J Aschan

Risk factors for chronic graft-versus-host disease after bone marrow transplantation: a retrospective single centre analysis.

Among 551 consecutive recipients of allogeneic bone marrow transplants, 451 survived more than 3 months and were evaluated for chronic graft-versus-host disease (GVHD). Most of the donors were HLA-identical siblings or parents (n = 334). Patients with HLA-mismatched donors (n = 30) and matched unrelated donors (MUD) (n = 87) were also included in the study. In the analysis of all patients, the 5-year cumulative incidence of chronic GVHD was 45%. We analysed 34 risk factors. High recipient age was the single most important risk factor (P < 0.001). other significant risk factors in multivariate analysis were: acute gvhd grades i–iv (P < 0.001), immune female donor to male recipient (P = 0.006) and chronic myelogenous leukaemia (CML), compared with all other diagnoses (P = 0.014). The cumulative 5-year incidence of chronic GVHD, with no significant risk factors present, was 9%, 29% with one risk factor, 53% with two, 68% with three and 75% with all four risk factors present. In patients with HLA-identical sibling donors and GVHD prophylaxis consisting of a combination of methotrexate (MTX) and cyclosporin A (CsA) (n = 208), increasing recipient age (P < 0.001) and cml (P = 0.007), were found to be significant risk factors for chronic GVHD. Finally, a multivariate analysis in recipients of bone marrow from unrelated donors (n = 89) showed recipient age alone (P = 0.006) to be significantly associated with chronic GVHD.

Risk factors for fatal infectious complications developing late after allogeneic stem cell transplantation

Infectious complications remain a major problem contributing to significant mortality after hematopoietic allogeneic stem cell transplantation (HSCT). Few studies have previously analyzed mortality due to late infections. Forty-four patients dying from an infectious complication were identified from a cohort of 688 consecutive patients surviving more than 6 months without relapse. A control group of 162 patients was selected using the year of HSCT as the matching criterion. Out of 44 patients, 30 (68%) died from pneumonia, 7/44 (16%) from sepsis, 5/44 (11%) from central nervous system infection and 2/44 (4.5%) from disseminated varicella. The cumulative incidences of different types of infection were 1.6% for viral, 1.5% for bacterial and 1.3% for fungal infections and 0.15% for Pneumocystis jirovecii pneumonia. The majority (66%) of the lethal infections occurred within 18 months after HSCT. Acute GVHD (relative risk (RR): 7.19, P<0.0001), chronic GVHD (RR: 6.49, P<0.001), CMV infection (RR: 4.69, P=0.001), mismatched or unrelated donor (RR: 3.86, P=0.004) and TBI (RR: 2.65, P=0.047) were independent risk factors of dying from a late infection. In conclusion, infections occurring later than 6 months after HSCT are important contributors to late non-relapse mortality after HSCT. CMV infection or acute GVHD markedly increase the risk.

Treatment of severe acute graft‐versus‐host disease with anti‐thymocyte globulin

Severe acute graft‐versus‐host disease (GVHD) is one of the major complications after haematopoietic stem‐cell transplantation (HSCT). Treatment of severe GVHD is difficult and the condition is often fatal. One proposed method of improving the therapy is to include anti‐thymocyte globulin (ATG). Here, we will report our results in 29 patients using ATG as part of treatment for severe steroid‐resistant acute GVHD. Four patients suffered from grade II, 13 from grade III and 12 from grade IV GVHD. Median time to grade II GVHD was 24 d (range 7–91 d) and to grade III was 29 d (range 8–55 d) after HSCT. Five different ATG preparations were used, rabbit ATG (R‐ATG), BMA 031, OKT®‐3, ATG‐Fresenius and Thymoglobuline®. All patients had skin involvement, 26 also had gut involvement and 25 had liver involvement. The rate of response to treatment was best in skin involvement (72%), while liver and gut involvement showed lower response rates (38%). Eleven patients survived more than 90 d, 7 of them developed chronic GVHD, 1 developed mild GVHD, 1 developed moderate GVHD and 5 developed severe GVHD. Survival at 100 d was 37% and at 1 yr it was 12%. Most patients died of GVHD, with virus or fungal infections as contributing causes of death. u2028 To conclude, treatment of severe acute GVHD is difficult and ATG, in our hands, adds nothing to conventional pharmacological treatment.

N-acetylcysteine for hepatic veno-occlusive disease after allogeneic stem cell transplantation

Three patients developed veno-occlusive disease of the liver (VOD) after allogeneic stem cell transplantation. On the day after diagnosis, N-acetylcysteine (NAC) was given, initially in loading doses and thereafter 50–150 mg/kg/day for 12 to 31 days. The maximum bilirubin levels were 137, 58 and 138 mmol/l in the three patients, respectively. After the introduction of NAC, bilirubin, aspertate aminotransferase, sIL-2 receptor and IL-8 decreased. All three patients achieved normal bilirubin levels and prothrombin times. To conclude, NAC may be useful for treatment of VOD. Bone Marrow Transplantation (2000) 25, 993–996.

