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Given the selection of elderly patients with AML in first complete remission (CR1) the advantage of consolidation with allogeneic hematopoietic cell transplantation (HCT) over chemotherapy is still unclear. Newly diagnosed AML patients in CR1 aged 60-75 years were registered and a donor search initiated. After one consolidation cycle, patients with a matched donor were randomized to HCT with fludarabine/lowdose total body irradiation and cyclosporine/mycophenolate mofetil immunosuppression or conventional non-HCT. Primary outcome was restricted mean leukemia-free survival (RM-LFS) up to five years. Between 2010 and 2017, 245 patients (median age 67 years) were registered at CR1. After one consolidation, 26.9% of patients failed inclusion criteria. Of the 179 (73%) patients still on study, 75.4% had an HLA identical donor. Ten ineligible patients were excluded, and 125 randomized to HCT (n=83) or non-HCT (n=42). The primary outcome RM-LFS up to 5 years was 24.5 months (95%CI:18.9-30.1) in the HCT and 15.6 months (95%CI:10.4-20.8) in the non-HCT arm (p=0.022) due to a decrease in cumulative relapse incidence from 91.1 (95%CI:80.7-100.0) after non-HCT to 37.8 (95%CI:27.2-48.4)% after HCT (p

Promoting access to and excellence in hematopoietic cell transplantation (HCT) by collecting and disseminating data on global HCT activities is one of the principal activities of the Worldwide Network for Blood and Marrow Transplantation, a non-Governmental organization in working relations with the World Health Organization. HCT activities are recorded annually by member societies, national registries and individual centers including indication, donor type (allogeneic/autologous), donor match and stem cell source (bone marrow/peripheral blood stem cells/cord blood). In 2018, 1,768 HCT teams in 89 countries (six WHO regions) reported 93,105 (48,680 autologous and 44,425 allogeneic) HCT. Major indications were plasma cell disorders and lymphoma for autologous, and acute leukemias and MDS/MPN for allogeneic HCT. HCT number increased from 48,709 in 2007. Notable increases were seen for autoimmune diseases in autologous and hemoglobinopathies in allogeneic HCT. The number of allogeneic HCT more than doubled with significant changes in donor match. While HCT from HLA identical siblings has seen only limited growth, HCT from non-identical related donors showed significant increase worldwide. Strongest correlation between economic growth indicator of gross national income/capita and HCT activity/ten million population was observed for autologous HCT (r=0.79). HCT from unrelated donors showed strong correlation (r=0.68), but only moderate correlation (r=0.51) was detected from related donors. The use of HCT doubled in about a decade worldwide at different speed and with significant changes regarding donor match as a sign of improved access to HCT worldwide. Although narrowing, significant gaps remain between developing and non-developing countries.

Background: Thrombocytopenia is a common feature of myelofibrosis (MF), a myeloproliferative neoplasm driven by dysregulated JAK/STAT signaling; however, pivotal trials assessing the efficacy of ruxolitinib (a JAK1/2 inhibitor) excluded MF patients with low platelet counts (

ObjectiveCancer affects the patients as well as their partners. Couples use different strategies to cope with cancer and the associated burden: individual coping, dyadic coping, and support from the social network and from professional health care. The aim of this qualitative dyadic interviews is to gain a deeper and more differentiated understanding of the support system inside and outside of the couple.MethodsTen heterosexual couples (patients: seven men and three women) with different ages (patients: range = 22–75; spouses: range = 22–74), different hematological cancer (e.g., acute myeloid leukemia, non-Hodgkin’s lymphoma) and cancer stages (initial diagnosis or relapse) participated in the study. Semi-structured dyadic interviews were conducted. Data of the verbatim transcripts were systematically coded and analyzed following structuring content analysis.ResultsThree main categories (individual coping, dyadic coping, and outside support) and ten subcategories about coping and support strategies in hematological cancer patients and their spouses could be identified. All couples described cohesion in relationship as an essential common dyadic coping strategy. Most strategies were focused on the patient’s wellbeing. Furthermore, couples reported different common plans for the future: while some wanted to return to normality, others were reaching out for new goals.ConclusionCouples used various coping and support strategies, that differed in type and frequency between patients and spouses. Most of the strategies were perceived as beneficial, but some also triggered pressure. Overall, spouses seem to need more psychological support to improve their own wellbeing.

Sezary Syndrome (SS) is a rare leukemic variant of primary cutaneous T-cell lymphoma. Relapsed or refractory disease is generally considered incurable by conventional therapeutic approaches, although durable responses can be achieved with novel monoclonal antibodies. Allogeneic hematopoietic stem cell transplantation (alloHSCT) may have potential value by inducing graft vs-lymphoma (GvL) effects, but there is currently no consensus regarding the timing of alloHSCT or type of conditioning regimen. Here we present the case of a male patient who achieved a complete remission (CR) of primary refractory SS after non-myeloablative alloHSCT. Patient: Two years prior to HSCT, the patient had been refractory to CHOEP-based chemotherapy, interferon, extracorporeal photopheresis (ECP), and bexarotene. Directly prior to alloHSCT brentuximab-vedotin (BV) was applied resulting in a partial remission of the skin compartment and overall in a stable disease. Prior to HSCT, flow cytometry of the bone marrow and peripheral blood showed an infiltration with T-cells positive for CD5, CD4, low CD3, low CD2 and negative for CD7, CD38, HLA-DR and CD8. The trephine biopsy showed a 7% infiltration of SS cells. The CD4:CD8 ratio in peripheral blood (pb) was massively increased at 76.67, with 63.5% of white blood cells expressing a SS immune phenotype. The conditioning regimen included 30 mg/m2 fludarabine on days -5, -4 and -3 and total body irradiation with 2 Gy on day -1. Immunosuppression consisted of cyclosporine A from day-1 and mycophenolate mofetil from day 0. The patient received 6.55x106 CD34+ cells and 1.11x108 CD3+ cells/kg body weight. Bone marrow evaluation on day 28 still showed persistent SS cells by flow cytometry. After tapering immunosuppression until day 169, the CD4:CD8 ratio in pb normalized. CR was documented on day 169 after alloHSCT and is now ongoing for almost 3 years after alloHSCT. Conclusions: We confirm that an alloHSCT can be a curative option for refractory patients with SS. The achievement of a CR after tapering the immunosuppressive therapy indicates a significant role of the GvL effect. In present treatment algorithms for patients with SS, the timing of an alloHSCT and the intensity of conditioning should be further explored.

