Friedrich Schuening

Autologous hematopoietic stem cell transplantation in refractory rheumatoid arthritis: Sustained response in two of four patients

OBJECTIVE To investigate the safety and efficacy of immune ablation with subsequent autologous hematopoietic stem cell transplantation (HSCT) in severe rheumatoid arthritis (RA). METHODS Four patients with refractory RA and poor prognostic indicators were treated. Stem cells were collected and lymphocytes were depleted by 2.3-4.0 logs. The conditioning regimen included cyclophosphamide (200 mg/kg), antithymocyte globulin (90 mg/kg), and, for 1 patient, total body irradiation (TBI) with 400 cGy. Improvement was evaluated according to the American College of Rheumatology (ACR) preliminary definition of improvement in RA (ACR 20), and also according to the ACR 50 and ACR 70 criteria. RESULTS HSCT was well tolerated. Three patients fulfilled the ACR 70 criteria at 1 month and 3 months post-HSCT. One patient did not fulfill the ACR 20 criteria because of persistent joint tenderness, despite improvement of the joint swelling. At 6 months post-HSCT, 1 patient fulfilled the ACR 70 criteria and 1 fulfilled the ACR 50 criteria, and these 2 patients fulfilled the ACR 70 criteria at 9 months post-HSCT. The other 2 patients (including the patient who received TBI) did not meet the ACR 20 criteria at 6 months and 9 months post-HSCT. The only patient with followup of >9 months fulfilled the ACR 70 criteria at 20 months post-HSCT. CONCLUSION In this series, autologous HSCT was safe and effective in inducing major clinical response and maintained significant benefit for 2 patients at 9 months and 20 months posttreatment, respectively. Sustained response did not occur for 2 of 4 patients. A regimen dose-response effect may exist, but the addition of TBI did not prevent disease relapse for 1 of the patients. More aggressive T cell depletion of the autograft, use of a myeloablative regimen, or use of an allograft may be necessary to decrease relapse rates.

Marrow toxicity of fractionated vs. single dose total body irradiation is identical in a canine model

PURPOSE We explored in dogs the marrow toxicity of single dose total body irradiation delivered from two opposing 60Co sources at a rate of 10 cGy/min and compared results to those seen with total body irradiation administered in 100 cGy fractions with minimum interfraction intervals of 6 hr. Dogs were not given marrow transplants. RESULTS We found that 200 cGy single dose total body irradiation was sublethal, with 12 of 13 dogs showing hematopoietic recovery and survival. Seven of 21 dogs given 300 cGy single dose total body irradiation survived compared to 6 of 10 dogs given 300 cGy fractionated total body irradiation (p = .18). One of 28 dogs given 400 cGy single dose total body irradiation survived compared to none of six given fractionated radiation (p > .20). With granulocyte colony stimulating factor administered from day 0-21 after 400 cGy total body irradiation, most dogs survived with hematological recovery. Because of the almost uniform success with granulocyte colony stimulating factor after 400 cGy single dose total body irradiation, a study of granulocyte colony stimulating factor after 400 cGy fractionated total body irradiation was deemed not to be informative and, thus, not carried out. Additional comparisons between single dose and fractionated total body irradiation were carried out with granulocyte colony stimulating factor administered after 500 and 600 cGy of total body irradiation. As with lower doses of total body irradiation, no significant survival differences were seen between the two modes of total body irradiation, and only 3 of 26 dogs studied survived with complete hematological recovery. Overall, therefore, survival among dogs given single dose total body irradiation was not different from that of dogs given fractionated total body irradiation (p = .67). Similarly, the slopes of the postirradiation declines of granulocyte and platelet counts and the rates of their recovery in surviving dogs given equal total doses of single versus fractionated total body irradiation were indistinguishable. CONCLUSION Within the limitations of the experimental design, we conclude that single-dose and fractionated total body irradiation have comparable marrow toxicity in dogs.

Extracorporeal photopheresis in patients with refractory bronchiolitis obliterans developing after allo-SCT

Extracorporeal photopheresis (ECP) has been shown to be a promising treatment for chronic graft-versus-host disease; however, only a few case reports are available that examine the effectiveness of ECP for bronchiolitis obliterans (BO) after allo-SCT. Because of the poor response to traditional therapies, ECP has been explored as a possible therapeutic option for severe BO after allo-SCT. Nine patients received ECP between July 2008 and August 2009 after a median follow-up of 23 months (range 9–93 months) post transplant. The primary indication for ECP was the development of BO in patients who had failed prior multidrug regimens. The median number of drugs used for BO management before ECP was 5 (range 2–7); this included immunosuppressive therapy. Six of nine (67%) patients responded to ECP after a median of 25 days (range 20–958 days). No ECP-related complications occurred. ECP seemed to stabilize rapidly declining pulmonary function tests in about two-thirds of patients with severe and heavily pretreated BO that developed after allo-SCT. This finding supports the need for a larger prospective study to confirm the impact of ECP on BO, and to consider earlier intervention with ECP to improve the outcome of BO after allo-SCT.

