HLA-C KIR-Ligands Determine the Impact of Anti-Thymocyte Globulin (ATG) on Graft versus Host and Graft versus Leukemia Effects Following Hematopoietic Stem Cell Transplantation.

Rabbit anti-thymocyte globulins (ATGs) are widely used for the prevention of acute and chronic graft versus host disease (aGVHD, cGVHD) following allogeneic hematopoietic stem cell transplantation (HSCT). However, most prospective and retrospective studies did not reveal an overall survival (OS) benefit associated with ATG. Homozygosity for human leukocyte antigen (HLA)-C group 1 killer-cell immunoglobulin-like receptor ligands (KIR-L), i.e. C1/1 KIR-L status, was recently shown to be a risk factor for severe aGVHD. Congruously, we have previously reported favorable outcomes in C1/1 recipients after ATG-based transplants in a monocentric analysis. Here, within an extended cohort, we test the hypothesis that incorporation of ATG for GVHD prophylaxis may improve survival particularly in HSCT recipients with at least one C1 KIR-ligand. Retrospectively, 775 consecutive allogeneic (excluding haploidentical) HSCTs were analyzed, including peripheral blood and bone marrow grafts for adults with hematological diseases at two Austrian HSCT centers. ATG-Fresenius/Grafalon, Thymoglobuline, and alemtuzumab were applied in 256, 87, and 7 transplants, respectively (subsequently summarized as "ATG"), while 425 HSCT were performed without ATG. Median follow-up of surviving patients is 48 months. Adjusted for age, disease-risk, HLA-match, donor and graft type, sex match, cytomegalovirus serostatus, conditioning intensity, and type of post-grafting GVHD prophylaxis, Cox regression analysis of the entire cohort (n = 775) revealed a significant association of ATG with decreased non-relapse mortality (NRM) (risk ratio (RR), 0.57; p = 0.001), and overall mortality (RR, 0.71; p = 0.014). Upon stratification for HLA-C KIR-L, the greatest benefit for ATG emerged in C1/1 recipients (n = 291), by reduction of non-relapse (RR, 0.34; p = 0.0002) and overall mortality (RR, 0.50; p = 0.003). Less pronounced, ATG decreased NRM (RR, 0.60; p = 0.036) in HLA-C group 1/2 recipients (n = 364), without significantly influencing overall mortality (RR, 0.70; p = 0.065). After exclusion of higher-dose ATG-based transplants, serotherapy significantly improved both NRM (RR, 0.54; p = 0.019; n = 322) and overall mortality (RR, 0.60; p = 0.018) in C1/2 recipients as well. In both, C1/1 (RR, 1.70; p = 0.10) and particularly in C1/2 recipients (RR, 0.94; p = 0.81), there was no statistically significant impact of ATG on relapse incidence. By contrast, in C2/2 recipients (n = 121), ATG neither reduced NRM (RR, 1.10; p = 0.82) nor overall mortality (RR, 1.50; p = 0.17), but increased the risk for relapse (RR, 4.38; p = 0.02). These retrospective findings suggest ATG may provide a survival benefit in recipients with at least one C1 group KIR-L, by reducing NRM without significantly increasing the relapse risk.

Total body irradiation with volumetric modulated arc therapy: Dosimetric data and first clinical experience.

BACKGROUND: To implement total body irradiation (TBI) using volumetric modulated arc therapy (VMAT). We applied the Varian RapidArc™ software to calculate and optimize the dose distribution. Emphasis was placed on applying a homogenous dose to the PTV and on reducing the dose to the lungs. METHODS: From July 2013 to July 2014 seven patients with leukaemia were planned and treated with a VMAT-based TBI-technique with photon energy of 6 MV. The overall planning target volume (PTV), comprising the whole body, had to be split into 8 segments with a subsequent multi-isocentric planning. In a first step a dose optimization of each single segment was performed. In a second step all these elements were calculated in one overall dose-plan, considering particular constraints and weighting factors, to achieve the final total body dose distribution. The quality assurance comprised the verification of the irradiation plans via ArcCheck™ (Sun Nuclear), followed by in vivo dosimetry via dosimeters (MOSFETs) on the patient. RESULTS: The time requirements for treatment planning were high: contouring took 5-6 h, optimization and dose calculation 25-30 h and quality assurance 6-8 h. The couch-time per fraction was 2 h on day one, decreasing to around 1.5 h for the following fractions, including patient information, time for arc positioning, patient positioning verification, mounting of the MOSFETs and irradiation. The mean lung dose was decreased to at least 80 % of the planned total body dose and in the central parts to 50 %. In two cases we additionally pursued a dose reduction of 30 to 50 % in a pre-irradiated brain and in renal insufficiency. All high dose areas were outside the lungs and other OARs. The planned dose was in line with the measured dose via MOSFETs: in the axilla the mean difference between calculated and measured dose was 3.6 % (range 1.1-6.8 %), and for the wrist/hip-inguinal region it was 4.3 % (range 1.1-8.1 %). CONCLUSION: TBI with VMAT provides the benefit of satisfactory dose distribution within the PTV, while selectively reducing the dose to the lungs and, if necessary, in other organs. Planning time, however, is extensive.