The Worldwide Network of Blood and Marrow Transplantation (WBMT) pursues the mission of promoting hematopoietic cell transplantation (HCT) for instance by evaluating activities through member societies, national registries and individual centers. In 2016, 82,718 first HCT were reported by 1,662 HCT teams in 86 of the 195 World Health Organization member states representing a global increase of 6.2% in autologous HCT and 7.0% in allogeneic HCT and bringing the total to 1,298,897 procedures. Assuming a frequency of 84,000/year, 1.5 million HCT were performed by 2019 since 1957. Slightly more autologous (53.5%) than allogeneic and more related (53.6%) than unrelated HCT were reported. A remarkable increase was noted in haploidentical related HCT for leukemias and lymphoproliferative diseases, but even more in non-malignant diseases. Transplant rates (TR; HCT/10 million population) varied according to region reaching 560.8 in North America, 438.5 in Europe, 76.7 in Latin America, 53.6 in South East Asia/Western Pacific (SEA/WPR) and 27.8 in African/East Mediterranean (AFR/EMR). Interestingly, haploidentical TR amounted to 32% in SEA/WPR and 26% in Latin America, but only 14% in Europe and EMR and 4.9% in North America of all allogeneic HCT. HCT team density (teams/10 million population) was highest in Europe (7.7) followed by North America (6.0), SEA/WPR (1.9), Latin America (1.6) and AFR/EMR (0.4). HCT are increasing steadily worldwide with narrowing gaps between regions and greater increase in allogeneic compared to autologous activity. While related HCT is rising, largely due to increase in haploidentical HCT, unrelated HCT is plateauing and cord blood HCT is in decline.

Background: The role of conditioning intensity and stem cell source on modifying pre-transplantation risk in allogeneic haematopoietic stem cell transplantation (HSCT) is a matter of debate, but crucial when benchmarking centres. Methods: This Retrospective, multicenter exploratory-validation analysis of 9103 patients, (55.5% male, median age 50 years; 1–75 years range) with an allogeneic HSCT between 2010 and 2016 from a matched sibling (N = 8641; 95%) or matched unrelated donor (N = 462; 5%) for acute myeloid (N = 6432; 71%) or acute lymphoblastic (N = 2671; 29%) leukaemia in first complete remission, and reported by 240 centres in 30 countries to the benchmark database of the European Society for Blood and Marrow Transplantation (EBMT) searched for factors associated with use of transplant techniques (standard N = 6375;70% or reduced intensity conditioning N = 2728;30%, respectively bone marrow N = 1945;21% or peripheral blood N = 7158;79% as stem cell source), and their impact on outcome. Findings: Treatment groups differed significantly from baseline population (p

Abstract Background Suffering from cancer confronts both the patient and their partner with a number of psychosocial challenges in various aspects of their life. These challenges may differentially impact on quality of life, coping ability and compliance to treatment. This especially holds true for haemato-oncological diseases. To date, psychological interventions have predominantly been developed for oncological patients however specific interventions for partners of haemato-oncological patients are rare. In this study we aim to conduct a psycho-oncological group-intervention for partners of patients with haemato-oncological diseases. The aim of the intervention is to significantly reduce symptoms of depression and anxiety in the partners and the patient, as well as enhancing dyadic coping. Methods The design of the INPART-study is an unblinded, randomised controlled trial with 2 treatment conditions (experimental and control) and assessments at baseline, 3 and 6 months. It will be conducted at three study centres: the university medical centre’s in Leipzig, Hannover and Ulm. The outcome criteria will be a reduction in depressive and anxiety symptoms as well as an improvement of dyadic coping. Discussion This trial shall provide information regarding the efficiency of a psycho-oncological intervention for partners of patients with haemato-oncological diseases and give references to the possible outcome in terms of dyadic coping and the reduction of mental strain. The study was supported by a grant from the German José Carreras Leukaemia Foundation. Trial registration ISRCTN16085028; 20/03/2019.

Abstract Background Limited data is available to guide the choice of the conditioning regimen for patients with acute myeloid leukemia (AML) undergoing transplant with persistent disease. Methods We retrospectively compared outcome of fludarabine-treosulfan (FT), thiotepa-busulfan-fludarabine (TBF), and sequential fludarabine, intermediate dose Ara-C, amsacrine, total body irradiation/busulfan, cyclophosphamide (FLAMSA) conditioning in patients with refractory or relapsed AML. Results Complete remission rates at day 100 were 92%, 80%, and 88% for FT, TBF, and FLAMSA, respectively (p = 0.13). Non-relapse mortality, incidence of relapse, acute (a) and chronic (c) graft-versus-host disease (GVHD) rates did not differ between the three groups. Overall survival at 2 years was 37% for FT, 24% for TBF, and 34% for FLAMSA (p = 0.10). Independent prognostic factors for survival were Karnofsky performance score and patient CMV serology (p = 0.01; p = 0.02), while survival was not affected by age at transplant. The use of anti-thymocyte globulin (ATG) was associated with reduced risk of grade III–IV aGVHD (p = 0.02) and cGVHD (p = 0.006), with no influence on relapse. Conclusions In conclusion, FT, TBF, and FLAMSA regimens provided similar outcome in patients undergoing transplant with active AML. Survival was determined by patient characteristics as Karnofsky performance score and CMV serology, however was not affected by age at transplant. ATG appears able to reduce the incidence of acute and chronic GVHD without influencing relapse risk.

The nutritional status at diagnosis, as well as weight loss during chemotherapy, are important factors for morbidity and mortality in cancer patients. They might also influence outcomes in patients with acute myeloid leukemia (AML) receiving allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated the body mass index (BMI) at diagnosis, prior to HSCT, and the BMI difference (ΔBMI = BMIHSCT–BMIdiagnosis) in 662 AML patients undergoing allogeneic HSCT. Patients being obese at AML diagnosis had significantly higher nonrelapse mortality (NRM) and shorter overall survival (OS) after HSCT, but no distinct cumulative incidence of relapse than nonobese patients. Weight loss during chemotherapy (ΔBMI > –2) was a strong predictor for higher NRM and shorter OS in univariate and multivariate analyses. These results were observed across all European LeukemiaNet (ELN) 2017 risk groups but especially in patients with favorable or intermediate ELN2017 risk and patients transplanted in morphologic complete remission. Only in patients being obese at AML diagnosis, weight loss did not result in adverse outcomes. ΔBMI > –2 represents a strong, independent, and modifiable risk factor for AML patients treated with HSCT. Nutritional monitoring and supplementation during disease course might improve patients’ outcomes.