Mixed chimaerism is common at the time of acute graft-versus-host disease and disease response in patients receiving non-myeloablative conditioning and allogeneic stem cell transplantation.

We report the clinical outcome and results of chimaerism analysis in various cell lineages of 30 patients given non‐myeloablative conditioning, followed by allogeneic stem cell transplantation (SCT). The commonest diagnoses were chronic myelogenous leukaemia (nu2003=u200311) and solid tumours (nu2003=u200311). Twenty‐one patients received SCT from human leucocyte antigen (HLA)‐identical siblings and nine from matched unrelated donors. Median patient age was 53 (28–77)u2003years. Four non‐myeloablative protocols were used, including fludarabine (30u2003mg/m2u2003×u20033–6), busulphan (4u2003mg/kgu2003×u20032), cyclophosphamide (Cy) (30u2003mg/kg/dayu2003×u20032) or total body irradiation (2u2003Gy), and anti‐thymocyte globulin. The patients were analysed by polymerase chain reaction (PCR) analysis of minisatellites on days 14, 21 and 28, then every other week up to 3u2003months and monthly thereafter. All samples were cell separated for T, B and myeloid cells using immunomagnetic beads. Eighteen patients were alive at a median follow‐up of 11 (6–20)u2003months. Acute graft‐versus‐host disease (GVHD) occurred in 22 patients. Eighteen of the 22 patients with acute GVHD showed mixed chimaerism (MC) in the T‐cell fraction at the time of acute GVHD. However, all patients with acute GVHD showed donor chimaerism (DC) in the T‐cell fraction median 76 (7–414) days after onset versus three out of eight patients without acute GVHD, Pu2003<u20030·001]. Disease response was diagnosed in 15 patients, median 100 (37–531) days after SCT. At the time of disease response, six out of15 patients showed MC in the T‐cell fraction. In conclusion, mixed chimaerism in the T‐cell fraction is common at the time of acute GVHD and disease response in patients conditioned with non‐myeloablative therapy.

Evaluation of intervention strategy based on CMV-specific immune responses after allogeneic SCT

Late occurring CMV disease is an important problem after allogeneic SCT and has been associated with poor CMV-specific immunity. We conducted a prospective study of 58 patients studied at 3–6 months after allo-SCT, to base the antiviral therapy on monitoring of CMV-specific immunity. Reactivation of CMV was measured by quantitative PCR, and intracellular IFN-γ production was analysed by FACS and enzyme-linked immunospot. Antiviral therapy was deferred in patients with documented CMV-specific immunity without symptoms of CMV disease or severe GVHD. Nineteen episodes of CMV reactivation were assessable. The strategy was correctly applied in 16/19 episodes. Therapy was deferred in 5/19 (none of these patients developed CMV disease) and was given according to the strategy in 11/19 episodes. Two patients received antiviral therapy despite having T cell-specific immunity. There was a tendency that patients with late CMV reactivation had weak CD8 T cell immunity at 3 months (P=0.06). The donors serostatus influenced the strength of both CD4 and CD8 immunity at 3 months after SCT (P<0.01). There was no effect as regards the type of conditioning, donor type, stem cell source or acute GVHD. Monitoring the immunity of SCT patients may allow more targeted use of antiviral therapy.

G-CSF given after haematopoietic stem cell transplantation using HLA-identical sibling donors is associated to a higher incidence of acute GVHD II-IV.

Summary:The effect of granulocyte colony-stimulating factor (G-CSF), given after transplantation, was studied in 155 patients transplanted with haematopoietic stem cells (HSCT) from HLA-identical sibling donors at Huddinge University Hospital between 1993 and 2001. Only patients with haematological malignancies were included. Conditioning consisted of total-body irradiation in 118 and busulphan in 37 patients. They were all given methotrexate combined with cyclosporine as graft-versus-host disease (GVHD) prophylaxis. Of the 155 patients, 66 (43%) received G-CSF after HSCT. Those given G-CSF had a significantly shorter time to neutrophil engraftment (P<0.001). G-CSF treatment had no effect on erythrocyte transfusions, platelet engraftment and infections. However, patients treated with G-CSF had a significantly higher incidence of grades II–IV acute GVHD than those not given this treatment (34 vs 9%, P<0.001). The multivariate analysis showed that the effect of G-CSF was independent of other known risk factors for grades II–IV acute GVHD. Death from GVHD occurred in four and two cases (P=0.06) in the two groups, respectively. The cumulative incidences of transplant-related mortality, survival, chronic GVHD, relapse and relapse-free survival were similar in both groups. In conclusion, G-CSF given after HLA-identical sibling HSCT was associated with a higher risk of grades II–IV acute GVHD, but not transplant-related mortality.

