Anthony Oakhill

Outcome and clinical course of 100 patients with adenovirus infection following bone marrow transplantation

We conducted a retrospective review of the clinical features and outcome of adenovirus infection in 572 consecutive patients transplanted in a single centre over a 10 year period. One hundred patients (17%) had a total of 105 episodes of adenovirus infection diagnosed at a median of 18 days post transplant (range 2–150 days). The incidence was higher in children than adults (21% vs 9%, P < 0.001) and in unrelated donor vs matched sibling donor transplants (26% vs 9%, P < 0.001). Diarrhoea and fever were the most common presenting features. Reflecting these symptoms, the most common site of isolation was the stool. Serotypes 1, 2 and 7 were the most frequently seen (total of 41/68 or 60% of evaluable cases). In six patients (6%) adenovirus infection was the direct cause of death occurring at a median of 72 days post transplant (range 18–365 days). Five of these six patients had pulmonary involvement and four had associated graft-versus-host disease (GVHD). Three further patients were considered to have severe adenoviral disease (total incidence 9%). Isolation of virus from multiple sites correlated with a poor outcome (P < 0.001). Comorbid viral infection was common in this group with 50% of all patients having other viruses isolated (predominantly polyoma virus and cytomegalovirus). We conclude that adenovirus is commonly isolated after bone marrow transplant and is a cause of significant morbidity but was a rare cause of mortality (6/572 = 1%) in our patient group as a whole. The relative infrequency of severe infection will make it difficult for the transplant physician to decide which patients should receive experimental antiviral drugs such as ribavirin and cidofovir or immunomodulatory therapy with donor white cell infusions. Bone Marrow Transplantation (2000) 26, 1333–1338.

Unrelated donor bone marrow transplantation for children with relapsed acute lymphoblastic leukaemia in second complete remission

Allogeneic sibling bone marrow transplantation (BMT) is the recommended treatment for relapsed childhood acute lymphoblastic leukaemia (ALL), but appropriate donors are only available in 30% of cases. Unfortunately, BMT from unrelated donors (UD) has been associated with high rates of severe graft‐versus‐host disease (GvHD) and transplant‐related mortality (TRM). In an attempt to improve outcome in UD‐BMT we have assessed the impact of T‐cell depletion using CAMPATH‐1 (anti‐CD52) monoclonal antibodies in 50 consecutively referred patients with relapsed ALL in second remission. All were previously treated according to MRC protocols UKALL X and XI, and then given chemotherapy on MRC R1 from relapse until UD‐BMT. 19 patients had relapsed on and 31 off therapy.

Infections in adults undergoing unrelated donor bone marrow transplantation

This study retrospectively reviews infections over a 7‐year period in 60 consecutive adults (median age 25 years) undergoing their first unrelated donor bone marrow transplant (UD‐BMT). T‐cell depletion was employed in 93%. More than half the patients had one or more severe, potentially life‐threatening, infections. There was a high incidence of invasive fungal infections (Aspergillus 17, Candida four), despite the use of itraconazole or amphotericin prophylaxis. Ten Aspergillus infections occurred beyond 100  d. Two patients (11%) with invasive aspergillosis survived. Clustering of infections was noted, with invasive fungal infections significantly associated with bacteraemias (OR 3.73, P = 0.06) and multiple viral infections (OR 4.25, P = 0.05). There were 21 severe viral infections in 16 patients, with CMV disease occurring in four patients only; viral pneumonitis was predominantly due to ‘community respiratory’ viruses. Most early bacteraemias (68%) were due to Gram‐positive organisms. The majority of episodes of Gram‐negative sepsis were caused by non‐fastidious non‐fermentative bacteria, such as Pseudomonas spp. and Acinetobacterspp., historically regarded as organisms of low pathogenicity. In patients with successful engraftment and minimal graft‐versus‐host disease, late infections suggestive of continued immune dysfunction (shingles, recurrent lower respiratory infections, Salmonella enteritis and extensive warts) were common.

The UK experience in treating relapsed childhood acute lymphoblastic leukaemia: a report on the medical research council UKALLR1 study.

