Aloysius Ho

Alemtuzumab with fludarabine and cyclophosphamide reduces chronic graft-versus-host disease after allogeneic stem cell transplantation for acquired aplastic anemia

We evaluated a novel alemtuzumab-based conditioning regimen in HSCT for acquired severe aplastic anemia (SAA). In a multicenter retrospective study, 50 patients received transplants from matched sibling donors (MSD; n = 21) and unrelated donors (UD; n = 29), using fludarabine 30 mg/m² for 4 days, cyclophosphamide 300 mg/m² for 4 days, and alemtuzumab median total dose of 60 mg (range:40-100 mg). Median age was 35 years (range 8-62). Overall survival at 2 years was 95% ± 5% for MSD and 83% for UD HSCT (p 0.34). Cumulative incidence of graft failure was 9.5% for MSD and 14.5% for UD HSCT. Full-donor chimerism (FDC) in unfractionated peripheral blood was 42%; no patient achieved CD3 FDC. Acute GVHD was observed in only 13.5% patients (all grade I-II) and only 2 patients (4%) developed chronic GVHD. A low incidence of viral infections was seen. Factors influencing overall survival were HSCT comorbidity 2-year index (92% with score 0-1 vs 42% with score ≥ 2, P < .001) and age (92% for age < 50 years vs 71% ≥ 50 years, P < .001). Our data suggest that the use of an alemtuzumab-based HSCT regimen for SAA results in durable engraftment with a low incidence of chronic GVHD.

Impact of pre-transplant serum ferritin on outcomes of patients with myelodysplastic syndromes or secondary acute myeloid leukaemia receiving reduced intensity conditioning allogeneic haematopoietic stem cell transplantation

We report on a retrospective analysis examining the influence of pre-transplant serum ferritin on transplant outcomes of 99 MDS patients receiving reduced intensity conditioning (RIC) HSCT. The median pre-transplant ferritin value was 1992 ng/ml (range: 6-9580 ng/ml). No patients received iron chelation therapy preceding transplantation. On univariate analysis, there was a strong correlation between a higher pre-transplant serum ferritin (>1500 ng/ml) and a significantly inferior 3-year OS (64.6+/-7.5% vs 39.6+/-7.3%, p=0.01). However, pre-transplant serum ferritin did not influence 3-year TRM (20.2+/-7% vs 27.4+/-7%, p=0.24). There was no difference in infection-related mortality, and incidence of acute or chronic GvHD between cohorts. On multivariate analysis, a raised serum ferritin (HR: 2.00, 95% CI: 0.97-3.57, p=0.03), and the presence of >5% bone marrow blasts at time of transplantation (HR: 2.14, 95% CI: 0.84-4.58, p=0.06) were independent predictors of an inferior overall survival. However, pre-transplant serum ferritin was not a significant predictor of disease-free survival, relapse or TRM. When compared with myeloablative regimens, RIC regimens may attenuate the impact of iron overload related end-organ toxicity. Prospective studies incorporating alternative biomarkers of iron metabolism alongside serum ferritin levels are needed to improve our understanding of the significance of iron overload in MDS patients undergoing allogeneic transplantation.

Outcomes of alemtuzumab-based reduced intensity conditioning stem cell transplantation using unrelated donors for myelodysplastic syndromes

This prospective study evaluated the outcomes of 75 successive patients receiving a FBC (fludarabine, busulphan, alemtuzumab) reduced‐intensity conditioning (RIC) regimen for myelodysplastic syndromes (MDS) using volunteer unrelated donors(VUD). The prognostic significance of a variety of clinical variables including the recently described haematopoietic cell transplantation co‐morbidity index (HCT‐CI) was assessed. The median age of the cohort was 52·0 years (range: 19–68 years) with a median follow‐up of 1038·5 d. Forty‐nine patients (65%) had an International Prognostic Scoring System stage of ≥Intermediate‐2, 35 (46%) had intermediate or poor risk cytogenetics, and 23 patients(31%) were human leucocyte antigen‐mismatched. The actuarial 3‐year overall survival (OS) and disease‐free survival (DFS) was 43% [95% confidence interval (CI): 37–49] and 41% (95%CI: 35–47) respectively, and the cumulative incidence of extensive chronic graft‐versus‐host disease was 22%. On multivariate analysis, presence of either one class II mismatch or a two‐antigen mismatch adversely influenced transplant‐related mortality, DFS and OS. In addition, disease status at transplantation and the haematopoietic cell transplantation‐specific comorbidity index were independent variables for overall survival. In contrast, both advanced age and pre‐transplant cytogenetic status did not significantly affect overall outcomes. RIC regimens using VUD was associated with durable long‐term survival even in older patients with MDS, and the use of a pre‐transplant comorbidity index may help to improve patient selection for transplantation.

