic stem sell transplantation is increasingly considered for treatment of patients with high-risk chronic lymphocytic leukemia. Patients not eligible for allogeneic hematopoietic stem cell transplantation with poor prognosis disease, documented chemosensitivity, and a minimal tumor burden at the time of hematopoietic stem cell transplantation can be treated with autologous hematopoietic stem cell transplantation currently using peripheral blood stem cells. Different purging methods to obtain sources of stem cells free of tumor contamination are currently being evaluated. Major concerns are judicious selection of which patients may benefit from this approach, the subsequent risk of relapse of disease, and the long-term risk of development of secondary malignancies, including myelodysplastic syndrome and acute myelogenous leukemia. Recognizing and reducing the risk factors that contribute to relapse and complications of the procedure should improve outcome after autologous hematopoietic stem cell transplantation. With the increasing use, increasing effectiveness, and low treatment-related mortality associated with nonmyeloablative conditioning regimens, the question of whether a patient should be offered autologous or allogeneic hematopoietic stem sell transplantation can be a difficult one. Defining salvage settings for relapse and implementing a tandem autologous/allogeneic hematopoietic stem cell transplantation approach may provide a method to improve outcome for selected patients.     

Allogeneic hematopoietic stem cell transplantation in ovarian carcinoma: results of five patients

Allogeneic hematopoietic stem cell transplantation is often used to treat hematologic malignancies. The efficacy of this procedure is due to both myeloablative conditioning and graft-versus-leukemia (GVL). However, the disadvantages of allogeneic transplantation include graft-versus-host disease (GVHD), relapse from the original tumor, and patient susceptibility to opportunistic infections. Lately, allogeneic transplantation has been developed to treat solid tumors, with the expectation that graft-versus-tumor (GVT), like GVL, will have a significant anti-tumor effect. This effect has been demonstrated in renal carcinomas, and with less evidence in breast cancers. Five patients with malignant ovarian tumors resistant to chemotherapy underwent allogeneic transplantation, four from bone marrow, and one from peripheral blood stem cells. All donors were HLA-identical siblings. One patient received a myeloablative conditioning regimen, while the other four received a non-myeloablative regimen. Two patients received donor lymphocyte infusions (DLI). Four of the patients presented with acute or chronic GVHD associated with tumor regression of at least 50%. These tumor regressions were measured by CA-125 levels and CT scans. The fifth patient died of rapid progression just after transplantation. Of the four transplantation survivors, three received a non-myeloablative regimen which did not seem to reduce treatment effectiveness. While it did reduce toxicity, one of these patients died of GVHD after 127 days. DLI was administered to two patients. These infusions seemed to promote GVHD which was able to control disease progression for one patient and had no apparent effect on the other. Allograft of hematopoietic stem cells might be of interest in ovarian cancer. The results in one patient also suggest that DLI may be an effective immunotherapy, although doses and timing need to be determined. The number of cases presented is small, however, and clinical experience on a larger scale will be required to determine the real clinical efficacy of graft versus cancerous ovarian cells.     

Umbilical cord blood transplantation: Pros, cons and beyond

Large body of clinical and scientific data has been generated since the first cord blood transplantation (CBT) was performed in 1989. Superior immune plasticity of CB grafts, that allows for less stringent HLA matching, is especially valuable in the face of a persistently growing need for unrelated donor (UD) transplants. Limited cell dose remains the main setback of CBT, particularly in adult population. New strategies, such as transplantation with two cord blood units or using non-myeloablative conditioning, have remarkably expanded the availability of CB transplants in adults with hematological malignancies. Clinical trials with in vitro expanded CB-derived stem cells are under way. Currently cord blood is considered a second best choice after matched bone marrow. However, results of recent international studies indicate that in particular clinical settings, such as in children with leukemia, CB may become a frontline hematopoietic stem cell (HSC) source for transplantation. Recent advances in understanding the unique biology of cord blood will further expand indications for its use in different settings, including those beyond hematopoietic stem cells transplantation (HSCT).     

Bone marrow transplantation for the treatment of immune deficiency states

The first successful allogeneic bone marrow transplants were performed in children with severe combined immune deficiency (SCID). Bone marrow transplants for patients with SCID have been in the forefront of clinical bone marrow transplantation including the first successful use of T lymphocyte-depleted haploidentical bone marrow and matched unrelated donors. Successful bone marrow transplantation for most forms of SCID requires only the engraftment of donor lymphoid stem cells; donor hematopoietic stem cell engraftment is usually not required. The Wiskott-Aldrich syndrome was the first genetic disease involving the hematopoietic stem cell to be completely corrected by allogeneic bone marrow transplantation. The successful transplantation of Wiskott-Aldrich syndrome patients demonstrated that agents with adequate anti-lymphoid and hematopoietic stem cell activity were necessary in order to achieve complete donor lymphoid and hematopoietic stem cell engraftment. Initially, total body irradiation and now busulfan are used to ablate recipient hematopoietic stem cells, while cyclophosphamide is used to ablate recipient lymphoid stem cells. No single agent/drug is capable of eliminating both stem cell populations. Histocompatible bone marrow transplantation has a role in the treatment of patients with immune deficiency due to primary defects of the hematopoietic stem cell. The recent introduction of cytokines (gamma-interferon and granulocyte colony stimulating factor) may reduce the need for bone marrow transplantation for myeloid immune deficiency states. Initial attempts to treat patients with the acquired immune deficiency syndrome by bone marrow transplantation were limited by the lack of effective concomitant anti-viral therapy. Bone marrow transplantation for immune deficiency states continues to be in the forefront of human bone marrow transplantation.     

