[Salvage Treatment and the Role of Transplantation in Lymphomas]. / Záchranná lécba a role transplantací u lymfomu.

Despite achieving promising treatment results in patients with lymphoma, there is still a significant proportion of patients who relapse or have refractory disease. Salvage therapy followed by high dose treatment with autologous stem- cell transplantation is the standard of care in many of them. The role allogeneic stem- cell transplantation, especially after reduced intensity conditioning, is under extensive investigation. This review article presents current knowledge and recommendation in the salvage treatment of relapsed/ refractory lymphomas.

The effect of allogeneic stem cell transplantation on high risk chronic lymphocytic leukaemia: a single centre retrospective analysis.

In recent years, many studies have confirmed that allogeneic stem cell transplantation (allo-SCT) can provide long-term disease control and possible cure in selected patients with chronic lymphocytic leukaemia (CLL), including those with a biologically highly unfavourable risk profile. A retrospective analysis of allo-SCT in 30 patients with CLL whose risk profile was unfavourable and who were treated in the years 2000-2009 was performed. The aim was to compare the results of allo-SCT by prognostic factors and conditioning type and evaluate the results of unrelated transplantation. The median age was 54 years. Donors were 8 HLA-matched siblings and 22 unrelated volunteers, 11 of whom were mismatched. Eighteen patients were treated with reduced intensity conditioning. Twelve patients received myeloablative conditioning. Estimated overall survival (OS) at 3 years was 78%, progression-free survival (PFS) 71%, relapse incidence 10% and non-relapse mortality (NRM) 16%, respectively, with a median follow-up of 35 months. According to molecular/cytogenetic characteristics, OS and PFS for the high risk group (17p- or 11q-) were 89 and 77%, respectively, not significantly different from those with standard risk. Graft-versus-host disease (GVHD) was associated with greater toxicity; significantly higher NRM for patients with aGVHD (p = 0.04) and worse PFS for patients with cGVHD (p = 0.04). Our results for the refractory disease group (77% responses) indicate that chemoresistance may be overcome by the GVL effect. Transplants from unrelated donors may be considered comparable to those from related donors.

Comparison of three single platform methods for CD34+ hematopoietic stem cell enumeration by flow cytometry.

In the present study, we compared three single platform methods for CD34+ hematopoietic stem cell (HSC) enumeration by flow cytometry. For this purpose, we analyzed the performance characteristics and results obtained from different HSC sources. Interlaboratory coefficients of variation (CV) for precision/reproducibility analysis varied from 4.0% to 6.7% / 6.7% to 9.2% for the low and 3.2% to 4.1% / 4.3% to 6.7%, respectively, for the high stem cell control. Correlation between methods ranged from 0.92% to 0.99%; Wilcoxon test showed no significant differences (p > 0.05); Bland-Altman analysis confirmed good agreement between assays (mean bias ranging from -0.48 to 6.91). Our results demonstrate very good intralaboratory correlation and agreement between methods, confirm the major impact of single platform strategy for accurate and reproducible HSC enumeration and suggest that high interlaboratory variability could be influenced by incorrect performance of validated methods.

Retrospective analysis of the results of high-dose chemotherapy with the support of autologous blood stem cells in patients with multiple myeloma. The experience of a single centre.

Despite new medical products introduced in multiple myeloma therapy, autologous stem cell transplant (ASCT) remains a standard procedure in younger patients with symptomatic disease. We analyzed a group of 190 patients who underwent ASCT at our clinic for multiple myeloma as primary therapy in years 1995-2008. The total number of transplants performed in this group was 291. 110 patients underwent one ASCT, 59 patients had double transplant, out of which 51 patients underwent tandem transplant, 21 patients underwent triple ASCT, out of which 15 patients were transplanted front-line throughout a clinical trial and 6 patients underwent follow-up transplants due to disease progression. The assessment of the best therapeutic effect of ASCT showed the total rates of patients with complete remission--22%, very good partial remission (VGPR)--8%, partial remission--63%, stabilized disease--6% and progression--1%. The transplant related mortality (TRM) was 4.1%. With the median follow-up of surviving patients 2.6 years, the median progression-free survival (PFS) and overall survival (OS) were 21 and 54 months, respectively; the likelihood of a 7-year overall survival was 28%. Comparing tandem versus single transplants, there was a significant increase in the median PFS (25.8 versus 20.8 months, respectively); however, there was no difference in overall survivals. The IVE mobilization regimen was found to be more efficacious for PBPC collection than high-dosed cyclophosphamide.

Radioimmunotherapy-augmented BEAM chemotherapy vs BEAM alone as the high-dose regimen for autologous stem cell transplantation (ASCT) in relapsed follicular lymphoma (FL): a retrospective study of the EBMT Lymphoma Working Party.