Classic and Overlap Chronic Graft-versus-Host Disease (cGVHD) Is Associated with Superior Outcome after Extracorporeal Photopheresis (ECP)

The National Institutes of Health (NIH) classification of graft-versus-host disease (GVHD) is a significant improvement over prior classifications, and has prognostic implications. We hypothesized that the NIH classification of GVHD would predict the survival of patients with GVHD treated with extracorporeal photopheresis (ECP). Sixty-four patients with steroid refractory/dependent GVHD treated with ECP were studied. The 3-year overall survival (OS) was 36% (95% confidence interval [CI] 13-59). Progressive GVHD was seen in 39% of patients with any acute GVHD (aGVHD) (classic acute, recurrent acute, overlap) compared to 3% of patients with classic chronic GVHD (cGVHD) (P=.002). OS was superior for patients with classic cGVHD (median survival, not reached) compared to overlap GVHD (median survival, 395 days, 95% CI 101 to not reached) and aGVHD (delayed, recurrent or persistent) (median survival, 72 days, 95% CI 39-152). In univariate analyses, significant predictors of survival after ECP included GVHD subtype, bilirubin, platelet count, and steroid dose. In multivariate analyses overlap plus classic cGVHD was an independent prognostic feature predictive of superior survival (hazard ratio [HR] 0.34, 95% CI 0.14-0.8, p=.014). This study suggests that NIH classification can predict outcome after ECP for steroid refractory/dependent GVHD.

Pegfilgrastim after high-dose chemotherapy and autologous peripheral blood stem cell transplant: phase II study.

Summary:Pegfilgrastim is equivalent to daily filgrastim after standard dose chemotherapy in decreasing the duration of neutropenia. Daily filgrastim started within 1–4 days after autologous stem cell transplant (ASCT) leads to significant decrease in time to neutrophil engraftment. We undertook a study of pegfilgrastim after high-dose chemotherapy (HDC) and ASCT. In all, 38 patients with multiple myeloma or lymphoma, eligible to undergo HDC and ASCT, were enrolled. Patients received a single dose of 6 mg pegfilgrastim subcutaneously 24 h after ASCT. There were no adverse events secondary to pegfilgrastim. All patients engrafted neutrophils and platelets with a median of 10 and 18 days, respectively. The incidence of febrile neutropenia was 49% (18/37). Neutrophil engraftment results were compared to a historical cohort of patients who received no growth factors or prophylactic filgrastim after ASCT. Time to neutrophil engraftment using pegfilgrastim was comparable to daily filgrastim and was shorter than in a historical group receiving no filgrastim (10 vs 13.7 days, P<0.001). Pegfilgrastim given as a single fixed dose of 6 mg appears to be safe after HDC and ASCT. It accelerates neutrophil engraftment comparable to daily filgrastim after ASCT. Pegfilgrastim may be convenient to use in outpatient transplant units.

Prevention of transfusion-induced sensitization to minor histocompatibility antigens on DLA-identical canine marrow grafts by gamma irradiation of marrow donor blood

Dogs given total-body irradiation and marrow transplants from DLA-identical littermates exhibit prompt and sustained hematopoietic engraftment. However, animals given three preceding blood transfusions from the marrow donor before transplant become sensitized and reject the marrow graft. Rejection is due to exposure to polymorphic minor non-DLA histocompatibility antigens expressed on blood mononuclear cells. We sought to determine whether heat treatment would prevent blood from sensitizing recipients in this model since heating blood to 45°C for 45 min abrogates the ability of blood mononuclear cells to stimulate in mixed lymphocyte culture. Three of 4 evaluable dogs given heat-treated blood before transplant rejected their marrow grafts. To prevent possible reexpression/reacquisition of mononuclear cell functional activity in vivo after transfusion, subsequent dogs were given heated blood that was additionally exposed to 2000 cGy gamma irradiation. Eight of 10 evaluable dogs given blood treated in this fashion engrafted. Unexpectedly, 9 out of 10 evaluable dogs transfused with blood treated only with gamma irradiation also engrafted. These results demonstrate that treatment of blood with gamma irradiation alone or in combination with heat prevents transfusion-induced sensitization to minor histocompatibility antigens. Results from this canine model suggest that blood products be gamma irradiated before transfusion in patients who are transplant candidates in order to prevent sensitization to minor histocompatibility antigens and reduce the risk of marrow graft rejection.

