Thrombotic thrombocytopenic purpura after allogeneic stem cell transplantation: a survey of the European Group for Blood and Marrow Transplantation (EBMT)

A survey was carried out among the European Group for Blood and Marrow Transplantation (EBMT) centres to determine the incidence, risk factors, treatment and outcome of thrombotic thrombocytopenic purpura (TTP) following allogeneic haematopoietic stem cell transplantation. TTP was defined as the simultaneous occurrence of red cell fragmentation, laboratory findings of haemolysis, red cell transfusion requirement and de novo or persistent thrombocytopenia caused by consumption, in the absence of disseminated intravascular coagulation. Forty-five centres reported all patients (n = 406) transplanted between July and December 1996. Twenty-three patients developed TTP; the risk of developing TTP was 6.7% at 2 years (95% CI: 4.1% to 9.3%). The median time of onset was 44 d (range 13-319) post transplantation. Significant risk factors for the development of TTP were female gender (P = 0.005) and an unrelated donor (P = 0.046). To treat TTP, cyclosporin administration was discontinued in 10 cases, plasma exchanges were performed in five cases and 12 patients received plasma infusions without plasma exchange. TTP resolved in 13 of the 23 patients (57%). The only factor predictive of resolution of TTP was the absence of nephropathy. Seven patients (30%) were alive at follow-up of 38-45 months from the onset of TTP. Sixteen patients died; the causes were multiple, only three patients had TTP as a central factor. The median time to death was 41 d (range 1-762 d) from the onset of TTP. TTP is a relatively frequent complication of allogeneic stem cell transplantation and it is associated with high mortality, though death is usually caused by multiple factors.     

Haematopoietic stem cell transplantation for patients with myelo-dysplastic syndromes and secondary acute myeloid leukaemias: a report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

Allogeneic stem cell transplantation from an HLA-identical sibling donor is a curative treatment option for a young patient with myelodysplastic syndrome, limited by age and lack of sibling donors. Alternative stem cell sources have been used more recently, such as unrelated donors, non-identical family members or autologous transplants. This analysis of 1378 transplants reported to the European Group for Blood and Marrow Transplantation (EBMT) addresses the outcome of the varying procedures according to the known risk factors. The estimated disease-free survival (DFS) and estimated relapse risk at 3 years were both 36% for 885 patients transplanted with stem cells from matched siblings. In the multivariate analysis, age and stage of disease had independent prognostic significance for DFS, survival and treatment-related mortality. Patients transplanted at an early stage of disease had a significantly lower risk of relapse than patients transplanted at more advanced stages. The estimated DFS at 3 years was 25% for the 198 patients with voluntary unrelated donors, 28% for the 91 patients with alternative family donors and 33% for the 126 patients autografted in first complete remission. The non-relapse mortality was 58% for patients with unrelated donors, 66% for patients with non-identical family donors and 25% for autografted patients. The relapse rate of 18% was relatively low for patients with non-identical family donors, 41% for patients with unrelated donors and 55% for patients treated with autologous stem cell transplantation. Both allogeneic and autologous stem cell transplantation have emerged as treatment options for patients with myelodysplastic syndromes. Transplantation with an HLA-identical sibling donor is the preferred treatment option. Patients without an HLA-identical sibling donor may be treated with either autologous stem cell transplantation or an alternative donor transplantation. Patients younger than 20 years may be treated with an unrelated donor transplantation. Patients older than 40 years, and probably also patients between 20 and 40 years, may benefit most from an autologous stem cell transplantation.     

Allogeneic stem cell transplantation of adult chronic myelomonocytic leukaemia. A report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

