Gabrielle Meyers

Control of an Outbreak of Human Parainfluenza Virus 3 in Hematopoietic Stem Cell Transplant Recipients

Human parainfluenza virus 3 (HPIV3) infection can cause significant morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). There are no standard guidelines for the prevention and control of HPIV3 in the outpatient setting. After 2 HSCT inpatients diagnosed with HPIV3 were noted to have had multiple recent HSCT outpatient clinic (OPC) visits, an investigation of policy and procedures in the HSCT OPC was undertaken, and active surveillance for respiratory viral illness was instituted in the at-risk HSCT population. Between July 19 and August 30, 2005, 13 patients were diagnosed with HPIV3 infection. Morbidity in affected patients was significant, and mortality was high (38.5%) and not affected by antiviral therapy. Molecular typing identified several genetically distinct groups of the hemagglutinin-neuraminidase gene of the 11 available isolates. Based on sequence relatedness among the isolates and the demographic and exposure history of the patients, in many of these cases HPIV3 infection likely was acquired in the HSCT OPC. The major infection control interventions were introduced between August 20 and August 24. An epidemic curve revealed that HPIV3 infection frequency peaked between August 17 and August 26, with no cases identified after August 30. Prompt attention and focus on infection control interventions were associated with a rapid decrease in the number of incident cases. Policies and procedures regarding patients with respiratory viral illnesses in HSCT OPC populations should be formulated and universally reinforced with HSCT clinic staff to prevent the spread of these infections.

Single and Multiple Dose MultiStem (Multipotent Adult Progenitor Cell) Therapy Prophylaxis of Acute Graft-versus-Host Disease in Myeloablative Allogeneic Hematopoietic Cell Transplantation: A Phase 1 Trial

We conducted a multicenter, phase 1 dose escalation study evaluating the safety of the allogeneic multipotent adult progenitor cell (MAPC, MultiStem, Athersys, Inc., Cleveland, OH) stromal product administered as an adjunct therapy to 36 patients after myeloablative allogeneic hematopoietic cell transplantation (HCT). Patients received increasing doses of MAPC (1, 5, or 10 million cells per kilogram recipient weight) as a single i.v. dose on day +2 after HCT (n = 18), or once weekly for up to 5 doses (1 or 5 million cells per kilogram; n = 18). Infusional and regimen-related toxicities were assessed for 30 days after the last MAPC dose. Of 36 allogeneic HCT donors (17 related and 19 unrelated), 35 were 6/6 HLA matched. MAPC infusions were well tolerated without associated infusional toxicity, graft failure, or increased incidence of infection. Median times to neutrophil (n = 36) and platelet (n = 31) engraftment were 15 (range, 11 to 25) and 16 (range, 11 to 41) days, respectively. The overall cumulative incidences of grades II to IV and III and IV acute graft-versus-host disease (GVHD) at day 100 were 37% and 14%, respectively (n = 36). In the group that received the highest single MAPC dose (10 million cells/kg), day 100 incidence of grade II to IV GVHD was 11.1% (1 of 9) with no observed cases of grade III and IV GVHD. We found no evidence for MHC class II allogeneic antibody induction, although some patients showed an increase in serum anticlass I titers compared with baseline. MAPC contribution to blood chimerism was negligible. These phase I data support the safety of stromal stem cell therapy and suggest that MAPC should be tested prospectively as a novel therapeutic option for GVHD prophylaxis after HCT.

The Management of Paroxysmal Nocturnal Hemoglobinuria: Recent Advances in Diagnosis and Treatment and New Hope for Patients

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, clonal hematopoietic stem cell disorder that can manifest clinically as chronic hemolysis, a propensity for venous thrombosis, and bone marrow failure (Figure 1).1 Figure 1 Paroxysmal Nocturnal Hemoglobinuria (PNH): A Triad of Clinical Features While many physicians have little or no experience treating patients with PNH, there have been many recent advances in the management of this disease. These advances were discussed by a panel of international experts at a satellite symposium that preceded the 49th American Society of Hematology Annual Meeting in Atlanta, Georgia. This symposium was sponsored by an educational grant from Alexion Pharmaceuticals, Inc.

