Tomasz Czerw

Status of minimal residual disease determines outcome of autologous hematopoietic SCT in adult ALL

The role of autologous hematopoietic SCT (autoHSCT) in the treatment of high-risk (HR) adult ALL is controversial. In this study, we retrospectively analyzed the results of autoHSCT according to the status of minimal residual disease (MRD) at transplantation, as a joint analysis of the European Study Group for Adult ALL (EWALL). Data on 123 recipients of autoHSCT, aged 31 (16–59) years, with B-lineage (n=77) or T-lineage (n=46) ALL were included. In a cohort of Ph-negative ALL, the probability of leukemia-free survival at 5 years was higher for patients with MRD <0.1% compared with those with MRD ⩾0.1% (57 vs 17%, P=0.0002). The difference was significant for T-lineage ALL (62 vs 8%, P=0.001), and a tendency was observed for B-lineage ALL (54 vs 26%, P=0.17). In a multivariate analysis, adjusted for other potential prognostic factors, high MRD level remained the only independent factor associated with increased risk of failure (risk ratio, 2.8; P=0.0005). We conclude that MRD determines the outcome of autoHSCT in HR adult ALL. Our results suggest the need to reevaluate the role of this treatment option in prospective trials.

Activating killer immunoglobulin-like receptor incompatibilities enhance graft-versus-host disease and affect survival after allogeneic hematopoietic stem cell transplantation.

Objectives:  Killer immunoglobulin‐like receptors (KIRs) regulate function of natural killer (NK) cells and a subset of T cells. In this study, we prospectively evaluated the impact of donor and recipient activating KIR genes on outcome of allogeneic hematopoietic stem cell transplantation (alloHSCT) for patients with hematological malignancies.

Sequential recovery of NK cell receptor repertoire after allogeneic hematopoietic SCT

Alloreactivity of natural killer (NK) cells contributes to the GVL reaction after allogeneic hematopoietic SCT (allo-HSCT). However, various procedure-related factors may affect NK cell maturation and their ability to recognize and kill leukemic cells. In this study, we prospectively evaluated expression of NK cell inhibitory receptors in 83 adults treated with myeloablative, killer cell Ig-like receptor (KIR)-ligand-matched allo-HSCT. NK cell maturation was evaluated by comparing the phenotypic patterns after allo-HSCT with the donor ones. The frequencies of KIR3DL1 were comparable to the donor ones on day +28, while they decreased significantly starting from day +100. The expression of KIR2DL2/3 was significantly lower in patients compared with donors up to day +100. The expression of KIR2DL1, despite continues growth, remained significantly decreased for 1 year after allo-HSCT. NKG2A was over-expressed up to day +180. Within 1 year after allo-HSCT, the NK cell phenotypic pattern tended to recapitulate the donor type. The process was disturbed by the use of steroids with significant differences observed on days +56 (P=0.01) and +100 (P=0.04). Up to day +100, reconstitution of NK cell receptor repertoire correlated with the absolute numbers of circulating CD3+, CD3+CD4+ and CD3+CD8+ cells. Our observations should be taken into account when trying to predict potential benefit from NK cell alloreactivity.

Intermediate-dose Ara-C plus G-CSF for stem cell mobilization in patients with lymphoid malignancies, including predicted poor mobilizers

The optimal protocol for mobilization of hematopoietic stem cells in patients with lymphoid malignancies has not been determined so far. We retrospectively analyzed the efficacy and safety of Ara-C at a dose of 1.6 g/m2 compared with CY at a dose of 4.0 g/m2, both combined with filgrastim. Seventy and forty-five patients, respectively, were included, among whom 60% were defined as ‘predicted poor mobilizers’. The use of Ara-C was associated with significantly higher peak number of circulating CD34+ cells compared with CY (P<0.0001). In the Ara-C group, 95% of patients with multiple myeloma (MM) collected at least 5 × 106 CD34+ cells/kg required for tandem transplantation, and 97% of lymphoma patients collected at least 2 × 106 CD34+ cells/kg, needed for a single autologous hematopoietic SCT (autoHSCT), which was achieved with a single leukapheresis in 91% of cases. Results for the CY group were significantly inferior (P<0.0001). No patient mobilized with Ara-C experienced febrile neutropenia, whereas 35% required platelet transfusions. Among patients who proceeded to autoHSCT, the time of both neutrophil and platelet recovery was significantly shorter for those mobilized with Ara-C than CY. We conclude that intermediate-dose Ara-C+filgrastim is a very effective and relatively safe mobilization protocol for patients with lymphoid malignancies.