Relapse remains the most common cause of treatment failure in patients receiving autologous stem cell transplantation (ASCT) for follicular lymphoma (FL). The aim of this study was to evaluate the effect of adding radioimmunotherapy or rituximab (R) to BEAM (carmustine, etoposide, ara-c, melphalan) high-dose therapy for ASCT in patients with relapsed FL. Using the European Society for Blood and Marrow Transplantation registry, we conducted a cohort comparison of BEAM (n=1973), Zevalin-BEAM (Z-BEAM) (n=207) and R-BEAM (n=179) and also a matched-cohort analysis of BEAM vs Z-BEAM including 282 and 154 patients, respectively. BEAM, Z-BEAM and R-BEAM groups were well balanced for age, time from diagnosis to ASCT and disease status at ASCT. The cumulative incidences of relapse (IR) at 2 years were 34, 34 and 32% for Z-BEAM, R-BEAM and BEAM, respectively. By multivariate analysis, there were no significant differences with Z-BEAM or R-BEAM compared with BEAM for IR, non-relapse mortality, event-free survival or overall survival. With the caveat that the limitations of registry analyses have to be taken into account, this study does not support adding radioimmunotherapy or R to BEAM in ASCT for relapsed FL. However, we cannot rule out the existence a particular subset of patients who could benefit from Z-BEAM conditioning that cannot be identified in our series, and this should be tested in a randomized trial.

Autologous stem cell transplantation for relapsed/refractory diffuse large B-cell lymphoma: efficacy in the rituximab era and comparison to first allogeneic transplants. A report from the EBMT Lymphoma Working Party.

In the era of chemoimmunotherapy, the optimal treatment paradigm for relapsed and refractory diffuse large B-cell lymphoma has been challenged. We reviewed the outcome of standard salvage therapy with an autologous stem cell transplant (autoSCT) over the last two decades and the outcome of allogeneic SCT (alloSCT) in the most recent decade. AutoSCT recipients diagnosed between 1992 and 2002 (n=2737) were compared with those diagnosed between 2002 and 2010 (n=3980). Patients diagnosed after 2002 had a significantly lower non-relapse mortality (NRM) and relapse incidence (RI) and a superior PFS and overall survival (OS). A total of 4210 patients diagnosed between 2002 and 2010 underwent either an autoSCT or an alloSCT as their first transplant procedure. Two-hundred and thirty patients received an alloSCT (myeloablative (MACalloSCT) n=132, reduced intensity (RICalloSCT) n=98). The 4-year NRM rates were 7%, 20% and 27% for autoSCT, RICalloSCT and MACalloSCT, respectively. The 4-year RI was 45%, 40% and 38% for autoSCT, RICalloSCT and MACalloSCT, respectively (NS). The 4-year PFS were 48%, 52% and 35% for autoSCT, RICalloSCT and MACalloSCT, respectively. The 4-year OS was 60%, 52% and 38% for autoSCT, RIC alloSCT and MACalloSCT, respectively. After adjustment for confounding factors NRM was significantly worse for patients undergoing alloSCT whilst there was no difference in the RI.

Echocardiographic evaluation of acute cardiotoxicity in the treatment of Hodgkin disease according to the German Hodgkin's Lymphoma Study Group.

Echocardiography is a sensitive method for detecting wall motion abnormalities, as well as for monitoring cardiotoxicity during treatment with anthracyclines. Using echocardiography, this study investigated possible acute cardiotoxicty associated with primary treatment of Hodgkin's disease according to German Hodgkin's Lymphoma Study Group (GHSG) clinical trial protocols for adults. A group of 88 patients (48 men) was registered in the prospective, randomized clinical trial involving the treatment of Hodgkin's disease using third and fourth generation GHSG protocols. These patients were monitored by echocardiography. The average age was 34 years (range, 18-65; median, 32). The average anthracycline dose was 174 mg/m2 (median 200 mg/m2), and the average mediastinum irradiation dose was 21 Gy (median 30 Gy). Left ventricle end-systolic diameter (ESD) and left ventricle end-diastolic diameter (EDD), as well as fractional shortening (FS) and ejection fraction (EF) (M-mode calculation) were evaluated, as was the presence of pericardial effusion and wall motion abnormalities. The examinations were conducted before and at the end of therapy (up to 2 months). Results show that all evaluated parameters changed from one follow-up examination to the other, but these changes did not reach statistical significance. ESD increased from 30 +/- 4 to 31 +/- 4 mm. EDD increased from 49 +/- 4 to 49 +/- 5 mm. Ejection fraction changed from 69 +/- 7 to 66 +/- 7% and fractional shortening was unchanged (from 38 +/- 7 to 38 +/- 7%). In seven patients (8%), we observed new wall motion abnormalities characterized by hypokinesis without decrease of left ventricular function. Significant changes in the amount of pericardial effusion were not observed. In four patients (5%), there was progression of Hodgkin's disease. In conclusion, treatment according to third and fourth generation clinical trial protocols of the GHSG leads only to minimal wall motion changes, without concomitant reduction of left ventricular function, thus not meeting the criteria, acute cardiotoxicity.

