Trials Of Hematopoietic Stem Cell Transplantation Research Articles

Graft-Versus-Solid-Tumor Effect: From Hematopoietic Stem Cell Transplantation to Adoptive Cell Therapies.

After allogeneic hematopoietic stem cell transplantation (HSCT), donor lymphocytes may contribute to the regression of hematological malignancies and select solid tumors, a phenomenon referred to as the graft-versus-tumor effect (GVT). However, this immunologic reaction is frequently limited by either poor specificity resulting in graft-versus-host disease or the frequency of tumor-specific T cells being too low to induce a complete and sustained anti-tumor response. Over the past 2 decades, it has become clear that the driver of GVT following allogeneic HSCT is T-cell-mediated recognition of antigens presented on tumor cells. With that regard, even though the excitement for using HSCT in solid tumors has declined, clinical trials of HSCT in solid tumors provided proof of concept and valuable insights leading to the discovery of tumor antigens and the development of targeted adoptive cell therapies for cancer. In this article, we review the results of clinical trials of allogeneic HSCT in solid tumors. We focus on lessons learned from correlative studies of these trials that hold the potential for the creation of tumor-specific immunotherapies with greater efficacy and safety for the treatment of malignancies.

Pitfalls and Successes in Trials in Older Transplant Patients with Hematologic Malignancies.

Recent medical advances have allowed a greater number of older patients to undergo hematopoietic stem cell transplantation (HSCT) and participate in HSCT trials. In this review, we outline recent advances in HSCT that have made this possible, general setbacks, and their effects on the landscape of HSCT trials in older adults. Reduced-intensity conditioning regimens and a more physiological approach to transplant candidate selection have given older patients an opportunity to participate in HSCT trials. However, difficulties in allogeneic donor selection, post-transplant complications, and the misalignment of trial goals with patient goals may pose challenges for future trial recruitment and success. While increasing amounts of evidence show that older adults may benefit from participation in HSCT trials, clinicians, investigators, and patients must carefully weigh the benefits with potential repercussions.

Prognostic Impact of a Modified European LeukemiaNet (ELN) Genetic Risk Stratification in Predicting Outcomes for Adults with Acute Myeloid Leukemia (AML) Undergoing Allogeneic Hematopoietic Stem Cell Transplantation (HCT). a Center for International Blood and Marrow Transplant Research (CIBMTR) Analysis for the CIBMTR Acute Leukemia Writing Committee

Prognostic Impact of a Modified European LeukemiaNet (ELN) Genetic Risk Stratification in Predicting Outcomes for Adults with Acute Myeloid Leukemia (AML) Undergoing Allogeneic Hematopoietic Stem Cell Transplantation (HCT). a Center for International Blood and Marrow Transplant Research (CIBMTR) Analysis for the CIBMTR Acute Leukemia Writing Committee

What Prompts Parents of Children with Sickle Cell Disease to Consider a Curative Option in This Era of Novel Hematopoietic Cell Donor Sources and Gene Modification?

Background Hematopoietic stem cell transplantation (HCT) from matched sibling donors has been associated with excellent outcomes in patients with SCD but has been limited by the availability of HLA identical related donors and acceptability of HCT. Improved outcomes and the availability of clinical trials of HCT from haploidentical related donors and HLA matched unrelated donors and autologous hematopoietic progenitor cells modified by gene addition and gene editing has expanded the applicability of HCT for SCD. The objective of this study was to determine from the perspective of the parent about what motivates parents of a child with SCD to consider HCT/gene therapy in the setting of alternate donors and gene modification? Methods We conducted semi-structured qualitative interviews with at least one parent of a child with SCD who had scheduled a BMT consultation. Interviews were conducted pre-consultation and a second time post-consultation Audio recordings were transcribed verbatim. Data were analyzed using open and axial coding stages of grounded theory methodology. Results We interviewed 22 parents and one caregiver (18 mothers, 2 fathers, and 1 grandmother). Six participants were only available for the post-consultation interview. The median age of caregivers was 43 years (range 31 to 64 years.) Median age of the child was 13 years (range 14 months to 18 years). Three main themes relevant to the research question emerged. First, the child's quality of life, limitations placed by the disease and the concern for future potential to live independently because of SCD complications. Second, knowledge acquired by parents about curative options through multiple sources. Third, recent disease exacerbation or new SCD complication. Conclusion These results provide insight into the factors that prompt parents of children with SCD to HCT and gene therapy and have the potential to inform efforts to raise awareness about curative options for patients with SCD.

