Elke Dammann

Cytoreductive treatment with clofarabine/ara‐C combined with reduced‐intensity conditioning and allogeneic stem cell transplantation in patients with high‐risk, relapsed, or refractory acute myeloid leukemia and advanced myelodysplastic syndrome

The combination of cytoreductive chemotherapy with reduced‐intensity conditioning (RIC) is a highly effective antileukemic therapy. Purpose of this retrospective analysis was to evaluate the antileukemic efficacy and toxicity of clofarabine‐based chemotherapy followed by RIC and allogeneic stem cell transplantation (SCT) for high‐risk, relapsed, or refractory acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). From May 2007 until October 2009, a total of 27 patients underwent allogeneic SCT after treatment with clofarabine and ara‐C for 5 d and RIC (4 Gy TBI/cyclophosphamide/ATG). Prophylaxis of graft‐versus‐host disease (GvHD) consisted of cyclosporine and mycophenolate mofetil. Unmanipulated G‐CSF mobilized PBSC (n = 26) or bone marrow cells (n = 1) were transplanted from unrelated (n = 21) or matched related (n = 6) donors. Non‐hematological toxicities of this regimen mainly affected liver and skin and were all reversible. Seven patients relapsed within a median time of 5.7 months. The overall survival (OS) and relapse‐free survival rates were 56% and 52% at 2 yr, respectively. In this cohort of patients, cytoreduction with clofarabine/ara‐C (ClAraC) followed by RIC allogeneic SCT was well tolerated and showed good antileukemic efficacy even in patients with high‐risk AML or MDS, with engraftment and GvHD‐incidence comparable to other RIC regimens.

Increased risk of complicated CMV infection with the use of mycophenolate mofetil in allogeneic stem cell transplantation

Mycophenolate mofetil (MMF) is increasingly used for prophylaxis and therapy of GVHD in allogeneic stem cell transplantation. In some recent reports of use of MMF in solid organ transplantation a high incidence of CMV disease has been described. We evaluated the frequency and course of active CMV infection in patients who received MMF compared to those who did not receive MMF after allogeneic stem cell transplantation. We retrospectively analyzed 48 adult patients who consecutively underwent unmanipulated allogeneic bone marrow (n = 15) or peripheral stem cell transplantation (n = 33) from HLA-compatible family donors (n = 30) or unrelated donors (n = 18) from February 1997 to September 2000 at our institution. Only patients who were evaluable for the first 100 days were included in this analysis. Sixteen patients received MMF post transplant (MMF+). CMV-antigenemia was monitored by CMV-pp65 antigen. CMV-antigenemia occurred in 14 patients and was virtually only observed in CMV-IgG+ recipients (13/23, 56%). CMV-IgG+/MMF+ patients developed a higher incidence of CMV-antigenemia (8/9, 89%) compared to the CMV-IgG+/MMF− patients (5/14, 35%; P < 0.05). Moreover, five of six patients with persistent or recurrent CMV-antigenemia received MMF. No patient in either group developed CMV disease or died of CMV-related complications. In multivariate analysis including MMF treatment, unrelated vs related donor, GVHD, CMV-serostatus of the donor and stem cell graft type, only MMF treatment was found to be a significant risk factor for both overall and complicated CMV infection.

High lethality of human adenovirus disease in adult allogeneic stem cell transplant recipients with high adenoviral blood load

BACKGROUND Human adenoviruses (HAdV) can cause disseminated disease as a severe complication after haematopoietic stem cell transplantation (SCT) and may originate from the reactivation of latent infections. However, data about the clinical relevance of HAdV DNAaemia and disease in adults are scarce. OBJECTIVES To retrospectively analyse the outcome of adult allogeneic SCT recipients with high HAdV loads in peripheral blood. STUDY DESIGN Our diagnostic database was screened for allogeneic SCT recipients with peak HAdV DNAaemia above 1.0×10(4)copies/ml (tested by quantitative real-time PCR) and medical records were reviewed retrospectively. RESULTS From 1674 adult allogeneic SCT recipients 539 (32.2%) received HAdV DNAaemia testing. In twenty-seven of these HAdV blood loads above 1.0×10(4) (range: 1.6×10(4)-1.8×10(9))copies/ml were observed. Seven of these 27 succumbed to HAdV disease and their median peak HAdV DNAaemia was significantly higher than in patients without HAdV-associated death (1.0×10(8) vs. 3×10(5)copies/ml, p<0.001). T-cell depletion was a risk factor for fatal HAdV disease. HAdV of species C predominated (66.7%) and were of high virulence (6 of 7 fatal cases). HAdV of species B were observed more frequently (n=6) in our study than reported for paediatrics, indicating a different pattern of HAdV reactivation in adults. CONCLUSIONS The presence of several HAdV-associated deaths in adult SCT recipients with high-level HAdV DNAaemia confirmed the clinical relevance of HAdV DNAaemia testing in adults. Quantitative HAdV DNAaemia testing is a promising tool to predict the outcome of HAdV disease.

