Lauri Burroughs

Transplantation Outcomes for Severe Combined Immunodeficiency, 2000–2009

BACKGROUND The Primary Immune Deficiency Treatment Consortium was formed to analyze the results of hematopoietic-cell transplantation in children with severe combined immunodeficiency (SCID) and other primary immunodeficiencies. Factors associated with a good transplantation outcome need to be identified in order to design safer and more effective curative therapy, particularly for children with SCID diagnosed at birth. METHODS We collected data retrospectively from 240 infants with SCID who had received transplants at 25 centers during a 10-year period (2000 through 2009). RESULTS Survival at 5 years, freedom from immunoglobulin substitution, and CD3+ T-cell and IgA recovery were more likely among recipients of grafts from matched sibling donors than among recipients of grafts from alternative donors. However, the survival rate was high regardless of donor type among infants who received transplants at 3.5 months of age or younger (94%) and among older infants without prior infection (90%) or with infection that had resolved (82%). Among actively infected infants without a matched sibling donor, survival was best among recipients of haploidentical T-cell-depleted transplants in the absence of any pretransplantation conditioning. Among survivors, reduced-intensity or myeloablative pretransplantation conditioning was associated with an increased likelihood of a CD3+ T-cell count of more than 1000 per cubic millimeter, freedom from immunoglobulin substitution, and IgA recovery but did not significantly affect CD4+ T-cell recovery or recovery of phytohemagglutinin-induced T-cell proliferation. The genetic subtype of SCID affected the quality of CD3+ T-cell recovery but not survival. CONCLUSIONS Transplants from donors other than matched siblings were associated with excellent survival among infants with SCID identified before the onset of infection. All available graft sources are expected to lead to excellent survival among asymptomatic infants. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Comparison of Outcomes of HLA-Matched Related, Unrelated, or HLA-Haploidentical Related Hematopoietic Cell Transplantation following Nonmyeloablative Conditioning for Relapsed or Refractory Hodgkin Lymphoma

We compared the outcome of nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) for patients with relapsed or refractory Hodgkin lymphoma (HL) based on donor cell source. Ninety patients with HL were treated with nonmyeloablative conditioning followed by HCT from HLA-matched related, n=38, unrelated, n=24, or HLA-haploidentical related, n=28 donors. Patients were heavily pretreated with a median of 5 regimens and most patients had failed autologous HCT (92%) and local radiation therapy (83%). With a median follow-up of 25 months, 2-year overall survivals, progression-free survivals (OS)/(PFS), and incidences of relapsed/progressive disease were 53%, 23%, and 56% (HLA-matched related), 58%, 29%, and 63% (unrelated), and 58%, 51%, and 40% (HLA-haploidentical related), respectively. Nonrelapse mortality (NRM) was significantly lower for HLA-haploidentical related (P=.02) recipients compared to HLA-matched related recipients. There were also significantly decreased risks of relapse for HLA-haploidentical related recipients compared to HLA-matched related (P=.01) and unrelated (P=.03) recipients. The incidences of acute grades III-IV and extensive chronic graft-versus-host disease (aGVHD, cGVHD) were 16%/50% (HLA-matched related), 8%/63% (unrelated), and 11%/35% (HLA-haploidentical related). These data suggested that salvage allogeneic HCT using nonmyeloablative conditioning provided antitumor activity in patients with advanced HL; however, disease relapse/progression continued to be major problems. Importantly, alternative donor stem cell sources are a viable option.

Long-term outcome and lineage-specific chimerism in 194 patients with Wiskott-Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980-2009: an international collaborative study.