Lenalidomide and dexamethasone for acute light chain-induced renal failure: a phase II study.

We prospectively evaluated the activity and tolerance of lenalidomide-dexamethasone in 35 patients with acute light chain-induced renal failure. The lenalidomide dose was adapted to the estimated glomerular filtration rate and dexamethasone was given at high dose in cycle one and at low dose thereafter. Four patients died within the first two cycles, and five discontinued therapy leaving 26 patients for the per-protocol analysis. Responses were observed in 24/35 (68.6%) patients of the intent-to-treat population. Complete response was noted in seven patients (20%), very good partial response in three patients (8.6%), partial response in 14 patients (40%), and minimal response in one patient (2.9%). Renal response was observed in 16 (45.7%) patients: five (14.2%) achieved complete, four (11.4%) partial and seven (20%) minor renal responses. Five of 13 patients who were dialysis dependent at baseline became dialysis independent. The median time to myeloma and to renal response was 28 days for both parameters, while the median time to best myeloma and best renal response was 92 and 157 days, respectively. The median estimated glomerular filtration rate increased significantly in patients with partial response or better from 17.1 mL/min at baseline to 39.1 mL/min at best response (P=0.001). The median progression-free and overall survival was 5.5 and 21.8 months, respectively, in the intent-to-treat population and 12.1 and 31.4 months, respectively, in the per-protocol group. Infections, cardiotoxicity, anemia and thrombocytopenia were the most frequent toxicities. In conclusion, the lenalidomide-dexamethasone regimen achieved rapid and substantial myeloma and renal responses. The trial was registered under EUDRACT number 2008-006497-15.

Bendamustine-bortezomib-dexamethasone is an active and well-tolerated regimen in patients with relapsed or refractory multiple myeloma.

Bendamustine with bortezomib and dexamethasone was evaluated in 79 patients with relapsed/refractory multiple myeloma. Median age was 64 years, and patients had a median of 2 prior treatment lines (range, 1 to 6 lines). Bendamustine 70 mg/m(2) days 1 and 4; bortezomib 1.3 mg/m(2) intravenously days 1, 4, 8, and 11; and dexamethasone 20 mg days 1, 4, 8, and 11 once every 28 days was given for up to 8 cycles. Primary end point was overall response rate (ORR). Secondary end points were progression-free survival (PFS), overall survival, time to response, and toxicity. ORR was 60.8%, and when minor responses were included, 75.9%. Median time to response was 31 days. ORR rate was similar in patients previously exposed to bortezomib, lenalidomide, and bortezomib plus lenalidomide. PFS was 9.7 and OS was 25.6 months. Multivariate analysis showed high lactate dehydrogenase, ≥3 prior treatment lines, and low platelet counts correlating with short survival. Grade 3/4 thrombocytopenia was noted in 38%, and grade 3/4/5 infections were noted in 23%. Grade ≤2 polyneuropathy increased from 19% at baseline to 52% at cycle 8 and grade 4, from 0% to 7%. Bendamustine-bortezomib-dexamethasone is active and well tolerated in patients with relapsed/refractory myeloma. This trial was registered in the EudraCT database as No. 2008-006421-13.

Plerixafor and granulocyte-colony-stimulating factor (G-CSF) in patients with lymphoma and multiple myeloma previously failing mobilization with G-CSF with or without chemotherapy for autologous hematopoietic stem cell mobilization: the Austrian experience on a named patient program.

BACKGROUND: Plerixafor in combination with granulocyte-colony-stimulating factor (G-CSF) has been shown to enhance stem cell mobilization in patients with multiple myeloma, non-Hodgkin's lymphoma, and Hodgkin's disease who demonstrated with previous mobilization failure. In this named patient program we report the Austrian experience in insufficiently mobilizing patients. STUDY DESIGN AND METHODS: Twenty-seven patients from eight Austrian centers with a median (range) age of 58 (19-70) years (18 female, nine male) were included in the study. Plerixafor was limited to patients with previous stem cell mobilization failure and was given in the evening of Day 4 of G-CSF application. RESULTS: A median increase of circulating CD34+ cells within 10 to 11 hours from administration of plerixafor by a factor of 4.7 over baseline was noted. Overall, 20 (74%) patients reached more than 10 × 10(6) CD34+ cells/L in the peripheral blood, resulting in 17 (63%) patients collecting at least 2 × 10(6) CD34+ cells/kg body weight (b.w.; median, 2.6 × 10(6) CD34+ cells/kg b.w.; range, 0.08 × 10(6) -8.07 × 10(6) ). Adverse events of plerixafor were mild to moderate and consisted of gastrointestinal side effects and local reactions at the injection site. Thirteen (48%) patients underwent autologous transplantation receiving a median of 2.93 × 10(6) CD34+ cells/kg (range, 1.46 × 10(6) -5.6 × 10(6) ) and showed a trilinear engraftment with a median neutrophil recovery on Day 12 and a platelet recovery on Day 14. CONCLUSION: Our study confirms previous investigations showing that plerixafor in combination with G-CSF is an effective and well-tolerated mobilization regimen with the potential of successful stem cell collection in patients with previous mobilization failure.