Solid organ transplantation after allogeneic hematopoietic stem cell transplantation: a retrospective, multicenter study of the EBMT.

To analyze the outcome of solid organ transplantation (SOT) in patients who had undergone allogeneic hematopoietic stem cell transplantation (HSCT), a questionnaire survey was carried out within 107 European Group of Blood and Marrow Transplantation centers. This study covered HSCT between 1984 and 2007 in Europe. Forty‐five SOT in 40 patients were reported. Fifteen liver, 15 renal, 13 lung, 1 heart and 1 skin transplantations were performed in 28 centers. Overall survival (OS) of patients after SOT was 78% at 5 years (95% confidence interval [CI], 64% to 92%). OS at 5 years was 100% for renal, 71% (95% CI, 46% to 96%) for liver and 63% (95% CI, 23% to 100%) for lung transplant recipients. The 2‐year‐incidence of SOT failure was 20% (95% CI, 4% to 36%) in patients with graft‐versus‐host disease (GvHD) and 7% (95% CI, 0% to 21%) in patients without GvHD before SOT. The relapse incidence for underlying malignant diseases was 4% at 5 years (95% CI, 0% to 12%). In summary, this study shows that selected patients receiving SOT after HSCT have a remarkably good overall and organ survival. These data indicate that SOT should be considered in selected patients with single organ failure after HSCT.

Donor cell-derived acute myeloid leukemia developing 14 months after matched unrelated bone marrow transplantation for chronic myeloid leukemia

We report a patient with Ph-positive CML who developed a Ph-negative AML in donor cells 14 months after BMT from an HLA-identical male unrelated donor. The Ph translocation could not be detected by either conventional cytogenetics, FISH or RT-PCR analysis excluding relapse of CML in myeloid blast crisis. Chimerism studies were performed by variable number of tandem repeats (VNTR) analysis. These revealed donor-type hematopoiesis in both unseparated mononuclear cells and CD34+ selected blasts proving the leukemia to be of donor origin. The patient received three cycles of polychemotherapy with mitoxantrone, topotecan and ara-c resulting in CR after the first treatment cycle and reconstitution with donor hematopoiesis. A second transplant from a female alternative matched unrelated donor was performed after conditioning with fludarabine and 200 cGy TBI and was well tolerated. Nine months after the second transplant the patient is at home and in CR. T cell chimerism was studied by sex chromosome analysis and revealed complete female donor chimerism. Bone Marrow Transplantation (2001) 28, 705–707.

Sequential anti-cytomegalovirus response monitoring may allow prediction of cytomegalovirus reactivation after allogeneic stem cell transplantation

Background Reconstitution of cytomegalovirus-specific CD3+CD8+ T cells (CMV-CTLs) after allogeneic hematopoietic stem cell transplantation (HSCT) is necessary to bring cytomegalovirus (CMV) reactivation under control. However, the parameters determining protective CMV-CTL reconstitution remain unclear to date. Design and Methods In a prospective tri-center study, CMV-CTL reconstitution was analyzed in the peripheral blood from 278 patients during the year following HSCT using 7 commercially available tetrameric HLA-CMV epitope complexes. All patients included could be monitored with at least CMV-specific tetramer. Results CMV-CTL reconstitution was detected in 198 patients (71%) after allogeneic HSCT. Most importantly, reconstitution with 1 CMV-CTL per µl blood between day +50 and day +75 post-HSCT discriminated between patients with and without CMV reactivation in the R+/D+ patient group, independent of the CMV-epitope recognized. In addition, CMV-CTLs expanded more daramtaically in patients experiencing only one CMV-reactivation than those without or those with multiple CMV reactivations. Monitoring using at least 2 tetramers was possible in 63% (n = 176) of the patients. The combinations of particular HLA molecules influenced the numbers of CMV-CTLs detected. The highest CMV-CTL count obtained for an individual tetramer also changed over time in 11% of these patients (n = 19) resulting in higher levels of HLA-B*0801 (IE-1) recognizing CMV-CTLs in 14 patients. Conclusions Our results indicate that 1 CMV-CTL per µl blood between day +50 to +75 marks the beginning of an immune response against CMV in the R+/D+ group. Detection of CMV-CTL expansion thereafter indicates successful resolution of the CMV reactivation. Thus, sequential monitoring of CMV-CTL reconstitution can be used to predict patients at risk for recurrent CMV reactivation.