Rituximab (R) is increasingly incorporated in reduced intensity conditioning (RIC) regimens for allogeneic hematopoietic cell transplantation (alloHCT) in patients with B-cell malignancies, not only to improve disease control, but also to prevent graft-versus-host disease (GVHD). There are no randomized prospective data to validate this practice, although single center data and the CIBMTR analysis have shown promising results. We aimed at validation of these findings in a large registry study. We conducted a retrospective analysis using the EBMT registry of 3,803 adult patients with B-cell malignancies undergoing alloHCT (2001–2013) with either rituximab (R-RIC-9%) or non-rituximab (RIC-91%) reduced intensity regimens respectively. Median age and median follow up were 55 years (range 19.1–77.3) and 43.2 months (range 0.3–179.8), respectively. There was no difference in transplant outcomes (R-RIC vs RIC), including 1-year overall survival (69.9% vs 70.7%), 1-year disease-free survival (64.4% vs 62.2%), 1-year non-relapse mortality (21% vs 22%), and day-100 incidence of acute GVHD 2-4° (12% vs 12%). In summary, we found that addition of rituximab in RIC regimens for B-cell malignancies had no significant impact on major transplant outcome variables. Of note, data on chronic GVHD was not available, limiting the conclusions that can be drawn from the present study.

Acute graft-vs.-host disease (aGvHD) is one of the most frequent causes of transplant-related mortality (TRM) after allogeneic hematopoietic cell transplantation (alloHCT). Its treatment is complex and costly. The aim of this study was to retrospectively analyze the impact of country-specific socioeconomic factors on outcome of patients who experience severe aGvHD. Adults with hematological malignancies receiving alloHCT from either HLA-matched siblings (n = 1,328) or unrelated donors (n = 2,824) developing grade 3 or 4 aGvHD were included. In univariate analysis, the probability of TRM at 2 years was increased for countries with lower current Health Care Expenditure (HCE, p = 0.04), lower HCE as % of Gross Domestic Product per capita (p = 0.003) and lower values of the Human Development Index (p = 0.02). In a multivariate model, the risk of TRM was most strongly predicted by current HCE (HR = 0.76, p = 0.006). HCE >median was also associated with reduced risk of the overall mortality (HR 0.73, p = 0.0006) and reduced risk of treatment failure (either relapse or TRM; HR 0.77, p = 0.004). We conclude that country-specific socioeconomic factors, in particular current HCE, are strongly associated with survival of patients who experience severe aGvHD.

Abstract: Patients with secondary AML (sAML) with antecedent myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPNs) tend to have high-risk disease based on the older age of patients, high-risk cytogenetics, and higher number of prior treatments. Allogeneic hematopoietic cell transplant (HCT) is the only potentially curative therapy available. Eight hundred and two adults with sAML and prior MDS/MPN who received a first HCT between 2000 and 2016 were included in the European Society for Blood and Marrow Transplant (EBMT) Acute Leukemia Working Party (ALWP) study. Median age of the cohort was 59.6 years (range, 18.6-78.6 years). Myeloablative conditioning (MAC) was given to 40% of patients, and 60% received reduced-intensity conditioning (RIC). Overall, the 2-year cumulative incidence of relapse (RI) was 37%, leukemia-free survival (LFS) was 40%, overall survival (OS) was 46%, nonrelapse mortality (NRM) was 23%, and chronic graft-versus-host disease (cGVHD) was 39%. In univariate analysis, a statistical difference between conditioning regimens 6 months after HCT in favor of the MAC group was noted with regard to RI (hazard ratio [HR], 1.47; P = .03), LFS (HR, 1.43; P = .01), and OS (HR, 1.55; P < .05). There was no difference in the cumulative incidence of NRM (HR, 1.38; P = .15). This effect was similarly seen in multivariate analysis (MVA): cumulative incidence of relapse (HR, 1.79; P < .05), LFS (HR, 1.43; P = .02), and OS (HR, 1.53; P = .005) with no difference in NRM (HR, 1; P = .98). This EBMT ALWP analysis suggests that long-term survival can be achieved in patients with sAML with antecedent MDS/MPN and that MAC is a suitable conditioning regimen in patients with sAML.

Abstract Background Acute myeloid leukemia (AML) is both more common and with more biologically aggressive phenotype in the elderly. Allogenic stem cell transplantation (allo-SCT) is the best treatment option in fit patients. Either HLA-matched unrelated donor (MUD) or haploidentical (Haplo) donor are possible alternative for patients in need. Methods We retrospectively compared non-T-cell-depleted Haplo (n = 250) to 10/10 MUD (n = 2589) in AML patients ≥ 60 years. Results Median follow-up was 23 months. Disease status at transplant differs significantly between the two groups (p

Abstract Background Approximately 10% of the individuals experiencing the death of a loved one develop prolonged grief disorder (PGD) after bereavement. Family members of haematological cancer patients might be particularly burdened since their loss experience is preceded by a very strenuous time of disease and aggressive treatment. However, support needs of relatives of cancer patients often remain unmet, also after the death of the patient. Therapeutic possibilities are enhanced by providing easily available and accessible Internet-based therapies. This study will adapt and evaluate an Internet-based grief therapy for bereaved individuals after the loss of a significant other due to haematological cancer. Methods The efficacy of the Internet-based grief therapy is evaluated in a randomized controlled trial with a wait-list control group. Inclusion criteria are bereavement due to hematological cancer and meeting the diagnostic criteria for PGD. Exclusion criteria are severe depression, suicidality, dissociative tendency, psychosis, posttraumatic stress disorder, substance use disorder, and current psychotherapeutic or psychopharmacological treatment. The main outcome is PGD severity. Secondary outcomes are depression, anxiety, somatization, posttraumatic stress, quality of life, sleep quality, and posttraumatic growth. Data is collected pre- and posttreatment. Follow-up assessments will be conducted 3, 6, and 12 months after completion of the intervention. The Internet-based grief therapy is assumed to have at least moderate effects regarding PGD and other bereavement-related mental health outcomes. Predictors and moderators of the treatment outcome and PGD will be determined. Discussion Individuals bereaved due to haematological cancer are at high risk for psychological distress. Tailored treatment for this particularly burdened target group is missing. Our study results will contribute to a closing of this healthcare gap. Trial registration German Clinical Trial Register UTN: U1111–1186-6255. Registered 1 December 2016.

