ALBERT

Description: FDG PET scanning provides useful information that is now being integrated into treatment algorithms for patients with lymphomas. Its use in relation to allogeneic transplantation has not been assessed. We have performed a prospective study to assess the role of PET scans in directing immune manipulation (withdrawal of immune suppression and donor lymphocyte infusions (DLI)) following reduced intensity transplants (RIT) in patients with lymphoid malignancies. Methods: All patients referred to University College Hospital from May 2002 with lymphoid malignancies, suitable for RIT were invited to participate. Patients had PET and CT scans pre-RIT and at 3, 6, 9, 15 and 24 months post RIT. Patients were conditioned with fludarabine and melphalan and in vivo T cell depletion with alemtuzumab. Ciclosporin was given from day −1 to 3 months after RIT. Initial management for positive imaging was withdrawal of immune suppression. DLI was subsequently given to patients who progressed or relapsed at escalating doses of 1 x 106/kg T cells up to 1 x 108/kg. Patients with active GVHD were excluded from DLI. Results: 29 patients, median age 44 years (range 20 to 64 years) entered the study; 24 (6 Hodgkin lymphoma (HL), 2 Mantle cell (MC), 16 Non-Hodgkin Lymphoma (NHL)) are evaluable with 〉 3 months follow-up. 13 of 24 had positive PET scans before RIT, 9 had negative scans and 2 were not scanned before RIT. Of the 13 patients who had positive PET scans, there were 3 transplant related mortalities: CMV pneumonitis (n=1, HL), severe GVHD (n=2, NHL). The 10 remaining patients with positive PETs pre-RIT have a median 10.5 months follow up (range 6 to 24 months). 9 of 10 patients had a response to RIT (7CR and 2PR). Subsequently 5 of these 10 have relapsed/progressed at 6 to 9 months from RIT. Two were treated by withdrawal of immune supression. Both developed GVHD and died of progressive disease. 3 were treated with DLI. One patient (NHL) responded 3 months after 1 x106/kg, one (MC) after 1 x 107/kg and the third (NHL) showed a CR following both 1 x 107/kg and rituximab given for immune cytopenia. The remaining 5 patients (1HL, 4NHL) with positive pre-RIT PET scans remain in remission a median of 9 months (range 6 to 15 months) after RIT. One of 9 patients (NHL) with negative pre-RIT PET scans had progression of disease at 9 months, treated with escalating DLI up to 1 x 107/kg with no response. The remaining 8 patients with negative pre-RIT PET scans have remained in CR a median of 9 months (range 3 to 24 months) from RIT. One patient who did not receive pre-RIT scan died at 9 months of GVHD without evidence of disease progression. The second progressed at 12 months and is awaiting biopsy. 6 patients had nodes on CT scan of unclear significance, with negative PET scans. One of these patients has subsequently relapsed. The remaining patients continue in CR. 3 patients have had positive PET scans and received DLI 3 to 6 months before positive CT findings. This study suggests that PET imaging provides additional information beyond that available from CT scanning aiding patient management including earlier intervention (n=3) and deferring unnecessary treatment (n=6). 3/4 patients receiving DLI have responded. Positive PET scanning pre-RIT was associated with inferior outcome but does not preclude CR (6/13). Further follow-up and larger event numbers are required to establish the role of PET imaging in modulating treatment following RIT in patients with lymphoid malignancies.

Description: The use of GSCF-mobilised Peripheral Blood Stem Cells (PBSC) for unrelated donor (UD) transplantation has increased dramatically since 2000. The association of PBSC with more rapid engraftment and with an increase in chronic Graft versus Host Disease (GvHD), compared to bone marrow (BM) has been reported in a number of studies. More recently the use of PBSC has been associated with an increase in transplant related mortality (TRM) and decrease in survival (OS) in T-cell replete transplants. We sought to analyse the impact of PBSC compared to BM in a cohort of UD transplant recipients, where T-cell depleting agents (in-vivo campath in 〉90%) were included in the transplant conditioning. The study included 145 patients transplanted between January 2000 and March 2006: CML- 35 in 1CP; acute leukaemia (AML in 61, ALL in 49)-110 in CR1 or 2. All had myeloablative conditioning regimens and received grafts with 9–10/10 matched HLA alleles. 86 patients received BM and 59 PBSC. There were no associations between the stem cell source and any transplant variable (including disease and stage). There was a trend to an increased use of PBSC in patients with a single antigen mismatch (p=0.052). All evaluable patients achieved neutrophil engraftment, with a significantly faster time to engraft in recipients of PBSC compared to BM (16 vs 20 days; p=0.0003). The incidence of acute GvHD was 46% (grade I in 50%, II in 41%, III in 8%, IV in 2%). This was significantly higher in recipients of PBSC (60%) compared to BM (36%; p=0.006), however there was no increase in either II/IV (p=0.69) or III/IV (p=0.18) disease in PBSC recipients. In univariate analysis, the presence of a single HLA mismatch (p=0.026) was the only other variable to be associated with an increase in acute GvHD. In a logistic regression model including both these variables, the use of PBSC remained significantly associated with an increase in aGvHD (OR=2.3; 95% CI 1.1,4.7;p=0.020). The TRM was 14%, 27% and 39% at 100 days, 1 and 5 years respectively. At none of these time points was the stem cell source associated with a significant difference in TRM. The 5-year incidence of chronic GvHD was 58% (BM 55%, PBSC 60%; NS), extensive disease in one third, and of relapse was 61% (BM 60%, PBSC 62%; NS). The 5-years OS was 41% with a median follow-up of 3.4 years (0.5–7.1). This was 44% using PBSC and 40% using BM (NS). In conclusion, although we observed an increase in acute GVHD with PBSC this was only of grade 1 disease. We found no association between the use of PBSC and an increased risk of chronic GVHD or of a worse transplant outcome, when compared to BM, in recipients of T-cell depleted myeloablative transplants for leukaemia.

