K. Trinkaus

Treatment of steroid-resistant acute graft-versus-host disease with anti-thymocyte globulin

Acute graft-versus-host disease (aGVHD) is a major cause of mortality after allogeneic stem cell transplantation. Although initial treatment with corticosteroids is effective in the majority of patients, 30–60% develop steroid resistance. Anti-thymocyte globulin (ATG) is commonly used as first-line therapy for steroid resistant (SR) aGVHD. However, data on its efficacy are limited. At two institutions we reviewed the results of treatment with ATG of 58 patients with SR aGVHD. Initial manifestations of aGVHD were treated with 2 mg/kg/day of methylprednisolone (MP). Equine ATG was administered as first-line therapy for SR aGVHD, a median of 9 days (range, 3 to 39) after initiation of MP. At the time of initiation of ATG, IBMTR severity indices B, C and D were observed in 6%, 40% and 54% of patients, respectively. Improvement was observed in 30% of patients treated with ATG. Skin disease was more likely to improve with ATG (79%), while progression of gut and liver aGVHD was observed in 40% and 66% of patients, respectively. Despite initial improvement, 52 patients (90%) died a median of 40 days after ATG therapy from progressive aGVHD and/or infection (74%), ARDS (15%), or relapse (11%). Only six patients (10%), three of whom had aGVHD limited to the skin at the time ATG was administered, are long-term survivors. We conclude that initial improvement of SR aGVHD occurs with ATG in a minority of patients, and very few patients become long-term survivors. Furthermore, this treatment is associated with a high rate of major complications. Bone Marrow Transplantation (2001) 27, 1059–1064.

Outcomes of High-Dose Chemotherapy and Autologous Stem-Cell Transplantation in Stage IIIB Inflammatory Breast Cancer

PURPOSE To evaluate the disease-free survival (DFS) and overall survival (OS), prognostic factors, and treatment-related mortality of women with stage IIIB inflammatory breast cancer (IBC) treated with combined modality therapy (CMT) and high-dose chemotherapy (HDCT) with autologous stem-cell transplantation. PATIENTS AND METHODS Between 1989 and 1997, 47 consecutive patients with stage IIIB IBC were treated with CMT and HDCT and were the subject of this retrospective analysis. Chemotherapy was administered to all patients before and/or after definitive surgery. Neoadjuvant and adjuvant chemotherapy was administered to 33 and 34 patients, respectively, and 20 patients received both. All patients received HDCT with autologous stem-cell transplantation, and 41 patients received locoregional radiation therapy. Tamoxifen was prescribed to patients with estrogen receptor (ER)-positive cancer. RESULTS The mean duration of follow-up from diagnosis was 30 months (range, 6 to 91 months) and from HDCT was 22 months (range, 0.5 to 82 months). At 30 months, the Kaplan-Meier estimates of DFS and OS from diagnosis were 57.7% and 59.1%, respectively. At 4 years, the Kaplan-Meier estimates of DFS and OS from diagnosis were 51.3% and 51.7%, respectively. In a multivariate analysis, the only factors associated with better survival were favorable response to neoadjuvant chemotherapy (P =.04) and receipt of tamoxifen (P =.06); however, the benefit of tamoxifen was only demonstrated in patients with ER-positive breast cancer. At last follow-up, 28 patients (59. 6%) were alive and disease-free. Seventeen patients (36.2%) developed recurrent breast cancer. Seventeen patients died: 15 from disease recurrence and two (4.2%) from treatment-related mortality due to HDCT. CONCLUSION In this analysis, the early results of treatment with CMT and HDCT compare favorably with other series of patients with stage IIIB IBC treated with CMT alone. These outcomes must be confirmed with longer follow-up and controlled studies.

Low incidence of transplantation-related acute complications in patients with chronic myeloid leukemia undergoing allogeneic stem cell transplantation with a low-dose (550 cGy) total body irradiation conditioning regimen

