Skin response using NIH consensus criteria vs Hopkins scale in a phase II study for steroid-refractory chronic GVHD.

One of the obstacles to chronic GVHD research is the lack of standardized response criteria. The National Institute of Health (NIH) has recommended response criteria at a Consensus Conference. These need to be validated. We recently completed and reported a trial of pentostatin in treating steroid-refractory chronic GVHD. During the trial, we prospectively collected percent body-surface-area (BSA) involvement of rash, superficial sclerosis and deep sclerosis. Here, we compare cutaneous responses using the NIH scale and the Hopkins scale. The two scales produced similar overall response rates but different domain response rates. There was 80% agreement in overall response at the final treatment evaluation, but only a 64% agreement for fasciitis/non-moveable sclerosis. There was more disparity in the measurement of sclerosis than in that of erythema, which highlights the difficulty of quantifying sclerosis. For sclerosis, the Hopkins scale, which used skin softening, was more predictive of early response as compared with the NIH scale, which focused on percent BSA. Early assessment of skin softening may be important if trying to detect the activity of a particular agent in chronic GVHD. Further validation of the NIH scale is ongoing, which should produce a clinically useful and predictive scale.

Oral PUVA and topical steroids for treatment of oral manifestations of chronic graft-vs.-host disease.

BACKGROUND: Oral manifestations of chronic graft-vs.-host disease (cGVHD) can significantly affect the quality of life and severity often does not correlate with systemic manifestations. We evaluated the use of topical corticosteroids and the intraoral application of psoralen-UVA (PUVA) for treatment of oral manifestations of cGVHD. METHODS: Overall, 18 patients with oral manifestations of cGVHD were treated with either intraoral PUVA (n=7) or with topical corticosteroids (n=16). Four patients received intraoral PUVA after failure of topical steroids and one patient was treated with topical corticosteroids after failing treatment with intraoral PUVA. A glass fiber extension of an UVA source was used for manual intraoral application. Treatment with topical corticosteroids consisted of 0.1 mg/ml dexamethasone mouth wash four times a day in combination with antifungal prophylaxis. RESULTS: Four patients showed complete local response (CR) due to intraoral PUVA, two improved and one did not respond. Topical corticosteroids resulted in nine patients in CR, two improved and five did not respond. CONCLUSION: Intraoral PUVA as well as topical corticosteroids are effective in treatment of oral manifestations of oral GVHD with few side-effects and improve quality of life in patients with cGVHD.

High incidence of graft failure in children receiving CD34+ augmented elutriated allografts for nonmalignant diseases.

T-cell depletion of the marrow graft using counterflow centrifugal elutriation reduces the risk of graft-versus-host disease (GVHD). However, because of high rates of graft failure and relapse, elutriation alone has not improved survival. We have carried out a phase II clinical trial in 54 pediatric patients to determine if CD34+ selection to rescue pluripotent stem cells from the small lymphocyte fraction improves engraftment. The processed grafts contained a mean of 5.5 x 10(7) cells/kg IBW, 4.7 x 10(6) CD34+ cells/kg IBW, and 6.3 x 10(5) CD3+cells/kg IBW. Patients achieved an ANC >500 at a median of 16 days and platelet count >20 000 at a median of 28 days. The incidence of clinically significant GVHD was 19%. In total, 10 patients enrolled in this study experienced graft failure, with eight of the 14 patients transplanted for nonmalignant indications failing to engraft stably. Graft failure was statistically significantly associated with nonmalignant diagnosis (P<0.001), but was not associated with CMV seropositivity, donor gender, or cell counts of the allograft. We conclude that although time to engraftment is similar to that seen with unmanipulated grafts, graft failure remains a significant problem in patients with hereditary, nonmalignant diseases. Future efforts will seek to preserve the benefits of elutriation with CD34+ selection by increasing immune ablation of the preparative regimen and/or increasing posttransplant immune suppression.

Nonmyeloablative bone marrow transplantation from partially HLA-mismatched related donors using posttransplantation cyclophosphamide.