Genetically Modified Donor Leukocyte Transfusion and Graft-Versus-Leukemia Effect After Allogeneic Stem Cell Transplantation

Seven patients with acute myeloid leukemia (AML) and two patients with chronic myelogenous leukemia (CML) were transplanted from HLA-identical sibling donors with CD34(+) cell-enriched stem cells (HSCTs) without further immunosuppression. The myeloablative standard transplantation protocol was adapted to include transfusion of gene-modified donor T cells after HSCT. Donor T cells were transduced with the replication-deficient retrovirus SFCMM-3, which expresses herpes simplex thymidine kinase (HSV-Tk) and a truncated version of low-affinity nerve growth factor receptor (ΔLNGFR) for selection and characterization of transduced cells. Transduced T cells were detectable in all patients during follow-up for up to 5 years after transfusion. Proteomic screening for development of acute graft-versus-host disease (aGvHD) was applied to five of the seven patients with AML. No positivity for the aGvHD grade II-specific proteomic pattern was observed. Only one patient developed aGvHD grade I. To date, three of the patients with AML relapsed; one responded to three escalating transfusions of lymphocytes from the original donor and is in complete remission. Two were retransplanted with non-T cell-depleted peripheral blood stem cells from their original donors and died after retransplantation of septic complications or relapse, respectively. In one patient with CML, loss of bcr-abl gene expression was observed after an expansion of transduced cells. Seven of nine patients are alive and in complete remission.

Radioimmunotherapy with [188Re]-labelled anti-CD66 antibody in the conditioning for allogeneic stem cell transplantation for high-risk acute myeloid leukemia

Between July 2000 and June 2003 a total of 21 patients with high-risk acute myeloid leukemia (AML; n = 14), AML after myelodysplastic syndrome (MDS; n = 6) or advanced MDS (n = 1) were treated with an 188-Re labelled anti-CD66 antibody in the conditioning regimen for allogeneic stem cell transplantation. Radioimmunotherapy (RIT) was followed by standard full-dose conditioning with busulfan and high-dose cyclophosphamide in 11 patients and reduced intensity conditioning regimen in 10 patients. All patients received an unmanipulated allogeneic graft from alternative donors (n = 15) or a HLA-identical familiy donor (n = 6). With a median follow up of 42 months (23–60) disease free survival for all patients was 43%. Nine patients are still alive and in ongoing complete hematological remission. The treatment related mortality was 28.6% (n = 6) and an equal number of patients died of relapsing disease within 30–385 days after transplantation. Late organ toxicity, monitored for more than 1 year, was mild and not clinically relevant. The combination of RIT with chemotherapeutic conditioning seems to be a therapy with an acceptable risk of treatment related morbidity and mortality as well as occurrence of severe acute GvHD.

Prognostic factors in allo-SCT of elderly patients with AML.

The prognosis of elderly patients with AML after chemotherapy is poor. Allo-SCT is feasible in these patients, but data on prognostic factors and outcome are limited. We analyzed all 102 AML patients ⩾55 years, who underwent allo-SCT at our institution from 1997 to 2008. OS and relapse-free survival (RFS) rates at 3 years are 39 and 37%, respectively. Multivariate analysis for OS revealed age ⩾60 years and active (refractory or untreated before allo-SCT) or advanced (>CR1) disease as adverse prognostic factors. Patients transplanted in CR1 had a 3-year OS of 67 vs 27% for patients with active/advanced disease. Multivariate analysis for RFS revealed active/advanced disease as the only adverse factor. Patients transplanted in CR1 had a 3-year RFS of 70 vs 22% for patients with active/advanced disease. In all, 17% of patients suffered from acute GVHD ⩾grade II. The risk for severe acute GVHD was increased after allo-SCT from mismatched donors. Nonrelapse mortality (NRM) was 23% at 1 year. The only risk factor for NRM was active/advanced disease. In conclusion, allo-SCT from related or unrelated donors yields very good results in elderly AML patients transplanted in CR1. Disease status at transplantation is the most important prognostic factor for transplantation success.

Prolonged isolated red blood cell transfusion requirement after allogeneic blood stem cell transplantation: identification of patients at risk.

BACKGROUND: Delayed donor red blood cell chimerism (DRCC), pure red blood cell aplasia (PRCA), and autoimmune hemolytic anemia (AIHA) are poorly documented complications after hematopoietic cell transplantation (HCT). The clinical variable “prolonged isolated red blood cell transfusion requirement” (PRTR) was evaluated as a trigger for an extended diagnostic workup.