Management issues in paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) arises in the setting of bone marrow injury. Thus, management decisions must take into account whether symptoms are a consequence of the underlying marrow failure or of the expansion of the clone of thePIG-A mutant hematopoietic cells. The primary clinical manifestations of PNH are intravascular hemolysis and thrombophilia. Currently available options for treatment of the hemolysis of PNH are unsatisfactory, but the recent development of specific inhibitors of complement for use in treating human disease should make possible effective management of this pathology. The fundamental basis of the thrombophilia of PNH has not been elucidated. Currently, empiric anticoagulant therapy is the foundation for treating the thromboembolic complications of PNH. The role of warfarin prophylaxis, however, remains an area of active debate. Pregnancy in a patient with PNH presents special concerns about fetal/maternal well-being because of the high potential for thromboembolic complications. Bone marrow transplantation can be considered curative, but the decision to recommend this treatment must take into account factors related both to PNH and to comorbid conditions. Refining the technology for both gene therapy (by transducing stem cells with a functionalPIG-A gene) and autotransplantation (by using stem cells selected for the expression of glycosyl phosphatidylinositol-anchored proteins) remain challenges for the future.

Is it time for a change? The case for early application of unrelated allo-SCT for severe aplastic anemia

Severe aplastic anemia (SAA) is a BM failure syndrome in which allo-SCT remains a highly effective curative option. Its application remains limited by donor availability and by the potential for treatment-related morbidity and mortality. The improved outcomes with unrelated transplantation are a result of the advent of molecular donor–recipient matching, generation of effective novel conditioning regimens, improvement of supportive care and expansion of the donor registry. Decision making regarding the earlier use of unrelated transplant procedures is rapidly evolving. This paper reviews critical data relevant to these treatment options and recommends early consideration of related SCT for patients with SAA who show failure of immune suppressive therapy.

Induction Bortezomib in AL Amyloidosis Followed By High Dose Melphalan and Autologous Stem Cell Transplantation: A Single Institution Retrospective Study

INTRODUCTION/BACKGROUND High-dose melphalan (HDM) followed by autologous stem cell transplant (ASCT) for light chain amyloidosis (AL) was performed in 31 patients at Oregon Health and Science University between 2005 and 2012. Fifteen patients had cardiac involvement. PATIENTS AND METHODS Patients received melphalan 200 mg/m(2) or dose-adjusted HDM (100-140 mg/m(2)) depending on high risk features. Thirteen patients proceeded directly to ASCT after diagnosis, 12 patients received a bortezomib-containing regimen, and 6 received a variety of other induction regimens. RESULTS The day 100 treatment-related mortality was 9.6%. Overall hematologic (ORR) and organ response rates (OR) in the whole cohort after ASCT were 77% and 58%. ORR and OR in the bortezomib pretreated group were 92% and 75% vs. 69% and 54% in the group that received no pretreatment. The median time to maximum hematologic response after ASCT was reduced in the group that received bortezomib induction (3 vs. 14 months). Overall cardiac response rate was 60%; 100% in patients pretreated with bortezomib and 43% in those without induction treatment. With a median follow-up of 2.9 years, the 3-year progression-free and overall survival rates in the entire cohort were 66% and 73% and in those with cardiac involvement, 73% and 80%. CONCLUSION We observed that bortezomib-based induction is well tolerated in patients with and without cardiac involvement and suggest that this approach be studied in prospective multi-institutional trials.

Cross-sectional validation study of patient-reported outcomes in patients with paroxysmal nocturnal haemoglobinuria

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, acquired, clonal haemopoietic stem cell disorder that causes chronic intravascular haemolysis, increases the risk of thrombosis and results in significant patient morbidity and mortality. The symptoms of PNH may have a major impact on patient quality of life.