Low-dose cyclosporine of short duration increases the risk of mild and moderate GVHD and reduces the risk of relapse in HLA-identical sibling marrow transplant recipients with leukaemia.

Low-dose cyclosporine (CsA), starting at 1u2009mg/kg/day i.v. with early discontinuation, and four doses of methotrexate (MTX), was given to 82 consecutive leukaemic patients receiving HLA-identical sibling marrow transplants. Retrospective controls (nu2009=u200940) received CsA, starting at 5–7.5u2009mg/kg/day i.v., given for 1 year, and MTX. In the low-dose group, the risk of acute GVHD grades I–II was 78% as compared to 57% among the controls (Pu2009<u20090.01). the risk of acute gvhd grades iii–iv was 2% and 5%, respectively (ns). chronic gvhd occurred in 60% in the low-dose group and 24% in the controls (Pu2009<u20090.001). extensive chronic gvhd did not differ between the groups (3% vs6%). In multivariate analyses, low-dose CsA was the only factor associated with acute GVHD grades I–IV (Pu2009=u20090.02). Significant risk factors for chronic GVHD included low-dose CsA (Pu2009=u20090.002) and CML (Pu2009=u20090.03). Transplant-related mortality at 3 years post-BMT was 22% and 19%, in the low-dose group and controls, respectively (NS). The probability of relapse was 26% in the low-dose group and 53% in the controls (Pu2009=u20090.06). In multivariate analysis, high-dose CsA was the strongest risk factor for relapse (Pu2009=u20090.03). The 3-year relapse-free survival was 58% in the low-dose group and 43% in the controls (Pu2009=u20090.1).

Booster marrow or blood cells for graft failure after allogeneic bone marrow transplantation

Twenty allogeneic bone marrow transplant patients were treated with an additional dose of donor cells (boost dose) for graft failure (nu2009=u20097), partial graft failure (nu2009=u200911) or extensive hemolysis caused by remaining recipient cells producing anti-erythrocyte antibodies (nu2009=u20092). Donors were in 12 cases HLA-identical siblings, three mismatched related donors and five unrelated donors. Cell source was in 13 cases bone marrow and in seven peripheral blood progenitor cells. Median time from BMT to booster dose was 3.4 months (range 0.7–59.3). Median infused cell dose was 2.4u2009×u2009108/kg patient (range 0.5–19.0). As GVHD prophylaxis most patients were already receiving different combinations of cyclosporine, prednisolone and methotrexate. No preparative treatment was given prior to boost in 16 patients; four received ATG. After boost, 11 patients developed acute GVHD, six grade I, four grade II and one grade III. Except for one patient, acute GVHD after boost was less, or the same grade as after BMT. Six patients developed chronic GVHD, three limited and three extensive. Five patients died within 30 days of the boost. Nine of 15 (60%) evaluable patients became transfusion independent within 30 days and three more within 60 days. Causes of death were: infections six (IP four, pneumonia two), relapse three; and GVHD three. Three out of five patients transplanted with unrelated marrow suffered from severe immunological reactions and died 2–3 months after the boost dose. Patient survival 1 and 3 years after boost was 55% and 43%, respectively. Among patients with hematological malignancies, leukemia-free survival at 3 years was 41%.

The effect of metronidazole on busulfan pharmacokinetics in patients undergoing hematopoietic stem cell transplantation

Summary:Busulfan (Bu) is an important component of some myeloablative regimens prior to stem cell transplantation (SCT). Over the last few years it has been shown that other drugs administered concomitantly can influence Bu pharmacokinetics. In the present study, we compared Bu concentrations (trough levels) in three groups of patients. Group A (n=5) received metronidazole as graft-versus-host disease prophylaxis during Bu treatment. Group B (n=9) received Bu only for 2 days followed by 2 days of Bu and metronidazole. Group C (n=10) was a control group that received Bu without metronidazole. The mean Bu levels for Group A receiving metronidazole during conditioning was significantly (P<0.001) higher (948±280u2009ng/ml), compared to those observed in the control group (507±75u2009ng/ml). In Group B, the administration of metronidazole resulted in a significant (P<0.001) increase in Bu levels (807±90u2009ng/ml) during the last 2 days, compared to 452±68u2009ng/ml during the first 2 days. In Group A, one patient died with multiorgan failure, three experienced veno-occlusive disease (VOD) and one developed hemorrhagic cystitis. Elevated liver transaminases (AST, ALT) and bilirubin were detected in all Group A patients. In Group B, six patients had elevated liver function tests but no VOD was observed. We conclude that metronidazole should not be administered simultaneously with Bu to avoid the high plasma levels of Bu, which may lead to severe toxicity and/or treatment related mortality.