We have examined the toxicity and overall outcome of the Medical Research Council UKALL R1 protocol for 256 patients with relapsed childhood acute lymphoblastic leukaemia (ALL). Second remission was achieved in over 95% of patients. Two patients died during induction and seven patients died of resistant disease. The overall actuarial event‐free survival (EFS) at 5 years for all patients experiencing a first relapse was 46% (95% CI 40–52). Duration of first remission, site of relapse, age at diagnosis and sex emerged as factors of prognostic significance. Five‐year EFS was only 7% for children relapsing in the bone marrow within 2 years of diagnosis, but was 77% for those relapsing without bone marrow involvement > 2.5 years from diagnosis. All analyses in this report are by treatment received. For those receiving chemotherapy alone, the 5‐year EFS was 48%; for autologous bone marrow transplantation (BMT), the 5‐year EFS was 47%; for unrelated donor BMT, it was 52%; and for related donor BMT, the 5‐year EFS was 45%. The groups, however, were not comparable with respect to risk factor profile, and therefore direct comparison of EFS is misleading. Adjustment for time to transplant and prognostic factors was used to reduce the effects of biases between treatment groups, but did not suggest benefit for any particular treatment. There was failure of our planned randomization scheme in this trial with only 9% of those eligible being randomized, which highlights the difficulties in running randomized trials especially in patients who have relapsed from a previous trial. The optimal treatment for relapsed ALL therefore remains uncertain. Alternative approaches are clearly needed for those with early bone marrow relapse if outcome is to improve.

Minimal residual disease status as a predictor of relapse after allogeneic bone marrow transplantation for children with acute lymphoblastic leukaemia.

We have analysed the behaviour of minimal residual disease (MRD) after allogeneic bone marrow transplantation (allo-BMT) in 71 children with acute lymphoblastic leukaemia (ALL). The method relied on PCR of IgH, TCRdelta and/or TCRgamma gene rearrangements followed by electrophoretic size resolution and allele-specific oligoprobing. Patients were similarly conditioned; 55 received marrow from unrelated donors and 16 from related donors. MRD was assessed at various time-points up to 24 months after BMT. Three children were not evaluable due to transplant-related mortality. MRD was detected in 28/32 patients (88%) who relapsed post-BMT; 16 were positive at all times and 12 were initially negative but became positive at a median of 3 months (range 1.5-11) prior to relapse. In contrast, only eight of 36 (22%) patients who remained in continuing complete remission (CCR) (median follow-up 43 months, range 20-94) showed MRD at any time after BMT (P<0.0001). In these eight patients MRD was found up to 9 months after transplant and at low levels (0.01-0.001%). All eight (median follow-up 39 months, range 24-87) had at least two MRD-negative samples tested subsequently and five of the eight had evidence of grade I-II acute graft-versus-host disease (GvHD), raising the possibility of a graft-versus-leukaemia effect. In general, any evidence of MRD after allo-BMT is a poor prognostic sign. However, if immunotherapy were to be targeted towards patients with evidence of persisting MRD after BMT, the method described would expose only a small proportion of patients to unnecessary additional toxicity.

The outcome of 26 patients with respiratory syncytial virus infection following allogeneic stem cell transplantation

Respiratory syncytial virus (RSV) is known to cause acute lung injury in the immunocompromised host, especially recipients of bone marrow allografts. Specific prognostic factors for the development of severe life-threatening disease remain to be identified as does the optimum treatment of established disease. Over a 5-year period the incidence and outcome of RSV in BMT recipients was analysed retrospectively. Prognostic factors assessed included type of transplant, engraftment status at the time of infection, the presence of lower respiratory tract disease, viral genotype and treatment received. During the study period, 26 of 336 (6.3%) allogeneic stem-cell recipients were identified as having RSV. Five patients (19.2%) died as a direct result of RSV. One patient died secondary to an intracranial bleed with concomitant RSV. There were four patients with graft failure (two primary and two secondary) attributable to the presence of RSV, two of whom subsequently died of infections related to prolonged myelosuppression. The presence of lower respiratory tract infection and a poor overall outcome was the only statistically significant association. Unrelated donor transplants and AML as the underlying disease appeared to be associated with a poorer outcome. Engraftment status, viral genotype and RSV treatment received did not correlate with outcome. We conclude that future studies are required to identify early sensitive and reproducible prognostic factors of RSV in the immunocompromised host. The roles of intravenous and nebulised ribavirin need to be clarified by prospective controlled trials.

Minimal residual disease analysis for the prediction of relapse in children with standard-risk acute lymphoblastic leukaemia

We report a largely retrospective analysis of minimal residual disease (MRD) in a cohort of 66 children suffering from acute lymphoblastic leukaemia (ALL). All patients lacked high‐risk features at diagnosis, i.e. the presenting white cell count was <50 × 109/l, age 1–16 years and translocations t(9;22) and t(4;11) were not present. All were treated according to either the MRC protocols UKALL X or XI. PCR of IgH, TCRδ and TCRγ gene rearrangements and allele‐specific oligoprobing were employed for the detection of MRD. Sensitivity was at least 10−4 in 78/82 (93%) probes examined.