Abstract: The only curative treatment in patients with intermediate or high-risk myelodysplastic syndrome (MDS) is allogeneic hematopoietic stem cell transplantation (HSCT), which usually results in a long-term, disease-free survival rate of between 30% and 50%, depending on the disease risk and the type of donor. In patients without an HLA-matched sibling donor, a family haploidentical donor is an alternative option. The present study reports the European Group for Blood and Marrow Transplantation activity for haploidentical transplantation in MDS patients. A total of 228 patients transplanted from a mismatched HLA-related donor between 2007 and 2014 were studied. The median age at transplant was 56 years. Eighty-four (37%) patients had MDS transformed into acute myeloid leukemia at the time of transplant. Ex vivo T-cell depletion was used in 34 patients. One hundred ninety-four patients received a T-cell replete transplant and 102 patients received posttransplant cyclophosphamide (PT-CY) as graft-versus-host disease (GVHD) prophylaxis. The cumulative incidences of acute and chronic GVHD in PT-CY vs other patients were 25% vs 37% and 37% vs 24%, respectively. The cumulative incidence of nonrelapse mortality was 55% in patients who did not receive PT-CY (no PT-CY) and 41% in patients who did receive PT-CY. Three-year overall survival was 28% in no PT-CY patients and 38% in PT-CY patients. In multivariable analysis, the main risk factors were the intensity of the conditioning regimen and the use of PT-CY. In conclusion, the outcomes of MDS patients who received an haploidentical transplant are close to the results other transplantations from HLA-mismatched donors with approximately one-third of patients alive and free of disease 3 years after transplant, and the use of PT-CY may improve their outcomes.

C/EBPα is a critical transcription factor involved in myelopoiesis and its inactivation is associated with acute myeloid leukemia (AML). Here the authors show a negative feedback loop between C/EBPα and miR-182 and identify this miRNA as a marker of high-risk AML.

Allogeneic hematopoietic stem cell transplant remains the only curative treatment for myelofibrosis. Most post-transplantation events occur during the first two years and hence we aimed to analyze the outcome of 2-year disease-free survivors. A total of 1055 patients with myelofibrosis transplanted between 1995 and 2014 and registered in the registry of the European Society for Blood and Marrow Transplantation were included. Survival was compared to the matched general population to determine excess mortality and the risk factors that are associated. In the 2-year survivors, disease-free survival was 64% (60-68%) and overall survival was 74% (71-78%) at ten years; results were better in younger individuals and in women. Excess mortality was 14% (8-21%) in patients aged

EEXPAND (phase Ib, dose-finding study) evaluated the starting dose of ruxolitinib in patients with myelofibrosis with baseline platelet counts of 50-99×109/L. The study consisted of dose-escalation and safety-expansion phases. Based on the baseline platelet counts, patients were assigned to stratum 1 (75-99×109/L) or stratum 2 (50-74×109/L), with the primary objective of determining the maximum safe starting dose (MSSD); key secondary objectives included safety and efficacy. At week 48 data cutoff (stratum 1, n=44; stratum 2, n=25), 24.6% (17 out of 69) of patients were still receiving treatment. The MSSD was established as ruxolitinib 10 mg twice daily in both strata. Thrombocytopenia [grade 4 (stratum 1, n=1; stratum 2, n=2)] was the only reported dose-limiting toxicity (study drug related) at 10 mg twice daily. In the MSSD cohort (stratum 1, n=20; stratum 2, n=18), adverse events (regardless of study drug relationship) led to treatment discontinuation in 15.0% and 33.3% of patients in stratum 1 and stratum 2, respectively, and dose adjustment/interruption in 45.0% and 66.7% of patients in stratum 1 and stratum 2, respectively. Three cases of on-treatment deaths were reported at the MSSD. Spleen response was achieved at week 48 in 33.3% and 30.0% of patients in stratum 1 and stratum 2, respectively. Improvements in the Total Symptom Score were also observed. In this study, ruxolitinib demonstrated acceptable tolerability in both the strata at the MSSD of 10 mg twice daily. (Registered at: clinicaltrials.gov identifier: 01317875).

The aim of this study was to develop and validate a clinical and transplant-specific prognostic score using data from a large cohort of patients with myelodysplastic syndromes reported to the European Society for Blood and Marrow Transplantation registry. A Cox model was fitted to detect clinical and transplant-related variables prognostic of outcome. Then, cross-validation was performed to evaluate the validity and consistency of the model. Seven independent risk factors for survival were identified: age ≥50 years, matched unrelated donor, Karnofsky Performance Status 1%, and platelet count ≤50 × 109/L prior to transplantation. Incorporating these factors into a four-level risk score yielded hazard ratios for death, with low-risk (score of 0-1) as reference, of 2.02 (95% CI: 1.41-2.90) for the intermediate-risk group (score of 2-3), 3.49 (95% CI: 2.45-4.97) for the high-risk group (score of 4-5), and 5.90 (95% CI: 4.01-8.67) for the very high-risk group (score of >5). The score was predictive of survival, relapse-free survival, relapse, and non-relapse mortality (P

Abstract. High expression of the leukemia-associated gene meningioma-1 (MN1) is frequently found at diagnosis of acute myeloid leukemia (AML) and associates with adverse outcomes. The presence of measurable residual disease (MRD) in complete remission (CR) indicates high risk of relapse and worse outcome in AML patients. However, the prognostic impact of MN1 expression levels as MRD marker has not been evaluated. Digital droplet polymerase chain reaction (ddPCR) is a novel technique allowing sensitive and specific absolute gene expression quantification. We retrospectively analyzed 124 AML patients who received allogeneic hematopoietic stem cell transplantation (HSCT) in CR or CR with incomplete peripheral recovery. Absolute MN1 copy numbers in peripheral blood were assessed prior to HSCT (median 7; range 0–29 days) using ddPCR. High pre-HSCT MN1/Abelson murine leukemia viral oncogene homolog 1 gene (ABL1) copy numbers associated with a higher cumulative incidence of relapse after HSCT and—in relapsing patients—shorter time to relapse. In multivariable analysis, high pre-HSCT MN1/ABL1 copy numbers remained an independent prognosticator for relapse after HSCT. Patients with the highest pre-HSCT MN1/ABL1 copy numbers also had the highest risk of relapse. MN1 copy number assessment also added prognostic information to nucleophosmin 1 gene (NPM1) mutation- and brain and acute leukemia, cytoplasmic (BAALC) and Wilm's tumor gene 1 (WT1) expression-based MRD evaluation. Our study demonstrates the feasibility of the novel ddPCR technique for MN1/ABL1 copy number assessment as a marker for MRD. Evaluation of MN1/ABL1 copy numbers allows the identification of patients at high risk of relapse, independently of other diagnostic risk factors and MRD markers.

