Keiren Kirkland

Outcome following Reduced-Intensity Allogeneic Stem Cell Transplantation (RIC AlloSCT) for relapsed and refractory mantle cell lymphoma (MCL): a study of the British Society for Blood and Marrow Transplantation.

Reduced-intensity allogeneic stem cell transplantation (RIC-AlloSCT) is being increasingly considered for patients with aggressive lymphoma, but limited evidence exists in mantle cell lymphoma (MCL). We report a retrospective study of transplant outcomes of RIC-AlloSCT for MCL in 70 patients (median age, 48 years, range: 30-67 years), with 57 patients receiving an Alemtuzumab-containing regimen. Thirty-four percent of patients had received a prior autologous stem cell transplant. The 1- and 5-year nonrelapse mortality (NRM) was 18% (95% confidence interval [CI] 10-27) and 21% (95% CI 12-31), respectively. The incidence of severe (grade III and IV) acute graft-versus-host disease (aGVHD) was 10%, and the 5-year incidence of chronic GVHD (cGVHD) was 61%. The cumulative relapse risk was 65% (95% CI 48-77) at 5 years, significantly affected by disease status at transplant (P = .0495), specifically the presence of chemosensitive disease (P = .0364). Fifteen of 18 relapsed patients received donor lymphocyte infustion (DLI) (n = 14) or a second RIC-AlloSCT (n = 1), with 11 of 15 currently in CR. The 5-year overall survival (OS) and progression-free survival (PFS) were 37% (95% CI 25%-56%) and 14% (95% CI 6%-34%), respectively. Age at transplantation and having <2 prior lines of therapy influenced the OS, whereas having <2 prior lines of therapy was the only factor to influence PFS. The use of Alemtuzumab in the conditioning was associated with an improved OS at 3 years (P = .0271). RIC-AlloSCT is a potential treatment modality for aggressive MCL. For patients relapsing post-AlloSCT, the disease is salvageable with DLI. The timing of RIC-AlloSCT should be explored in prospective studies to establish the optimal role in the management of this aggressive lymphoma.

The role of allogeneic SCT in primary myelofibrosis: a British Society for Blood and Marrow Transplantation study

Fifty-one patients with primary myelofibrosis (PMF) received allogeneic haematopoietic stem cell transplants from related (n=33) or unrelated (n=18) donors. Twenty-seven patients, 19–54 years old, were prepared with myeloablative regimens including CY plus BU (n=4) or TBI (n=23). Twenty-four patients, 40–64 years old, received reduced-intensity conditioning (RIC) regimens. All RIC regimens contained fludarabine, combined with melphalan (n=19) or BU (n=5), and alemtuzumab or anti-thymocyte globulin (ATG) in the majority (n=19). Four patients (17%) in the RIC group had primary graft failure. Previous splenectomy reduced time to engraftment in the RIC group (13 versus 20 days; P=0.008). For MA and RIC groups, respectively, at 3 years, overall survival rates were 44 and 31% (P=0.67), progression-free survival 44 and 24% (P=0.87), and actuarial relapse rates 15 and 46% (P=0.06). Non-relapse mortality at 3 years was 41% for the myeloablative and 32% for the RIC group. Acute GVHD occurred in 29 and 38% of patients in the myeloablative and RIC groups, respectively. Extensive chronic GVHD developed in 30 and 35% of evaluable patients, respectively.

Retrospective study of alemtuzumab vs ATG-based conditioning without irradiation for unrelated and matched sibling donor transplants in acquired severe aplastic anemia: a study from the British Society for Blood and Marrow Transplantation

This retrospective national study compared the use of alemtuzumab-based conditioning regimens for hematopoietic SCT (HSCT) in acquired severe aplastic anemia with antithymocyte globulin (ATG)-based regimens. One hundred patients received alemtuzumab and 55 ATG-based regimens. A matched sibling donor (MSD) was used in 87 (56%), matched unrelated donor (MUD) in 60 (39%) and other related or mismatched unrelated donor (UD) in 8 (5%) patients. Engraftment failure occurred in 9% of the alemtuzumab group and 11% of the ATG group. Five-year OS was 90% for the alemtuzumab and 79% for the ATG groups, P=0.11. For UD HSCT, OS of patients was better when using alemtuzumab (88%) compared with ATG (57%), P=0.026, although smaller numbers of patients received ATG. Similar outcomes for MSD HSCT using alemtuzumab or ATG were seen (91% vs 85%, respectively, P=0.562). A lower risk of chronic GVHD (cGVHD) was observed in the alemtuzumab group (11% vs 26%, P=0.031). On multivariate analysis, use of BM as stem cell source was associated with better OS and EFS, and less acute and cGVHD; young age was associated with better EFS and lower risk of graft failure. This large study confirms successful avoidance of irradiation in the conditioning regimens for MUD HSCT patients.