In this retrospective collaborative study, we have analyzed long-term outcome and donor cell engraftment in 194 patients with Wiskott-Aldrich syndrome (WAS) who have been treated by hematopoietic cell transplantation (HCT) in the period 1980- 2009. Overall survival was 84.0% and was even higher (89.1% 5-year survival) for those who received HCT since the year 2000, reflecting recent improvement of outcome after transplantation from mismatched family donors and for patients who received HCT from an unrelated donor at older than 5 years. Patients who went to transplantation in better clinical conditions had a lower rate of post-HCT complications. Retrospective analysis of lineage-specific donor cell engraftment showed that stable full donor chimerism was attained by 72.3% of the patients who survived for at least 1 year after HCT. Mixed chimerism was associated with an increased risk of incomplete reconstitution of lymphocyte count and post-HCT autoimmunity, and myeloid donor cell chimerism < 50% was associated with persistent thrombocytopenia. These observations indicate continuous improvement of outcome after HCT for WAS and may have important implications for the development of novel protocols aiming to obtain full correction of the disease and reduce post-HCT complications.

Shwachman Diamond Syndrome – a review of the clinical presentation, molecular pathogenesis, diagnosis, and treatment

Shwachman-Diamond syndrome is a rare autosomal-recessive, multisystem disease characterized by exocrine pancreatic insufficiency, impaired hematopoiesis, and leukemia predisposition. Other clinical features include skeletal, immunologic, hepatic, and cardiac disorders. This article focuses on the clinical presentation, diagnostic work-up, clinical management, and treatment of patients with Shwachman-Diamond syndrome.

Stable hematopoietic cell engraftment after low-intensity nonmyeloablative conditioning in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

BACKGROUND Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is characterized by severe systemic autoimmunity caused by mutations in the forkhead box protein 3 (FOXP3) gene. Hematopoietic cell transplantation is currently the only viable option for long-term survival, but patients are frequently very ill and may not tolerate traditional myeloablative conditioning regimens. OBJECTIVE Here we present the outcome of hematopoietic cell transplantation using a low-intensity, nonmyeloablative conditioning regimen in 2 patients with IPEX syndrome and significant pretransplant risk factors. METHODS Two high-risk patients with IPEX syndrome received HLA-matched related bone marrow or unrelated peripheral blood stem cell grafts following conditioning with 90 mg/m(2) fludarabine and 4 Gy total body irradiation. Postgrafting immunosuppression consisted of mycophenolate mofetil and cyclosporine. Immune reconstitution and immune function was evaluated by measurement of donor chimerism, regulatory T-cell numbers, absolute lymphocyte subsets, and T-cell proliferation assays. RESULTS Both patients experienced minimal conditioning toxicity and successfully engrafted after hematopoietic cell transplantation. With a follow-up of 4 and 1 years, respectively, patients 1 and 2 have full immune function and normal FOXP3 protein expression. CONCLUSION A low-intensity, nonmyeloablative conditioning regimen can establish stable engraftment and correct the life-threatening immune deficiency and enteropathy of IPEX syndrome despite the presence of comorbidities that preclude conventional hematopoietic cell transplantation.

Intensive postgrafting immune suppression combined with nonmyeloablative conditioning for transplantation of HLA-identical hematopoietic cell grafts: results of a pilot study for treatment of primary immunodeficiency disorders

This study was designed to determine the safety of a nonmyeloablative regimen in patients with primary immunodeficiency disorders (PID) who had infections, organ dysfunction or other risk factors that precluded conventional hematopoietic cell (HC) transplant. Fourteen patients received HLA-matched related (n=6) or unrelated (n=8) HC grafts from marrow (n=8), peripheral blood mononuclear cells (n=5) or umbilical cord blood (n=1), either without conditioning (n=1), or after 200 cGy total body irradiation alone (n=3) or with 90 mg/m2 fludarabine (n=10). All patients were given postgrafting immunosuppression with mycophenolate mofetil and cyclosporine. Mixed (n=5) or full (n=8) donor chimerism was established in 13 patients, and one patient rejected the graft. Eight patients developed acute grade III (n=1) and/or extensive chronic GVHD (n=8). With a median follow-up of 4.9 (range, 0.7–8.1) years, the 3-year overall survival, event-free survival and transplant-related mortality were 62, 62 and 23%, respectively. Correction of immune dysfunction was documented in 8 of 10 patients with stable donor engraftment. These preliminary results indicated that this approach was associated with stable donor engraftment and a low incidence of early mortality and, thus, can be considered for certain high-risk patients with PID. However, there was a risk of GVHD, which is an undesirable outcome for this group of patients.