Regulatory T cell expression of CLA or α 4 β 7 and skin or gut acute GVHD outcomes

Regulatory T cells (Tregs) are a suppressive subset of CD4+ T lymphocytes implicated in the prevention of acute GVHD (aGVHD) after allo-SCT (ASCT). To determine whether increased frequency of Tregs with a skin-homing (cutaneous lymphocyte Ag, CLA+) or a gut-homing (α4β7+) phenotype is associated with reduced risk of skin or gut aGVHD, respectively, we quantified circulating CLA+ or α4β7+ on Tregs at the time of neutrophil engraftment in 43 patients undergoing ASCT. Increased CLA+ Tregs at engraftment was associated with the prevention of skin aGVHD (2.6 vs 1.7%; P=0.038 (no skin aGVHD vs skin aGVHD)), and increased frequencies of CLA+ and α4β7+ Tregs were negatively correlated with severity of skin aGVHD (odds ratio (OR), 0.67; 95% confidence interval (CI), 0.46–0.98; P=0.041) or gut aGVHD (OR, 0.93; 95% CI, 0.88–0.99; P=0.031), respectively. This initial report suggests that Treg tissue-homing subsets help to regulate organ-specific risk and severity of aGVHD after human ASCT. These results need to be validated in a larger, multicenter cohort.

Genetic variation in recipient B-cell activating factor modulates phenotype of GVHD

B-cell activating factor (BAFF) single nucleotide polymorphisms (SNPs) are associated with autoimmune diseases. Because patients with classic and overlap chronic GVHD (cGVHD) have features of autoimmune diseases, we studied the association of recipient and/or donor BAFF SNPs with the phenotype of GVHD after allogeneic stem cell transplantation. Twenty tagSNPs of the BAFF gene were genotyped in 164 recipient/donor pairs. GVHD after day 100 occurred in 124 (76%) patients: acute GVHD (aGVHD) subtypes (n = 23), overlap GVHD (n = 29), and classic cGVHD (n = 72). In SNP analyses, 9 of the 20 tag SNPs were significant comparing classic/overlap cGVHD versus aGVHD subtypes/no GVHD. In multivariate analyses, 4 recipient BAFF SNPs (rs16972217 [odds ratio = 2.72, P = .004], rs7993590 [odds ratio = 2.35, P = .011], rs12428930 [odds ratio2.53, P = .008], and rs2893321 [odds ratio = 2.48, P = .009]) were independent predictors of GVHD subtypes, adjusted for conventional predictors of cGVHD. This study shows that genetic variation of BAFF modulates GVHD phenotype after allogeneic stem cell transplantation.

Addition of high-dose Ara-C to the BMT conditioning regimen reduces leukemia relapse without an increase in toxicity

The optimal conditioning regimen for allogeneic BMT for hematological malignancies is still to be determined. We used a conditioning regimen including high-dose Ara-C (HDAC)/CY/TBI for patients at high risk for leukemic relapse (regimen A, Ara-C 3 g/m2 every 12 h for six doses followed by CY 45 mg/kg for 2 days and TBI 13.2 Gy in eight fractions) and a standard CY/TBI conditioning regimen for patients at low risk (regimen B, CY 60 mg/kg for 2 days and TBI 13.2 Gy in eight fractions). We analyzed 55 patients treated with regimen A (group A) and 36 patients with regimen B (group B). Relapse rates (10.9% in group A, 2.9% in group B, P = 0.23), 5-year overall (53.2% in group A and 60.8% in group B, P = 0.26) and disease-free (47.7% in group A and 60.8% in group B, P = 0.11) survival rates were not significantly different between these groups, although group A consisted of high-risk patients. Regimen-related toxicities were not significantly different between the two groups. This result suggests that adding HDAC to CY/TBI conditioning regimen may reduce leukemic relapse and improve survival without increasing regimen-related toxicities.

Valacyclovir for the prevention of cytomegalovirus infection after allogeneic stem cell transplantation: a single institution retrospective cohort analysis

A retrospective single center study was performed to evaluate the safety and efficacy of valacyclovir for prevention of cytomegalovirus (CMV) infection (reactivation) after allogeneic stem cell transplantation (SCT). We compared a group of 31 patients at risk for CMV reactivation (donor, recipient or both seropositive for CMV) who received valacyclovir at an oral dose of 1 g three times a day for CMV prophylaxis with a matched cohort of 31 patients who did not receive the drug or any other form of CMV prophylaxis. Valacyclovir was used as primary prophylaxis in 12 patients and as secondary prophylaxis (after a prior CMV reactivation was effectively treated with either ganciclovir or foscarnet and without CMV antigenemia at the start of valacyclovir) in the remaining 19 patients. The two treatment groups were well matched for the donor–recipient CMV serological status and other pre-transplant characteristics. CMV reactivation was detected by blood antigenemia testing using a commercially available immunofluorescence assay for CMV lower matrix protein pp65 in circulating leukocytes. For primary prophylaxis, 3/12 patients who received valacyclovir reactivated CMV compared to 24/31 patients in the control group (P < 0.001). For secondary prophylaxis, 5/19 valacyclovir patients reactivated compared to 16/24 control patients (P < 0.05). Valacyclovir was well tolerated except for infrequent and mild gastrointestinal side-effects. There was no difference in the incidence of CMV disease in the two groups. Prophylaxis with valacyclovir appears to be safe and efficacious in preventing both primary and secondary CMV reactivation in at-risk patients after allogeneic SCT. Larger prospective randomized studies will be required to confirm these observations. Bone Marrow Transplantation (2001) 28, 265–270.