We report the results of 50 allogeneic transplantations from related (n = 43) or unrelated (n = 7) donors, performed for chronic myelomonocytic leukaemia (CMML) in 43 European centres. The median age at transplant was 44 years (range 19-61). Eighteen patients had excess blasts ranging from 5% to 30% at the time of transplantation. Two graft failures were observed (4%). Neutrophil (> 0.5 x 109/l) and platelet engraftment (> 50 x 109/l) was reached after a median of 17 d (range 11-38) and 27 d (range 11-48) respectively. Acute graft-versus-host disease (GvHD grade II-IV was seen in 35% of patients, while 20% developed severe-acute GvHD grade III/IV. Twenty-six patients (52%) died of treatment-related causes. After a median follow-up of 40 months (range 11-110), the 5-year-estimated overall survival was 21% (95% CI: 15-27%) and the 5-year-estimated disease-free survival (DFS) was 18% (95% CI: 13-23%). Earlier transplantation in the course of disease, male donor, use of unmanipulated grafts, allogeneic transplantation and occurrence of acute GvHD favoured better DFS, but did not reach statistical significance. The 5-year estimated probability of relapse was 49%. The data showed a trend for a lower relapse probability of acute GvHD grade II-IV (24% vs 54%; P = 0.07), and for a higher relapse rate in patients with T cell-depleted grafts (62% vs 45%), suggesting a 'graft-versus-CMML effect'.     

Factors affecting long-term outcome after allogeneic haematopoietic stem cell transplantation for acute myelogenous leukaemia: a retrospective study of 172 adult patients reported to the Austrian Stem Cell Transplantation Registry

Between 1982 and 2000, 172 patients with acute myelogenous leukaemia (AML) received haematopoietic stem cell transplants (SCT) from related (n = 132) or unrelated (n = 40) donors at four Austrian transplant centres and their results were reported to the Austrian Stem Cell Transplantation Registry. Conditioning for SCT consisted of cyclophosphamide and total body irradiation in 156 (91%) patients. Graft-versus-host disease (GVHD) prophylaxis was with standard cyclosporine and methotrexate in 95 (55%) patients. Median post-transplant follow-up was 5.6 years (range, 0.2--16.7). Multivariate analysis of transplant-related mortality (TRM) identified four variables associated with a lower risk: disease status of first complete remission (CR) at SCT, patient age of 45 years and younger, transplant performed during or after 1995, and lack of acute GVHD. Variables associated with significantly improved leukaemia-free survival were: bone marrow as the stem cell source, disease status of first CR at SCT, and occurrence of chronic GVHD. In multivariate analysis, transplantation performed during or after 1995, first CR at SCT, occurrence of limited chronic GVHD and lack of acute GVHD grades III to IV were associated with increased overall survival. Based on these analyses, options for the improvement of results obtained with allogeneic SCT in patients with AML could be defined.     

Second allogeneic stem cell transplantation in patients with acute lymphoblastic leukaemia: a study on behalf of the Acute Leukaemia Working Party of the European Society for Blood and Marrow Transplantation

Although second allogeneic haematopoietic cell transplantation (allo-HCT2) is a therapeutic option for patients relapsing after first HCT (allo-HCT1), there is limited data on allo-HCT2 in patients with acute lymphoblastic leukaemia (ALL). We retrospectively studied 245 patients receiving allo-HCT2 as a salvage treatment for relapse following allo-HCT1 between the 2000 and 2017. The median age at allo-HCT2 was 34·6 years (range: 18–74). One hundred and one patients (41%) received sibling donor and 144 (59%) unrelated donor allo-HCT2. Acute graft-versus-host disease (GVHD) grade II–IV and III–IV occurred in 33% and 17% of the patients, respectively. The incidence of 2-year total and extensive chronic GVHD was 38% and 19%, respectively. The 2- and 5-year cumulative incidence of non-relapse mortality, relapse incidence, leukaemia-free survival, overall survival and GVHD-free, relapse-free survival (GRFS) were 24% and 26%, 56% and 62%, 20% and 12%, 30% and 14% and 12% & 7%, respectively. In multivariate analysis, factors associated with overall survival were age, time from allo-HCT1 to relapse, conditioning for allo-HCT1, Karnofsky score at allo-HCT2 and donor type for allo-HCT2. In conclusion, outcomes of allo-HCT2 in ALL patients were poor, with only 14% overall survival and 7% GRFS at 5 years with very high relapse incidence.     

