Search

It is currently unknown what degree of human leukocyte antigen (HLA)-mismatching is acceptable in unrelated donor hematopoietic stem cell transplantation (UD-HSCT). Mismatches at some loci may be more permissive than others. We have analyzed the effect of high-resolution HLA-matching on outcome of all 214 consecutive recipients of UD-HSCT carried out in Switzerland. All typing was by the Swiss reference laboratory. Donor-recipient pairs were HLA-10/10 matched (n=130) or mismatched for either HLA-A/-B/-DRB1/multiple loci (n=33; (HLA-A/-B=10); (-DRB1=8); (multiple=15)); HLA-C (n=29) or HLA-DQ/-DRB3 (n=22; (DQ=16); (-DRB1=6)). The median follow-up was 32 months. Survival probabilities (+/-95% confidence interval) at 3 years were 57 (+/-10)% for recipients of HLA 10/10-matched transplants, 53 (+/-22)% for recipients of HLA-DQ/-DRB3-mismatched transplants, 44 (+/-20)% for recipients of HLA-C-mismatched transplants and 0% for recipients of transplants mismatched at HLA-A/-B/-DRB1/multiple loci (P<0.0001). In multivariate analyses, HLA compatibility was the variable most significantly associated with survival and treatment-related mortality. We found important differences in survival in recipients of UD-HSCT with best results for transplants from 10/10 matched donors. Single mismatches at HLA-DQ/-DRB3 were well tolerated, mismatches at HLA-C had intermediate results and mismatches at HLA-A/-B/-DRB1/multiple loci resulted in poor survival.

In contrast to solid organ transplantation, ABO incompatibility is generally not associated with survival differences in hematopoietic stem cell transplantation. Therefore, patients receiving ABO-incompatible stem cell transplantation can be analyzed to study the mechanism of tolerance induction after antigen-mismatched transplantation. The goal of this study was to analyze the levels of anti-A/B antibodies after ABO-incompatible transplantation. Host-derived antidonor antibodies disappeared rapidly after transplantation and did not reappear in the further posttransplant course. Donor-derived antihost antibodies did not significantly increase and compatible anti-A/B antibodies remained positive after hematopoietic stem cell transplantation. Thus, there is no evidence for stimulation of donor B lymphocytes to produce antirecipient antibodies suggesting a potential B cell tolerance.

The multikinase inhibitor sorafenib has shown a strong anti-leukemic effect in FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML); however, remission is often transient. To better understand the role of sorafenib, we performed a retrospective analysis of all patients who received sorafenib in combination with allogeneic hematopoietic stem cell transplantation (HSCT) at our center. Seventeen patients with FLT3-ITD positive AML were treated with sorafenib in combination with allogeneic HSCT. Seven patients received sorafenib therapy pre- and posttransplant, and 10 patients were given sorafenib only posttransplant. Median duration of sorafenib treatment was 13 months (range 1-42); median dose was 600 mg (range 100-1200). Fourteen patients (82 %) achieved a complete remission (CR), while 5 patients (29 %) eventually developed progressive disease. Developing chronic graft-versus-host disease (GvHD) had a strong protective influence on the risk of sorafenib resistance (p = 0.028, HR 0.08, 95 % CI 0.01-0.76). In a total of 8 patients, sorafenib had to be stopped, paused or dose-reduced due to toxicity. In 5 patients with pronounced toxicity, we switched to an alternating dosing schedule with 1 month on/1 month off sorafenib. These patients subsequently remained in sustained complete molecular remission, with a median follow-up of 20 months. Our data indicate that sorafenib can achieve high rates of sustained remission in high-risk patients treated in combination with HSCT. [ABSTRACT FROM AUTHOR]

A record number of 39 209 HSCT in 34 809 patients (14 950 allogeneic (43%) and 19 859 autologous (57%)) were reported by 658 centers in 48 countries to the 2013 survey. Trends include: more growth in allogeneic than in autologous HSCT, increasing use of sibling and unrelated donors and a pronounced increase in haploidentical family donors when compared with cord blood donors for those patients without a matched related or unrelated donor. Main indications were leukemias, 11 190 (32%; 96% allogeneic); lymphoid neoplasias, 19 958 (57%; 11% allogeneic); solid tumors, 1543 (4%; 4% allogeneic); and nonmalignant disorders, 1975 (6%; 91% allogeneic). In patients without a matched sibling or unrelated donor, alternative donors are used. Since 2010 there has been a marked increase of 96% in the number of transplants performed from haploidentical relatives (802 in 2010 to 1571 in 2013), whereas the number of unrelated cord blood transplants has slightly decreased (789 in 2010 to 666 in 2013). The use of donor type varies greatly throughout Europe. [ABSTRACT FROM AUTHOR]

