Volker Runde

Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: results of the AML Study Group (AMLSG).

In this study, we evaluated the frequency and prognostic impact of DNMT3A mutations (DNMT3A(mut)) in 1770 younger adult patients with acute myeloid leukemia (AML) in the context of other genetic alterations and the European LeukemiaNet (ELN) classification. DNMT3A(mut) were found in 20.9% of AMLs and were associated with older age (P < .0001), higher white blood cell counts (P < .0001), cytogenetically normal AML (CN-AML; P < .0001), NPM1 mutations (P < .0001), FLT3 internal tandem duplications (P < .0001), and IDH1/2 mutations (P < .0001). In univariable and multivariable analyses, DNMT3A(mut) did not impact event-free, relapse-free (RFS), or overall survival (OS) in either the entire cohort or in CN-AML; a negative prognostic effect was found only in the ELN unfavorable CN-AML subset (OS, P = .011). In addition, R882 mutations vs non-R882 mutations showed opposite clinical effects-unfavorable for R882 on RFS (all: hazard ratio [HR], 1.29 [P = .026]; CN-AML: HR, 1.38 [P = .018]) and favorable for non-R882 on OS (all: HR, 0.77 [P = .057]; CN-AML: HR, 0.73 [P = .083]). In our statistically high-powered study with minimized selection bias, DNMT3A(mut) represent a frequent genetic lesion in younger adults with AML but have no significant impact on survival end points; only moderate effects on outcome were found, depending on molecular subgroup and DNMT3A(mut) type.

Infectious complications after allogeneic stem cell transplantation: epidemiology and interventional therapy strategies Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO)

The risk of infection after allogeneic stem cell transplantation is determined by the underlying disease, the intensity of previous treatments and complications that may have occurred during that time, but above all, the risk of infection is determined by the selected transplantation modality (e.g. HLA-match between the stem cell donor and recipient, T cell depletion of the graft, and others). In comparison with patients treated with high-dose chemotherapy and autologous stem cell transplantation, patients undergoing allogeneic stem cell transplantation are at a much higher risk of infection even after hematopoietic reconstitution, due to the delayed recovery of T and B cell functions. The rate at which immune function recovers after hematopoietic reconstitution greatly influences the incidence and type of post-transplant infectious complications. Infection-associated mortality, for example, is significantly higher following engraftment than during the short neutropenic period that immediately follows 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).

Summary. 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 × 109/l) and platelet engraftment (> 50 × 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’.

Positive serum crossmatch as predictor for graft failure in HLA-mismatched allogeneic blood stem cell transplantation

Background. Evaluation of patient sera for complement-fixing anti-donor antibodies (serum crossmatch [XM]) before allogeneic blood stem cell transplantation (BSCT) is routine in most centers. However, in contrast to kidney transplantation, the predictive value of a positive XM for outcome of BSCT is still unclear, and a positive XM is presently not regarded as an absolute contraindication to proceed to transplant. Methods. To clarify the role of a positive XM as predictor for overall survival (OS) and graft failure (GF) after BSCT, a retrospective, single-center, matched-pair analysis was performed. Enrolled were all XM-positive BSCT performed at our institution from 1985 to 2000 (n=30). Controls (n=30) were matched for disease, disease stage, patient age, period of transplant, conditioning regimen, protocol for prevention of graft-versus-host disease, and type of donor (related vs. unrelated, HLA-identical vs. HLA-mismatched). Results. Multivariate statistical analysis of all enrolled 60 transplants revealed GF as the all-dominating, independent risk factors for low OS (relative risk [RR]: 59.5, P <0.0001). Univariate (Kaplan-Meier) analysis could attribute inferior OS and high incidence of GF to the subgroup of HLA-mismatched, XM-positive transplants (P =0.01). Conclusions. A XM should always be performed in patients awaiting a BSCT from HLA-mismatched donors, because a positive XM is a predictor for inferior OS due to GF in BSCT.

Transfer of humoral and cellular hepatitis B immunity by allogeneic hematopoietic cell transplantation.

Background. Previous data indicate that a transfer of specific humoral and cellular immunity by way of allogeneic hematopoietic cell transplantation (HCT) should, in principle, be possible. Methods. In the HCT setting with a follow-up of up to 55 months, we studied the transfer of hepatitis B virus (HBV) specific immunity from electively immunized donors into HLA compatible recipients suffering from chronic myeloid leukemia (CML). After excluding preexisting HBV specific immunity in donor–recipient pairs, 27 prospective donors were vaccinated against HBV. In addition, on an average of 22 months postHCT, 8 of the 19 recipients were immunized once for HBV. Results. Donor vaccination resulted in detectable hepatitis B surface (HBs) antibodies in 85% of donors and specific cellular in vitro responses in 77%. Two weeks postHCT, 86 and 67% of the recipients displayed positive humoral and cellular HBV reactions, respectively, which then decreased. Afterwards, HBV immunity reappeared in 83% of the recipients without revaccination. Following a single vaccination in recipients, seven of eight displayed a typical memory response. An HBV specific response was already detectable 1 week after vaccination, approximately 1,300-fold (humoral) and 60-fold (cellular) higher than observed in the corresponding donors after a single immunization. Conclusions. The “spontaneous” recurrence of HBV immunity and the memory response in recipients give evidence for an elective immune transfer (e.g., for viral antigens) by way of allogeneic HCT.

Transplantation Of Peripheral Blood Progenitor Cells From Unrelated Donors

Six patients with high risk haematological malignancies received peripheral blood progenitor cells (PBPC) from unrelated donors. Four patients received PBPC as primary treatment and 2 following graft failure. Five donors were HLA-A, -B and -DR identical and one had a one antigen mismatch. PBPC were mobilised by treatment with G-CSF for 4-6 days. The patients received a range of 3.4 to 11.4 x 10(8) mononuclear cells/kg and 1.0 to 15.0 x 10(6) CD34 positive cells/kg. Four patients were given Campath 1G and 2 ATG prior to transplantation. The patient with one antigen mismatch received in vitro T-cell depleted PBPC using Campath 1M. All received cyclosporin and 5 in addition methotrexate. All recipients were given G-CSF and all engrafted. The patients developed no or mild acute GVHD. Two patients had limited chronic GVHD of the skin. The recipient of the mismatched graft died from extensive chronic GVHD. Three patients have had a relapse and two are alive and free of leukaemia.