Bone Marrow Transplant

Reduced mortality following bone marrow transplantation for breast cancer with the addition of peripheral blood progenitor cells is due to a marked reduction in veno-occlusive disease of the liver.

Fisher DC. Vredenburgh JJ. Petros WP. Hussein A. Berry DA. Elkordy M. Rubin P. Gilbert CJ. Peters WP.
Bone Marrow Transplant Program, Dept of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Clinical trials involving breast cancer in the Duke University Bone Marrow Transplant Program were evaluated to assess the association between type of hematopoietic support and treatment-related morbidity/mortality. Case histories of patients treated with high-dose chemotherapy and hematopoietic rescue on three separate protocols between 1986 and 1994 were reviewed. This included 307 patients with stage IV disease and 85 patients with high-risk (10 or more positive axillary lymph nodes) stage II or III disease. One hundred and twenty-eight of these patients were rescued with autologous bone marrow (BM) alone and 264 additionally received autologous peripheral blood progenitor cells (PBPC). The 100 day transplant-related mortality rate in those patients who received BM alone was 20.3%, with an overall mortality rate due to the high-dose chemotherapy procedure of 24.2%. The PBPC-treated group experienced a 100 day transplant-related mortality of only 6.1% and an overall trans-plant- related mortality of 10.2%. Sixteen of 31 deaths were attributed to veno-occlusive disease (VOD) in the group that received BM alone compared to only one VOD-related death in the PBPC group. These data demonstrate a marked improvement in transplant-related mortality which is related to the use of PBPC. This effect has been almost entirely due to a reduction in mortality from hepatic veno-occlusive disease.

Use of intravenous immune globulin in addition to antiviral therapy in the treatment of CMV gastrointestinal disease in allogeneic bone marrow transplant patients: a report from the European Group for Blood and Marrow Transplantation (EBMT). Infectious

Year 1998
Ljungman P. Cordonnier C. Einsele H. Bender-Gotze C. Bosi A. Dekker A. De la Camara R. Gmur J. Newland AC. Prentice HG. Robinson AJ. Rovira M. Rosler W. Veil D.
No information.
The best treatment of CMV gastrointestinal disease has been controversial, with some centers adding intravenous (i.v.) Ig to antiviral chemotherapy. The aim of this retrospective survey was to compare the outcome of antiviral chemotherapy with or without i.v. Ig. A questionnaire was sent to centers belonging to the EBMT. Thirty-three patients with CMV gastrointestinal disease were reported, 22 patients were given antiviral chemotherapy alone and 11 patients a combination of antiviral chemotherapy and i.v. Ig. Eighteen of 33 (55%) patients responded to therapy, 13 of those treated with antiviral chemotherapy alone and five (45%) of those treated with the combination (P = NS). Patients with acute GVHD of grades II-IV had significantly worse outcomes than patients with acute GVHD grades 0-I. In a Cox proportional hazards model corrected for acute GVHD there was no difference in outcome of CMV gastrointestinal disease with or without addition of Ig. Survival at 100 days after diagnosis of CMV gastrointestinal disease was 64%. There was no difference in survival in patients treated with or without i.v. Ig. The results of this retrospective survey indicate that addition of i.v. Ig to antiviral chemotherapy might not improve outcome in patients with biopsy-proven CMV gastrointestinal disease.

Hyperbaric oxygen therapy in a case of post-total body irradiation colitis.

Year 1998
Favre C. Ventura A. Nardi M. Massimetti M. Papineschi F. Macchia P.
Bone Marrow Transplant Unit, Institute of Pediatrics, University of Pisa, Italy.
We report a 21-year-old man who experienced symptoms of colitis following autologous TBI-conditioned PBSC transplantation, which persisted despite conventional treatment. Abdominal echography showed a thickened, stratified wall of the cecum, of the right colon and of part of the transverse colon. Hyperbaric oxygen therapy (20 sessions of 100% oxygen inhalation at 2.5 bar for 120 min in a hyperbaric chamber) achieved a prompt clinical recovery as well as complete disappearance of the ultrasound abnormalities.

Pseudomembraneous clostridium after autologous bone marrow transplantation.