Patients with refractory/relapsing lymphoma are rarely cured by chemotherapy. High-dose chemotherapy (HDC) for tumor debulking followed by reduced-intensity conditioning (RIC) hematopoietic stem-cell transplantation (HSCT) has been advocated as a concept. We previously treated 10 patients (group A) with BEAM chemotherapy followed by delayed RIC HSCT at day 28. We now report on the subsequent 11 patients receiving BEAM followed immediately by fludarabine/total body irradiation and allogeneic HSCT (group B), and compare the outcome to group A patients. Non-hematological toxicity before engraftment was comparable, only gut toxicity was higher in group B. Days in aplasia, days on antibiotics and length of hospital stay were significantly longer in group A. Cumulative incidence of acute (GvHD) grade II and incidence of chronic GvHD were lower in group B. At last follow-up, seven patients in group A were alive, with six of them in complete remission. In group B, nine patients were alive, seven of them in complete remission. No significant difference in estimated 3-year overall survival was seen. These data challenge the initial concept of debulking first and delaying allogeneic RIC HSCT. Allogeneic HSCT with standard BEAM conditioning is a valid alternative for patients with resistant/relapsed lymphoma, which might be considered earlier in the disease course.Bone Marrow Transplantation (2007) 39, 335–340. doi:10.1038/sj.bmt.1705597 [ABSTRACT FROM AUTHOR]

Summary:We studied occurrence, risk factors and outcome of patients with transplant-associated microangiopathy (TAM) after allogeneic stem cell transplantation (HSCT). A total of 221 consecutive patients were transplanted between 1995 and 2002. TAM is defined as evidence of hemolysis and schistocytes in the first 100 days. Outcomes analyzed included TAM and overall survival. Of 221 patients, 68 had TAM. The cumulative incidence was 31 (25–38)% at 100 days. Patients with TAM had higher LDH, higher bilirubin, higher creatinine and more often neurologic symptoms. TAM was not associated with stem cell source, cyclosporine levels and was not more frequent in recent years. In multivariate analysis, risk factors for TAM included donor type, age, gender, ABO-incompatibility and acute graft-versus-host disease (aGvHD). In patients with TAM, 1-year survival was lower than in patients without TAM (27±18% for TAM with high schistocyte counts; 53±15% for TAM with low schistocyte counts; vs 78±7% in patients without TAM; P<0.0001). TAM was independently associated with mortality adjusting for donor type, age and aGvHD occurrence and severity. TAM is frequent after HSCT and is associated with mortality even after adjustment for aGvHD grade. Risk factors of TAM are similar to aGvHD. TAM may represent endothelial damage driven by donor–host interactions.Bone Marrow Transplantation (2005) 36, 993–1000. doi:10.1038/sj.bmt.1705160; published online 26 September 2005 [ABSTRACT FROM AUTHOR]

Summary:Severe graft-versus-host disease (GvHD) refractory to corticosteroids responds poorly to experimental treatment and is often fatal. Attempts have been made to‘rescue’such patients by transfusing autologous cells in order to ablate the lymphoid component of the graft or to introduce regulatory cells capable of suppressing the GvHD. Here, we report details of eight patients with severe grade III-IV acute GvHD (n=7) or extensive chronic GvHD (n=1) who after failing a median of four lines of treatment were then treated with either autologous or syngeneic nucleated cell transfusions. Patients received standard conditioning (n=3), low intensity (n=2) or no conditioning (n=3) before the rescue procedure. In four of the five patients who received some form of conditioning, mixed chimerism or complete recipient hematopoiesis was restored. The GvHD resolved in four patients, of whom one died subsequently of multiorgan failure and two died of leukemia; one is still alive. A fifth patient had transient improvement in GvHD, which recurred when the corticosteroids were reduced. Three patients obtained no benefit from the procedure. We conclude that‘rescue’by transfusion of autologous or syngeneic nucleated cells may be valuable to treat severe refractory GvHD; the best approach to conditioning remains to be defined.Bone Marrow Transplantation (2004) 34, 995-998. doi:10.1038/sj.bmt.1704658 Published online 18 October 2004 [ABSTRACT FROM AUTHOR]