Abstract Background Myeloablative (MAC) and reduced-intensity conditioning (RIC) are established approaches for allogeneic stem cell transplantation (SCT) in acute myeloid leukemia (AML). Most deaths after MAC occur within the first 2 years after SCT, while patients surviving leukemia-free for 2 years can expect a favorable long-term outcome. However, there is paucity of data on the long-term outcome (beyond 10 years) and the pattern of late events following RIC due to the relative recent introduction of this approach. Methods We analyzed long-term outcomes in a cohort of 1423 AML patients, age ≥50 years, after SCT from HLA-matched siblings, during the years 1997–2005, median follow-up 8.3 years (0.1–17). Results The 10-year leukemia-free survival (LFS) was 31 % (95CI, 27–35) and 32 % (28–35) after MAC and RIC, respectively (P = 0.57). The 10-year GVHD/ relapse-free survival (GRFS), a surrogate for quality of life was 22 % (18–25) and 21 % (18–24), respectively (P = 0.79). The 10-year non-relapse mortality (NRM) was higher and relapse rate was lower after MAC, throughout the early and late post-transplant course. The 10-year LFS among 584 patients surviving leukemia-free 2 years after SCT was 71 % (65–76) and 73 % (67–78) after MAC and RIC, respectively (P = 0.76). Advanced leukemia at SCT was the major predictor of LFS subsequent to the 2-year landmark. Relapse was the major cause of late death after both regimens; however, NRM and in particular chronic graft-versus-host disease and second cancers were more common causes of late death after MAC. Conclusions Long-term LFS and GRFS are similar after RIC and MAC. Most events after RIC or MAC occur within the first 2 years after SCT. Patients who are leukemia-free 2 years after SCT can expect similar good subsequent outcome after both approaches.

Abstract Background Data comparing fully matched and mismatched-unrelated-donor (M- and mM-URD) allogeneic hematopoietic stem cell transplant (allo-SCT) following reduced intensity conditioning regimens for acute myeloid leukemia are limited. Methods We retrospectively compared the outcome of 3398 patients above the age of 50 years who underwent 10/10 M-URD (n = 2567), 9/10 (n = 723), or 8/10 (n = 108) mM-URD allo-SCT for acute myeloid leukemia after reduced intensity conditioning regimen between 2000 and 2013. The Kaplan-Meier estimator, the cumulative incidence function, and Cox proportional hazards regression models were used where appropriate. Results HLA matching had no impact on engraftment (p = 0.31). In univariate analysis, in comparison to 10/10 M-URD, mM-URD was associated with higher incidence of grade II–IV acute graft-versus-host disease (GVHD) (p = 0.0002), similar rates of chronic GVHD (p = 0.138) but increased incidence of its extensive form (p = 0.047). Compared to 10/10 M-URD, patients transplanted in the first complete remission (CR1) with a 9 or an 8/10 mM-URD had decreased 2-year leukemia free (LFS) (p = 0.005) and overall survivals (OS) (56.7, 46.1, and 50.2 %, respectively, p = 0.005), while outcomes were comparable between all groups for patients transplanted beyond CR1. In multivariate analysis, 9/10 versus 10/10 URD was associated with higher non-relapse mortality (HR 1.34, p = 0.001), similar risk of relapse and chronic GVHD and inferior LFS (HR 1.25, p = 0.0001), and OS (HR 1.27, p = 0.0001). There was no difference in adjusted transplant outcomes between 9/10 and 8/10 mM-URD. Conclusions Reduced intensity conditioned allo-SCT with a 10/10 M-URD remains the preferable option for AML patients above the age of 50 years. The use of a 9/10 or an 8/10 mM-URD in patients not having a fully matched donor represents an alternative therapeutic option that should be compared to other alternative donor transplant strategies.

Hematopoietic stem cell transplantation (HSCT) is a lifesaving expensive medical procedure. Hence, more transplants are performed in more affluent countries. The impact of economic factors on patient outcome is less defined. We analyzed retrospectively a defined cohort of 102,549 patients treated with an allogeneic (N = 37,542; 37%) or autologous (N = 65,007; 63%) HSCT. They were transplanted by one of 404 HSCT centers in 25 European countries between 1999 and 2006. We searched for associations between center-specific microeconomic or country-specific macroeconomic factors and outcome. Center patient-volume and center program-duration were significantly and systematically associated with improved survival after allogeneic HSCT (HR 0·87; 0·84–0·91 per 10 patients; p

The success of hematopoietic stem cell transplantation is determined by multiple factors. Additional complexity is conferred by covariables showing time-dependent effects. We evaluated the effect of predictors on competing-risk outcomes after hematopoietic stem cell transplantation in a time-dependent manner. We analyzed 14951 outcomes of adult patients with hematologic malignancies who underwent a first allogeneic transplant. We extended the combined endpoints of disease-free and overall survival to competing-risk settings: disease-free survival was split into relapse and non-relapse mortality. Overall survival was divided into transplant-related mortality, death from other causes and death from unknown causes. For time-dependent effects we computed estimators before and after a covariable-specific cut-point. Patients treated with reduced intensity conditioning had a constantly higher risk of relapse compared to patients treated with myeloablative conditioning. For non-relapse mortality, patients treated with reduced intensity conditioning had a reduced mortality risk but this effect was only seen in the first 4 months after transplantation (hazard ratio: 0.76, P

No standard exists for the treatment of myelodysplastic syndrome relapsing after allogeneic stem cell transplantation. We performed a retrospective registry analysis of outcomes and risk factors in 698 patients, treated with different strategies. The median overall survival from relapse was 4.7 months (95% confidence interval: 4.1–5.3) and the 2-year survival rate was 17.7% (95% confidence interval: 14.8–21.2%). Shorter remission after transplantation (P

We investigated a possible interaction between age-associated risk and HLA-mismatch associated risk on prognosis in different age categories of recipients of unrelated hematopoietic stem cell transplants (HSCT) (n=3019). Patients over 55 years of age transplanted with 8/10 donors showed a mortality risk of 2.27 (CI 1.70–3.03, P

Natural Killer cells (NK) are lymphocytes with the potential to recognize and lyse cells which escaped T-cell mediated lysis due to their aberrant HLA expression profiles. Killer cell immunoglobulin-like receptors (KIR) influence NK-cell activity by mediation of activating or inhibitory signals upon interaction with HLA-C (C1, C2) ligands. Therefore, absence of ligands for donor inhibitory KIRs following hematopoietic stem cell transplantation (HSCT) may have an influence on its outcome. Previous studies showed that C1 negative patients have a decreased HSCT outcome. Our study, based on a cohort of 200 C1-negative patients, confirmed these findings for the endpoints: overall survival (OS: HR = 1.41, CI = 1.14-1.74, p = 0.0012), disease free survival (DFS: HR = 1.27, CI = 1.05-1.53, p = 0.015), treatment related mortality (TRM: HR = 1.41, CI = 1.01-1.96, p = 0.04), and relapse incidence (RI: HR = 1.33, CI = 1.01-1.75, p = 0.04) all being inferior when compared to C1-positive patients (n = 1246). Subsequent analysis showed that these findings applied for patients with myeloid malignancies but not for patients with lymphoproliferative diseases (OS: myeloid: HR = 1.51, CI = 1.15-1.99, p = 0.003; lymphoblastic: HR = 1.26, CI = 0.91-1.75, p = 0.16; DFS: myeloid: HR = 1.31, CI = 1.01-1.70, p = 0.04; lymphoblastic: HR = 1.21, CI = 0.90-1.61, p = 0.21; RI: myeloid: HR = 1.31, CI = 1.01-1.70, p = 0.04; lymphoblastic: HR = 1.21, CI = 0.90-1.61, p = 0.21). Interestingly, within the C1-negative patient group, transplantation with KIR2DS2 resulted in better OS (9/10 matched: HR = 0.24, CI = 0.08-0.67, p = 0.007) as well as DFS (9/10 matched: HR = 0,26, CI = 0.11-0.60, p = 0.002), and transplantation with KIR2DS1 positive donors was associated with a decreased RI (HR = 0.30, CI = 0.13-0.69, p = 0.005). TRM was increased when the donor was positive for KIR2DS1 (HR = 2.61, CI = 1.26-5.41, p = 0.001). Our findings suggest that inclusion of KIR2DS1/2/5 and KIR3DS1-genotyping in the unrelated donor search algorithm of C1-ligand negative patients with myeloid malignancies may prove to be of clinical relevance.

