Reprint of: B Cells in Chronic Graft-versus-Host Disease

AbstractChronic graft-versus-host disease (cGVHD) continues to be a common complication of allogeneic hematopoietic stem cell transplantation. Unlike acute graft-versus-host disease, which is mediated almost entirely by donor T cells, the immune pathology of cGVHD is more complex and donor B cells have also been found to play an important role. Recent studies from several laboratories have enhanced our understanding of how donor B cells contribute to this clinical syndrome and this has led to new therapeutic opportunities. Here, Dr Sarantopoulos reviews some of the important mechanisms responsible for persistent B cell activation and loss of B cell tolerance in patients with cGVHD. Dr Blazar describes recent studies in preclinical models that have identified novel B cell–directed agents that may be effective for prevention or treatment of cGVHD. Some B cell–directed therapies have already been tested in patients with cGVHD and Dr Cutler reviews the results of these studies documenting the potential efficacy of this approach. Supported by mechanistic studies in patients and preclinical models, new B cell–directed therapies for cGVHD will now be evaluated in clinical trials

Blood and Marrow Transplant Clinical Trials Network Toxicity Committee Consensus Summary: Thrombotic Microangiopathy after Hematopoietic Stem Cell Transplantation

AbstractThe syndrome of microangiopathic hemolysis associated with renal failure, neurologic impairment, or both is a recognized complication of hematopoietic stem cell transplantation. This entity is often called hemolytic uremic syndrome (HUS) or thrombotic thrombocytopenic purpura (TTP), yet it is clear that the pathophysiology of transplant-associated HUS/TTP is different from that of classic HUS or TTP. Furthermore, the incidence of this syndrome varies from 0.5% to 76% in different transplant series, primarily because of the lack of a uniform definition. The toxicity committee of the Blood and Marrow Transplant Clinical Trials Network has reviewed the current literature on transplant-related HUS/TTP and recommends that it be henceforth renamed posttransplantation thrombotic microangiopathy (TMA). An operational definition for TMA based on the presence of microangiopathic hemolysis and renal and/or neurologic dysfunction is proposed. The primary intervention after diagnosis of TMA should be withdrawal of calcineurin inhibitors. Plasma exchange, although frequently used in this condition, has not been proven to be effective. In the absence of definitive trials, plasma exchange cannot be considered a standard of care for TMA. It is hoped that these positions will improve the identification and reporting of this devastating complication after hematopoietic stem cell transplantation and facilitate future clinical studies for its prevention and treatment

Pharmacokinetics of a novel transdermal rivastigmine patch for the treatment of Alzheimer’s disease: a review

Cholinesterase inhibitors have all been available in oral formulations, but a rivastigmine transdermal patch has now been developed and is approved in many countries worldwide for the treatment of mild-to-moderate Alzheimer's disease (AD) (including the USA, Latin America, Europe and Asia)

A Prognostic Score for Patients with Acute Leukemia or Myelodysplastic Syndromes Undergoing Allogeneic Stem Cell Transplantation

AbstractAllogeneic hematopoietic stem cell transplantation (SCT) has the potential to cure patients with acute leukemia or myelodysplastic syndromes (MDS), but a number of prognostic factors can influence the outcome of transplantation. At present, no transplantation-specific risk score exists for this patient population. We propose a simple scoring system for patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), or MDS, based on a retrospective analysis of 445 patients undergoing SCT at our institution (divided into training and validation subsets). The score depends on 5 variables: age, disease, stage at transplantation, cytogenetics, and pretransplantation ferritin. It divides patients into 3 groups of comparable size, with 5-year overall survival (OS) of 56% (low risk), 22% (intermediate risk), and 5% (high risk). This prognostic score could be useful in making treatment decisions for individual patients, in stratifying patients entering clinical trials, and in adjusting transplantation outcomes across centers under the new federal reporting rules

Overlap subtype of chronic graft-versus-host disease is associated with an adverse prognosis, functional impairment, and inferior patient-reported outcomes: A Chronic Graft-versus-Host Disease Consortium study

