Combination Therapy With Casirivimab/Imdevimab and Remdesivir for Protracted SARS-CoV-2 Infection in B-cell-Depleted Patients.

Profoundly B-cell-depleted patients can have prolonged severe acute respiratory syndrome coronavirus 2 infections with evidence of active viral replication, due to inability to mount an adequate humoral response to clear the virus. We present 3 B-cell-depleted patients with prolonged coronavirus disease 2019 infection who were successfully treated with a combination of casirivimab/imdevimab and remdesivir.

Narrowband ultraviolet B phototherapy for the treatment of steroid-refractory and steroid-dependent acute graft-versus-host disease of the skin.

BACKGROUND: Acute graft-versus-host disease (aGvHD) is a common complication of allogeneic stem cell transplantation. It is usually treated with high doses of corticosteroids and other immunosuppressive agents. When cutaneous features are predominant, narrowband ultraviolet B (NB-UVB) phototherapy may be an attractive option for its steroid-sparing effect. OBJECTIVE: We sought to examine the clinical efficacy of NB-UVB in the treatment of steroid-refractory and steroid-dependent cutaneous aGvHD. METHODS: We conducted a retrospective chart review of patients with steroid-refractory and steroid-dependent aGvHD, who received NB-UVB between 2005 and 2009 at our institution. RESULTS: We identified 14 patients with aGvHD treated with NB-UVB between 2005 and 2009. The median number of treatments was 15, administered over a median of 43 days. Eight of 14 patients (57%) achieved a complete response at the end of treatment; an additional 3 patients (21%) achieved a partial response; and 3 patients (21%) showed no improvement at the time when phototherapy was discontinued (nonresponders). Four patients developed chronic graft-versus-host disease (GvHD). Three of the 8 complete responders remained free of GvHD at 6 months' follow-up. LIMITATIONS: The rarity of steroid-refractory aGvHD limited the study to a small number of participants. Because GvHD is variable in its presentation and course, and life-threatening in many cases, large controlled prospective trials for potential therapies are difficult. CONCLUSIONS: NB-UVB is a viable option for the treatment of steroid-refractory and steroid-dependent aGvHD of the skin.

Induction of autologous graft-versus-host disease: results of a randomized prospective clinical trial in patients with poor risk lymphoma.

The results of blood or marrow transplantation in patients with chemorefractory aggressive lymphoma, that is, those not responding to conventional-dose chemotherapy at the time of transplant, have been poor. The relapse rate has been high after autologous bone marrow transplant, whereas allogeneic transplantation has been associated with excessive transplant-related toxicity. Administration of cyclosporine after autologous transplantation can induce an autoreactive syndrome that resembles graft-versus-host disease (GVHD). This syndrome, named autologous graft-versus-host disease, has clear antitumor activity in animal models that can be enhanced by the addition of cytokines such as gamma-interferon and interleukin-2. A randomized, prospective study was conducted to evaluate the antitumor effect of autologous graft-versus-host disease induced with cyclosporine, and augmented by the administration of gamma-interferon and interleukin-2 in patients with chemorefractory Hodgkin and aggressive non-Hodgkin lymphomas. Fifty-one patients were randomized, 24 to the autologous GVHD induction arm, and 27 to the noninduction arm after autologous transplant using mobilized peripheral blood stem cell (PBSC) grafts. There were no differences in treatment-related mortality, overall and event-free survival (OS, EFS) between both groups; however, in the induction arm, GVHD developed only in 4 patients. The administration of oral cyclosporine followed by interleukin-2 and gamma-interferon is generally not well tolerated, and does not appear to be an effective method to induce autologous GVHD in patients receiving autologous PBSC grafts.

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.

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.

Infliximab for steroid-refractory acute GVHD: a case series.

Acute and chronic graft-versus-host disease (GVHD) remain major barriers to successful hematopoietic stem cell transplantation (SCT). TNF-alpha has been implicated in the pathogenesis of GVHD and TNF-alpha blockade has been explored for treatment of GVHD. The development of a chimeric mouse/human monoclonal antibody (infliximab) which binds to cells producing TNF-alpha, allowing for not only the neutralization of TNF-alpha but also lysis of the cells producing the TNF-alpha, makes this an attractive drug to explore in GVHD. We report on 11 patients with acute GVHD who were treated with infliximab after failing other therapies. The survival was very poor, in keeping with previously published reports of steroid-refractory acute GVHD. Two patients with severe diarrhea from acute GI GVHD resolved their symptoms after treatment with infliximab. Only these two patients survived. It appears that of all acute GVHD manifestations, gastrointestinal GVHD may be more responsive to treatment with infliximab than others. Caution is recommended when using this agent since it may exacerbate active infections, particularly aspergillosis. Furthermore, we do not know the correct dose or schedule to use with this drug. Given these data, controlled studies assessing dose and timing of administration may be warranted to study infliximab in acute GVHD.

Pentostatin for the treatment of chronic graft-versus-host disease in children.