Cyclophosphamide (Cy) is a potent immunosuppressive agent that is selectively toxic to lymphocytes proliferating in response to recent antigen stimulation. In animal models, both graft rejection and GVHD after histoincompatible BMT can be inhibited by the posttransplantation administration of high-dose Cy. Therefore, a phase I clinical trial was undertaken to determine the minimal conditioning, including posttransplantation Cy, that permits the stable engraftment of partially HLA-mismatched marrow (up to 3 HLA antigens) from first-degree relatives. Thirteen patients (median age, 53 years) with high-risk hematologic malignancies received conditioning with fludarabine, 30 mg/m2 per day from days -6 to -2, and TBI, 2 Gy on day -1. All patients received Cy, 50 mg/kg on day 3, mycophenolate mofetil from day 4 to day 35, and tacrolimus from day 4 to day > or = 50. Three patients in cohort 1 received no additional conditioning, and 2 experienced graft rejection. Ten patients in cohort 2 received identical conditioning with the addition of Cy 14.5 mg/kg on days -6 and -5. Sustained donor cell engraftment occurred in 8 of these patients, with a median time to absolute neutrophil count > 500/microL of 15 days (range, 13-16 days) and to unsupported platelet count > 20,000/microL of 14 days (range, 0-26 days). All patients with engraftment achieved > or = 95% donor chimerism within 60 days of transplantation. Two patients with myelodysplastic syndrome rejected their grafts but experienced autologous neutrophil recovery at 24 and 44 days. Histologic acute GVHD developed in 6 patients (grade II in 3 patients, grade III in 3 patients) at a median of 99 days (range, 38-143 days) after transplantation and was fatal in 1 patient. At a median follow-up of 191 days (range, 124-423 days), 6 of 10 patients in cohort 2 were alive, and 5 were in complete remission of their disease, including both patients with graft rejection. These data demonstrate that partially HLA-mismatched bone marrow can engraft rapidly and stably after nonmyeloablative conditioning that includes posttransplantation Cy. Clinically significant antitumor responses occur, even among patients who reject their donor grafts.

Weight loss and malnutrition in patients with chronic graft-versus-host disease.

It is well known that weight loss occurs in patients with chronic graft-versus-host disease. However, the severity and frequency of weight loss in this population have not been adequately described. Recent data suggest that a body-mass index (BMI) below 21.9 is an independent risk factor for mortality. In our analysis we have shown that out of 93 patients with cGVHD, 43% are malnourished as evidenced by a BMI less than 21.9 and 14% are severely malnourished (BMI less than 18.5). In addition, there is a clear trend showing that patients with active, ongoing cGVHD have lower BMIs (P = 0.02). Furthermore, we show that many symptoms thought to contribute to weight loss in patients with cGVHD, such as odynophagia and oral sensitivity, are not related to weight loss in our population. We conclude that, in all likelihood, unknown causes still exist that are responsible for weight loss in this group of patients. Elevated resting energy expenditure and elevated serum tumor necrosis factor-alpha are potential contributors to weight loss that will be tested in future studies. We also conclude that treating cGVHD aggressively may help reverse weight loss and malnutrition, which may be independent risk factors for mortality in this population.

Risk factors for post-stem cell transplant sinusitis.

An understanding of the factors that place the post-transplant patient at increased risk for sinusitis would help identify patients likely to develop disease and possibly allow for interventions that would decrease the incidence or severity of sinus disease. This retrospective study investigates the ability of screening paranasal sinus computed tomographic scans (CTs), clinical history, and potential risk factors for sinusitis, including history of tobacco use, history of allergies or asthma, IgG level, history of sinusitis, remission status and acute graft-versus-host disease (GVHD) to predict post-transplant sinusitis. Medical records and sinus CTs of 100 allogeneic bone marrow recipients were reviewed. There was no increased risk of developing sinusitis post SCT for patients with significant disease on screening CT, symptoms at time of transplant, a history of tobacco use, asthma or allergies, low IgG level, history of sinusitis or for patients at high risk of relapse. Patients with GVHD were 4.3 times more likely than patients without GVHD to develop sinusitis post transplant (95% CI: 1.7-11.0, P = 0.002). Acute GVHD places patients at greater risk of developing sinus infections.

Long-term results of blood and marrow transplantation for Hodgkin's lymphoma.

