David A. Jacobsohn

National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report.

The 2005 National Institutes of Health (NIH) Consensus Conference proposed new criteria for diagnosing and scoring the severity of chronic graft-versus-host disease (GVHD). The 2014 NIH consensus maintains the framework of the prior consensus with further refinement based on new evidence. Revisions have been made to address areas of controversy or confusion, such as the overlap chronic GVHD subcategory and the distinction between active disease and past tissue damage. Diagnostic criteria for involvement of mouth, eyes, genitalia, and lungs have been revised. Categories of chronic GVHD should be defined in ways that indicate prognosis, guide treatment, and define eligibility for clinical trials. Revisions have been made to focus attention on the causes of organ-specific abnormalities. Attribution of organ-specific abnormalities to chronic GVHD has been addressed. This paradigm shift provides greater specificity and more accurately measures the global burden of disease attributed to GVHD, and it will facilitate biomarker association studies.

Long-Term Survival and Late Deaths After Allogeneic Hematopoietic Cell Transplantation

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) is curative but is associated with life-threatening complications. Most deaths occur within the first 2 years after transplantation. In this report, we examine long-term survival in 2-year survivors in the largest cohort ever studied. PATIENTS AND METHODS Records of 10,632 patients worldwide reported to the Center for International Blood and Marrow Transplant Research who were alive and disease free 2 years after receiving a myeloablative allogeneic HCT before 2004 for acute myelogenous or lymphoblastic leukemia, myelodysplastic syndrome, lymphoma, or severe aplastic anemia were reviewed. RESULTS Median follow-up was 9 years, and 3,788 patients had been observed for 10 or more years. The probability of being alive 10 years after HCT was 85%. The chief risk factors for late death included older age and chronic graft-versus-host disease (GVHD). For patients who underwent transplantation for malignancy, relapse was the most common cause of death. The greatest risk factor for late relapse was advanced disease at transplantation. Principal risk factors for nonrelapse deaths were older age and GVHD. When compared with age, sex, and nationality-matched general population, late deaths remained higher than expected for each disease, with the possible exception of lymphoma, although the relative risk generally receded over time. CONCLUSION The prospect for long-term survival is excellent for 2-year survivors of allogeneic HCT. However, life expectancy remains lower than expected. Performance of HCT earlier in the course of disease, control of GVHD, enhancement of immune reconstitution, less toxic regimens, and prevention and early treatment of late complications are needed.

Patient-reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: report on baseline data from the Chronic GVHD Consortium

Quality of life (QOL) after hematopoietic cell transplantation (HCT) is compromised by chronic GVHD. In a prospectively assembled multicenter cohort of adults with chronic GVHD (n = 298), we examined the relationship between chronic GVHD severity defined by National Institutes of Health (NIH) criteria and QOL as measured by the SF-36 and FACT-BMT instruments at time of enrollment. Chronic GVHD severity was independently associated with QOL, adjusting for age. Compared with population normative data, SF-36 scores were more than a SD (10 points) lower on average for the summary physical component score (PCS) and role-physical subscale, and significantly lower (with magnitude 4-10 points) for several other subscales. Patients with moderate and severe cGVHD had PCS scores comparable with scores reported for systemic sclerosis, systemic lupus erythematosus, and multiple sclerosis, and greater impairment compared with common chronic conditions including diabetes, hypertension, and chronic lung disease. Moderate to severe cGVHD as defined by NIH criteria is associated with significant compromise in multiple QOL domains, with PCS scores in the range of other systemic autoimmune diseases. Compromised QOL provides a functional assessment of the effects of chronic GVHD, and may be measured in cGVHD clinical studies using either the SF-36 or the FACT-BMT.

Acute graft versus host disease

Acute graft-versus-host disease (GVHD) occurs after allogeneic hematopoietic stem cell transplant and is a reaction of donor immune cells against host tissues. Activated donor T cells damage host epithelial cells after an inflammatory cascade that begins with the preparative regimen. About 35%–50% of hematopoietic stem cell transplant (HSCT) recipients will develop acute GVHD. The exact risk is dependent on the stem cell source, age of the patient, conditioning, and GVHD prophylaxis used. Given the number of transplants performed, we can expect about 5500 patients/year to develop acute GVHD. Patients can have involvement of three organs: skin (rash/dermatitis), liver (hepatitis/jaundice), and gastrointestinal tract (abdominal pain/diarrhea). One or more organs may be involved. GVHD is a clinical diagnosis that may be supported with appropriate biopsies. The reason to pursue a tissue biopsy is to help differentiate from other diagnoses which may mimic GVHD, such as viral infection (hepatitis, colitis) or drug reaction (causing skin rash). Acute GVHD is staged and graded (grade 0-IV) by the number and extent of organ involvement. Patients with grade III/IV acute GVHD tend to have a poor outcome. Generally the patient is treated by optimizing their immunosuppression and adding methylprednisolone. About 50% of patients will have a solid response to methylprednisolone. If patients progress after 3 days or are not improved after 7 days, they will get salvage (second-line) immunosuppressive therapy for which there is currently no standard-of-care. Well-organized clinical trials are imperative to better define second-line therapies for this disease. Additional management issues are attention to wound infections in skin GVHD and fluid/nutrition management in gastrointestinal GVHD. About 50% of patients with acute GVHD will eventually have manifestations of chronic GVHD.