Outcome of BEAM-autologous and BEAM-alemtuzumab allogeneic transplantation in relapsed advanced stage follicular lymphoma

The role of haematopoietic stem cell transplantation (HSCT) in relapsed follicular lymphoma remains controversial. This study analysed 126 patients with relapsed, advanced stage follicular lymphoma who received BEAM (BCNU [carmustine], cytarabine, etoposide, melphalan)‐alemtuzumab allogeneic HSCT (BEAM‐allo) (n = 44) or BEAM‐autologous HSCT (BEAM‐auto) (n = 82). The BEAM‐allo group had a younger median age (48 years vs. 56 years, P < 0·001) but received a higher median number of therapies pretransplant (P = 0·015) compared with the BEAM‐auto group. There was a higher non‐relapse mortality (NRM) in the BEAM‐allo group compared with the BEAM‐auto group at 1 year (20% vs. 2%, P = 0·001). Older age and heavily pretreated patients were associated with a higher NRM and poorer survival in the BEAM‐allo group. There was, however, a significantly lower relapse rate (20% vs. 43%, P = 0·01) at 3 years with BEAM‐alemtuzumab, with no relapses after 2 years, compared with a continued pattern of relapse in the autologous group. No difference in overall survival (OS) (P = 0·99) or disease‐free survival (DFS) (P = 0·90) was identified at 3 years, whereas a plateau in OS and DFS with crossing of the survival curves in favour of BEAM‐allo group was observed. Furthermore, the ability to re‐induce remissions with donor leucocytes provides additional benefit in favour of allogeneic HSCT.

Impact of pretransplant comorbidities on alemtuzumab-based reduced-intensity conditioning allogeneic hematopoietic SCT for patients with high-risk myelodysplastic syndrome and AML

We report a retrospective analysis of 128 consecutive patients with high-risk myelodysplastic syndrome (MDS) and AML who received an alemtuzumab-based reduced-intensity conditioning hematopoietic SCT (RIC HSCT). The median recipient age was 53 years (range 21–72 years). A total of 49 (38%) recipients had a sibling donor and 79 (62%) had a volunteer-unrelated donor. The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was assigned to all patients with a score of 0 in 40 (31%), of 1–2 in 45 (35%) and ⩾3 in 43 (34%) patients. The 3-year non-relapse mortality (NRM) was 31%, disease-free survival (DFS) was 41% and overall survival (OS) was 46%. The 3-year NRM for patients with a HCT-CI score of 0, 1–2 or ⩾3 was 16, 24 and 42%, respectively. The 3-year DFS and OS by HCT-CI was 58 and 69% (score 0), 39 and 39% (score 1–2) and 24 and 32% (score ⩾3), respectively. On multivariate analysis, HCT-CI was an independent variable affecting 3-year NRM, DFS and OS (P-value=0.04, 0.01 and <0.01, respectively). Although the disease stage at the time of transplant was an additional independent predictive variable on transplant outcomes, recipient age (>/<50 years) did not have a significant predictive impact. In MDS or AML patients with advanced disease receiving alemtuzumab-based RIC HSCT, the HCT-CI provides an important means of stratifying patients with a high risk of inferior transplant outcomes.

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.

Delayed attainment of full donor chimaerism following alemtuzumab-based reduced-intensity conditioning haematopoeitic stem cell transplantation for acute myeloid leukaemia and myelodysplastic syndromes is associated with improved outcomes