Hematopoietic Stem Cell Transplantation From a Related Donor with Human Leukocyte Antigen 1-Antigen Mismatch in the Graft-Versus-Host Direction Using Low-dose Anti-thymocyte Globulin

Hematopoietic stem cell transplantation (HSCT) from a related donor with an human leukocyte antigen (HLA) 1-antigen mismatch without in vivo T cell depletion is associated with an elevated risk of severe, acute, and chronic graft-versus-host (GVH) disease (GVHD) and poor survival. Therefore, we conducted a multicenter phase II trial of HSCT using low-dose anti-thymocyte globulin (ATG, thymoglobulin). We recruited patients aged 16–65 years with leukemia, myelodysplastic syndrome, or lymphoma who planned to receive HSCT from a related donor with HLA 1-antigen mismatch in the GVH direction at the HLA-A, -B, or -DR locus. Pretransplantation ATG was administered with standard GVHD prophylaxis consisting of tacrolimus and methotrexate. Thirty-eight patients were eligible for the analysis. The 1-year GVHD-free relapse-free survival (GRFS) was 47%. The 3-year overall survival (OS) was 57%. Age of less than 50 years was associated with better OS. OS in patients with high/very high refined disease risk indexes (rDRIs) was comparable to that in those with low/intermediate rDRIs. The 100-day cumulative incidences of grades II–IV and III–IV acute GVHD were 45% and 18%, respectively. HSCT from a related donor with two allele mismatches showed higher incidences of grades II–IV and III–IV acute GVHD. Three-year cumulative incidences of moderate to severe or severe chronic GVHD were 13% and 3%, respectively. HSCT from a related donor with one locus mismatch at the antigen level using low-dose ATG showed lower incidences of acute and chronic GVHD, which led to acceptable GRFS, OS, relapse, and nonrelapse mortality.

Infectious Risk after Allogeneic Hematopoietic Cell Transplantation Complicated by Acute Graft-versus-Host Disease

The occurrence of infections after allogeneic hematopoietic stem cell transplantation (HCT) is nearly universal. However, the relationship between infections and graft-versus-host disease (GVHD) is complex and attribution of infectious-related mortality is highly inconsistent, making comparison of infectious complication rates across allogeneic HCT clinical studies difficult. We categorized infectious complications from diagnosis or 1 year before HCT (whichever occurred later) through 2 years after HCT according to timing, frequency, causative organism, severity, and contribution to mortality for 431 consecutive patients who underwent allogeneic HCT from 2008 to 2011. We then assessed the contribution of risk factors, such as the frequency of pre-HCT infections and post-HCT GVHD, on post-HCT infection frequency and severity. We found that each pre-HCT bacterial infection/year leads to an additional 2.15 post-HCT bacterial infection/year (P = .004). Pre-HCT viral and fungal infections were not predictors for post-HCT infections. Acute GVHD (aGVHD) significantly increased the risk of developing life-threatening (hazard ratio [HR], 1.97; 95% confidence interval [CI], 1.33 to 2.90) and fatal (HR, 2.8; 95% CI, 1.10 to 7.08) infections. Furthermore, patients who develop aGVHD experienced ~60% more infections than patients who never develop aGVHD. Quantification of infection frequency and severity for patients with and without GVHD may facilitate comparison of infectious outcomes across allogeneic HCT trials.