PURPOSE: To evaluate the long-term outcome after allogeneic (allo) and autologous (auto) blood or marrow transplantation (BMT) in patients with relapsed or refractory Hodgkin's lymphoma (HL). PATIENTS AND METHODS: We analyzed the outcome of 157 consecutive patients with relapsed or refractory HL, who underwent BMT between March 1985 and April 1998. Patients

A high-dose pulse steroid regimen for controlling active chronic graft-versus-host disease.

Corticosteroids remain essential for controlling active chronic graft-versus-host disease (cGVHD). However, the optimum dose and administration schedule is unknown. We have reviewed our results in 61 patients with severe refractory cGVHD who were treated with a high-dose pulse steroid regimen (PS) consisting of methylprednisolone at 10 mg/kg per day for 4 consecutive days, with subsequent tapering doses. After 4 days, all patients received a course of additional immunosuppressive therapy. The median age of the 56 patients who were evaluable for response was 32 years (range, 0.2-57 years). Patients had failed a median of 2 (range, 1-5) treatments prior to the PS. The median follow-up for 45 surviving patients after PS was 1.5 years. The probability of survival at 1 year and 2 years after PS was 88% (95% confidence interval [CI], 76%-95%) and 81% (95% CI, 65%-91%), respectively. Twenty-seven patients (48%) showed a major response to PS with substantial improvement of cGVHD manifestations, including softening of the skin, increased range of motion, and improved performance status; 15 patients (27%) showed a minor response, defined as improvement in some but not all symptoms of cGVHD. Of the 42 responders, 21 (50%) had progression of their cGVHD afterwards. The median time to progression was 1.9 years. The probability of progression at 1 and 2 years after PS was 36% (95% CI, 23%-53%) and 54% (95% CI, 38%-71%), respectively. The probability of progression at 1 year was 25% (95% CI, 12%-47%) and 55% (95% CI, 32%-81%) for patients who had major and minor response, respectively (hazard ratio, 2.13). Ten of the 42 responders (24%) were able to discontinue all systemic immunosuppressive treatments. The probability of discontinuation at 1 and 2 years after PS was 9% (95% CI, 3%-25%) and 27% (95% CI, 15%-48%), respectively. The treatment was well tolerated with no serious adverse events. Our results suggest that PS is a well-tolerated regimen for achieving rapid clinical response in the majority of patients with cGVHD who failed on multiple previous therapies. Further studies are warranted to maintain the efficacy of this regimen by combining with new active agents in cGVHD.

Acute bleeding complications in patients after bone marrow transplantation.

Acute bleeding is a frequent complication that commonly associates with increased morbidity after bone marrow transplantation. Except for diffuse alveolar hemorrhage and cerebral hemorrhage, bleeding is infrequently recorded as a direct cause of death. Yet outcome analyses showed that bleeding from any reviewed site was associated with reduced survival. Reduced survival was correlated with bleeding intensity and the number of bleeding sites. These data point to the need to monitor all manifestations of bleeding, as bleeding may identify patients at risk for bone marrow transplantation toxicity. Until recently, prophylactic platelet transfusions were commonly given at a trigger of 20 x 10(9)/L. Whereas bleeding is more likely to occur when platelet counts drop to low levels, most bleeding episodes were recorded with platelet counts greater than 20 x 10(9)/L, suggesting causes other than profound thrombocytopenia in the pathogenesis of bleeding. Given that a trigger of 10 x 10(9)/L has become accepted for prophylactic platelet transfusions, care should be taken to ensure that parameters other than the incidence of bleeding have not been adversely affected.

Mycophenolate mofetil for the prevention and treatment of graft-versus-host disease following stem cell transplantation: preliminary findings.

The therapeutic benefits of allogeneic stem cell transplantation in patients with hematologic disorders are limited by the significant morbidity and mortality of graft-versus-host disease (GVHD). Current agents for the prevention and treatment of GVHD have limited efficacy and often result in toxic side-effects. Mycophenolate mofetil (MMF) is a new immunosuppressant with a selective mechanism of action. When employed following solid organ transplantation, MMF reduces the incidence and severity of acute rejection episodes. By selectively targeting activated lymphocytes, the active metabolite of MMF, mycophenolic acid (MPA), appears to augment the actions of standard immunosuppressant agents without adding overlapping toxicities. Studies of combination regimens that include MMF report that this agent permits a dose reduction of cyclosporine, tacrolimus, or corticosteroid, without increasing the incidence of acute rejection in solid organ transplants. Reports on the efficacy of MMF following stem cell transplantation in animal studies were mixed. However, the use of a non-myeloablative conditioning regimen with a post-graft immunosuppressive regimen of MMF and cyclosporine was able to sustain stable mixed chimeras in 60% to 80% of dogs who received hematopoietic grafts from DLA-identical littermates. MMF has demonstrated activity in preliminary clinical trials for GVHD prophylaxis, and treatment of acute or chronic GVHD. Larger clinical trials are warranted to determine the optimum dose and route of MMF administration for GVHD, as well as the comparative safety and efficacy of MMF-containing regimens.