Global and organ-specific chronic graft-versus-host disease severity according to the 2005 NIH Consensus Criteria

In 2005, the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic GVHD proposed a new scoring system for individual organs and an algorithm for calculating global severity (mild, moderate, severe). The Chronic GVHD Consortium was established to test these new criteria. This report includes the first 298 adult patients enrolled at 5 centers of the Consortium. Patients were assessed every 3-6 months using standardized forms recommended by the Consensus Conference. At the time of study enrollment, global chronic GVHD severity was mild in 10% (n = 32), moderate in 59% (n = 175), and severe in 31% (n = 91). Skin, lung, or eye scores determined the global severity score in the majority of cases, with the other 5 organs determining 16% of the global severity scores. Conventional risk factors predictive for onset of chronic GVHD and nonrelapse mortality in people with chronic GVHD were not associated with NIH global severity scores. Global severity scores at enrollment were associated with nonrelapse mortality (P < .0001) and survival (P < .0001); 2-year overall survival was 62% (severe), 86% (moderate), and 97% (mild). Patients with mild chronic GVHD have a good prognosis, while patients with severe chronic GVHD have a poor prognosis. This study was registered at www.clinicaltrials.gov as no. NCT00637689.

Reduced intensity haemopoietic stem-cell transplantation for treatment of non-malignant diseases in children

BACKGROUND Transplantation of allogeneic haemopoietic stem cells can cure several non-malignant disorders in children. Transplantation with reduced intensity preparation might achieve the same goals but with less toxicity. We undertook a pilot study to determine engraftment rates, kinetics of engraftment, toxicity, and acute graft-versus-host disease (GVHD) associated with a uniform reduced intensity haemopoietic stem-cell transplant (HSCT) regimen for children with non-malignant diseases. METHODS We studied 13 paediatric patients with non-malignant disorders who underwent reduced intensity HSCT at Childrens Memorial Hospital from January, 2000, to February, 2004. Stem-cell sources included unrelated donor, matched-sibling peripheral blood stem cells, and unrelated cord blood. A uniform preparative regimen was used, consisting of fludarabine, busulfan, and anti-thymocyte globulin. Major endpoints were engraftment, transplant-related mortality at day 100, short-term toxicities, and incidence of acute GVHD. RESULTS 72% of evaluable patients achieved full donor engraftment. There was rapid reconstitution of platelets (median 13.5 days) and neutrophils (median 18 days). Short-term toxicities were minimal, as seen by a median length of hospital stay of 7 days (between days 0-100). Incidence of grade II-IV acute GVHD was 8%. Two patients died before day 100 from underlying disease and viral infection, respectively (day 100 transplant-related mortality of 15%). The 1-year overall survival was 84% (95% CI 64-100). Most patients with immunodeficiencies and metabolic disorders had excellent donor engraftment and disease resolution or stabilisation, but most of those with haemoglobinopathies rejected their graft. INTERPRETATION This reduced intensity regimen followed by HSCT provides a good alternative to myeloablative HSCT for children with non-malignant disorders, except for haemoglobinopathies, in which engraftment is poor. Even patients with unrelated donor haemopoietic stem-cell transplants had adequate engraftment with acceptable toxicities.

Pentostatin in Steroid-Refractory Acute Graft-Versus-Host Disease

PURPOSE Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic bone marrow transplantation. In steroid-refractory aGVHD, mortality is very high. Pentostatin, a potent inhibitor of adenosine deaminase, induces lymphocyte apoptosis and may be useful in the treatment of this condition. PATIENTS AND METHODS We have conducted a phase I dose escalation study of pentostatin in patients with steroid-refractory aGVHD. Twenty-three patients were enrolled. Starting dose was 1 mg/m2/d by intravenous injection for 3 days. RESULTS The maximum tolerated dose was found to be 1.5 mg/m2/d. Late infections at the 2-mg/m2/d dose level were believed to be dose limiting toxicities. Lymphopenia was universal, but the neutrophil count was generally not affected. Fevers associated with neutropenia were not observed. Otherwise, the drug was well tolerated, with only modest elevations of liver function tests and thrombocytopenia, each being observed in a single patient. Twenty-two patients were assessable for response, including 14 complete responses (63%) and three partial responses (13%). Median survival after therapy for the group was 85 days (range, 5 to 1,258 days). CONCLUSION The suggested intravenous dose for a phase II study will be 1.5 mg/m2/d for 3 days. Pentostatin has activity in patients with steroid-refractory aGVHD that is worth exploring in future trials.