The outcome of patients undergoing HLA-matched unrelated donor allogeneic hematopoietic cell transplantation following reduced-intensity conditioning or myeloablative regimens is reported to be equivalent; however, it is not known if the intensity of the conditioning impacts outcomes after mismatched unrelated donor transplantation for acute myeloid leukemia. Eight hundred and eighty three patients receiving reduced-intensity conditioning were compared with 1041 myeloablative conditioning regimen recipients in the setting of mismatched unrelated donor transplantation. The donor graft was HLA-matched at 9/10 in 872 (83.8%) and at 8/10 in 169 (16.2%) myeloablative conditioning recipients, while in the reduced-intensity conditioning cohort, 754 (85.4%) and 129 (14.6%) were matched at 9/10 and 8/10 loci, respectively. Myeloablative conditioning regimen recipients were younger, 70% being

Increasing numbers of patients are receiving reduced intensity conditioning regimen allogeneic hematopoietic stem cell transplantation. We hypothesized that the use of bone marrow graft might decrease the risk of graft-versus-host disease compared to peripheral blood after reduced intensity conditioning regimens without compromising graft-versus-leukemia effects. Patients who underwent reduced intensity conditioning regimen allogeneic hematopoietic stem cell transplantation from 2000 to 2012 for acute leukemia, and who were reported to the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation were included in the study. Eight hundred and thirty-seven patients receiving bone marrow grafts were compared with 9011 peripheral blood transplant recipients after reduced intensity conditioning regimen. Median follow up of surviving patients was 27 months. Cumulative incidence of engraftment (neutrophil ≥0.5×109/L at day 60) was lower in bone marrow recipients: 88% versus 95% (P

In a randomized, phase III trial of nilotinib versus imatinib in patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase, more patients had suboptimal response or treatment failure on front-line imatinib than on nilotinib. Patients with suboptimal response/treatment failure on imatinib 400 mg once or twice daily or nilotinib 300 mg twice daily could enter an extension study to receive nilotinib 400 mg twice daily. After a 19-month median follow up, the safety profile of nilotinib 400 mg twice daily in patients switching from imatinib (n=35) was consistent with previous reports, and few new adverse events occurred in patients escalating from nilotinib 300 mg twice daily (n=19). Of patients previously treated with imatinib or nilotinib 300 mg twice daily, respectively, 15 of 26 (58%) and 2 of 6 (33%) without complete cytogenetic response at extension study entry, and 11 of 34 (32%) and 7 of 18 (39%) without major molecular response at extension study entry, achieved these responses at any time on nilotinib 400 mg twice daily. Estimated 18-month rates of freedom from progression and overall survival after entering the extension study were lower for patients switched from imatinib (85% and 87%, respectively) versus nilotinib 300 mg twice daily (95% and 94%, respectively). Nilotinib dose escalation was generally well tolerated and improved responses in about one-third of patients with suboptimal response/treatment failure. Switch to nilotinib improved responses in some patients with suboptimal response/treatment failure on imatinib, but many did not achieve complete cytogenetic response (clinicaltrials.gov identifiers:00718263, 00471497 - extension).

We have reported encouraging results of unrelated cord blood transplantation for patients with lymphoid malignancies. Whether those outcomes are comparable to matched unrelated donor transplants remains to be defined. We studied 645 adult patients with mature lymphoid malignancies who received an allogeneic unrelated donor transplant using umbilical cord blood (n=104) or mobilized peripheral blood stem cells (n=541) after a reduced-intensity conditioning regimen. Unrelated cord blood recipients had more refractory disease. Median follow-up time was 30 months. Neutrophil engraftment (81% vs. 97%, respectively; P

Fifty-five years after publication of the first hematopoietic stem cell transplantation this technique has become an accepted treatment option for defined hematologic and non-hematologic disorders. There is considerable interest in understanding differences in its use and trends on a global level and the macro-economic factors associated with these differences. Data on the numbers of hematopoietic stem cell transplants performed in the 3-year period 2006–2008 were obtained from Worldwide Network for Blood and Marrow Transplantation member registries and from transplant centers in countries without registries. Population and macro-economic data were collected from the World Bank and from the International Monetary Fund. Transplant rates were analyzed by indication, donor type, country, and World Health Organization regional offices areas and related to selected health care indicators using single and multiple linear regression analyses. Data from a total of 146,808 patients were reported by 1,411 teams from 72 countries over five continents. The annual number of transplants increased worldwide with the highest relative increase in the Asia Pacific region. Transplant rates increased preferentially in high income countries (P=0.02), not in low or medium income countries. Allogeneic transplants increased for myelodysplasia, chronic lymphocytic leukemia, acute leukemias, and non-malignant diseases but decreased for chronic myelogenous leukemia. Autologous transplants increased for autoimmune and lymphoproliferative diseases but decreased for leukemias and solid tumors. Transplant rates (P

The risk profile and prognosis of patients with myelofibrosis is well described by the Dynamic International Prognostic Scoring System risk categorization. Allogeneic stem cell transplantation is considered for intermediate-2/high risk disease. However, indicators of prognosis after transplantation are still lacking. Seventy simultaneously collected pairs of trephine and blood samples were quantified for JAK2 p.V617F allele burden to compare test sensitivity. The course of 30 patients with JAK2 p.V617F-positive myeloproliferative neoplasia was correlated with allele burden after transplantation. Monitoring can be performed on full blood samples as well as trephine biopsies, provided that techniques with ample sensitivity (0.01% to 0.001%) are available. Measurement of allele burden on day 28 after transplantation discriminates two prognostic groups: patients with a JAK2 p.V617F allele burden >1% have a significantly higher risk of relapse of JAK2 p.V617F positive neoplasia (P=0.04) and a poorer overall survival (P