Pancreatic insufficiency in patients with chronic graft-versus-host disease.

Diarrhea is a difficult diagnostic problem in patients with chronic graft-versus-host disease (cGVHD) because there are many causes of it. Although intestinal involvement has been reported in early studies of untreated cGVHD, this is now a very rare presentation of the disease. In addition to other etiologies, pancreatic insufficiency should also be considered in patients with cGVHD who demonstrate malabsorption. The pathogenesis of pancreatic insufficiency in these patients is unknown. Pancreatic enzyme supplements can be very effective in treating this rare condition.

Acute bleeding and thrombocytopenia after bone marrow transplantation.

The relationship between hemorrhage and low platelet count was first established in patients with acute leukemia, and has been widely applied to thrombocytopenic patients, including BMT patients. Yet, the role of thrombocytopenia in bleeding post BMT has not been systematically studied. We evaluated the risk of bleeding and outcome associated with thrombocytopenia in BMT patients who had prophylactic platelet transfusions at a trigger of 20 x 10(9)/l. Thrombocytopenia was investigated in 321 patients with moderate or severe bleeding (BLD), and in a matched comparison group of 287 patients who did not bleed (NBLD). Profound thrombocytopenia (< or = 10 x 10(9)/l) was found in 8.6% of the BLD patients during the week before the bleeding onset, significantly more frequent than in NBLD patients (2.1% to 4%, P < 0.02), during weeks 2 to 6 post BMT (the period when 75% of the bleeding initiated). On the first day of bleeding, platelet counts < or = 10 x 10(9)/l were found in 13.5%, 11-20 x 10(9)/l in 20.4%, and > 20 x 10(9)/l in 66.1% of all episodes. Overall survival in BLD patients was not associated with the severity of thrombocytopenia before bleeding onset. Severity of thrombocytopenia was significantly associated with reduced survival in NBLD patients. We concluded that bleeding post BMT was significantly associated with thrombocytopenia, but the attributable risk of bleeding from profound thrombocytopenia was not large. Thrombocytopenia may be an important clinical sign in NBLD patients, and should be further explored in relation to acute toxicities other than bleeding.

How I treat chronic graft-versus-host disease.

Allogeneic stem cell transplantation (SCT) is now a commonplace procedure. Clinicians who care for patients with hematologic malignancies and aplastic anemia are almost certain to follow up patients after SCT. This review is intended to help clinicians observe patients for probably the most important late complication of SCT, chronic graft-versus-host disease (GVHD). It reviews the pathophysiology, risk factors, clinical manifestations, evaluation, treatment, and supportive care of chronic GVHD.

Development of a prognostic model for grading chronic graft-versus-host disease.

The disease-specific survival (DSS) of 151 patients with chronic graft-versus-host disease (cGVHD) was studied in an attempt to stratify patients into risk groups and to form a basis for a new grading of cGVHD. The data included the outcome and 23 variables at the diagnosis of cGVHD and at the primary treatment failure (PTF). Eighty-nine patients (58%) failed primary therapy for cGVHD. Nonrelapse mortality was 44% after a median follow-up of 7.8 years. The probability of DSS at 10 years after diagnosis of cGVHD (DSS1) and after PTF (DSS2) was 51% (95% confidence interval [CI] = 39%, 60%) and 38% (95% CI = 28%, 49%), respectively. According to multivariate analysis, extensive skin involvement (ESI) more than 50% of body surface area; hazard ratio (HR) of 7.0 (95% CI = 3.6-13.4), thrombocytopenia (TP) (< 100 000/microL; HR, 3.6; 95% CI = 1.9-6.8), and progressive-type onset (PTO) (HR, 1.7; 95% CI = 0.9-3.0) significantly influenced DSS1. These 3 factors and Karnofsky Performance Score of less than 50% at PTF were significant predictors for DSS2. The DSS1 at 10 years for patients with prognostic factor score (PFS) at diagnosis of 0 (none), 1.9 and below [corrected] (ESI only or TP and/or PTO), above 1.9 and not above 3.5 [corrected] (ESI plus either TP or PTO), and more than 3.5 (all 3 factors) was 82%, 68%, 34%, and 3% (P =.05, <.001, <.001), respectively. The DSS2 at 5 years for patients with PFS at PTF of 0, 2 or less, 2 to 3.5, and more than 3.5 were 91%, 71%, 22%, and 4% (P =.2,.005, and <.001), respectively. It was concluded that these prognostic models might be useful in grouping the patients with similar outcome.