Mesenchymal stromal cells for cell therapy: besides supporting hematopoiesis

Mesenchymal stromal cells (MSC) have attracted the attention of scientists and clinicians due to their self-renewal, capacity for multipotent differentiation, and immunomodulatory properties. Some essential problems remain to be solved before the clinical application of MSC. Platelet lysate (PL) has recently been used as a substitute for FBS in MSC amplification in vitro to achieve clinically applicable numbers of MSC. In addition to promising trials in regenerative medicine, such as in the treatment of major bone defects and myocardial infarction, MSC have shown therapeutic effect other than direct hematopoiesis support in hematopoietic reconstruction. It has been confirmed that MSC promote hematopoietic cell engraftment and immune recovery after allogeneic hematopoietic stem cell transplantation, probably through the provision of cytokines, matrix proteins, and cell-to-cell contacts. Their suppressive effects on immune cells, including T cells, B cells, NK cells and DC cells, suggest MSCs as a novel therapy for GVHD and other autoimmune disorders. These cells thus present as promising candidates for cellular therapy in the fields of regenerative medicine, allogeneic hematopoietic stem cell transplantation, and autoimmune disorders.     

Current status of hematopoietic stem cell transplantation after nonmyeloablative conditioning

PURPOSE OF REVIEW: Allogeneic hematopoietic stem cell transplantation was originally developed as a form of rescue from high-dose chemoradiotherapy, which is given both to eradicate malignancy and provide sufficient immunosuppression for allogeneic engraftment. However, it was observed that allogeneic immunocompetent cells transplanted with the stem cells, or arising from them, mediated therapeutic antitumor effects independent of the action of the high-dose therapy. This was termed a graft-versus-tumor effect. This has prompted the recent development of nonmyeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation that have opened the way to include elderly patients and those with comorbid conditions. RECENT FINDINGS: Recent retrospective studies comparing hematopoietic stem cell transplantation after myeloablative or nonmyeloablative regimens suggested that the use of nonmyeloablative conditioning might be associated with lower transplant-related toxicity, lower nonrelapse mortality, and at least similar intermediate-term progression-free survival. SUMMARY: Hematopoietic stem cell transplantation after nonmyeloablative conditioning might become the procedure of choice also for younger patients. Phase 3 studies are needed to determine outcomes for different diseases and age groups.     

Update on non-myeloablative stem cell transplantation for hematologic malignancies

Allogeneic stem cell transplantation is an established treatment modality for a variety of hematologic malignancies. Unfortunately it carries a high risk of complications and toxicities related to the intensive preparative regimen which is traditionally used for pre-transplant myeloablation and the graft versus host disease, which may be life threatening. Thus allogeneic stem cell transplantation has been used only for younger patients with a good performance status, excluding many other potential candidates due to advanced age or comorbid conditions. Non ablative or reduced intensity preparative regimens for allogeneic stem cell transplantation (NST) have been proposed as a strategy that would allow exploiting the graft versus tumor effect of allogeneic transplantation without the toxicity of myeloablative therapy. After more than five years of cumulative clinical experience, it is now well established that NST is a feasible treatment option for patients with suboptimal performance status and is mostly effective in slow proliferating malignancies, which gives time for a graft versus malignancy effect to take place. Additionally achievement of stable donor cell engraftment with NSTs provides a platform for adoptive immune cell treatments and may allow to extend indications of stem cell transplantation in the future.     

Update on non-myeloablative stem cell transplantation for hematologic malignancies

Allogeneic stem cell transplantation is an established treatment modality for a variety of hematologic malignancies. Unfortunately it carries a high risk of complications and toxicities related to the intensive preparative regimen which is traditionally used for pre-transplant myeloablation and the graft versus host disease, which may be life threatening. Thus allogeneic stem cell transplantation has been used only for younger patients with a good performance status, excluding many other potential candidates due to advanced age or comorbid conditions. Non ablative or reduced intensity preparative regimens for allogeneic stem cell transplantation (NST) have been proposed as a strategy that would allow exploiting the graft versus tumor effect of allogeneic transplantation without the toxicity of myelo-ablative therapy. After more than five years of cumulative clinical experience, it is now well established that NST is a feasible treatment option for patients with suboptimal performance status and is mostly effective in slow proliferating malignancies, which gives time for a graft versus malignancy effect to take place. Additionally achievement of stable donor cell engraftment with NSTs provides a platform for adoptive immune cell treatments and may allow to extend indications of stem cell transplantation in the future.