Factors Influencing the Outcome of a Second Autologous Stem Cell Transplant (ASCT) in Relapsed Multiple Myeloma: A Study from the British Society of Blood and Marrow Transplantation Registry

Autologous stem cell transplant as primary (first ASCT) therapy in multiple myeloma (MM) is standard practice. The role of a second ASCT as management of relapsed disease remains uncertain. We conducted a retrospective case-matched control analysis on patients (n = 106) who underwent a second ASCT compared with conventional chemotherapy (CCT) as for relapsed MM. The median age was 53 years (range: 26-75) and median follow-up 48 months (range: 8, 136). The cumulative incidence of 1 and 5 years nonrelapse mortality (NRM) was 7% (95% confidence interval [CI] 3%-13%) and 12% (95% CI 7%-19%), with a second ASCT inducing a greater partial remission (PR) rate of 63%. The 4-year overall survival (OS) rate was 33% (95% CI 24%-45%). Factors associated with improved OS and progression-free survival (PFS) included younger age (<55 years), β(2)MG <2.5 mg/L at diagnosis, a remission duration of >9 months from first ASCT, and a greater PR in response to their first ASCT. In a matched-cohort analysis with patients receiving conventional chemotherapy (CCT), the same factors were associated with improved OS, with the exception of a longer remission duration (>18 months) from first ASCT. Second ASCT in relapsed MM is associated with superior OS and PFS compared with CCT, offering a potential consolidative option for selected patients.

Favorable outcomes with alemtuzumab-conditioned unrelated donor stem cell transplantation in adults with high-risk Philadelphia chromosome-negative acute lymphoblastic leukemia in first complete remission

T-cell depletion is generally believed to effectively prevent graft-versus-host disease (GVHD), yet to impose an adverse effect on disease-free survival that eventually affects overall survival of leukemia patients undergoing allogeneic hematopoietic stem cell transplantation. In this study, however, Dr. Patel and co-workers demonstrate that T-cell-depleted hematopoietic stem cell transplantation from unrelated donors can result in good overall survival and low non-relapse mortality for adults with high-risk acute lymphoblastic leukemia in first complete remission. Background Approximately 40% of adults with Philadelphia chromosome-negative acute lymphoblastic leukemia achieve long-term survival following unrelated donor hematopoietic stem cell transplantation in first complete remission but severe graft-versus-host disease remains a problem affecting survival. Although T-cell depletion abrogates graft-versus-host disease, the impact on disease-free survival in acute lymphoblastic leukemia is not known. Design and Methods We analyzed the outcome of 48 adults (median age 26 years) with high-risk, Philadelphia-chromosome-negative acute lymphoblastic leukemia undergoing T-cell depleted unrelated donor-hematopoietic stem cell transplantation (67% 10 of 10 loci matched) in first complete remission reported to the British Society of Blood and Marrow Transplantation Registry from 1993 to 2005. Results T-cell depletion was carried out by in vivo alemtuzumab administration. Additional, ex vivo T-cell depletion was performed in 21% of patients. Overall survival, disease-free survival and non-relapse mortality rates at 5 years were 61% (95% CI 46–75), 59% (95% CI 45–74) and 13% (95% CI 3–25), respectively. The incidences of grades II–IV and III–IV acute graft-versus-host disease were 27% (95% CI 16–44) and 10% (95% CI 4–25), respectively. The actuarial estimate of extensive chronic graft-versus-host disease at 5 years was 22% (95%CI 13–38). High-risk cytogenetics at diagnosis was associated with a lower 5-year overall survival (47% (95% CI 27–71) vs. 68% (95% CI 44–84), p=0.045). Conclusions T-cell depleted hematopoietic stem cell transplantation from unrelated donors can result in good overall survival and low non-relapse mortality for adults with high-risk acute lymphoblastic leukemia in first complete remission and merits prospective evaluation.

Haematopoietic stem cell transplantation (HSCT) in severe autoimmune diseases: analysis of UK outcomes from the British Society of Blood and Marrow Transplantation (BSBMT) data registry 1997-2009.

The British Society of Blood and Marrow Transplantation Data Registry was used to analyse outcomes of haematopoietic stem cell transplantation (HSCT) in severe autoimmune diseases (SADs) from 1997 to 2009. 55 autologous and 15 allogeneic HSCT were registered (0·22% of overall UK HSCT activity). Sustained responses were observed following HSCT, although toxicity was significant. This is the first reported national analysis of long‐term outcomes of HSCT in SADs, and should be viewed in the context of translational and developmental phases of HSCT in poor prognosis and refractory SADs. Treatment of poor‐risk but reversible SADs with adequate fitness for HSCT in accordance with current guidelines is warranted.