The BCR-ABL T315I mutation causes resistance to imatinib, nilotinib and dasatinib in chronic myeloid leukemia. Forty BCR-ABL positive patients with imatinib resistance were analyzed for T315I mutated clones after six months on nilotinib or dasatinib treatment by quantitative allele-specific ligation polymerase chain reaction with a sensitivity of 0.05%. Ligation polymerase chain reaction revealed 10 patients with more than 10−5 BCR-ABLT315I%/GUS (high levels), none of whom achieved major molecular response after 12 months, and a further 8 patients with 10−5 or below BCR-ABLT315I%/GUS (low levels) who all achieved major molecular response (P

Allogeneic stem cell transplantation (ASCT) from related or unrelated donors may cure patients with myelodysplastic syndromes (MDS), a heterogeneous group of clonal stem cell disorders. We analysed 384 elderly patients (55-69 years) with advanced MDS who received either ASCT (n=247) and were reported to The European Group for Blood and Marrow Transplantation (EBMT) or a non -transplant approach (n=137) reported to the Düsseldorf registry. Besides an attempt to answer the question of "comparison", the purpose of this work is to explain the difficulties in comparing a non-transplant with a transplant cohort, when death before transplant is likely but unknown and the selection of patients for transplant is based on assumptions. It shows which methods are almost always biased and that even the most sophisticated approaches crucially rely on clinical assumptions. Using the most appropriate model for our data, we derive an overall univariate non-significant survival disadvantage for the transplant cohort (HR: 1.29, p = 0.11). We show that such an "average" hazard ratio is however misleading due to non-proportionality of the hazards reflecting early treatment related mortality, the occurring of which is logically correlated with the interval between diagnosis and transplant creating a disproportional drop in the (reconstructed) survival curve of the transplanted patients. Also in multivariate analysis (correcting for age > 60 (HR: 1.4, p = 0.02) and abnormal cytogenetics (HR: 1.46, p = 0.01)), transplantation seems to be worse (HR: 1.39, p = 0.05) but only in the (incorrect but commonly applied) model without time varying covariates. The long term (time depending) hazard ratio is shown to be virtually 1 and overall survival is virtually identical in both groups. Nonetheless no conclusion can be reached from a clinical point of view without assumptions which are by their very nature untestable unless all patients would be followed from diagnosis.

Background Bone marrow fibrosis in patients with myelodysplastic syndrome is associated with a poor outcome, but whether the outcome after allogeneic stem cell transplantation is related to the degree of bone marrow fibrosis is unknown.Design and Methods Patients with myelodysplastic syndrome and known bone marrow histology (n=721) who underwent hematopoietic stem cell transplantation were classified according to the degree of bone marrow fibrosis into those without fibrosis (n=483), those with mild or moderate fibrosis (n=199) and those with severe fibrosis (n=39) and analyzed regarding engraftment, treatment-related mortality, relapse and survival.Results The degree of fibrosis was not associated with disease status or abnormal cytogenetics. The cumulative incidence of engraftment achieved at day +30 in non-fibrotic patients was 93% and was significantly lower in those with mild or moderate fibrosis (89%) and severe fibrosis (75%) (P=0.009). Neutrophil engraftment occurred later in patients with mild or moderate fibrosis and severe fibrosis than in patients without fibrosis (median 17 versus 20 versus 16 days, respectively; P=0.002). The cumulative incidence of relapse at 3 years was significantly higher in patients with severe fibrosis than in those with a lesser degree of fibrosis or no fibrosis (47% versus 28% versus 27%, respectively; P=0.04), resulting in comparable 3-year disease-free survival rates in patients without fibrosis and in those with mild or moderate fibrosis (42% versus 38%, respectively) but a lower disease-free survival rate in those with severe fibrosis (18%; P=0.002). Severe fibrosis remained an independent factor for reduced survival (hazard ratio, 1.9; P=0.006).Conclusions Among patients with myelodysplastic syndromes, only severe fibrosis affects survival after hematopoietic stem cell transplantation while patients with mild or moderate fibrosis have an outcome comparable to that of patients without bone marrow fibrosis.

The only way to cure leukemia is by cooperative research. To optimize research, the European LeukemiaNet integrates 105 national leukemia trial groups and networks, 105 interdisciplinary partner groups and about 1,000 leukemia specialists from 175 institutions. They care for tens of thousands of leukemia patients in 33 countries across Europe. Their ultimate goal is to cure leukemia. Since its inception in 2002, the European LeukemiaNet has steadily expanded and has unified leukemia research across Europe. The European LeukemiaNet grew from two major roots: 1) the German Competence Network on Acute and Chronic Leukemias; and 2) the collaboration of European Investigators on Chronic Myeloid Leukemia. The European LeukemiaNet has improved leukemia research and management across Europe. Its concept has led to funding by the European Commission as a network of excellence. Other sources (European Science Foundation; European LeukemiaNet-Foundation) will take over when the support of the European Commission ends.

Hepcidin is upregulated by inflammation and iron. Inherited (HFE genotype) and treatment-related factors (blood units (BU), Iron overload) affecting hepcidin (measured by C-ELISA) were studied in 42 consecutive patients with AML prior to and after allogeneic hematopoietic cell transplantation (HCT). Results. Elevated serum ferritin pre- and post-HCT was present in all patients. Median hepcidin pre- and post-HCT of 358 and 398 ng/mL, respectively, were elevated compared to controls (median 52 ng/mL) (P

Background As rare myelomas, i.e. the IgD, IgE, IgM and non-secretory forms, constitute only a small proportion of any study, relatively little is known about their prognosis in the era of peripheral stem cell transplantation.Design and Methods We used the European Group for Blood and Marrow Transplantation Myeloma Database to compare the outcome following autologous transplantation of over 20,000 patients with common myelomas (IgG, IgA and light chain myeloma) with the outcome of patients with rare myelomas: 379 IgD, 13 IgE, 72 IgM and 976 non-secretory cases.Results The study confirms the multiple adverse prognostic factors seen in IgD myeloma. Somewhat surprisingly, patients with IgD and non-secretory myeloma both had higher complete remission rates before and after transplantation than patients with common myelomas. However, while the overall survival of patients with non-secretory myeloma was similar to that of the patients with common myelomas, the survival of patients with IgD myeloma was significantly worse (although better than survival rates reported for non-transplanted patients); this was due to higher transplant-related mortality and relapse/progression rates. The post-transplantation survival of patients with IgE or IgM myeloma appears to be very poor.Conclusions This study provides data on the biological features of rare myelomas. The overall survival of patients with IgD, IgE or IgM myeloma is poor following autologous transplantation but substantially better than that reported for patients who were not transplanted.