Year 1998
Kavan P. Sochor M. Nyc O. Lochmann O. Koutecky J. Skala PJ. McClain LK.
Department of Pediatric Oncology, 2nd Faculty of Medicine, Charles University Hospital Motol, Prague, Czech Republic.
Clostridium difficile (C. difficile) pseudomembraneous colitis was diagnosed in a 13-year-old boy with Hodgkin's disease 3 months after autologous bone marrow transplantation. Hematopoiesis was fully reconstituted at the time. C. difficile infection occurred after gall bladder empyema had been treated conservatively with i.v. antibiotics and prophylactic 4-week administration of oral amoxicillin. C. difficile colitis was diagnosed early and intensive supportive therapy combined with administration of i.v. and subsequently oral vancomycin therapy failed. It is a phenomenon rarely seen and successful eradication of the clostridium infection was only achieved by a combination of higher dose vancomycin with metronidazole. During the post-colitis recovery the patient experienced a relapse of Hodgkin's disease and died following further surgical intervention 137 days post-transplantation.

Reduction in the frequency of transplant-related complications in patients with chronic myeloid leukemia undergoing BMT preconditioned with a new, non-myeloablative drug combination.

Year 1998
Kelemen E. Masszi T. Remenyi P. Barta A. Paloczi K.
National Institute of Hematology and Immunology, Budapest, Hungary.
A radiation-free, non-myeloablative, myelosuppressive protocol, containing dibromomannitol and cytosine arabinoside, that remarkably reduced the frequency of transplant-related complications, such as veno-occlusive liver disease (VOLD), severe mucositis, bacterial sepsis, hemorrhagic cystitis, interstitial pneumonitis, has been applied in 19 CML patients, allotransplanted from identical siblings. Five patients were in accelerated phase. Acute GVHD developed in two patients and chronic GVHD occurred in 66% of patients. Follow-up was 3 to 7 1/2 years. Although only eight patients were under 30 years of age, and only two patients had a history of less than 1 year, the leukemia-free survival was 82%. There were four hematological relapses. The reduction in post-BMT complications has greatly enhanced quality of life. The nurses reported significant reduction of work-load. Savings in eliminating the need for irradiation, parenteral nutrition, and several antibiotics are also remarkable. The remarkable reduction of certain transplant-related complications shows some advantage against busulphan-preconditioning.

Monitoring soluble interleukin-2 receptor levels in related and unrelated donor allogenic bone marrow transplantation.

Year 1998
Foley R. Couban S. Walker I. Greene K. Chen CS. Messner H. Gauldie J.
Department of Pathology, McMaster University, Hamilton, Ontario, Canada.
Acute graft-versus-host disease (GVHD) is effected by donor T lymphocytes which have been stimulated by host antigens. Activated donor T lymphocytes express interleukin-2 receptor (IL-2R), which is comprised of three subunits (alpha, beta, gamma). During activation, the a IL-2R subunit (CD25) is shed from the receptor complex and can be measured in the circulation. Soluble IL-2Ralpha (sIL-2R) levels are increased in states of immune activation including GVHD, and could theoretically be used as a guide to therapy. Since IL-2Ralpha expression is an early marker of T cell activation, we investigated: (1) if an increase in sIL-2R is specific for acute GVHD; and (2) if serial sIL-2R levels can identify patients with early GVHD, prior to the onset of clinical tissue damage (effector function). Weekly sIL-2R levels were monitored in 36 patients undergoing matched related (n=23) or matched unrelated (n=13) allogeneic bone marrow transplantation (BMT). There was no significant difference in sIL-2R levels between matched related and matched unrelated recipients. Patients with acute GVHD (n=19, 53%) demonstrated higher sIL-2R levels, than those without during weeks 2 and 3 post-BMT (P=0.02 and 0.04, Mann-Whitney U test, two-tailed). In patients with acute GVHD, the rise in sIL-2R preceded the clinical signs of GVHD (16/19 patients). However, patients with sepsis demonstrated a trend towards higher sIL-2R levels at week 1 and significantly greater levels by week 4 (P=0.02). Furthermore, patients with veno-occlusive disease (VOD) (25%) also had significantly higher sIL-2R levels at week 2 (P=0.03). We conclude that although sIL-2R levels increase in patients with acute GVHD, similar increases are seen in patients with VOD and/or sepsis and therefore, as a single biochemical marker, we find that serial measurements of sIL-2R lacks sufficient specificity to guide GVHD therapy.

Glutamine and vitamin E in the treatment of hepatic veno-occlusive disease following high-dose chemotherapy.