Background The National Institutes of Health Consensus Conference proposed the term “overlap” graft-versus-host disease to describe the situation when both acute and chronic graft-versus-host disease are present. Design and Methods We examined whether the overlap subtype of graft-versus-host disease was associated with a different prognosis, functional limitations, or patient-reported outcomes compared to “classic” chronic graft-versus-host disease without any acute features. Results Prospective data were collected from 427 patients from nine centers. Patients were classified as having overlap (n=352) or classic chronic (n=75) graft-versus-host disease based on reported organ involvement. Overlap cases had a significantly shorter median time from transplantation to cohort enrollment (P=0.01), were more likely to be incident cases (P\u3c0.001), and had a lower platelet count at onset of the graft-versus-host disease (P\u3c0.001). Patients with overlap graft-versus-host disease had significantly greater functional impairment measured by a 2-minute walk test, higher symptom burden and lower Human Activity Profile scores. Quality of life was similar, except patients with overlap graft-versus-host disease had worse social functioning, assessed by the Short Form-36. Multivariable analysis utilizing time-varying covariates demonstrated that the overlap subtype of graft-versus-host disease was associated with worse overall survival (HR 2.1, 95% CI 1.1–4.7; P=0.03) and higher non-relapse mortality (HR 2.8, 95% CI 1.2–8.3; P=0.02) than classic chronic graft-versus-host disease. Conclusions These findings suggest that the presence of acute features in patients with chronic graft-versus-host disease is a marker of adverse prognosis, greater functional impairment, and higher symptom burden

Mucositis after Allogeneic Hematopoietic Stem Cell Transplantation: A Cohort Study of Methotrexate- and Non-Methotrexate-Containing Graft-versus-Host Disease Prophylaxis Regimens

AbstractOral mucositis occurs in up to 75% of recipients of high-dose chemoradiotherapy conditioning regimens used for allogeneic hematopoietic stem cell transplantation (HSCT). As a result of mucositis, narcotic analgesia and total parenteral nutrition (TPN) are commonly required after HSCT. Methotrexate, an antiproliferative graft-versus-host disease (GVHD) prophylaxis agent, impairs mucosal regeneration and worsens and prolongs mucositis. We assessed the effect of substituting sirolimus for methotrexate as GVHD prophylaxis on outcomes associated with mucositis. Two patient cohorts undergoing allogeneic HLA-matched related donor peripheral blood stem cell transplantation with cyclophosphamide/total body irradiation conditioning were prospectively analyzed for mucositis severity and retrospectively reviewed for correlative outcomes. GVHD prophylaxis consisted of sirolimus/tacrolimus (ST) in the study group and tacrolimus/methotrexate (TM) in the control group. Thirty patients received ST and 24 patients received TM as GVHD prophylaxis between October 2000 and May 2003. Mild, moderate, and severe mucositis was noted in 37%, 57%, and 7% of the ST group and 8%, 42%, and 50% of the TM group (P = .0002). Less TPN was used in the ST group than the TM group (17% versus 43% of posttransplantation hospital days; P = .02). The total number of narcotic days was lower in the ST group in comparison with the TM group (median, 13.5 versus 17 days; P = .08). The time to first hospital discharge was shorter in the ST group compared with the TM group (median, 18 versus 22 days; P = .07). The substitution of sirolimus for methotrexate as GVHD prophylaxis is associated with a reduction in mucositis severity. As a result, TPN and narcotic use are reduced, and hospitalization duration is shortened. Less toxic GVHD prophylaxis regimens without methotrexate may have a significant effect on patient quality of life, patient outcomes, and economic outcomes associated with allogeneic stem cell transplantation

Long-Term Follow-up of Reduced Intensity Allogeneic Stem Cell Transplantation for Chronic Lymphocytic Leukemia: Prognostic Model to Predict Outcome