Background Non-HLA gene polymorphisms have been shown to influence outcome after allogeneic hematopoietic stem cell transplantation. Results were derived from heterogeneous, small populations and their value remains a matter of debate.Design and Methods In this study, we assessed the effect of single nucleotide polymorphisms in genes for interleukin 1 receptor antagonist (IL1RN), interleukin 4 (IL4), interleukin 6 (IL6), interleukin 10 (IL10), interferon (IFNG), tumor necrosis factor (TNF) and the cell surface receptors tumor necrosis factor receptor II (TNFRSFIB), vitamin D receptor (VDR) and estrogen receptor alpha (ESR1) in a homogeneous cohort of 228 HLA identical sibling transplants for chronic myeloid leukemia. Three good predictors of overall survival, identified via statistical methods including Cox regression analysis, were investigated for their effects on transplant-related mortality and relapse. Predictive power was assessed after integration into the established European Group for Blood and Marrow Transplantation (EBMT) risk score.Results Absence of patient TNFRSFIB 196R, absence of donor IL10 ATA/ACC and presence of donor IL1RN allele 2 genotypes were associated with increased transplantation-related mortality and decreased survival. Application of prediction error and concordance index statistics gave evidence that integration improved the EBMT risk score.Conclusions Non-HLA genotypes were associated with survival after allogeneic hematopoietic stem cell transplantation. When three genetic polymorphisms were added into the EBMT risk model they improved the goodness of fit. Non-HLA genotyping could, therefore, be used to improve donor selection algorithms and risk assessment prior to allogeneic hematopoietic stem cell transplantation.

Background Primary plasma cell leukemia is a rare disorder accounting for less than 5% of malignant plasma cell diseases. It has a poor prognosis compared to multiple myeloma, with a median survival of 8–12 months. The results of conventional therapy are disappointing though autologous stem cell transplantation may improve survival.Design and Methods A retrospective analysis was undertaken of the European Group for Blood and Marrow Transplantation experience of 272 patients with plasma cell leukemia and 20844 with multiple myeloma undergoing first autologous transplantation between 1980 and 2006. All patients were reported to the European Group for Blood and Marrow Transplantation registry using MED-A (limited data) or MED-B (extensive data) forms. All patients were included regardless of availability of complete data.Results There was no difference in type of graft or use of total body irradiation between patients with plasma cell leukemia and multiple myeloma, but the group with plasma cell leukemia was transplanted earlier after diagnosis (6.0 versus 7.7 months, P=0.000). Patients with plasma cell leukemia were more likely to enter complete remission after transplantation but their overall survival (25.7 months, 95% confidence interval 19.5–31.9 months) was inferior to that of patients with multiple myeloma (62.3 months, 95% confidence interval 60.4–64.3 months) (P=0.000), due to the short duration of their post-transplant response and increased non-relapse-related mortality.Conclusions This largest study ever reported on plasma cell leukemia suggests that autologous transplantation can improve outcome, although results are markedly inferior to those achieved in patients with multiple myeloma, highlighting the need for novel approaches to this aggressive disorder.

Background Innovations in hematology spread rapidly. Factors affecting the speed of introduction, international diffusion, and durability of use of innovations are, however, poorly understood.Design and Methods We used data on 251,106 hematopoietic stem cell transplants from 591 teams in 36 European countries to analyze the increase and decrease in such transplants for breast cancer and chronic myeloid leukemia and the replacement of bone marrow by peripheral blood as the source of stem cells as processes of diffusion. Regression analyses were used to measure the quantitative impact of defined macro- and microeconomic factors, to look for significant associations (t-test), and to describe the coefficient of determination or explanatory content (R2).Results Gross national income per capita, World Bank category, team density, team distribution, team size, team experience and, team innovator status were all significantly associated with some or all of the changes. The analyses revealed different patterns of associations and a wide range of explanatory content. Macro- and micro-economic factors were sufficient to explain the increase of allogeneic hematopoietic stem cell transplants in general (R2 = 78.41%) and for chronic myeloid leukemia in particular (R2 = 79.39%). They were insufficient to explain the changes in stem cell source (R2 =26.79% autologous hematopoietic stem cell transplants; R2 = 9.67% allogeneic hematopoietic stem cell transplants) or the decreases in hematopoietic stem cell transplants (R2 =10.22% breast cancer; R2=33.17% chronic myeloid leukemia).Conclusions The diffusion of hematopoietic stem cell transplants is more complex than previously thought. Availability of resources, evidence, external regulations and, expectations were identified as key determinants. These data might serve as a model for diffusion of medical technology in general.

Background Various techniques have been employed to detect BCR-ABL kinase domain mutations in patients with chronic myeloid leukemia who are resistant to imatinib. This has led to different reported frequencies of mutations and the finding of a heterogeneous pattern of individual mutations.Design and Methods We compared direct sequencing alone and in combination with denaturing high-performance liquid chromatography and two high-sensitivity allele-specific oligonucleotide polymerase chain reaction approaches for analysis of BCR-ABL mutations in 200 blinded cDNA samples prior to and during second-line dasatinib or nilotinib therapy in patients with chronic myeloid leukemia in whom imatinib treatment had failed.Results One hundred and fourteen mutations were detected by both direct sequencing alone or in combination with high performance liquid chromatography and 13 mutations were additionally detected by the combined technique. Eighty of 83 mutations (96%) within a selected panel of 11 key mutations were confirmed by both allele-specific oligonucleotide polymerase chain reaction techniques and 62 mutations were identified in addition to those detected by combined liquid chromatography and direct sequencing, indicating the presence and a high prevalence of low-level mutations in this cohort of patients. Furthermore, 125 mutations were detected by only one allele-specific oligonucleotide polymerase chain reaction technique. Pre-existing mutations were traceable 4.5 months longer and emerging clones were detectable 3.0 months earlier by allele-specific oligonucleotide polymerase chain reaction than by direct sequencing together with liquid chromatography.Conclusions Our results suggest that denaturing high performance liquid chromatography combined with direct sequencing is a reliable screening technique for the detection of BCR-ABL kinase domain mutations. Allele-specific oligonucleotide polymerase chain reaction further increases the number of detected mutations and indicates a high prevalence of mutations at a low level. The clinical impact of such low-level mutations remains uncertain and requires further investigation. Allele-specific oligonucleotide polymerase chain reaction allows detection of defined mutations at a lower level than does denaturing high performance liquid chromatography combined with direct sequencing and may, therefore, provide clinical benefit by permitting early reconsideration of therapeutic strategies.