Thrombelastography monitoring of platelet substitution therapy and rFVIIa administration in haemato-oncological patients with severe thrombocytopenia.

Thrombocytopenic patients refractory to platelet concentrates (PC) could be treated during bleeding episodes with the recombinant activated FVII (rFVIIa). However, monitoring of administration of the rFVIIa or a response to platelet substitution therapy in thrombocytopenia patients is not well documented so far. Using of whole blood ROTEG analysis we monitored the changes in haemostatic parameters following in vivo platelet concentrate administration compared to ex vivo rFVIIa administration in patients with a severe to mild thrombocytopenia secondary to haemato-oncological disease. We use non-activated thrombelastography (NATEG) and a mild intrinsic activation thrombelastography (INTEG). NATEG analysis was sufficiently sensitive to monitor changes following PC and rFVIIa administration. Both, platelet infusion and rFVIIa treatment induced significant shortening of clotting time (CT) and clot formation time (CFT) parameters (p<0.05). When we compared the effect of platelet vs. rFVIIa treated whole blood by NATEG analysis we did not found any significant difference. Analysis with INTEG system was less sensitive and changes in CT and CFT were not significant. The monitoring with thrombelastography could enable efficient application of platelet concentrate and furthermore the using of rFVIIa as an alternative treatment of patients refractory to platelet infusion or with allergic reactions.

The outcome of reduced intensity allogeneic stem cell transplantation and autologous stem cell transplantation when performed as a first transplant strategy in relapsed follicular lymphoma: an analysis from the Lymphoma Working Party of the EBMT.

Both auto-SCT and reduced intensity allo-SCT (RIST) are employed in the treatment of relapsed follicular lymphoma (FL). We have analysed the outcome of these two transplant procedures when used as a first transplant in this setting. We conducted a retrospective comparison of 726 patients who underwent an auto-SCT and 149 who underwent a RIST as a first transplant procedure for relapsed FL as reported to the Lymphoma Working Party of the European Bone Marrow Transplant. The non-relapse mortality (NRM) was significantly worse for patients undergoing a RIST (relative risk (RR) 4.0, P<0.001). The 1-year NRM was 15% for those undergoing a RIST compared with 3% for those undergoing an auto-SCT. Disease relapse or progression were significantly worse for those receiving an auto-SCT (RR 3.1, P<0.001). Patients undergoing a RIST had a 5-year relapse rate of 20% compared with 47% for those undergoing an auto-SCT. The PFS at 5 years was 57% for patients receiving a RIST compared with 48% for those receiving an auto-SCT. There was no significant difference in OS between the two groups. RIST is associated with a higher NRM and lower relapse rate in patients with relapsed FL.

KIR genes and KIR ligands affect occurrence of acute GVHD after unrelated, 12/12 HLA matched, hematopoietic stem cell transplantation.

Interactions of polymorphic killer Ig-like receptor (KIR) receptors with KIR ligands have been shown to modify the outcome of hematopoietic SCT (HSCT). The association of these genetic factors with different transplantation endpoints, however, varies substantially, depending on clinical and study setup variables. We aimed to assess whether KIR ligands, KIR genes and KIR haplotypes are associated with HSCT outcome of 124 patients with various hematological malignancies, transplanted with 12/12 HLA matched grafts from unrelated donors. For this purpose, patient and donor KIR gene and KIR ligand polymorphisms were determined and correlated with clinical data in simple and multiple models. We found that a missing HLA-C2 ligand for donor inhibitory KIR2DL1 was significantly associated with an increased risk of acute GVHD (aGVHD) (II-IV) (hazard ratio (HR)=2.23, 95% confidence interval (95% CI): 1.21-4.10, P=0.010), as were the AA KIR haplotypes in patients and donors in HLA-C1CX (HR=2.37, 95% CI: 1.16-4.84, P=0.018) and in HLA-Bw4(-) (HR=3.20, 95% CI: 1.35-7.60, P=0.008) patients. On the contrary, transplantation of HLA-C1C2 patients with KIR2DS2 positive grafts were associated with a decreased risk of aGVHD (II-IV) (HR=0.24, 95% CI: 0.07-0.85, P=0.027). Thus, our single center study provides evidence for the modification of aGVHD risk by KIRs and their ligands.