Association of Macroeconomic Factors With Nonrelapse Mortality After Allogeneic Hematopoietic Cell Transplantation for Adults With Acute Lymphoblastic Leukemia: An Analysis From the Acute Leukemia Working Party of the EBMT

PURPOSE From a global perspective, the rates of allogeneic hematopoietic cell transplantation (alloHCT) are closely related to the economic status of a country. However, a potential association with outcome has not yet been documented. The goal of this study was to evaluate effects of health care expenditure (HCE), Human Development Index (HDI), team density, and center experience on nonrelapse mortality (NRM) after HLA-matched sibling alloHCT for adults with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS A total of 983 patients treated with myeloablative alloHCT between 2004 and 2008 in 24 European countries were included. RESULTS In a univariate analysis, the probability of day 100 NRM was increased for countries with lower current HCE (8% vs. 3%; p = .06), countries with lower HDI (8% vs. 3%; p = .02), and centers with less experience (8% vs. 5%; p = .04). In addition, the overall NRM was increased for countries with lower current HCE (21% vs. 17%; p = .09) and HDI (21% vs. 16%; p = .03) and for centers with lower activity (21% vs. 16%; p = .07). In a multivariate analysis, the strongest predictive model for day 100 NRM included current HCE greater than the median (hazard ratio [HR], 0.39; p = .002). The overall NRM was mostly predicted by HDI greater than the median (HR, 0.65; p = .01). Both lower current HCE and HDI were associated with decreased probability of overall survival. CONCLUSION Both macroeconomic factors and the socioeconomic status of a country strongly influence NRM after alloHCT for adults with ALL. Our findings should be considered when clinical studies in the field of alloHCT are interpreted.

Very high efficacy of intermediate-dose cytarabine in combination with G-CSF as a second-line mobilization of hematopoietic stem cells