Although allogeneic transplantation is a curative therapy for chronic myeloid leukemia (CML), treatment-related mortality is still a major cause of posttransplantation mortality, especially for patients older than 40 years. We investigated, in a phase II trial, the role of a low-dose (550 cGy) high-dose rate (35 cGy/min) single-exposure total body irradiation (TBI) conditioning regimen for allogeneic peripheral blood stem cell (PBSC) transplantation in patients with CML. Between June 1997 and August 2000, 30 adult patients with CML underwent cytokine-mobilized allogeneic PBSC transplantation from HLA-matched siblings following administration of cyclophosphamide (60 mg/kg per day intravenously on days -2 and -1) and single-dose TBI (550 cGy delivered at 30 cGy/min on day 0). Cyclosporine A alone was administered for prophylaxis against graft-versus-host disease (GVHD). Median patient age was 47 years (range, 21-63 years), with 23 patients (77%) older than 40 years. The preparative regimen was well tolerated. Grade 4 toxicities and oral mucositis were not observed. Graft failure did not occur. Severe acute GVHD was observed in 5 patients (17%). The median follow-up was 23 months (range, 6-39 months). Cytogenetic or hematologic relapse was detected in 3 patients (10%), 2 of whom subsequently entered remission following a taper of immunosuppression. Nonrelapse mortality occurred in 5 patients (17%), and the Kaplan-Meier estimate of survival at 2 years was 83% (95% confidence interval, 70%-97%). In summary, this low-dose TBI-based preparative regimen resulted in uniform donor engraftment, with markedly reduced organ toxicity and nonrelapse mortality, in this relatively older cohort of patients with CML.

Does early treatment with high-dose methylprednisolone alter the course of hepatic regimen-related toxicity?

Hepatic regimen-related toxicity (RRT) is a serious complication of stem cell transplantation. Cytokine activation may be involved in the pathogenesis. Corticosteroids are potent inhibitors of cytokine production, and, therefore could play a role in the treatment of hepatic RRT. Between January 1994 and June 1998, 28 of 782 consecutive transplant patients (3.6%) developed hepatic RRT (20 veno-occlusive disease (VOD) and eight liver dysfunction of uncertain etiology (LDUE) as defined by Seattle criteria), and were treated with high-dose methylprednisolone (MP, 500 mg/m2 i.v. every 12 h for six doses), initiated upon increase in serum total bilirubin to ⩾4 mg/dl. Other causes of liver dysfunction were excluded. Response to therapy with high-dose MP was defined as reduction in total bilirubin by 50% within 10 days of initiation of MP. Overall, 17 patients (61%) responded to treatment (12 patients with VOD, five patients with LDUE). The bilirubin in responding patients decreased from a mean of 8.6 mg/dl (range, 4–17.9) at the start of MP to 4.1 mg/dl (range, 0.5–17.9) 10 days later. There were no statistically significant differences between responders and non-responders in the day treatment with high-dose MP was initiated (P = 0.38), total serum bilirubin (P = 0.17) and percent weight gain at the time high-dose MP was started (P = 0.10) or the calculated probability of fatal outcome from VOD (18% for responders, 23% for non-responders; P = 0.30). A lower pre-transplant DLCOc was observed among non-responders (P = 0.04). At 100 days post-transplant, hepatic RRT resolved in all 13 survivors who responded to high-dose MP, and in one non-responding patient. No serious toxicities due to high-dose MP were observed. We conclude that resolution of hepatic RRT occurred in the majority of patients treated with high-dose MP in this study; however, randomized controlled trials are required to determine the efficacy of high-dose MP for treatment of hepatic RRT. Bone Marrow Transplantation (2000) 25, 737–743.

Reduced risk of acute GVHD following mobilization of HLA-identical sibling donors with GM-CSF alone

Summary:We retrospectively reviewed the results of transplanting peripheral blood progenitor cell (PBPC) allografts from HLA-matched sibling donors mobilized using various hematopoietic cytokines. Patients had received allografts mobilized with Granulocyte colony-stimulating factor (G-CSF) (G, N=65) alone, G plus Granulocyte-macrophage colony stimulating factor (GM-CSF) (G/GM, N=70), or GM-CSF alone at 10 or 15 μg/kg/day (GM, N=10 at 10 μg/kg/day and 21 at 15 μg/kg/day). The CD34+ and CD3+ cell content of grafts were significantly lower following GM alone compared to G alone (P<0.001 and 0.04, respectively). Nonhematopoietic toxicity observed in donors precluded dose escalation of GM-CSF beyond 10 μg/kg/day. Hematopoietic recovery was similar among all three groups. Grades II–IV acute graft-versus-host disease (GVHD) was observed in only 13% of patients in the GM alone group compared to 49 and 69% in the G alone or G/GM groups, respectively (P<0.001). In a multivariate analysis, receipt of PBPC mobilized with GM alone was associated with a lower risk of grades II–IV acute GVHD (hazard ratio 0.21; 95% CI 0.073, 0.58) compared to G alone or G/GM. There were no differences in relapse risk or overall survival among the groups. Donor PBPC grafts mobilized with GM-CSF alone result in prompt hematopoietic engraftment despite lower CD34+ cell doses and may reduce the risk of grades II–IV acute GVHD following HLA-matched PBPC transplantation.