Myelodysplasia and Acute Leukemia as Late Complications of Marrow Failure: Future Prospects for Leukemia Prevention

Patients who have acquired and inherited bone marrow failure syndromes are at risk for the development of clonal neoplasms including acute myeloid leukemia, myelodysplastic syndrome, and paroxysmal nocturnal hemoglobinuria. This article reviews the evidence supporting a model of clonal selection, a paradigm that provides a reasonable expectation that these often fatal complications might be prevented in the future.

Nonmyeloablative allogeneic hematopoietic stem cell transplant for the treatment of patients with hematologic malignancies using busulfan, fludarabine, and total body irradiation conditioning is effective in an elderly and infirm population

The BuFluTBI conditioning regimen was designed with the primary goal of reducing non-relapse mortality (NRM) while maximizing primary disease control in patients ineligible for myeloablative conditioning. Patients with hematologic malignancies for whom limited long-term survival was expected with standard therapy were administered an outpatient conditioning regimen of busulfan 3.2 mg/kg IV on day -5, fludarabine 30 mg/m(2) IV on days -4, -3, -2, and 200 cGy of total body irradiation (TBI) followed by stem cell infusion from related or unrelated donors. GVHD prophylaxis included cyclosporine and mycophenolate mofetil. 147 patients were enrolled from 2005-2011; 59% with myeloid disease and 41% with lymphoid disease. The median age was 64, and the median comorbidity index (HCT-CI) score was 3. Overall survival (OS), with 3.2 years median follow-up, was 60% at 1 year and 48% at 2 years, with projected OS 37% at 5 years. Relapse rates were 29% at 1 year and 33% at 2 years, with relapse mortality of 13% at 1 year, and 20% at 2 years. Nonrelapse mortality (NRM) at 1 year was 27% and 33% at 2 years. 54% of patients developed grade II-IV aGVHD and 67% of patients developed cGVHD within 2 years. On multivariate analysis, HCT-CI score 4 or greater, pre-transplant KPS less than 90, delayed platelet engraftment of more than 15 days, and grade II-IV aGVHD were found to be independent predictors of poor survival. There was no difference in OS or PFS between lymphoid and myeloid malignancies. BuFluTBI is an efficacious NMA regimen, active in both myeloid and lymphoid disease, and is ideally suited for use in patients age 65 and older or with an HCT-CI of 4 or greater.

Allogeneic stem cell transplantation in fully MHC-matched Mauritian cynomolgus macaques recapitulates diverse human clinical outcomes

Allogeneic hematopoietic stem cell transplantation (HSCT) is a critically important therapy for hematological malignancies, inborn errors of metabolism, and immunodeficiency disorders, yet complications such as graft-vs.-host disease (GvHD) limit survival. Development of anti-GvHD therapies that do not adversely affect susceptibility to infection or graft-vs.-tumor immunity are hampered by the lack of a physiologically relevant, preclinical model of allogeneic HSCT. Here we show a spectrum of diverse clinical HSCT outcomes including primary and secondary graft failure, lethal GvHD, and stable, disease-free full donor engraftment using reduced intensity conditioning and mobilized peripheral blood HSCT in unrelated, fully MHC-matched Mauritian-origin cynomolgus macaques. Anti-GvHD prophylaxis of tacrolimus, post-transplant cyclophosphamide, and CD28 blockade induces multi-lineage, full donor chimerism and recipient-specific tolerance while maintaining pathogen-specific immunity. These results establish a new preclinical allogeneic HSCT model for evaluation of GvHD prophylaxis and next-generation HSCT-mediated therapies for solid organ tolerance, cure of non-malignant hematological disease, and HIV reservoir clearance.Rhesus macaques are not ideal for studying response to allogeneic hematopoietic stem cell transplant (allo-HSCT) owing to complex MHC genetics that prevent full MHC-matching. Here the authors show that inbred Mauritian-origin cynomolgus macaques are a superior preclinical model of allogeneic stem cell transplantation that mimics diverse clinical outcomes of human allo-HSCT.