Allogeneic stem cell transplantation for sickle cell disease.

As the safety and availability of allogeneic hematopoietic stem cell transplantation (HSCT) have improved, this procedure is becoming a viable option for nonmalignant conditions such as sickle cell disease (SCD). There are very few treatment options available for SCD, and even with optimal care SCD patients still suffer from a myriad of comorbidities to multiple organ systems and have a decreased life span. In this review, we will summarize results from trials of HSCT for children or adults with SCD using a variety of graft sources as well as conditioning and graft-versus-host disease prophylaxis regimens, and discuss the unique challenges that arise in these patients. AlloHSCT for SCD has been performed on small numbers of patients at multiple centers around the world using several different transplant platforms, and early outcomes are encouraging. Overall survival is excellent, although graft failure remains a challenge. As alloHSCT becomes safer and more widely available, the procedure should be considered for patients with severe disease phenotypes in whom the potential benefits of transplantation outweigh the complications from the disease. AlloHSCT has been shown to reverse or at least halt the progression of end-organ damage secondary to SCD. More research is needed to understand the mechanisms underlying graft failure in SCD recipients, as well as to understand the biopsychosocial underpinnings of persistent pain in the posttransplant period to maximize the benefit from the transplant procedure.

Transplante de células-tronco hematopoéticas em doenças reumáticas parte 1: experiência internacional

Nesta revisão, discutem-se os resultados dos transplantes de células-tronco hematopoéticas (TCTH) para doenças reumáticas graves e refratárias à terapia convencional realizados no exterior. Revêem-se brevemente as bases clínicas e experimentais para a realização desses transplantes e os resultados internacionais obtidos em lúpus eritematoso sistêmico (LES) (33/50 remissões completas no registro europeu, com dez recidivas posteriores e 12 óbitos; 41/45 remissões duradouras em um centro americano, com dois óbitos pós-mobilização e quatro óbitos pós-transplante), artrite reumatóide (AR) do adulto (58/73 remissões parciais com 85% de recidivas posteriores e apenas um óbito no registro europeu), artrite idiopática juvenil (AIJ) (18/34 remissões duradouras e cinco óbitos no registro europeu), esclerose sistêmica (ES) (46/50 respostas em um estudo europeu multicêntrico, com 35% de recidivas e 23% de mortalidade, enquanto num estudo americano, houve quatro óbitos e duas pneumopatias progressivas dentre 19 pacientes e melhora cutânea e da qualidade de vida em todos os sobreviventes) e em uma miscelânea de outras doenças, incluindo as vasculites (9/15 respostas completas no registro europeu). Conclui-se que, na experiência internacional, o TCTH autólogo induz remissões prolongadas na maioria das doenças graves e refratárias em que foi utilizado, com exceção da AR do adulto, justificando o início de estudos prospectivos randomizados comparando-o com a terapia convencional otimizada.

Reassessment of Current Measures for Collecting Safety Data in Autologous Hematopoietic Stem Cell Transplantation (HSCT) for Non-Hodgkin's Lymphoma (NHL).