Year 1998
Goringe AP. Brown S. O'Callaghan U. Rees J. Jebb S. Elia M. Poynton CH.
Department of Haematology, University Hospital of Wales, College of Medicine, Cardiff, UK.
Hepatic veno-occlusive disease (VOD) of the liver is a common complication following high-dose cytotoxic therapy for bone marrow transplantation (BMT). Liver injury is believed to occur following free radical damage to endothelial cells of the sinusoids and small hepatic veins. Glutathione the main antioxidant of the cytosol becomes depleted following chemotherapy. Animal studies have shown that glutamine infusions can maintain glutathione levels and protect against free radical injury. We present two cases of established VOD successfully treated with intravenous glutamine (as dipeptide) and oral vitamin E. Although both cases have possible confounding factors we believe that these give support to the notion that glutamine/vitamin E may have a role in the prophylaxis and treatment of VOD. Further formal trials are indicated.

Hepatic veno-occlusive disease with severe capillary leakage after peripheral stem cell transplantation: treatment with recombinant plasminogen activator and C1-esterase inhibitor concentrate.

Year 1998
Heying R. Nurnberger W. Spiekerkotter U. Gobel U.
Department for Pediatric Hematology and Oncology, Heinrich-Heine-University Medical Center, Dusseldorf, Germany.
Severe veno-occlusive disease (VOD), characterised by elevated serum bilirubin levels, is a known complication in the first 3 weeks after peripheral blood stem cell transplantation (PBSCT). Severe VOD is associated with capillary leakage and multiple organ dysfunction and leads to high mortality. We report a 17-year-old male, who developed VOD with capillary leakage (CL) after allogeneic PBSCT. The patient presented with a maximum serum bilirubin of 25.4 mg/dl, weight gain (10% of baseline weight), generalized edema, cardiovascular insufficiency, complement activation, jaundice and a decreased AT and protein C functional activity. After VOD and CL were diagnosed the patient was treated with recombinant human plasminogen activator (rt-PA) and C1 esterase-inhibitor concentrate (C1-INH-C). The clinical symptoms resolved and the patient's status stabilized. The patient was in an adequate clinical state 5 months after transplantation. We noted that the combined therapy with rt-PA and C1-INH-C in this high-risk situation led to a resolution of VOD with CL.

Bronchiolitis obliterans organizing pneumonia and ulcerative colitis after allogeneic bone marrow transplantation.

Year 1998
Baron FA. Hermanne JP. Dowlati A. Weber T. Thiry A. Fassotte MF. Fillet G. Beguin Y.
Department of Medicine, University of Liege, Belgium.
A 37-year-old man with acute myeloblastic leukemia in first remission developed ulcerative colitis and bronchiolitis obliterans organizing pneumonia (BOOP) 7 months after bone marrow transplantation (BMT) from an HLA-matched brother who suffered from severe Crohn's disease. BOOP occurred 20 days after idiopathic interstitial pneumonia, in the context of severe ulcerative colitis. Lung and colon biopsies showed no signs of CMV infection or GVHD. The patient was treated with oral methylprednisolone 1 mg/kg/day and his clinical status and chest X-ray improved slowly. Remarkably, the symptoms of colitis also resolved with prednisone therapy and he is now symptom-free. We hypothesize that ulcerative colitis may have been transmitted from donor to recipient (adoptive autoimmunity) and that it was complicated by BOOP. However, other factors such as CMV may have contributed to the occurrence of BOOP.

Infections with hepatotropic viruses in children treated with allogeneic bone marrow transplantation.

Year 1998
Locasciulli A. Nava S. Sparano P. Testa M.
Clinica Pediatrica Universita di Milano, Ematologia Pediatrica, Ospedale S. Gerardo, Monza (Milano), Italy. masera@xquasar.it
Patients treated with BMT are extremely susceptible to infection with blood-borne viruses that can cause liver disease of variable clinical severity, from minimal biochemical changes to fulminant hepatic failure. Facing a patient with liver disfunction after BMT, one must bear in mind that more than one cause of liver disease, of viral and/or non-viral origin, may coexist. Moreover, besides the most important hepatotropic viruses, other agents, like herpesviruses (including CMV, adenoviruses, Epstein-Barr virus) may also be implicated, sometimes causing a life-threatening fulminant hepatitis, due to their cytopatic effect. Liver disease history and viral markers before transplant, together with the accurate assessment of the timing and type of clinical and biochemical deterioration are useful tools for a differential diagnosis. Liver biopsy, if taken in the early posttransplant period, is often difficult to interpret, while in case of liver disease occurring during immunosuppression tapering, histologic examination may discriminate between an exacerbation of viral hepatitis and an acute onset of chronic liver GVHD. While it seems that hepatitis G virus does not cause liver disease, the presence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection is a matter of concern for its consequences both early after BMT and for long-term survivors. Despite screening for blood and marrow donors for HBV and, more recently, for HCV markers, the rate of post-transplant infection (4% and 4-15% respectively, confirmed in prospective studies) with those viruses indicates that viral hepatitis still remains an important clinical problem in this setting, although the prognosis of chronic HCV and HBV infection appears more benign than expected, especially in children.