This study describes the outcome of patients receiving haematopoietic stem cell transplantation (HSCT) to treat severe refractory autoimmune cytopenia. The registry of the European Group of Blood and Marrow Transplantation holds data on 36 patients receiving 38 transplants, the first transplant was autologous for 27 and allogeneic for nine patients. Patients had autoimmune haemolytic anaemia (autologous: 5; allogeneic: 2), Evans's syndrome (autologous: 2; allogeneic: 5); immune thrombocytopenia (autologous: 12), pure red cell aplasia (autologous: 4; allogeneic: 1), pure white cell aplasia (autologous: 1; allogeneic 1), or thrombotic thrombocytopenic purpura (autologous: 3). Patients had longstanding disease having failed multiple prior treatments. Among 26 evaluable patients mobilized for autologous HSCT, three died of treatment-related causes, one died of disease progression, seven were non-responders, six patients had transient responses and nine had continuous partial or complete remission. Of the seven evaluable patients receiving allogeneic HSCT, one died of treatment-related complications, one with transient response died of progressive disease and five had a continuous response. Autologous and allogeneic HSCT may induce a response in a subset of patients with autoimmune cytopenia of long duration albeit at the price of considerable toxicity. [ABSTRACT FROM AUTHOR]

In patients with refractory lymphoma, we tested the hypothesis that high-dose chemotherapy (BEAM) without stem cell support followed by a reduced intensity (RIC) allogeneic transplant with fludarabine and 2 Gy TBI 28 days later results in tumor debulking and establishment of a graft vs lymphoma effect, with acceptable toxicity. In a pilot protocol we treated 10 patients, 22-62 (median 47) years of age with high-risk or refractory Hodgkin's or non-Hodgkin's lymphoma. Donors were HLA identical siblings (eight) or unrelated volunteers. None died during the neutropenic phase after BEAM which tasted up to the RIC HSCT. The duration of neutropenia was 31-43 (median 36) days. All patients engrafted and nine achieved CR. All developed acute GvHD (median grade III) and all patients at risk developed chronic GvHD. Three patients died of GvHD. One relapsed and six patients are in continuous CR 10-32 (median 15) months after HSCT. This approach appears feasible and results in a high response rate. Neutropenia duration is of concern. It remains to be tested whether separation of debulking chemotherapy and induction of allogeneic effects confers an advantage. [ABSTRACT FROM AUTHOR]

Patients with chronic myeloid leukemia (CML) relapsing in blast crisis after HLA-identical sibling bone marrow transplantation (BMT) are difficult to treat. Infusion of donor lymphocytes or retransplantation are unlikely to result in long-term disease-free survival. Treatment intensification with allogeneic double-BMT, made possible by using repeatedly mobilized peripheral blood stem cells, offers a new treatment option. We report two patients with Philadelphia chromosome positive CML transplanted in chronic phase, relapsing with CML in myeloid blast crisis. Both received intensive induction chemotherapy (ICE) followed by a first, T cell-depleted peripheral stem cell transplant from the initial donor. Both patients engrafted rapidly (day 15). Upon hematologic recovery, a second G-CSF mobilized non-T cell-depleted peripheral stem cell transplant from the same donor was given after pretransplant conditioning with busulphan and cyclophosphamide. Again, engraftment was rapid (days 18 and 16) and both patients are alive and disease-free 18 and 21 months after allogeneic double-BMT. G-CSF mobilized peripheral stem cells allow new ways of treatment intensification with double-BMT in refractory leukemias relapsing post-transplant. This approach warrants further study. [ABSTRACT FROM AUTHOR]

There is growing evidence for a graft-versus-myeloma effect following allogeneic stem cell transplantation. We add to this evidence by reporting complete remission achieved by withdrawal of immunosuppression in a patient with multiple myeloma progressing after HLA-identical sibling peripheral stem cell transplantation. De novo chronic graft-versus-host disease coincided with the anti-myeloma effect and responded to treatment. The patient remains in complete remission 3 years after transplant. [ABSTRACT FROM AUTHOR]