Description: Despite impressive primary response rates relatively few patients with multiply relapsed or refractory Hodgkin lymphoma (HL) are ultimately cured with conventional chemotherapy. The application of allogeneic stem cell transplantation has historically been limited in this group by high transplant related mortality (TRM) rates, and evidence for a clinically relevant graft-versus-lymphoma (GvL) effect has been limited. Reduced intensity transplantation (RIT) approaches enable durable engraftment of allogeneic stem cells with a low spectrum of toxicity, but graft-versus-host disease (GvHD) remains a significant cause of morbidity and mortality. In vivo T-cell depletion (TCD), using alemtuzumab, has been shown to reduce the incidence of GvHD. However, this approach potentially adversely impacts on disease response by abrogating GvL activity. To explore the impact of TCD in HL we have compared the results in 89 recipients of a RIT enrolled in 2 prospective studies based on conditioning with the same combination of fludarabine (30mg/m2 x 5) and melphalan (140 mg/m2). The studies differed in GvHD prophylaxis. The United Kingdom regimen (MF-A, n=49) used cyclosporin A plus alemtuzumab, whereas the Spanish regimen (MF, n=40) used cyclosporin A plus methotrexate. There were no significant differences in age (median 32 versus 35 years), sex or histological subtype (nodular sclerosis in 86% versus 88%). Median follow-up in surviving patients is 826 (MF-A) versus 376 (MF) days. In those with matched sibling donors use of alemtuzumab resulted in a trend towards a lower incidence of acute GvHD (29% versus 46% at day 180, P=0.09) and significantly less chronic GvHD (10% versus 57%, P=0.0003). This was associated with a trend towards lower TRM in the MF-A group (actuarial 2 year TRM 17% versus 33% for MF, P=0.06), but no apparent excess of relapse/progression (actuarial 2 year relapse risk 49% for MF-A versus 68% for MF, P=0.16). In this sibling transplant cohort both overall and event-free survival were superior in the MF-A group (actuarial 2 year OS 72% versus 48%, P=0.04; EFS 47% versus 19%, P=0.009). Sixteen patients in the MF-A group and 10 in the MF group received donor lymphocyte infusions (DLIs) to achieve disease control. Nine (8CR, 1PR) of the former, and 6 (3CR, 3PR) of the latter achieved a response. On univariate analysis of the entire cohort chemo-sensitivity significantly influenced relapse risk (p=0.01), OS (P=0.01) and EFS (P=0.003). TCD significantly improved EFS (P=0.01) despite an excess of unrelated/mismatched donors (18 versus 3, P=0.001) and patients who had failed a prior autograft in the MF-A cohort (44 versus 29, P=0.03). Prior autograft or donor source had no significant influence on TRM, relapse, OS or EFS. More patients were chemo-sensitive prior to RIT in the MF-A group (36 versus 20, P=0.03) but TCD retained independent positive prognostic significance for EFS in multivariate analysis (P=0.02; Hazard ratio 0.69(0.51–0.93)), as did chemo-sensitivity (P=0.01). In conclusion, alemtuzumab significantly reduced GvHD without resulting in an apparent impact on disease relapse. Both groups often required DLIs to achieve tumor control and the response rates support a significant GvL activity.

Description: The toxicity of allogeneic stem cell transplantation (SCT) can be substantially reduced by the use of a reduced intensity conditioning (RIC) regimen and this has increased the proportion of patients with myeloid malignancies eligible for allogeneic transplantation. However, the capacity of RIC allografts to produce durable remissions in patients with AML and MDS has not yet been defined and consequently their role in the management of these diseases remains conjectural. Seventy-six patients with high risk AML or MDS were allografted using a fludarabine/melphalan RIC regimen incorporating alemtuzumab. The median age of the cohort was 52 years (range 18–71 years). There were 46 males and 30 females; 41 patients received an allograft from an unrelated donor and 35 from a matched sibling donor. The 100 day transplant related mortality was 9% and no patient developed greater than Grade 2 graft-versus-host disease (GVHD). With a median follow-up of 36 months (range 13–70 months) 27 patients were alive and in remission with a 3y actuarial overall survival (OS) and disease-free survival (DFS) rate of 41% and 37% respectively. The 3y OS and DFS of patients with AML in complete remission (CR) at the time of transplantation was 48% and 42% respectively. In a multivariate setting, Cox regression analysis demonstrated prognostic significance of disease stage at the time of transplant with improved DFS in patients with AML in CR at the time of transplantation (HR=2.03, 95% CI=1.02–4.07). Disease relapse was the commonest cause of treatment failure occurring at a median time of 6 months post-transplant. Fourteen out of 27 (52%) patients relapsed within 6 months and 23/27 (85%) within twelve months defining a relatively narrow window for therapeutic intervention to prevent disease recurrence. The extended follow-up in this series identifies a high risk of early disease relapse but provides evidence that RIC allografts are capable of producing sustained disease free survival in a significant number of patients with AML who would be ineligible for allogeneic transplantation using a myeloablative conditioning regimen.