This prospective study evaluated the kinetics of lymphoid (CD3) engraftment in 110 patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) after allogeneic transplantation and conditioning with fludarabine, busulphan and alemtuzumab, using ciclosporin for post‐transplant immunosuppression. Declining donor CD3 chimaerism beyond day+100 was treated with pre‐emptive donor lymphocyte infusion (pDLI). The median age of patients was 53·0 years (range: 19–72 years), and the median follow‐up was 690 d (range:168–1470 d). Patients achieving full CD3 donor chimaerism (FDC, n = 46) by day+100 had a significantly inferior disease‐free survival (DFS) and overall survival (OS) compared to patients with mixed donor chimaerism (MDC, n = 59). Twenty patients had stable MDC and did not require pDLI. Patients attaining early FDC had a higher transplant‐related mortality compared to those who maintained stable levels of MDC (P = 0·02), with no difference between the FDC and pDLI groups (P = 0·07). There was no difference in relapse between all three groups (P = 0·21). On multivariate analysis, only CD3 chimaerism status at day+100 and disease status at transplantation had a significant effect on DFS and OS. In patients with AML/MDS undergoing alemetuzumab based‐RIC HSCT, prolonged MDC beyond day+100 is associated with an improved OS. Future studies need to be directed towards establishing the underlying factors that dictate T‐cell engraftment, expansion and homing post‐transplantation.

Outcomes of patients with haematological malignancies admitted to intensive care unit. A comparative review of allogeneic haematopoietic stem cell transplantation data

The outcomes of 55 consecutive haemato‐oncology patients admitted to the intensive care unit (ICU) were retrospectively analysed. Twenty‐eight patients were admitted following haemopoietic stem cell transplantation (HSCT). Thirty‐nine patients were admitted with respiratory failure, and all patients required respiratory support. Seventeen patients survived to be discharged from ICU, with an actuarial 1‐year survival of 18%. Overall survival between patients who received intensive chemotherapy and those who underwent allogeneic HSCT was not significantly different (19% vs. 10%, P = 0·19). None of the nine myeloablative HSCT recipients survived (median survival: 9 d). Six of the 15 reduced‐intensity conditioned HSCT recipients survived beyond 1 year (median survival: 1050 d, range: 438–1437).

An immune edited tumour versus a tumour edited immune system: prospects for immune therapy of acute myeloid leukaemia

Cell based therapies for acute myeloid leukaemia (AML) have made significant progress in the last decade benefiting the prognosis and survival of patients with this aggressive form of leukaemia. Due to advances in haematopoietic stem cell transplantation (HSCT) and particularly the advent of reduced intensity conditioning (RIC), the scope of transplantation has now extended to those patients previously ineligible due to age and health restrictions and has been associated with a decrease in transplant related mortality. The apparent graft versus leukaemia (GvL) effect observed following HSCT demonstrates the potential of the immune system to target and eradicate AML cells. Building on previously published pre-clinical studies by ourselves and others, we are now initiating a Phase I clinical study in which lentiviral vectors are used to genetically modify AML cells to express B7.1 (CD80) and IL-2. By combining allogeneic HSCT with immunisation, using the autologous AML cells expressing B7.1 and IL-2, we hope to stimulate immune eradication of residual AML cells in poor prognosis patients that have achieved donor chimerism. In this report we describe the background to cell therapy based approaches for AML, and discuss difficulties associated with the deployment of a chronically stimulated, hence exhausted/depleted immune system to eradicate tumour cells that have already escaped immune surveillance.

Reduced-intensity rituximab-BEAM-CAMPATH allogeneic haematopoietic stem cell transplantation for follicular lymphoma is feasible and induces durable molecular remissions

Summary:The indolent non-Hodgkins lymphomas are theoretically curable through allogeneic haematopoietic stem cell transplantation (allo-HSCT). The applicability of standard conditioning allo-HSCT is, however, restricted by its toxicity. Recently, reduced-intensity conditioning regimens have demonstrated efficacy with significantly reduced early morbidity and mortality. We examined the safety and efficacy of rituximab-BEAM-CAMPATH as reduced-intensity conditioning for allo-HSCT in follicular lymphomas. Minimal residual disease was assessed by polymerase chain reaction (PCR) for bcl-2/IgH translocations, and chimerism by X,Y-FISH or PCR amplification of short tandem repeat sequences. At a median follow-up of 521 days (371–719), four of five patients were alive and three were in complete molecular remission. Three patients required pre-emptive treatment for CMV reactivation. One succumbed to a perforated viscus and one had slowly progressive disease. A graft-versus-lymphoma effect was demonstrable and quantitative PCR for bcl-2/IgH may allow better accuracy in scheduling post-allograft rituximab and/or donor lymphocyte infusions. Although follow-up is short, reduced-intensity allo-HSCT with BEAM-CAMPATH conditioning appears to be safe, effective in inducing a molecular remission and is potentially curative. Further recruitment and much longer follow-up will be necessary to determine if this impacts favourably upon disease-free and overall survival.