CLL remains incurable with chemoimmunotherapy, and allogeneic hematopoietic stem cell transplantation (HSCT) offers potential for cure. We assessed the outcomes of 108 CLL patients undergoing first allogeneic HSCTs, 76 with reduced intensity (RIC) and 32 with myeloablative (MAC) conditioning between 1998 and 2009 at Dana-Farber Cancer Institute. With median follow-up 5.9 years in surviving patients, the 5 year OS for the entire cohort is 63% for RIC regimens and 49% for MAC regimens (p=0.18). The risk of death declined significantly starting in 2004 and we found that 5 year OS for HSCT between 2004–2009 was 83% for RIC regimens compared to 47% for MAC regimens (p=0.003). For RIC transplantation, we developed a prognostic model based on predictors of PFS, specifically remission status, LDH, comorbidity score and lymphocyte count, and found 5-year PFS 83% for score 0, 63% for score 1, 24% for score 2, and 6% for score >= 3 (p<0.0001). We conclude that RIC HSCT for CLL in the current era is associated with excellent long-term PFS and OS, and, as potentially curative therapy, should be considered early in the disease course of relapsed high-risk CLL patients

dynamics of immune cell reconstitution in allogeneic hematopoietic cell transplant patients receiving post transplant cyclophosphamide ptcy

In the setting of haploidentical hematopoietic cell transplantation (haplo-HCT), post-transplant cyclophosphamide (PTCy) selectively eliminates alloreactive T cells in-vivo, resulting in favorable graft versus host disease (GVHD), non-relapse mortality (NRM) and relapse outcomes. However, few studies have examined the impact of PTCy on immune reconstitution (IR). We quantified IR in 63 patients after haplo-HCT with PTCy, mofetil mycophenolate and tacrolimus (TAC) and compared results to 93 patients with 8/8 HLA matched related or unrelated donors (MD) receiving TAC, methotrexate and sirolimus for GVHD prophylaxis. Both groups received reduced intensity conditioning for hematologic malignancies. The median age of the Haplo-PTCy and MD cohorts was 55 and 57 years. Patient samples were analyzed using multi-color flow cytometry panels to characterize distinct lymphocyte populations. All IR values are expressed as median absolute cell count per μL. One month after HCT, recovery of all T cell subsets (CD3, CD4Tcon, Treg, CD8) was significantly reduced in the PTCy cohort compared to MD (Figure A, B, C). Recovery of CD4Tcon was also reduced at 2 and 3 months after PTCy (p NK cells were lower 1 month after PTCy (52.7 vs 91.1, p=0.08), but were significantly higher at 2, 3 and 6 months (153.4 vs 94.8, p=0.001, 153.7 vs 87.5, p=0.008, 180 vs 102, p=0.01, respectively, Figure D) compared to the MD cohort. Delayed NK cell recovery at 1 month after PTCy was due entirely to reduced numbers of CD56dim NK cells (Figure E). Subsequently recovery of CD56dim NK cells was similar in both cohorts. Recovery of CD56bright NK cells was significantly increased in the PTCy cohort (p Consistent with prior reports, 1 year cumulative incidence of extensive cGvHD was lower in the PTCy cohort compared to the MD cohort, 13% (5-26%, 95% CI) and 40% (30-50%, 95% CI) respectively, p=0.003, without increased NRM (p=0.28) or relapse (p=0.17). In summary, the effect of PTCy on IR was most pronounced 1 month after transplant with significantly delayed recovery of CD3, CD4Tcon, Treg, CD8 and CD56dim NK cells. Slow recovery of CD4Tcon persisted for 3 months and delayed recovery of Treg persisted for 1 year. Beginning 2 months after HCT, recovery of both CD56dim and CD56bright NK cells was more rapid in the PTCy cohort. Further studies will examine the effects of these differences in IR on clinical outcomes such as relapse, infections and GVHD

Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials.

The optimal treatment of acute myeloid leukemia (AML) in first complete remission (CR1) is uncertain. Current consensus, based on cytogenetic risk, recommends myeloablative allogeneic stem cell transplantation (SCT) for poor-risk but not for good-risk AML. Allogeneic SCT, autologous transplantation, and consolidation chemotherapy are considered of equivalent benefit for intermediate-risk AML