Prognostic relevance of ‘early‐onset’ graft‐versus‐host disease following non‐myeloablative haematopoietic cell transplantation

We retrospectively analysed outcomes among 395 patients with haematologic malignancies who underwent non‐myeloablative haematopoietic cell transplantation (HCT) from human leucocyte antigen (HLA)‐matched related (n = 297) or unrelated donors (n = 98) in order to identify a possible correlation between the time of onset of graft‐versus‐host disease (GVHD) and survival. The non‐myeloablative regimen consisted of 2 Gy total body irradiation with or without fludarabine, followed by postgrafting immunosuppression with mycophenolate mofetil and cyclosporine. The cumulative incidences of grades II–IV acute GVHD and extensive chronic GVHD were 45% and 47%, respectively, with related donors, and 68% and 68%, respectively, with unrelated donors. High‐dose corticosteroid treatment for acute or chronic GVHD was started at a median of 79 (range, 8–799) days and 30 (range, 5–333) days after transplantation from related and unrelated donors respectively. With related donors, the cumulative incidence of non‐relapse mortality among patients with GVHD was 55% at 4 years when prednisone was started before day 50 (n = 72), compared with 29% when treatment was started after day 50 (n = 115) (P < 0·001). With unrelated donors, time to onset of treatment for GVHD was not associated with survival. Patients with early‐onset GVHD after non‐myeloablative HCT from HLA‐identical related donors might benefit from intensified primary immunosuppressive treatment.

Low-intensity allogeneic hematopoietic stem cell transplantation for myeloid malignancies: separating graft-versus-leukemia effects from graft-versus-host disease.

Purpose of reviewOver the past several years, significant advances in allogeneic hematopoietic cell transplantation (HCT), specifically the development of nonablative and reduced-intensity conditioning regimens, have enabled the extension of transplantation to include older or medically infirm patients with myeloid malignancies. The regimens rely largely on graft-versus-leukemia effects rather than high-dose therapy to eliminate malignant cells. Studies have demonstrated that the regimens allow sustained engraftment with relatively low transplant-related mortality. However, conclusions regarding the ultimate efficacy of these regimens for myeloid malignancies have been limited, given the small numbers of patients who have had transplants so far. This review summarizes recent studies of nonablative or reduced-intensity regimens for patients with myeloid malignancies (acute and chronic myelogenous leukemia, myelodysplastic syndrome, and myeloproliferative disorders). In addition, this review evaluates what is currently known regarding the association of graft-versus-leukemia responses and graft-versus-host disease (GVHD). When possible, graft-versus-leukemia responses are highlighted in the articles discussed. Recent findingsThis review covers six articles and four abstracts that have been published since September 2003 on patients with myeloid malignancies who received HCT following nonmyeloablative or reduced-intensity conditioning. Due to the heterogeneity of the conditioning and GVHD prophylaxis regimens, direct comparisons between studies are difficult. However, these studies have demonstrated encouraging overall survivals (30 to 74%), disease-free/event-free or progression-free survivals (19 to 62%), and nonrelapse mortalities (15 to 55%). In addition, these studies demonstrated evidence for graft-versus-leukemia responses. However, relapse and progressive disease continued to be problems, particularly in patients with large tumor burdens at time of HCT. SummaryOver the past 10 years, significant advances have been made in the field of transplantation. Nonmyeloablative and reduced-intensity HCT have promised patients with hematologic and nonhematologic malignancies potential cures. However, disease relapse and nonrelapse mortality, mainly from GVHD and its therapy, continue to be problems. Future studies are needed to increase our understanding of GVHD and graft-versus-leukemia responses, which will greatly improve outcome. In addition, a better understanding of minor histocompatibility antigens may lead to more targeted immunotherapy and enhance the precision and success of transplantation.