Background and Purpose:Clinical trials on HSCT differ from those on conventional chemotherapy, which focus on a single drug, with regard to the inevitable combined use of multiple anticancer drugs in preparative regimens, and the variety of medications required for intensive supportive therapies. This makes the collection and analysis of data regarding adverse events and concomitant drugs, quite labor- and cost-intensive. Moreover, quality assurance and quality control practices to assure the reliability of the obtained data can be very difficult. Nevertheless, safety data handling procedures have not yet been validated in the field of HSCT. Thus, we examined the feasibility of current maneuvers in correlation with the clinical outcome in an autologous setting.Methods:In 41 patients with NHL who had bone marrow infiltration and who received autologous HSCT in 12 institutes between 1999 and 2002, all adverse events and information regarding concomitantly used drugs were analyzed.Results:Over a median follow-up of 90 days, 1,506 adverse events (37 events/person) were observed, and 3,426 concomitant drugs (84 drugs/person) were used. Ninety-one percent of the adverse events occurred in the early phase of transplantation (< day 30), with 80% caused by regimen-related toxicities (RRT), which was considered to be a characteristic of HSCT compared to conventional chemotherapy. The severity scores of adverse events were 46%, 23%, 17%, and 13%, for NCI-CTC grade I, II, III, and IV, respectively. No particular procedure or treatment was required for 65% of the grade I adverse events, and none progressed to more severe problems or patient death. Moreover, we found that the decision to report or not totally depended upon the widely variable individualized assessment by physicians, which makes reliable statistical analysis meaningless. Sixty-four percent of the concomitantly used drugs (2,204 of 3,426) were related to the treatment of RRT, and 51% (1,121 of 2,204) were used for prophylaxis of RRT. Moreover, 59% (2,007 of 3,426) were used in patients who had no adverse events: 20% of these (402/2,007) were over-the-counter drugs, and 16% (322/2,007) were inactive, such as injection solvents and iv solutions used simply to keep the line open, etc. These findings highlight the characteristics of HSCT compared to conventional chemotherapy.Conclusion:These findings clearly show the urgent need for a more efficient yet reliable data collection system in clinical trials of HSCT. We suggest that this can be accomplished by excluding the handling of grade I adverse events without the need of treatment and the less-significant information about concomitant drugs. In this study, we estimated that such modification would reduce the number of reported adverse events to 70% (1,055/1,506) and that of concomitant drugs to 78% (2,702/3,426). Hence, substantial reductions in cost and labor can be expected in clinical trials, with a greater focus on reliable safety assessment.

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.

Induction of tolerance in autoimmune diseases by hematopoietic stem cell transplantation: getting closer to a cure?

AbstractHematopoietic stem cells (HSCs) are the earliest cells of the immune system, giving rise to B and T lymphocytes, monocytes, tissue macrophages, and dendritic cells. In animal models, adoptive transfer of HSCs, depending on circumstances, may cause, prevent, or cure autoimmune diseases. Clinical trials have reported early remission of otherwise refractory autoimmune disorders after either autologous or allogeneic hematopoietic stem cell transplantation (HSCT). By percentage of transplantations performed, autoimmune diseases are the most rapidly expanding indication for stem cell transplantation. Although numerous editorials or commentaries have been previously published, no prior review has focused on the immunology of transplantation tolerance or development of phase 3 autoimmune HSCT trials. Results from current trials suggest that mobilization of HSCs, conditioning regimen, eligibility and exclusion criteria, toxicity, outcome, source of stem cells, and posttransplantation follow-up need to be disease specific. HSCT-induced remission of an autoimmune disease allows for a prospective analysis of events involved in immune tolerance not available in cross-sectional studies.

Induction of tolerance in autoimmune diseases by hematopoietic stem cell transplantation: getting closer to a cure?

Hematopoietic stem cells (HSCs) are the earliest cells of the immune system, giving rise to B and T lymphocytes, monocytes, tissue macrophages, and dendritic cells. In animal models, adoptive transfer of HSCs, depending on circumstances, may cause, prevent, or cure autoimmune diseases. Clinical trials have reported early remission of otherwise refractory autoimmune disorders after either autologous or allogeneic hematopoietic stem cell transplantation (HSCT). By percentage of transplantations performed, autoimmune diseases are the most rapidly expanding indication for stem cell transplantation. Although numerous editorials or commentaries have been previously published, no prior review has focused on the immunology of transplantation tolerance or development of phase 3 autoimmune HSCT trials. Results from current trials suggest that mobilization of HSCs, conditioning regimen, eligibility and exclusion criteria, toxicity, outcome, source of stem cells, and posttransplantation follow-up need to be disease specific. HSCT-induced remission of an autoimmune disease allows for a prospective analysis of events involved in immune tolerance not available in cross-sectional studies.