Jan-Erik Johansson

Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience

Background Autologous haematopoietic stem cell transplantation (HSCT) is a viable option for treatment of aggressive multiple sclerosis (MS). No randomised controlled trial has been performed, and thus, experiences from systematic and sustained follow-up of treated patients constitute important information about safety and efficacy. In this observational study, we describe the characteristics and outcome of the Swedish patients treated with HSCT for MS. Methods Neurologists from the major hospitals in Sweden filled out a follow-up form with prospectively collected data. Fifty-two patients were identified in total; 48 were included in the study and evaluated for safety and side effects; 41 patients had at least 1 year of follow-up and were further analysed for clinical and radiological outcome. In this cohort, 34 patients (83%) had relapsing-remitting MS, and mean follow-up time was 47 months. Results At 5 years, relapse-free survival was 87%; MRI event-free survival 85%; expanded disability status scale (EDSS) score progression-free survival 77%; and disease-free survival (no relapses, no new MRI lesions and no EDSS progression) 68%. Presence of gadolinium-enhancing lesions prior to HSCT was associated with a favourable outcome (disease-free survival 79% vs 46%, p=0.028). There was no mortality. The most common long-term side effects were herpes zoster reactivation (15%) and thyroid disease (8.4%). Conclusions HSCT is a very effective treatment of inflammatory active MS and can be performed with a high degree of safety at experienced centres.

Intestinal permeability in cirrhotic patients with and without ascites

Objective. It has been suggested that increased intestinal permeability plays a pathogenic role in bacterial infections, such as spontaneous bacterial peritonitis, in patients with liver cirrhosis. The aim of this study was to assess whether intestinal permeability is altered in cirrhotic patients with and without ascites. Material and methods. Intestinal permeability was assessed by a 51Cr-EDTA permeability test in 20 cirrhotic patients (10 with and 10 without ascites) along with 20 age- and gender-matched healthy controls. In six patients with ascites, the test was performed before and after therapeutic paracentesis. Results. The median (IQR) 24-h urinary excretion of 51Cr-EDTA was higher in patients with cirrhosis (1.94% (1.21–2.70%)) compared with that in controls (1.40% (1.09–1.99%); p<0.05). Patients with (2.05% (1.50–3.46%); p<0.05) but not those without ascites (1.94% (1.13–2.53%); p>0.1) had significantly higher excretion values compared with those of controls. Only one patient without ascites and a total of four patients with ascites had increased intestinal permeability (51Cr-EDTA excretion > 95% confidence than that of controls; p>0.1). Paracentesis did not affect urinary 51Cr-EDTA excretion significantly (1.69% (1.16–2.86%) versus 1.30% (1.08–1.79%) before and after, respectively; p>0.1). No significant correlation was found between clinical severity scores for liver disease and intestinal permeability. Conclusions. Only a small proportion of patients with liver cirrhosis have increased intestinal permeability and it is unlikely that this plays any major role in predisposing these patients to infections.

The gut mucosa barrier is preserved during allogeneic, haemopoietic stem cell transplantation with reduced intensity conditioning.

The efficacy of allogeneic, haemopoietic stem cell transplantation (HSCT) is limited by concomitant toxicity. This has led to the development of less toxic, reduced intensity conditioning (RIC) protocols, whose therapeutic benefit is largely related to an associated, immunity-mediated graft-versus-malignancy effect rather than by the cytotoxic treatment itself. Murine HSCT models suggests that acute graft-versus-host disease (GVHD) increases with the intensification of the conditioning regimen mediated by loss of integrity of the gut mucosa barrier. The present study was undertaken to investigate gastro-intestinal (GI) permeability during allogeneic HSCT with RIC. In 17 patients (myeloablative conditioning in nine, RIC in eight), intestinal permeability was assessed by a 51Cr-EDTA absorption test before the start of cytotoxic treatment the day before stem cell infusion (day −1) and 4, 7 and 14 days after stem cell infusion. Patients receiving RIC did not develop any significant increase in intestinal permeability during the transplantation course but in myeloablatively conditioned patients there was a significant increase in intestinal permeability the day before the stem cell infusion (P < 0.005), on day 4 (P < 0.005), on day 7 (P < 0.01) and on day 14 (P < 0.005) after stem cell infusion, compared with the baseline. Myeloablative conditioning also revealed increased intestinal permeability on day 7 compared with the RIC (P < 0.05). The finding of preserved intestinal-barrier function during allogeneic HSCT with RIC is discussed, with reference to the hypothesis that GI tract damage may be an important initiating event of GVHD. Bone Marrow Transplantation (2001) 28, 737–742.