Next‐generation sequencing‐based detection of circulating tumour DNA After allogeneic stem cell transplantation for lymphoma

Next‐generation sequencing (NGS)‐based circulating tumour DNA (ctDNA) detection is a promising monitoring tool for lymphoid malignancies. We evaluated whether the presence of ctDNA was associated with outcome after allogeneic haematopoietic stem cell transplantation (HSCT) in lymphoma patients. We studied 88 patients drawn from a phase 3 clinical trial of reduced‐intensity conditioning HSCT in lymphoma. Conventional restaging and collection of peripheral blood samples occurred at pre‐specified time points before and after HSCT and were assayed for ctDNA by sequencing of the immunoglobulin or T‐cell receptor genes. Tumour clonotypes were identified in 87% of patients with adequate tumour samples. Sixteen of 19 (84%) patients with disease progression after HSCT had detectable ctDNA prior to progression at a median of 3·7 months prior to relapse/progression. Patients with detectable ctDNA 3 months after HSCT had inferior progression‐free survival (PFS) (2‐year PFS 58% vs. 84% in ctDNA‐negative patients, P = 0·033). In multivariate models, detectable ctDNA was associated with increased risk of progression/death (Hazard ratio 3·9, P = 0·003) and increased risk of relapse/progression (Hazard ratio 10·8, P = 0·0006). Detectable ctDNA is associated with an increased risk of relapse/progression, but further validation studies are necessary to confirm these findings and determine the clinical utility of NGS‐based minimal residual disease monitoring in lymphoma patients after HSCT.     

Outcome and risk factors for late-onset complications 24 months beyond allogeneic hematopoietic stem cell transplantation

Objectives: The aim of this retrospective study was to assess the incidence of late complications occurring ≥2 years after allogeneic hematopoietic stem cell transplantation (HSCT) for malignant diseases using a T‐cell depletion strategy. Methods: Between 1984 and 2004, 142 patients were eligible for the study. Total body irradiation (TBI) was carried out in 85% of the patients and T‐cell depletion in 84%. Results: Non‐relapse mortality (NRM) was 3% (95% CI 0–11) at 10 years, and serious late events affected a substantial number of patients. The cumulative incidence (CI) of chronic graft‐versus‐host disease (cGvHD) was 30% (95% CI 23–40), and that of infectious complications was 17% (95% CI 11–23). Multivariate analysis showed a higher risk for late complications in patients with cGvHD (HR 1.9, 95% CI 1.2–3.2, P = 0.011) and patients receiving methylprednisolone during conditioning (HR 1.9, 95% CI 1.1–3.3, P = 0.019 1), patients with cGvHD also having a higher risk for NRM (HR 13.2, 95% CI 1.2–143, P = 0.03), as well as those receiving steroids for >3 months (HR 40.3, 95% CI 2.3–718, P = 0.02) and those receiving antithymocyte globulin (HR 9.6, 95% CI 0.8–68, P = 0.024). Conclusions: A significant proportion of long‐term survivors of HSCT had late complications. cGvHD remained an important risk factor for late complications despite T‐cell depletion resulting in immunosuppression and infectious complications.     

Validation and extension of the EBMT Risk Score for patients with chronic myeloid leukaemia (CML) receiving allogeneic haematopoietic stem cell transplants

The European Group for Blood and Marrow Transplantation (EBMT) devised a scoring system to predict survival after allogeneic haematopoietic stem cell transplantation (HSCT) for chronic myeloid leukaemia (CML). The present International Bone Marrow Transplant Registry study of 3211 patients tested the EBMT Risk Score in a independent population, investigated the value of adding other variables, evaluated a new risk score specifically for chronic phase and compared the allograft risk scores with risk scores established by Sokal in 1984 and Hasford in 1998 for survival with non-transplant treatments. The primary outcome was 5-year survival after HSCT; survival curves, regression models and measurements of explained variation were used to compare scores. Using the EBMT scoring system, survival in the independent dataset was almost identical to those in the original EBMT publication, thus validating the EBMT Risk Score. Adding one extra variable, performance status, or designing a score specifically for early chronic phase by using the original five variables with different breakpoints gave results only slightly better than the original EBMT Score. Sokal and Hasford Scores did not predict survival after HSCT. We concluded that the EBMT Risk Score does not currently require modification.     