Increasing Incidence of Chronic Graft-versus-Host Disease in Allogeneic Transplantation: A Report from the Center for International Blood and Marrow Transplant Research

Although transplant practices have changed over the last decades, no information is available on trends in incidence and outcome of chronic graft-versus-host disease (cGVHD) over time. This study used the central database of the Center for International Blood and Marrow Transplant Research (CIBMTR) to describe time trends for cGVHD incidence, nonrelapse mortality, and risk factors for cGVHD. The 12-year period was divided into 3 intervals, 1995 to 1999, 2000 to 2003, and 2004 to 2007, and included 26,563 patients with acute leukemia, chronic myeloid leukemia, and myelodysplastic syndrome. Multivariate analysis showed an increased incidence of cGVHD in more recent years (odds ratio = 1.19, P < .0001), and this trend was still seen when adjusting for donor type, graft type, or conditioning intensity. In patients with cGVHD, nonrelapse mortality has decreased over time, but at 5 years there were no significant differences among different time periods. Risk factors for cGVHD were in line with previous studies. This is the first comprehensive characterization of the trends in cGVHD incidence and underscores the mounting need for addressing this major late complication of transplantation in future research.

Chronic GVHD risk score: a Center for International Blood and Marrow Transplant Research analysis.

Several risk factors are associated with increased mortality in patients with chronic graft-versus-host disease (cGVHD), but there is considerable variability in the reported factors. Therefore, we evaluated patient, transplantation, and cGVHD characteristics to develop a risk score in 5343 patients with cGVHD. Ten variables were identified as being significant in multivariate analysis of overall survival and nonrelapse mortality (NRM): age, prior acute GVHD, time from transplantation to cGVHD, donor type, disease status at transplantation, GVHD prophylaxis, gender mismatch, serum bilirubin, Karnofsky score, and platelet count. These 10 variables were used to build a cGVHD risk score, and 6 risk groups (RGs) were identified. The 5-year NRM was 5% (1%-9%) in RG1, 20% (19%-23%) in RG2, 33% (29%-37%) in RG3, 43% (40%-46%) in RG4, 63% (53%-74%) in RG5, and 72% (59%-85%) in RG6. The 5-year overall survival was highest at 91% (95% confidence interval [CI]:85%-97%) in RG1, followed by 67% (65%-69%) in RG2, 51% (46%-55%) in RG3, 40% (37%-43%) in RG4, 21% (12%-30%) in RG5, and 4% (0%-9%) in RG6 (all P < .01). This analysis demonstrates the usefulness of data from a large registry to develop risk-score categories for major transplantation outcomes. Validation of this cGVHD risk score is needed in a different population to ensure its broad applicability.

Phase II Study of Pentostatin in Patients With Corticosteroid-Refractory Chronic Graft-Versus-Host Disease

PURPOSE Therapy for patients with chronic graft-versus-host disease (cGVHD) is based on prolonged immunosuppression with corticosteroids. There is no standard therapy for patients whose cGVHD does not resolve with corticosteroid treatment. Pentostatin, a potent inhibitor of adenosine deaminase, has activity in acute GVHD. We examined the toxicity and efficacy of pentostatin in a prospective phase II trial in corticosteroid-refractory cGVHD. PATIENTS AND METHODS Patients of any age were eligible. Patients received pentostatin 4 mg/m2 intravenously every 2 weeks for 12 doses, and continued therapy as long as benefit was documented. Corticosteroid taper was begun after three doses of pentostatin. Responses were graded in real time in the skin, mouth, and liver using objective response criteria. RESULTS Fifty-eight heavily pretreated (median, four prior regimens) patients (median age, 33 years) were enrolled. Results are shown as an intent-to-treat analysis. Of the 58 patients, a total of 32 (55%; 95% CI, 42% to 68%) had an objective response, as evaluated by use of a new grading scale. Infection was the most significant toxicity, with 11 grade 3 to 4 infectious events. The survival at 1 and 2 years was 78% (95% CI, 64% to 86%) and 70% (95% CI, 57% to 80%), with cGVHD with/without infection accounting for the majority of deaths. CONCLUSION Pentostatin has immunosuppressive effects that are currently being explored further for treatment of cGVHD.