A Pagliuca

Fludarabine, cytarabine, G‐CSF and idarubicin (FLAG‐IDA) for the treatment of poor‐risk myelodysplastic syndromes and acute myeloid leukaemia

Nineteen patients with high‐risk myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) received fludarabine, cytarabine, granulocyte‐colony stimulating factor (G‐CSF), and idarubicin chemotherapy (de novo MDS/MDS‐AML, nine; relapsed/refractory MDS/AML, seven; therapy‐related MDS, three). Median age was 44 years and median disease duration 10 months. 16/19 (84%) patients had abnormal cytogenetics with seven (37%) harbouring abnormalities of chromosome 7. 18/19 (94.7%) patients responded to FLAG‐idarubicin with 12 (63%) achieving complete remission (CR) (<5% blasts and normal cytogenetics). 7/9 (78%) patients with de novo MDS/MDS‐AML achieved CR compared to 5/10 (50%) with alternative diagnoses. Response was associated with age < 50 years, disease duration < 3 months, and cytogenetics other than abnormalities of chromosome 7. Haemopoietic regeneration was rapid in most patients and there were no toxic deaths. Nine patients received a second course of chemotherapy, three have proceeded to allogeneic bone marrow transplant and three to autologous blood stem cell/bone marrow transplantation. Follow‐up is short (median 10 months). 12/19 (63%) patients remain alive and 5/12 (42%) have relapsed at a median 5 months following CR achievement. FLAG‐idarubicin was well tolerated. High rates of morphological and cytogenetic remission, especially in de novo MDS, offer a window of opportunity for assessment of autologous BMT in this group of diseases where no treatment except alloBMT has led to prolongation of survival.

Outcome of second allogeneic transplants using reduced-intensity conditioning following relapse of haematological malignancy after an initial allogeneic transplant

Disease relapse following an allogeneic transplant remains a major cause of treatment failure, often with a poor outcome. Second allogeneic transplant procedures have been associated with high TRM, especially with myeloablative conditioning. We hypothesized that the use of reduced-intensity conditioning (RIC) would decrease the TRM. We performed a retrospective national multicentre analysis of 71 patients receiving a second allogeneic transplant using RIC after disease relapse following an initial allogeneic transplant. The majority of patients had leukaemia/myelodysplasia (MDS) (N=57), nine had lymphoproliferative disorders, two had myeloma and three had myeloproliferative diseases. A total of 25% of patients had unrelated donors. The median follow-up was 906 days from the second allograft. The predicted overall survival (OS) and TRM at 2 years were 28 and 27%, respectively. TRM was significantly lower in those who relapsed late (>11 months) following the first transplant (2 years: 17 vs 38% in early relapses; P=0.03). Two factors were significantly associated with a better survival: late relapse (P=0.014) and chronic GVHD following the second transplant (P=0.014). These data support our hypothesis that the second RIC allograft results in a lower TRM than using MA. A proportion of patients achieved a sustained remission even when relapsing after a previous MA transplant.

Myelofibrosis in primary myelodysplastic syndromes: a clinico-morphological study of 10 cases

Summary. We describe 10 cases of primary myelodysplastic syndrome in which marrow fibrosis was striking at presentation. All the cases showed trilineage dysplasia with increased megakaryopoiesis and marked reticulin fibrosis. Significant organomegaly was notably absent. This association has hitherto not been highlighted and it is important to distinguish these cases from those of idiopathic myelofibrosis with which they may be confused. Furthermore, their comparatively long survival distinguishes these cases from those previously described as acute myelodysplasia with myelofibrosis and malignant myelosclerosis. The pathogenesis of fibrosis in these cases may be related to disordered megakaryopoiesis and the platelet‐derived cytokines that may be released. The treatment of these fibrotic cases remains problematical and further investigation is required.

Diverging effects of HLA–DPB1 matching status on outcome following unrelated donor transplantation depending on disease stage and the degree of matching for other HLA alleles

Disease stage and recipient/donor human leukocyte antigen (HLA) matching are important determinants of outcome in transplantation using volunteer-unrelated donors (VUD). Matching for HLA-A, -B, -C, -DRB1, -DQB1 is beneficial, whereas the importance of DPB1 matching is more controversial. The impact of HLA matching status may differ dependent on disease stage. We investigated the outcome according to the degree of HLA matching at 6 loci, in 488 recipients of predominantly T-cell depleted bone marrow VUD transplants for leukaemia. Survival was significantly better in 12/12-matched transplants in those with early leukaemia (5 years: 63 versus 41% in 10/10 matched, P=0.006), but not late stage disease. Conversely, within the HLA-mismatched group (⩽9/10), there was a significant survival advantage to DPB1 mismatching (5 years: 39 versus 21% in DPB1 matched, P=0.008), particularly in late leukaemia (P=0.01), persisting in multivariate analysis (odds ratio 0.478; 95% confidence interval 0.30, 0.75; P=0.001). These novel findings suggest that the best outcome for patients with early leukaemia, with a 10/10-matched donor, is achieved by matching for DPB1. Conversely, our results suggest that in patients receiving an HLA-mismatched graft, the outcome is significantly better if they are also mismatched for DPB1. We recommend validation of these results in independent datasets.

Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation

Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life threatening complication that can develop after hematopoietic cell transplantation. Although SOS/VOD progressively resolves within a few weeks in most patients, the most severe forms result in multi-organ dysfunction and are associated with a high mortality rate (>80%). Therefore, careful attention must be paid to allow an early detection of SOS/VOD, particularly as drugs have now proven to be effective and licensed for its treatment. Unfortunately, current criteria lack sensitivity and specificity, making early identification and severity assessment of SOS/VOD difficult. The aim of this work is to propose a new definition for diagnosis, and a severity-grading system for SOS/VOD in adult patients, on behalf of the European Society for Blood and Marrow Transplantation.

Cord blood stem cells for hematopoietic stem cell transplantation in the UK: how big should the bank be?

The need for umbilical cord blood units as an alternative source of hematopoietic stem cells for transplantation is increasing. This study defines the optimal size of a cord blood bank for a population of various ethnic background. See related perspective article on page 451. Background A stored cord blood donation may be a valuable source of hemopoietic stem cells for allogeneic transplantation when a matched sibling donor is not available. We carried out a study to define the optimal size of a national cord blood bank for the UK. Design and Methods We calculated the actual numbers of possible donors and the chance of finding at least one donor for 2,000 unselected and for 722 non-North Western European patients for whom searches had been initiated as a function of three levels of HLA matching (4, 5 and 6 out of 6 alleles by HLA-A, -B low and -DRB1 high resolution HLA typing) according to various donor bank sizes. Results With a bank size of 50,000, 80% of patients will have at least one donor unit available at the 5 out of 6 HLA allele match level (median 9 donors per patient), and 98% will have at least one donor at the 4 out of 6 allele match level (median 261). Doubling the size of the bank yields at least one donor for only an additional 6% of patients at the 5 of 6 allele match level. Moreover, for non-North Western European patients a 50,000 unit bank provides a donor for 50% at the 5 allele match level, and for 96% at the 4 allele match level. Conclusions A bank containing 50,000 units is optimal for the UK and larger banks would only marginally increase the chance of finding suitable units.

Primary myelodysplastic syndrome in children: the clinical experience in 33 cases

Summary. We describe the clinicomorphological features in 33 cases of primary myelodysplastic syndrome classified according to the FAB classification which presented to a single centre over a 12 year period. Presenting features were typically related to pancytopenia although hepatosplenomegaly and granulocytic sarcomas were far more prevalent than in the adult population.

Management of cytomegalovirus infection in haemopoietic stem cell transplantation

● Cytomegalovirus (CMV) infection and CMV diseaseshould be diagnosed according to established, interna-tionally accepted, standardized criteria (Grade 1C).● Risk-adapted patient assessment should inform clinicalmanagement (Grade 1B).● All potential haemopoietic stem cell transplantation(HSCT) recipients should be tested for the presence ofCMV IgG antibody at diagnosis (Grade 1C).● Once optimum human leucocyte antigen (HLA) match-ing has been performed, a CMV IgG-negative donorshould be chosen for a CMV IgG-negative recipient anda CMV IgG-positive donor should be chosen for a CMVIgG-positive recipient when possible (Grade 1A).● Donors or recipients who are initially found to be CMVIgG-negative should be retested pre-transplant toexclude primary CMV infection (Grade 1C).● Apparent CMV seroconversion in potential allograftrecipients who have received unscreened blood productsshould be actively investigated to exclude passive acqui-sition of antibody (Grade 1C)● Any CMV IgG-negative HSCT recipient transplantedfrom a CMV IgG-negative donor who develops CMVinfection post-transplant must be reported to the SeriousHazards of Transfusion (SHOT) scheme (Grade 1C).● Primary prophylaxis with ganciclovir is not generallyrecommended as toxicity outweighs efficacy in HSCTpatients (Grade 1B).● Primary prophylaxis with aciclovir or valaciclovir canbe deployed but only in conjunction with appropriatemonitoring of CMV in blood (Grade 1B).● Valaciclovir or valganciclovir are valid treatmentoptions for secondary prophylaxis with appropriatemonitoring of CMV in blood (Grade 1C).● Intravenous immunoglobulin is not recommended forprophylaxis of CMV infection (Grade 1A).● Real time quantitative polymerase chain reaction (PCR)is the preferred choice for monitoring CMV DNA levelsin HSCT patients (Grade 1B).● All diagnostic laboratories should deploy the CMVinternational standard to allow viral loads to becompared between centres (Grade 1C).● Monitoring of CMV load should be undertaken atleast weekly for the first 3 months post-HSCT (Grade2C).● CMV viral load monitoring should continue for 6-12 months if the patient has chronic graft-versus-hostdisease (GvHD) or prolonged T-cell immunodeficiency(Grade 1B).● Each transplant centre should have a risk-adapted policydetailing threshold values for treatment of CMV infec-tion, taking into account patient factors and PCR meth-odology (Grade 2C).● Ganciclovir is recommended as first line pre-emptivetherapy for CMV in HSCT patients (Grade 1A).● Oral valganciclovir is a valid alternative when gastroin-testinal absorption is normal or only minimallyimpaired (Grade 1A).● Foscarnet is recommended as an alternative first-lineagent if neutropenia is present or for ganciclovir treat-ment failure (Grade 1A).