Prolonged immune deficiency following allogeneic stem cell transplantation: risk factors and complications in adult patients

To evaluate the long-term immune reconstitution after allogeneic haematopoietic stem cell transplantation (SCT), we prospectively screened standard immune parameters in a series of 105 patients, at a median time of 15 months after SCT. Analysing lymphoid phenotypes, in vitro immune functions and immunoglobulin levels, we found that, more than 1 year post SCT, cellular and humoral immunity was still altered in a significant number of patients. CD4+ T cells were < 200/microl in one third of patients, and the CD4/CD8 ratio was still reversed in 78% of patients. Almost all patients showed positive T-cell responses against mitogens, but antigen-specific proliferation assays identified 20% to 80% of non-responders. B-cell counts were reconstituted in 61% of the patients, but levels of total immunoglobulins were still low in 59%. In multivariate analyses, human leucocyte antigen (HLA) disparity between donor and recipient and chronic graft-versus-host disease were the leading causes affecting immune reconstitution. Interestingly, cytomegalovirus (CMV) infections were strongly associated with normal CD8+ T-cell counts. Studying the impact of impaired immune reconstitution on the rate of infections occurring in the 6 years following screening, we identified three parameters (low B-cell count, inverted CD4/CD8 ratio, and negative response to tetanus toxin) as significant risk factors for developing such late infections.     

Sequential chemotherapy followed by reduced‐intensity conditioning and allogeneic haematopoietic stem cell transplantation in adult patients with relapse or refractory acute myeloid leukaemia: a survey from the Acute Leukaemia Working Party of EBMT

This study analysed the outcome of 267 patients with relapse/refractory acute myeloid leukaemia (AML ) who received sequential chemotherapy including fludarabine, cytarabine and amsacrine followed by reduced‐intensity conditioning (RIC ) and allogeneic haematopoietic stem cell transplantation (HSCT ). The transplants in 77 patients were from matched sibling donors (MSD s) and those in 190 patients were from matched unrelated donors. Most patients (94·3%) were given anti‐T‐cell antibodies. The incidence of acute graft‐versus‐host disease (GVHD ) of grades II ‒IV was 32·1% and that of chronic GVHD was 30·2%. The 3‐year probability of non‐relapse mortality (NRM ) was 25·9%, that of relapse was 48·5%, that of GVHD ‐free and relapse‐free survival (GRFS ) was 17·8% and that of leukaemia‐free survival (LFS ) was 25·6%. In multivariate analysis, unrelated donor recipients more frequently had acute GVHD of grades II ‒IV [hazard ratio (HR ) = 1·98, P  = 0·017] and suffered less relapses (HR  = 0·62, P  = 0·01) than MSD recipients. Treatment with anti‐T‐cell antibodies reduced NRM (HR  = 0·35, P  = 0·01) and improved survival (HR  = 0·49, P  = 0·01), GRFS (HR  = 0·37, P  = 0·0004) and LFS (HR  = 0·46, P  = 0·005). Thus, sequential chemotherapy followed by RIC HSCT and use of anti‐T‐cell antibodies seems promising in patients with refractory AML .     

Progress in allogenic bone marrow and peripheral blood stem cell transplantation for multiple myeloma: a comparison between transplants performed 1983--93 and 1994--8 at European Group for Blood and Marrow Transplantation centres

Out of 690 allogeneic matched sibling donor transplants for multiple myeloma reported to the European Group for Blood and Marrow Transplantation (EBMT) registry, 334 were performed during the period 1983-93 (all with bone marrow) and 356 during 1994-98 [223 with bone marrow and 133 with peripheral blood stem cells (PBSCs)]. The median overall survival was 10 months for patients transplanted during the earlier time period and 50 months for patients transplanted with hone marrow during the later period. The use of PBSCs was associated with earlier engraftment but no significant survival benefit compared to bone marrow transplants during the same time period. The improvement in survival since 1994 with the result of a significant reduction in transplant-related mortality, which was 38%, 21% and 25% at 6 months and 46%, 30% and 37% at 2 years during the earlier period, and the later period with bone marrow and PBSCs respectively. Reasons for the reduced transplant-related mortality appeared to be fewer deaths owing to bacterial and fungal infections and interstitial pneumonitis, in turn a result of earlier transplantation and less prior chemotherapy. Better supportive treatment and more frequent use of cytokines may also play a role. The improvement in survival was not directly related to the increased use of PBSCs.