Gut Toxicity During Hemopoietic Stem Cell Transplantation May Predict Acute Graft-Versus-Host Disease Severity in Patients

Graft-versus-host disease (GVHD) is the primary complication of allogeneic, hemopoietic, stem cell transplantation (HSCT). Murine models suggest that gut toxicity, induced by the intensive chemotherapy preceding hematopoietic stem cell infusion, aggravates systemic GVHD. In HSCT patients gut toxicity correlates with chemotherapy intensity. The present study investigates acute GVHD severity and intestinal toxicity in patients undergoing allogeneic HSCT. In 38 patients intestinal permeability was assessed before and after chemotherapy (on days −1, +4, +7 and +14 as related to the stem cell infusion). Cumulative acute GVHD (days 0–100) and clinical intestinal toxicity (days 0–14) were evaluated in parallel. Patients with mild, acute GVHD (grades 0–I) had better-preserved intestinal barrier function (P=0.04) and less pronounced cumulative clinical intestinal toxicity (P=0.02) compared with patients with more severe acute GVHD (grades II–IV). Gut toxicity predicts acute GVHD severity. Therefore, gut protective strategies may diminish GVHD severity in allogeneic HSCT patients.

Gut protection by palifermin during autologous haematopoietic SCT

Conditioning therapy in connection with haematopoietic SCT (HSCT) induces a disruption of the intestinal barrier function facilitating the permeation of bacteria and endotoxin through the bowel wall with subsequent increased risk of septicaemia and a worsening of GVHD in the allogeneic setting. Palifermin (recombinant human keratinocyte growth factor) reduces the severity of oral mucositis with HSCT. The present trial investigates its effect on intestinal barrier function. Seventeen lymphoma patients undergoing autologous HSCT received palifermin. Intestinal permeability was assessed before the conditioning therapy and on days +4 and +14. Clinical oral and gastrointestinal toxicity was prospectively assessed in parallel. A comparison was made with matched historical study patients (n=21). Patients treated with palifermin had a significantly better preserved intestinal barrier function (P=0.01 on day +4) and were in less need of total parenteral nutrition (P=0.005) as compared with controls. No significant reduction of clinical gastrointestinal or oral toxicity was observed. The intestinal barrier function, normally disrupted by the conditioning therapy, is preserved by palifermin. Whether intestinal barrier preservation protects from invasive infections, and in the allogeneic setting diminishes GVHD severity, remains to be investigated in randomized controlled trials.

Allogeneic hematopoietic stem cell transplant with reduced-intensity conditioning for chronic lymphocytic leukemia in Sweden: does donor T-cell engraftment 3 months after transplant predict survival?

Abstract Thirty-eight adult patients with chronic lymphocytic leukemia (CLL) underwent reduced-intensity conditioning (RIC) allogeneic stem cell transplant (allo-SCT) in Sweden between 1999 and 2007. The cumulative incidences of acute graft-versus-host disease (GVHD) grades II–IV and chronic GVHD were 29% and 47%, respectively. Rates of non-relapse mortality, progression-free survival (PFS) and overall survival (OS) were 18%, 47% and 74% at 1 year, and 21%, 25% and 45% at 5 years, respectively. T-cell chimerism after transplant was measured in 31 out of 34 patients (91%) surviving beyond day +100. Seventeen patients achieved >90% donor T-cell engraftment at 3 months after allo-SCT and, compared with the 12 patients with ≤90% donor T-cell engraftment, they showed favorable PFS at 1 year (82% vs. 33%, p =0.002) and better long-term PFS and OS (p =0.002 and 0.046, respectively). Donor T-cell engraftment of >90% at 3 months after RIC allo-SCT for CLL seems to predict favorable short-term and long-term outcome.

Colonoscopy and Sigmoidoscopy are Equally Effective for the Diagnosis of Colonic Acute Graft-versus-Host Disease in Patients with Diarrhea after Allogeneic Stem Cell Transplantation: A Prospective Controlled Trial.