The clinical diversity and role of chemotherapy in lymphoproliferative disorder in liver transplant recipients

BACKGROUND/AIMS Post-transplant lymphoproliferative disorder is a well-documented complication with an incidence ranging from 2 to 10%, depending on the organ transplanted. Yet despite our increased understanding of the pathophysiology of this disease and the various treatments available, the mortality remains high at 60-80%. We present the clinical and histological features of ten adult liver transplant recipients with post-transplant lymphoproliferative disorder presenting over a 15-year period and review the therapeutic options. METHODS CD20/CD45RO immunostaining was used for T/B-cell markers; polymerase chain reaction and in-situ hybridisation for Epstein-Barr virus genome detection; kappa/lambda immunostaining and gene rearrangement analysis for clonality. RESULTS There were six females and four males (age range 24-56) with onset of post-transplant lymphoproliferative disorder-symptoms ranging from 3 to 72 months post transplant. Sites of post-transplant lymphoproliferative disorder included liver (n=4), lymph nodes (n=5), bone marrow (n=2), lungs (n=2), kidneys (n=2), brain, ovaries,: and pancreas (n=1). All lesions were classified as high-grade lymphoma, of B-cell lineage (9 tested); Epstein-Barr virus genome was detected in 7/10 cases. Three tumours were monoclonal; four were polyclonal and three undetermined. Treatment included immunosuppression reduction, antiviral therapy with acyclovir and/or chemotherapy (CHOP or VAPEC-B). Survival times for those patients not treated with chemotherapy were from 9 days to 30 months, whereas those receiving chemotherapy had remission times of 4 to 48 months. CONCLUSIONS Longer-term remissions can be achieved in patients treated with systemic chemotherapy, although not without morbidity. Clonality assessment is important but treatment decisions should be based primarily on clinical features of progression, as polyclonal tumours can behave as aggressively as monoclonal tumours.

Allogeneic haematopoietic SCT for chronic myelomonocytic leukaemia: a single-centre experience.

Haematopoietic SCT (HSCT) offers the only potentially curative option in chronic myelomonocytic leukaemia (CMML). In this study, we report on single-centre results of 18 patients with CMML who have undergone allogeneic HSCT. The median age of patients was 54 years. Seven patients had AML, which had transformed from CMML. Overall, 11 patients received stem cells from an unrelated donor. A total of 15 patients received a T-cell-depleted fludarabine/BU-based reduced-intensity conditioning HSCT. The actuarial 3-year OS, non-relapse mortality (NRM) and relapse incidence for the cohort was 31±11%, 31±14% and 47±13%, respectively. Patients with favourable cytogenetics had a 3-year disease-free survival of 65±17%, whereas none of the seven patients with intermediate or poor risk cytogenetics survived beyond 2 years (P<0.01). No patients with favourable risk cytogenetics died from NRM causes, while the 2-year NRM for the intermediate/poor risk cytogenetics subgroup was 71±22% (P<0.02). In terms of disease status at transplantation, patients who had <5% BM blasts had a 3-year disease-free survival of 46.9±19% compared with those with >5% blasts at the time of transplantation (that is, 20.0±13%). Recipient age, type of conditioning regimen or stem cell dose did not have a significant impact on overall outcomes. Our data support existing evidence that allogeneic HSCT is a feasible therapeutic option for CMML, with the ability to attain long-term remission among patient subgroups.