Extending Postgrafting Cyclosporine Decreases the Risk of Severe Graft-versus-Host Disease after Nonmyeloablative Hematopoietic Cell Transplantation

Background. It is unknown whether the duration of systemic immunosuppressive treatment after allogeneic nonmyeloablative hematopoietic cell transplantation (HCT) might influence the incidence, severity, timing, and/or corticosteroid-responsiveness of graft-versus-host disease (GVHD). Methods. We retrospectively analyzed outcomes among 185 patients with hematologic malignancies who were given grafts from HLA-matched related donors following conditioning with 2 Gy total body irradiation alone or in combination with fludarabine between December 1998 and March 2003. Postgrafting immunosuppression consisted of mycophenolate mofetil (days 0–27) in combination with 3 different cyclosporine (CSP) regimens: taper from (A) days 35 to 56 (n=107), (B) days 56 to 77 (n=35), and (C) days 56 to 180 (n=43). Results. The overall incidences of grades II–IV and III–IV acute GVHD, and extensive chronic GVHD were 52%, 13%, and 56%, respectively. The duration of CSP prophylaxis did not significantly influence the overall rate of acute GVHD (grade II–IV), extensive chronic GVHD, or non-relapse mortality. However, prolonged administration of CSP (group C) was associated with a significantly decreased hazard of grades III–IV acute GVHD (HR 0.2, 95% CI [0.04, 0.9]) and with an increased likelihood of discontinuing all systemic immunosuppression (HR 2.4, 95% CI [1.1, 5.2]) when compared to the shortest course of CSP (group A). Conclusion. Longer CSP duration decreased the risk of severe GVHD and increased the likelihood of discontinuing all systemic immunosuppression after nonmyeloablative HCT with HLA-matched related grafts.

Treosulfan-based conditioning for allogeneic HSCT in children with chronic granulomatous disease: a multicenter experience.

Chronic granulomatous disease (CGD) can be cured by allogeneic hemopoietic stem cell transplantation (HSCT). Complications include graft failure, graft-versus-host disease (GVHD), infection, and transplant-related mortality; therefore, reduced-intensity conditioning regimens are being used to improve outcomes. In this retrospective study, the aim was to determine the outcome of treosulfan-based conditioning in HSCT for pediatric patients with CGD. The following data were collected: risk features pre-HSCT, additional conditioning agents, donor type and stem cell source, toxicity, engraftment, GVHD, chimerism, viral reactivation, post-HSCT complications, length of follow-up, and outcome. Seventy patients (median age, 107 months; interquartile range [IQR], 46-232 months) from 16 centers worldwide were transplanted between 2006 and 2015. Ninety-one percent had high-risk features. Fifty-seven HLA-matched donors, 12 HLA-mismatched donors, and 1 CD3(+)TCR αβ/CD19 depleted parental haploidentical transplants were performed. No major toxicity was reported. Median times to neutrophil and platelet engraftment were 17 (IQR, 15-35) and 16 (IQR, 13-50) days. At a median follow-up of 34 months (IQR, 13-102 months), the overall survival was 91.4%, and event-free survival was 81.4%. The cumulative incidence of acute grade III-IV GVHD was 12%. Nine patients developed chronic GVHD. When split cell chimerism was available, 95% or more myeloid donor chimerism was documented in 80% of surviving patients. Secondary graft failure occurred in 12% of patients. Treosulfan-containing conditioning regimens can be used safely in HSCT for children with CGD and high-risk clinical features, achieving excellent survival with high myeloid chimerism. Further studies are needed to compare with other regimens and evaluate the long-term outcome, particularly on fertility.