Adverse side-effects associated with G-CSF in patients with chronic myeloid leukemia undergoing allogeneic peripheral blood stem cell transplantation

Administration of the myeloid growth factor G-CSF after allogeneic hematopoietic stem cell transplantation is usually well tolerated, and associated with rapid hematopoietic engraftment. We report a high incidence (50%) of side-effects associated with post-transplant G-CSF in patients with chronic phase chronic myeloid leukemia undergoing allogeneic HLA-identical sibling peripheral blood stem cell transplantation. One or more of the following signs and symptoms were observed shortly after the subcutaneous injection of G-CSF: dyspnea, chest pain, nausea, hypoxemia, diaphoresis, anaphylaxis, syncope and flushing. These reactions led to discontinuation of G-CSF in the majority of patients. Predictive factors could not be identified, and the underlying mechanism leading to these reactions is unknown. Bone Marrow Transplantation (2000) 25, 1197–1201.

Oral valganciclovir versus ganciclovir as delayed pre-emptive therapy for patients after allogeneic hematopoietic stem cell transplant: a pilot trial (04-0274) and review of the literature.

Cytomegalovirus (CMV) infection is an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplant (HSCT). This pilot prospective randomized clinical trial compares valganciclovir (VGV) to ganciclovir (GCV) as pre‐emptive therapy for CMV viremia in the post‐allogeneic HSCT population.

Early outcomes after allogeneic hematopoietic SCT in pediatric patients with hematologic malignancies following single fraction TBI

Fractionated TBI (FTBI) followed by allogeneic hematopoietic SCT results in donor engraftment and improves survival in children with high-risk hematologic malignancies. However, acute toxicities (skin, lung and mucosa) are common after FTBI. Late complications include cataracts, endocrine dysfunction, sterility and impaired neurodevelopment. Instead of FTBI, we used low-dose single fraction TBI (550 cGy) with CY as transplant conditioning for pediatric hematologic malignancies. GVHD prophylaxis included CYA and short-course MTX; methylprednisolone was added for unrelated donor transplants. A total of 55 children in first (40%) or second remission and beyond (60%) underwent transplantation from BM (65%) or peripheral blood; 62% from unrelated donors; 22% were mismatched. Median follow-up was 18.5 months (1–68). Overall survival and disease-free survival at 1 year were 60 and 47%, respectively. Acute toxicities included grade 3–4 mucositis (18%), invasive infections (11%), multiorgan failure/shock (11%), hemolytic anemia (7%), veno-occlusive disease (4%) and renal failure (4%). TRM was 11% at 100 days. Non-relapse mortality was 6% thereafter. Graft rejection occurred in 2%. Three patients (5%) died of GVHD. The regimen was well tolerated even in heavily pretreated children and supported donor cell engraftment; long-term follow up is in progress.

Outcomes of high-dose chemotherapy and autologous stem cell transplant in isolated locally recurrent breast cancer: a multicenter evaluation

To determine the outcomes of women with isolated loco-regional recurrence (LRR) of breast cancer treated with high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) following conventional therapy, we conducted a retrospective review of 58 patients from five institutions treated between 1990 and 1998. Forty-five patients (78%) had ⩾2 poor prognostic factors (PPF) (defined as disease-free interval preceding LRR ⩽2 years, hormone receptor negative/refractory disease, and incomplete resection). At median follow-up of 14.2 (0.5–72) months, 36 patients (62%) developed progressive disease. Disease progression usually occurred at local (27 patients) vs distant (nine patients) sites. Median time to disease progression following ASCT was 6.1 (1.3–31.4) months. At last follow-up, 23 patients (40%) had expired (all due to disease progression), and 13 (22%) were alive with, and 22 (38%) without progressive disease. By Kaplan–Meier analysis, the estimated median PFS and OS was 20.3 and 29.2 months, respectively. In a multivariate model, complete remission at time of HDCT and estrogen-receptor positive disease were predictive of significantly longer PFS and OS. The survival of this cohort was similar to previous reports of those treated with conventional therapy alone, and to those with distant metastases treated with HDCT. Frequent progression locally, suggests that strategies to improve local disease control are needed. Bone Marrow Transplantation (2000) 26, 947–953.