PCR assessment of bone marrow status in 'isolated' extramedullary relapse of childhood B-precursor acute lymphoblastic leukaemia.

SUMMARY. Approximately one‐third of first relapses of childhood ALL occur at an extramedullary site without morphological evidence of bone marrow disease. However, the high incidence of subsequent medullary relapse in these cases strongly suggests that leukaemia is present at submicroscopic levels at the time of ‘isolated’relapse. PCR analysis of immunoglobulin heavy chain (IgH) and T‐cell receptor (TCR) gene rearrangements now allows detection of leukaemia at levels as low as 0.001%. We have therefore used this technique to reassess bone marrow status at morphologically isolated relapse in 13 children with B‐lineage ALL (11 with off‐treatment relapses, two on treatment). In 12 of these 13 patients marrow disease was detectable by PCR at the time of this relapse—in all cases at levels below the threshold of light microscopy. Where relapse occurred off‐therapy this indicated re‐emergence of disease, since MRD has never been detected by PCR at this stage in patients remaining in long‐term remission. In both patients who relapsed on‐therapy the level of MRD at the time of relapse represented an increase on that seen in their previous marrow sample. We conclude that re‐emerging bone marrow disease can be detected in most cases of ‘isolated’relapse when investigated by this highly sensitive technique. Our findings at a molecular level confirm a long‐held clinical suspicion and indicate that full systemic re‐induction as well as local therapy is obligatory for these children.

FLAG (fludarabine, high-dose cytarabine, and G-CSF) for refractory and high-risk relapsed acute leukemia in children.

BACKGROUND The treatment of relapsed and refractory leukemia in children remains a challenge. The morbidity of further chemotherapy is considerable, as most patients have already been exposed to intensive multiagent chemotherapy. The FLAG (fludarabine, high-dose cytarabine, and G-CSF) regimen is as intensive but less cardiotoxic because of the avoidance of anthracyclines. PROCEDURE Nineteen children were treated in two U.K. centers with the FLAG regimen for relapsed and refractory acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). There were 13 males and 6 females, with an age range of 1.9 to 14.2 years. AML was the diagnosis in 12 children, ALL in 4, biphenotypic leukemia in 3. Eight patients had refractory disease, 11 were in relapse (5 in first relapse, 4 in second, and 2 in third). RESULTS Complete remission was obtained in 13 patients, partial remission was obtained in 4, and 2 patients were considered nonresponders. There were seven patients alive at 12 months (mean) posttherapy; one of these is awaiting bone marrow transplantation (BMT). All patients experienced grade 4 hematological toxicity; no patient died of infection. Thirteen patients received BMT as consolidation (seven unrelated donor; six sibling allografts). Six of these have died, four due to pneumonitis. CONCLUSIONS FLAG can be regarded as an effective protocol for inducing remission in a group of heavily pretreated children. Its toxicity is acceptable due to the avoidance of anthracyclines.

The outcome of children requiring admission to an intensive care unit following bone marrow transplantation

We report the results of a retrospective study of the role of intensive care unit (ICU) admission in the management of 367 children who underwent bone marrow transplantation (BMT) at a tertiary referral institution. 39 patients (11%) required 44 ICU admissions for a median of 6 d. 70% received marrow from unrelated donors, half of which were mismatched; 80% had leukaemia and two‐thirds were considered high‐risk transplants. Respiratory failure was the major reason for admission to ICU. 75% of admissions required mechanical ventilation (for a median of 5 d) and 20 patients had lung injury as defined by the criteria of the Seattle group. None of 11 patients with proven viral pneumonitis survived (P = 0.06) and only one of 20 patients with lung injury survived (P < 0.01). Six of seven patients with a primary neurological problem survived (P < 0.001); these appear to represent a good outcome group. Age, the presence of graft‐versus‐host disease, the use of inotropes, isolated renal or hepatic impairment, and paediatric risk of mortality (PRISM) score were not predictive of outcome. In total, 12 patients (27% of admissions) survived and were discharged from hospital 30 d or more after admission and eight (18%) survived >6 months. ICU admission can be beneficial to selected children post‐BMT but it may be less useful in proven viral pneumonitis. Where mechanical ventilation is required, the duration of this support should be limited unless there is rapid improvement.