Clinical significance of HLA-E*0103 homozygosity on survival after allogeneic hematopoietic stem-cell transplantation.

BACKGROUND: Hematopoietic stem-cell transplantation is a well-established treatment in various hematologic malignancies, but the outcome depends on disease relapse, infections, and the development and severity of acute and chronic graft-versus-host disease. Some evidence has revealed an important role for the nonclassical major histocompatibility complex class I molecules in transplantation, most notably human leukocyte antigen (HLA)-E. This study evaluates the impact of HLA-E alleles on transplantation outcome after HLA-matched allogeneic HSCT. METHODS: We genotyped DNA for HLA-E polymorphism from 83 recipients and their respective donors by real-time polymerase chain reaction after melting curve analysis and compared the results with clinical outcome. RESULTS: HLA-E*0103 homozygous patients showed a higher probability of overall survival (P=0.003) and disease-free survival (P=0.001) in a univariate model. Cox regression analysis confirmed HLA-E*0103, 0103 (P=0.006; relative risk 1.12; 95% confidence interval 0.31-1.94) and early stage of disease (P=0.005; relative risk 1.16; 95% confidence interval 0.45-1.86) as independent factors improving overall survival. Moreover, homozygosity for HLA-E*0103 was associated with a significant decreased incidence of transplant-related mortality (P=0.01). CONCLUSIONS: We found an association between HLA-E*0103 homozygosity and the significant reduction of transplant-related mortality in related and unrelated HSCT. The risk of posttransplant complications was significantly reduced when the donor possesses the HLA-E*0103, 0103 genotype, and this was translated in a better overall survival.

A single nucleotide polymorphism at chromosome 2q21.3 (LCT -13910C>T) associates with clinical outcome after allogeneic hematopoietic stem cell transplantation.

A single nucleotide polymorphism (SNP) responsible for lactase persistence (LCT -13910C>T) changes intestinal microflora. Considering the influence of bacterial microflora on various immune effects, we tested DNA from 111 recipients/donors and analyzed whether this SNP interferes with survival and the incidence of acute graft-versus-host disease (aGVHD) after allogeneic hematopoetic stem cell transplantations (HSCT). Median overall survival (OS) was significantly longer when donors had a CC genotype (not reached after 133 vs 11.1 months, P = .004). Multivariate analysis identified a donor T allele (hazard ratio 2.63, 95% confidence interval 1.29-5.33, P = .008) as independent risk factor for death. Surprisingly, recipient genotypes did not influence outcome and there were no differences regarding aGVHD. Transplantation-related mortality (TRM), relapse and pneumonia were significantly less frequent in patients with CC donors. These findings add to the growing list of non-HLA polymorphisms with impact on outcome after allogeneic HSCT.

Long-term results of autologous stem cell transplantation for Hodgkin's disease (HD) and low-/intermediate-grade B non-Hodgkin's lymphoma (NHL): a report from the Austrian Stem Cell Transplantation Registry (ASCTR).

Between 1990 and 2001, 68 patients with advanced Hodgkin's disease (HD) and 86 patients classified as low-/intermediate-grade B non-Hodgkin's lymphoma (NHL) were reported to the Austrian Stem Cell Transplantation Registry (ASCTR). Following autologous stem cell transplantation (SCT) for HD, overall survival was 56% [95% confidence interval (CI): 40-72%] with a disease-/progression-free survival of 49%, reaching a plateau at 5 years. Using multivariate Cox regression analysis BEAM conditioning (carmustine, cytarabine, etoposide and melphalan) was predictive for favourable outcome, better disease-/progression-free survival and a significantly lower risk for relapse. The cumulative incidence of relapse was 30%, even for patients in complete remission at time of SCT. The cumulative risk for developing a secondary malignancy increased continuously over time, achieving 20% at 7 years and 46% at 10 years with previous radiotherapy as the only risk factor in the multivariate analysis. Overall survival for NHL patients was 45% (95% CI: 26-64%) with a disease-/progression-free survival of 26% at 7 years. In the multivariate Cox regression analysis stage of disease at time of SCT was the most powerful parameter for overall survival, disease-/progression-free survival and relapse. Mantle cell lymphoma, greater than or equal to three lines of previous therapy, and a conditioning regimen other than BEAM were also predictive for death. The main reason for treatment failure was relapse (cumulative incidence 54-75%). Because of the high risk of relapse/progression in both disease categories and the additional high rate of second malignancies in HD patients, allogeneic stem cells should be considered a valuable alternative for selected patients. The efficacy of allotransplantation following reduced-intensity conditioning should be tested in randomised trials.