Autologous hematopoietic stem cell transplantation (autoHSCT) is used widely in the treatment of patients with lymphoid malignancies. Currently, 99 % of such procedures are performed using peripheral blood as a source of stem cells [1]. The generally accepted minimal level of CD34 cells required for rapid neutrophil and platelet recovery after autoHSCT is 2 9 10/kg. However, some data indicate that higher numbers are associated with less need for blood product transfusions and administration of antibiotics [2–4]. Mobilization regimens are based either on the use of granulocyte-colony stimulating factor (G-CSF) alone or G-CSF in combination with chemotherapy, most frequently cyclophosphamide 1.5–7 g/m or lymphoma-specific salvage regimens [5]. Unfortunately, a significant proportion of patients fail to mobilize sufficient number of CD34 cells, thus requiring additional attempts [6]. New mobilization strategies are being explored, including the use of plerixafor, CXCR4 inhibitor, in combination with G-CSF, with or without chemotherapy. This agent enabled sufficient CD34 cell harvest in 64.8–81.6 % of proven or predicted poor mobilizers [7, 8]. Unfortunately, such treatment is very expensive, which limits its worldwide application. Hence, the development of new strategies is still warranted. Although current studies focus on small molecules interfering with stem cell–stroma interactions, traditional chemotherapy-based salvage mobilization regimens have not been sufficiently explored. In our center, between November 2010 and September 2011, 14 patients who had failed chemotherapy-based mobilization were treated with salvage regimen including intermediate-dose cytarabine (ID-AraC) in combination with G-CSF. Most of the patients were referred for transplantation due to multiple myeloma (n = 8) or lymphoma (n = 5), while the remaining one had ovarian cancer. Patients had previously been treated with a median of 2 (range 1–5) lines of chemotherapy and most of them had received irradiation. Previous mobilization was usually based on cyclophosphamide plus G-CSF (Table 1). Six patients received AraC 400 mg/m (2 h infusions) every 12 h for three consecutive days (total dose, 2400 mg/m), while the following eight patients were treated with AraC for 2 days (total dose, 1600 mg/m). G-CSF 5–10 lg/kg was started on day 5 and continued daily until last leukapheresis. Leukaphereses were started once the peripheral blood CD34 cell count exceeded 15/lL and were performed using the Spectra-Optia Apheresis System (CaridianBCT Inc, Lakewood, CO, USA). The target number of CD34 cells collected was 5 9 10/kg for multiple myeloma (all planned for tandem autoHSCT) and 2 9 10/kg for the remaining patients. The maximum number of peripheral blood CD34 cells/lL after AraC ? G-CSF was 86 (17–312) and was significantly higher compared to the first-line mobilization: 8 (0–35) (Mann–Whitney U test, P = 0.002). No difference could be found according to the AraC dose: 80 (17–174) for 1.6 g/m versus 88 (24–312) for 2.4 g/m, P = 0.85. All patients collected required number of CD34 cells, which was achieved with a single apheresis in 10/14 (71.5 %) patients (Table 1). Although all patients experienced profound cytopenia and most required T. Kruzel M. Sadus-Wojciechowska J. Najda T. Czerw M. Glowala-Kosinska J. Holowiecki S. Giebel (&) Department of Bone Marrow Transplantation, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Wybrzeze Armii Krajowej 15 Street, 44-101 Gliwice, Poland e-mail: sgiebel@io.gliwice.pl

Use of G-CSF to hasten neutrophil recovery after auto-SCT for AML is not associated with increased relapse incidence: a report from the Acute Leukemia Working Party of the EBMT

Application of G-CSF in AML is controversial as leukemic blasts may express receptors interacting with the cytokine, which may stimulate leukemia growth. We retrospectively analyzed the impact of G-CSF use to accelerate neutrophil recovery after auto-SCT on outcome. Adults with AML in first CR autografted between 1994 and 2010 were included. Nine hundred and seventy two patients were treated with G-CSF after auto-SCT whereas 1121 were not. BM and PB were used as a source of stem cells in 454 (22%) and 1639 (78%) cases, respectively. The incidence of relapse at 5 years in the BM-auto-SCT group was 38% for patients receiving post-transplant G-CSF and 43% for those not treated with G-CSF, P=0.46. In the PB-auto-SCT cohort, respective probabilities were 48% and 49%, P=0.49. No impact of the use of G-CSF could be demonstrated with respect to the probability of leukemia-free survival: in the BM-auto-SCT group, 51% for G-CSF(+) and 48% for G-CSF(−), P=0.73; in PB-auto-SCT group, 42% for G-CSF(+) and 43% for G-CSF(−), P=0.83. Although G-CSF administration significantly shortened the neutropenic phase, no beneficial effect was observed with regard to non-relapse mortality. In patients with AML, the use of G-CSF after auto-SCT is not associated with increased risk of relapse irrespective of the source of stem cells used.

Dermoscopic Follow-Up of the Skin towards Acute Graft-versus-Host-Disease in Patients after Allogeneic Hematopoietic Stem Cell Transplantation

Background. Acute graft-versus-host disease (aGVHD) involving skin is one of the most frequent complications of allogeneic hematopoietic stem cell transplantation (alloHSCT), usually diagnosed based on clinical manifestations. So far, skin biopsy with histopathological evaluation is the only method to confirm the diagnosis. Objective. In this prospective study we monitored alloHSCT recipients by dermoscopy in order to assess its utility as an alternative noninvasive tool to early diagnose acute GVHD. Methods. Thirteen consecutive patients who received alloHSCT were examined clinically and dermoscopically towards aGVHD [days 28 (±7), 56 (±7), and 100 (±7)], as well as in each patient who developed cutaneous aGVHD diagnosed according to clinical criteria (Glucksberg scale). Results. Six patients (46%) developed symptoms of cutaneous acute GVHD (grade 1, n = 3; grade 2, n = 3). Dermoscopic evaluation revealed pinkish or reddish background and well-visible, multiple thin telangiectasias. Conclusion. To our knowledge, this is the first report on the use of dermoscopy to evaluate skin involvement in the course of acute GVHD suggesting its role as a diagnostic tool in follow-up of GVHD, which can be also used before clinical symptoms occur.