Life-threatening carboplatin hypersensitivity during conditioning for autologous PBSC transplantation: successful rechallenge after desensitization.

Year 1998
Kook H. Kim KM. Choi SH. Choi BS. Kim HJ. Chung SY. Choi SJ. Hwang TJ.
Department of Pediatrics, Chonnam University Medical School, Kwangju, Korea.
Carboplatin hypersensitivity has rarely been reported in patients receiving repeated cycles of therapy, but has not been reported in transplant settings. We report a case of carboplatin hypersensitivity during conditioning for autologous PBSC transplantation. The patient suddenly developed chest tightness, hemoptysis, hypoxia and hypotension, resulting in a transient myocardial ischemia. The pathophysiologic mechanism for the event seemed to be non-immune-mediated direct histamine release given the lack of prior exposure to platinum. Contrary to advice not to continue further treatment with carboplatin by some authors, we successfully desensitized the patient and subsequently gave more carboplatin as a part of conditioning. Awareness of carboplatin as one of the causes of hypersensitivity may help avoid further problems either by substitution or desensitization, along with premedications.

Color-flow imaging sonography of portal and hepatic vein flow to monitor fibrinolytic therapy with r-TPA for veno-occlusive disease following myeloablative treatment.

Year 1998
Sonneveld P. Lameris JS. Cornelissen J. Ogilvie A. Lowenberg B.
Department of Hematology, University Hospital Rotterdam, Dijkzigt, The Netherlands.
Veno-occlusive disease (VOD) is a serious complication of myeloablative therapy and stem cell transplantation. We here describe a case of VOD in a patient with acute myeloid leukemia (AML), who received an autologous peripheral blood stem cell graft after busulphan/cyclophosphamide conditioning in first complete remission and who developed severe VOD at day 17. Color-flow sonography of the portal and hepatic veins revealed hepatofugal blood flow in the portal vein and an absence of flow in the hepatic vein. Treatment with recombinant tissue plasminogen activator (t-PA) was started at a dose of 10 mg/day and increased to 20 mg/day because color-flow sonography indicated no change of blood flow. Daily sonography was continued to monitor the portal and hepatic blood flow in order to assess the need for continuation of t-PA. Once an objective sonographic improvement was observed, t-PA treatment was tapered and stopped. This case demonstrates that color-flow sonography can be used to confirm the clinical diagnosis of VOD. Furthermore this technique provides a way for easily and reliably evaluating the effect in relation to dose of thrombolytic therapy needed. It improves the quality of clinical monitoring which is needed for effective treatment of VOD while minimizing the risk of serious bleeding complications.

IGIV: a potential role for hepatitis B prophylaxis in the bone marrow peritransplant period.

Year 1998
Daily J. Werner B. Soiffer R. Fingeroth J.
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Prevention of hepatitis B virus infection in transplant recipients can be difficult. Patients may be unresponsive to vaccination and intolerant of the intramuscular injections required to administer hepatitis B immune globulin (HBIG). A recipient of HBsAg-positive donor cells for a bone marrow transplant received multiple i.m. injections of HBIG. This mode of antibody delivery was limited by his thrombocytopenia and neutropenia and alternative forms of passive immunization were sought. Four lots of IGIV were investigated for anti-hepatitis B surface antibody (anti-HBs) content and all were found to contain significant antibody titer. Moreover, IGIV that was administered to four bone marrow transplant recipients for medical purposes unrelated to HBV transmission produced protective anti-HBs titers in all. These studies suggest IGIV may be useful for HBV prophylaxis in the appropriate setting or if HBIG is unavailable. The optimum regimen for HBV prevention in distinct transplant settings needs to be determined.