The clinical features and outcome of 2009 H1N1 influenza infection in allo-SCT patients: a British Society of Blood and Marrow Transplantation study

The clinical course of 2009 H1N1 influenza in Allo-SCT patients is unknown. Data were collected in the UK from October 2009 to April 2010 on laboratory-confirmed cases of H1N1 influenza in Allo-SCT recipients. H1N1 infection was diagnosed in 60 patients, median age 42 years, at a median of 10 months post-SCT. Twenty-one patients (35%) developed pneumonia and nine (15%) required admission to intensive care units. Actuarial mortality was 7% at 28 days and 19% 4 months post-diagnosis of 2009 H1N1 influenza. Increasing age and pre-existing lung disease were risk factors for pneumonia (P=0.006 and 0.037, respectively); older age was a risk factor for death (P=0.012). Morbidity and mortality from 2009 H1N1 influenza in SCT patients exceeds that of immunocompetent patients, but parallels that in other critically ill hospitalised cohorts; the elderly and those with chronic pulmonary disease are at greatest risk.

Unrelated donor peripheral blood stem cell transplants incorporating pre-transplant in-vivo Alemtuzumab are not associated with any increased risk of significant acute or chronic graft-versus-host disease

There is little information published comparing peripheral blood stem cells (PBSC) with bone marrow (BM) as the stem cell source in the long‐term outcome in recipients of T‐cell depleted (TCD) unrelated donor (UD) transplants. We present retrospective outcome data on 306 recipients of myeloablative, human leucocyte antigen‐matched UD allografts using pre‐transplant in‐vivo Alemtuzumab. Transplants were performed between 2000 and 2007 for chronic myeloid leukaemia in first chronic phase and acute leukaemia in first or second complete remission; 184 patients received BM and 122 PBSC. The median age was 28·9 years (<1–58) and the median follow‐up was 48 months. Overall survival at 8 years was 53%. The incidence of acute graft‐versus‐host disease (GvHD) was significantly higher in PBSC (65%) than BM recipients (49%; P = 0·012). This represented only grade 1 GvHD with no difference in grade II–IV aGvHD (BM 23% PBSC 24%). The incidence of chronic GvHD, either overall (BM 47%, PBSC 49%) or extensive (BM 15%, PBSC 13%) was not increased with PBSC. The incidence of relapse, non‐relapse mortality and survival were not significantly different. Whilst accepting the limitations of retrospective analyses, we suggest the increased risk of GvHD in recipients of PBSC in T‐replete transplants is offset by in‐vivo Alemtuzumab, and that either stem cell source can be used with good outcomes in this setting.

Recipient/donor HLA and CMV matching in recipients of T-cell-depleted unrelated donor haematopoietic cell transplants

Improving haematopoietic cell transplantation outcomes by selection of an HLA-matched unrelated donor is best practice; however, donor selection by secondary characteristics is controversial. We studied 1271 recipients with haematological malignancies who underwent T-cell-depleted allografts and had complete data on HLA-matching status for six loci (HLA-A, -B, -C, -DRB1, -DQB1, -DPB1) and clinical outcome data. Five-year overall survival was 40.6%. HLA mismatching (at HLA-A, -B, -C, -DRB1, -DQB1) relative risk (RR) 1.22, 95% confidence interval (CI) 1.2–1.5, P=0.033 for 1 mismatch and RR 1.46, 95% CI 1.1–1.9, P=0.009 for >1 mismatch) and CMV mismatching (RR 1.37, 95% CI 1.2–1.6, P<0.001) were significantly associated with inferior survival. Donors aged <30 years showed a trend towards better survival. The multivariate model for mortality, combining CMV and HLA-match status, found an RR of 1.36 (95% CI 1.1–1.7, P=0.003) for HLA matched/CMV mismatched, an RR of 1.22 (95% CI 0.99–1.5, P=0.062) for HLA mismatched/CMV matched and an RR of 1.81 (95% CI 1.4–2.3, P=<0.001) for HLA/ CMV mismatched, compared with the HLA/CMV-matched recipients. These data suggest that HLA and CMV matching status should be considered when selecting unrelated donors and that CMV matching may abrogate the effect of an HLA mismatch.

Evidence for a GVL effect following reduced-intensity allo-SCT in ALL: a British Society of Blood and Marrow Transplantation study

Myeloablative allo-SCT decreases relapse incidence (RI) in ALL. Reduced intensity conditioning (RIC) may extend allo-SCT to older and less fit patients. Sixty-nine ALL patients reported to the BSBMT underwent fludarabine-based RIC allo-SCT, 38 from unrelated donors (UD). Forty-four patients received alemtuzumab. ALL was in CR in 64 patients (93%). This was a second or third SCT in 23 patients. Two-year OS and PFS were 36% and 32%, respectively. In multivariate analysis male recipients demonstrated better OS and PFS (hazard ratio (HR)=0.42, P=0.008 and HR=0.45, P=0.012, respectively). Two-year TRM was 29%: higher with younger age (HR=0.97/year, P=0.041), female recipient (HR=2.55, P=0.049) and increasing grade of acute GVHD (HR=1.87, P=0.001). Two-year RI was 38% and was lower in patients with acute and chronic GVHD (HR=0.62 per increasing grade, P=0.035 and HR=0.52, P=0.025, respectively). Long-term ALL-free survival is achievable following fludarabine-based RIC allo-SCT. The association between GVHD and decreased RI suggests the presence of a GVL effect.