Chronic graft-versus-host disease (cGVHD) is a major barrier to successful allogeneic stem cell transplantation. Pentostatin has been used to treat cGVHD in a small series of pediatric patients. The authors report the results of the first five pediatric patients receiving pentostatin for refractory cGVHD at Johns Hopkins Hospital. In this early experience, the authors saw considerable symptom response in their patients. Every patient in this series demonstrated a significant improvement in skin and oral symptoms. An increased incidence of infection secondary to pentostatin was not observed. No patient was permanently discontinued from pentostatin subsequent to side effects. If these promising results continue, a trial of pentostatin as a first-line therapy for cGVHD should be considered to potentially reduce our dependence on high-dose steroids for its treatment.

Gastrointestinal involvement in chronic graft-versus-host disease: a clinicopathologic study.

The original histopathologic description of chronic graft-versus-host disease (CGVHD) of the gastrointestinal (GI) tract was from autopsy series. There is little information on the evaluation of living patients with CGVHD and GI symptoms. We reviewed data on 40 consecutive patients with CGVHD and persistent GI symptoms who underwent endoscopic examinations. The diagnosis of CGVHD in these 40 patients was made on the basis of clinical criteria and confirmed by histology of other involved organs in 70%. Patients had progressive (in 19 patients, or 48%), quiescent (in 11, or 27%) or de novo-type (in 10, or 25%) onset of their CGVHD. Four groups were defined based on the following histologic criteria: (1) consistent with acute GI GVHD if there was marked apoptosis with or without cryptitis, (2) suggestive of acute GI GVHD if there was scattered apoptosis with or without cryptitis, (3) suggestive of chronic GI GVHD if there were at least 2 histologic indicators of chronicity such as fibrosis and significant crypt distortion, and (4) no histologic evidence of GVHD. Results of microbiologic, radiologic, and malabsorption studies, if performed, were also retrieved. Median time from diagnosis of CGVHD to GI endoscopy was 4.5 months (0-109 months). The major GI symptoms at the time of endoscopy were diarrhea, abdominal pain/cramping, nausea/vomiting, weight loss, dysphagia, and early satiety. The endoscopic examination was nonspecific for the diagnosis of GI GVHD except for diffuse mucosal sloughing. Based on the histologic criteria in 22 patients with biopsies, 13 cases (59%) were considered to have acute GI GVHD, and 3 cases (14%) were felt to show possible chronic GI GVHD; changes of both acute and chronic GVHD were seen in 6 (27%) cases. GI dysmotility was diagnosed in 7 (18%) patients, including 2 of the patients who had histologic changes suggestive of chronic GVHD. Other causes of the GI symptoms included infection, drug side effect, and malabsorption. In conclusion, GI involvement by acute GVHD appears to be a major cause of persistent GI symptoms in patients with chronic GVHD. An isolated form of chronic GI GVHD confirmed by histology is an uncommon phenomenon in the actual clinical setting.

Hepatitic variant of graft-versus-host disease after donor lymphocyte infusion.

Graft-versus-host disease (GVHD) of the liver is characterized by bile duct damage and portal lymphocytic infiltrate. We report acute hepatitislike presentation of GVHD after donor lymphocyte infusion (DLI). Between April 1998 and September 2001, 73 patients received 94 DLI treatments. Liver GVHD developed after DLI in 22 (30%) patients whose median age was 43 years (range, 21 to 61 years). Onset of liver dysfunction was at 35 days (range, 11 to 406 days) after DLI. Fifteen patients underwent liver biopsy, and the diagnosis of liver GVHD was confirmed in 13 (87%) patients. After viral hepatitis and recent drug exposure were excluded, 11 (50%) patients were given a diagnosis of a hepatitic variant of GVHD based on histologic evidence of lobular hepatitis (n = 5), elevation of maximum serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level more than 10 times the upper normal limit (n = 9), or both. There was a significant difference in maximum ALT (P =.002) and AST (P =.01) level between the hepatitic-variant and classical GVHD groups. GVHD progressed in 14 (64%) patients, and 10 patients died after a median follow-up of 221 days (range, 31-1284 days). These observations suggest that GVHD that occurs after DLI may have distinct clinical features. Hepatitic-variant GVHD should be considered in the differential diagnosis in DLI recipients with unexplained hepatitis.

Poor outcome in steroid-refractory graft-versus-host disease with antithymocyte globulin treatment.

Treatment of acute graft-versus-host disease (aGVHD) has relied on high-dose steroids, but less than 50% of patients show durable remission. Antithymocyte globulin (ATG) has become a standard salvage therapy. We now report our experience with ATG for the treatment of steroid-refractory GVHD in 69 patients treated from January 1, 1980, to May 1, 1999. Patients with GVHD were given an overall grade using standard criteria. Overall responses were similar to those in previously published literature. However, long-term survival for this group of patients was dismal. Of the 69 patients treated with ATG for steroid-refractory GVHD, only 3 (5%) are currently alive. The median survival of these patients by GVHD grade was 4.1 months for grade 2, 3.6 months for grade 3, and 2.7 months for grade 4. The age range of the surviving patients was 3 to 25 years. Only 5% of the deaths were due to relapse, with the remaining deaths due to GVHD, infection, and/or organ failure. In conclusion, ATG treatment can produce objective responses in patients with aGVHD, but these responses do not result in long-term survival. Given the poor survival rates of patients treated with ATG for steroid-refractory GVHD, treatment with ATG as standard therapy should be reconsidered. Patients with steroid-refractory GVHD should be enrolled in clinical study until there are data to support a standard salvage therapy.