Von Willebrand factor-cleaving protease activity and proteolysis of von Willebrand factor in bone marrow transplant-associated thrombotic microangiopathy.

INTRODUCTION: Thrombotic microangiopathy (TM) of the fulminant type occurring in patients following bone marrow transplant (BMT) has clinical manifestations that are similar to thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome, but the outcome is generally fatal despite conventional therapy. Idiopathic acquired TTP has been associated with IgG inhibitors to the cleaving protease of von Willebrand factor (vWF) in plasma. In this study, we investigated the role of the vWF protease and vWF proteolysis in the pathogenesis of BMT-associated TM of the fulminant type. METHODS: vWF antigen level, vWF multimeric pattern, and vWF metalloprotease activity were investigated in the plasma samples of six consecutive patients with acute BMT-associated TM. Histologic and immunohistochemical studies were also performed on autopsy kidney specimens from four of the patients. All six patients had the fulminant type of the disorder with a fatal outcome and none of the patients responded to plasma infusion. RESULTS: The vWF-cleaving protease activity in plasma was normal in all patients. However, analysis of the vWF multimeric pattern showed a decrease of high molecular weight multimers. The decrease of large multimers may be caused by vWF-platelet binding as well as shear enhanced proteolysis of vWF. In the four patients who had an autopsy, a pattern of arteriolar thrombosis, distinct from that of TTP, was detected in the kidneys. CONCLUSION: These findings suggest that BMT-associated TM of the fulminant type is a heterogeneous process and distinct from TTP in pathogenesis. Analysis of vWF protease and vWF multimeric distribution are valuable tools in making the distinction between BMT-associated TM and TTP.

Using point-of-care CD34 enumeration to optimize PBSC collection conditions.

BACKGROUND: A PBSC graft containing 4-5 x 10(6) CD34(+) cells/kg is considered optimal in terms of durable engraftment. Tracking CD34 kinetics via point-of-care testing during PBSC mobilization could determine which (and when) patients will yield an optimal product. We evaluated whether microvolume fluorimetry (MVF) would be useful in optimizing PBSC mobilization/harvest and if it will shorten our standard 6 h collection. METHODS: Absolute CD34 values were obtained using the IMAGN 2000 and STELLer CD34 assay (50 microL sample volume). Peripheral blood (PB) CD34 values from 30 patients undergoing PBSC mobilization were used to generate a PB CD34-based algorithm that would predict collection day/duration of apheresis. The algorithm was then used prospectively to collect PBSC products on 50 hematologic malignancy (HM) patients. RESULTS: Using the algorithm, patients were assigned to either a 6 (11-20 CD34/microL), 4 (21-49 CD34/microL) or 2 (> or = 50 CD34/microL) h collection. Patients with a CD34 value < or = 10/microL were re-tested. All patients (n = 43) predicted to mobilize reached the optimal CD34 (4-5 x 10(6)/kg) value with 1.0 apheresis procedure; seven patients had < or = 10/microL (nonmobilizers). The majority (75%) had apheresis charges decreased by 33-66%; 47% only required a 2 h procedure and 28% required 4 h. All patients demonstrated rapid trilineage engraftment. DISCUSSION: Absolute PB CD34 measurement using MVF offers a rapid and reliable approach to obtaining optimal PBSC products with minimal technical expertise. Although not a replacement for conventional flow cytometry, it meets the requirements for a point-of-care procedure.