Colonic acute graft-versus-host disease (aGVHD) affects approximately 10% of patients who have undergone allogeneic stem cell transplantation (allo-SCT). Diarrhea is a major clinical sign but also a common post-transplantation symptom in these patients. Comprehensive histopathologic examination of the colon is therefore regarded as crucial to establish a diagnosis, but the colonic segment that should be targeted for a diagnostic biopsy remains a topic of debate. The primary objective of this study was to compare prospectively colonoscopy with sigmoidoscopy regarding their capabilities to provide a histopathologically proven diagnosis of colonic aGVHD. Thirty-seven allo-SCT patients with diarrhea all underwent a colonoscopy. All biopsies collected from the descending colon were regarded as also attainable by sigmoidoscopy, whereas biopsies collected in regions further up the colon (from the transverse and ascending colon) were regarded as acquirable exclusively by colonoscopy. Biopsies attainable by colonoscopy and sigmoidoscopy were positive for GVHD in 25 (68%) and 24 (65%) patients, respectively (95% confidence interval for difference of proportions, -.185 to .245; P = .978; z = .0271 by the z-test). Sigmoidoscopy is as effective as colonoscopy in establishing a diagnosis of colonic aGVHD in patients who have diarrhea after allo-SCT.

Partially erupted third molars as a potential source of infection in patients receiving peripheral stem cell transplantation for malignant diseases: a retrospective study.

Forty-four patients with malignant diseases for which they received peripheral stem cell transplant therapy (PSCT) were retrospectively studied regarding local and systemic infection originating from around partially erupted third molars (PEMs). Twenty-two patients had one or more PEMs, while 22 patients had none. Data were retrieved from medical and dental records. Systemic and local signs of infection and treatment were assessed. We recorded the number of transplanted CD34(+) blood stem cells, days with white blood cell counts < 0.5 x 10(9) l(-1), days until engraftment, maximum level of C-reactive protein (CRP), days with fever, positive blood cultures, days taking antibiotics, days drinking < 0.5 l, days of total parenteral nutrition, days receiving intravenously administered analgesics, and number of admission days. No statistically significant difference was detected between patients with PEMs and those without PEMs regarding any of the studied parameters. Of patients with PEMs, 36% (8 of 22) developed local infections around PEMs during the PSCT period. The study indicates that PEMs pose no significant risk of causing systemic infection in patients receiving PSCT for malignant diseases but increase the risk of developing a local infection, justifying close supervision and early treatment in cases of local infection during PSCT treatment.

Allogeneic stem cell transplantation in patients with atypical chronic myeloid leukaemia: a retrospective study from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation

Atypical chronic myeloid leukaemia (aCML) is an aggressive malignancy for which allogeneic haematopoietic stem cell transplantation (allo‐HSCT) represents the only curative option. We describe transplant outcomes in 42 patients reported to the European Society for Blood and Marrow Transplantation (EBMT) registry who underwent allo‐HSCT for aCML between 1997 and 2006. Median age was 46 years. Median time from diagnosis to transplant was 7 months. Disease status was first chronic phase in 69%. Donors were human leucocyte antigen (HLA)‐identical siblings in 64% and matched unrelated (MUD) in 36%. A reduced intensity conditioning was employed in 24% of patients. T‐cell depletion was applied in 87% and 26% of transplants from MUD and HLA‐identical siblings, respectively. According to the EBMT risk‐score, 45% of patients were ‘low‐risk’, 31% ‘intermediate‐risk’ and 24% ‘high‐risk’. Following allo‐HSCT, 87% of patients achieved complete remission. At 5 years, relapse‐free survival was 36% and non‐relapse mortality (NRM) was 24%, while relapse occurred in 40%. Patient age and the EBMT score had an impact on overall survival. Relapse‐free survival was higher in MUD than in HLA‐identical sibling HSCT, with no difference in NRM. In conclusion, this study confirmed that allo‐HSCT represents a valid strategy to achieve cure in a reasonable proportion of patients with aCML, with young patients with low EBMT risk score being the best candidates.

Long-term survival following allogeneic or syngeneic stem cell transplant for follicular lymphoma in Sweden.

Long-term survival following allogeneic or syngeneic stem cell transplant for follicular lymphoma in Sweden