Comparable safety profile of BeEAM (bendamustine, etoposide, cytarabine, melphalan) and BEAM (carmustine, etoposide, cytarabine, melphalan) as conditioning before autologous haematopoietic cell transplantation.

Introduction BEAM (carmustine, etoposide, cytarabine, melphalan) is the most frequently used high-dose chemotherapy regimen for patients with lymphoma referred for autologous haematopoietic cell transplantation (autoHCT). Recently, a novel conditioning protocol containing bendamustine instead of carmustine (BeEAM) has been proposed to potentially increase the efficacy. Aim of the study The aim of this study was to retrospectively compare the safety profile of BEAM and BeEAM based on single-centre experience. Material and methods A total of 237 consecutive patients with lymphoma treated with either BEAM (n = 174) or BeEAM (n = 63), between the years 2011 and 2016, were included in the analysis. Clinical characteristics of both groups were comparable. Patients with Hodgkin’s lymphoma (HL) constituted 49% of the BEAM group and 40% of the BeEAM group. Results Median time to neutrophil > 0.5 × 109/l recovery was 10 days in both groups (p = 0.29), while median time to platelet > 50 × 109/l recovery was 13 and 14 days after BEAM and BeEAM, respectively (p = 0.12). The toxicity profile was comparable except for arterial hypertension and severe hypokalaemia, which occurred more frequently after BeEAM compared to BEAM (p = 0.02 and p = 0.004, respectively). The rate of early mortality was 1.7% and 1.6%, respectively. The probabilities of the overall and progression-free survival were comparable for both groups (p = 0.73 and p = 0.55, respectively). Conclusions Administration of bendamustine instead of carmustine as part of conditioning does not affect the engraftment or the toxicity profile of the regimen. Therefore, BeEAM may be safely used in patients with lymphoma undergoing autoHCT. Its efficacy requires evaluation in prospective studies.

HLA-inferred extended haplotype disparity level is more relevant than the level of HLA mismatch alone for the patients survival and GvHD in T cell-replate hematopoietic stem cell transplantation from unrelated donor

Serious risks in unrelated hematopoietic stem cell transplantation (HSCT) including graft versus host disease (GvHD) and mortality are associated with HLA disparity between donor and recipient. The increased risks might be dependent on disparity in not-routinely-tested multiple polymorphisms in genetically dense MHC region, being organized in combinations of two extended MHC haplotypes (Ehp). We assessed the clinical role of donor-recipient Ehp disparity levels in N = 889 patients by the population-based detection of HLA allele phase mismatch. We found increased GvHD incidences and mortality rates with increasing Ehp mismatch level even with the same HLA mismatch level. In multivariate analysis HLA mismatch levels were excluded from models and Ehp disparity level remained independent prognostic factor for high grade acute GvHD (p = 0.000037, HR = 10.68, 95%CI 5.50-32.5) and extended chronic GvHD (p < 0.000001, HR = 15.51, CI95% 5.36-44.8). In group with single HLA mismatch, patients with double Ehp disparity had worse 5-year overall survival (45% vs. 56%, p = 0.00065, HR = 4.05, CI95% 1.69-9.71) and non-relapse mortality (40% vs. 31%, p = 0.00037, HR = 5.63, CI95% 2.04-15.5) than patients with single Ehp disparity. We conclude that Ehp-linked factors contribute to the high morbidity and mortality in recipients given HLA-mismatched unrelated transplant and Ehp matching should be considered in clinical HSCT.