In fit patients with newly diagnosed acute myeloid leukemia (AML), immediate treatment start is recommended due to the poor prognosis of untreated acute leukemia. We explored the relationship between the time from diagnosis to treatment start (TDT) and prognosis in a large set of real-world data from the German SAL-AML registry. All registered non-APL patients from the registry with intensive induction treatment and a minimum follow-up time of 12 months were selected (n=2,263). We analyzed the influence of TDT on remission, early death and overall survival (OS) in univariable analyses for each day of treatment delay, in groups of 0-5, 6-10, 11-15 and >15 days of TDT, and adjusted for the influence of established prognostic variables on the outcomes. The median TDT was 3 days (IQR 2-7). The unadjusted 2-y OS rates stratified by TDT of 0-5, 6-10, 11-15, >15 days were 51, 48, 44, and 50% (p=0.211). In multivariable Cox regression analysis accounting for established prognostic variables, the HR for TDT as continuous variable was 1.00 (p=0.617). When OS was analyzed separately stratified for age ≤60 and >60 ys and for high versus lower initial WBC, no significant differences between TDT groups were observed. Our study suggests that TDT is not related to survival. As treatment stratification in intensive first-line treatment of AML evolves, the TDT data suggests that it may be a feasible approach to wait for genetic and other laboratory test results in order to assign clinically stable patients to the best available treatment option.

There is substantial need to improve the outcome of patients with high-risk acute myeloid leukemia (AML). The clinical trial reported here investigated a new approach of up-front allogeneic hematopoietic stem cell transplantation (HSCT), provided a median of 40 days (range 22-74) after diagnosis, in twenty-six consecutive patients with newly-diagnosed high-risk AML characterized by poor-risk cytogenetics (n ¼ 19) or inadequate blast clearance by induction chemotherapy (IC, n ¼ 7). The median age was 49 years (range 17-68). During IC-induced aplasia after the 1st (n ¼ 11) or 2nd (n ¼ 15) cycle, patients received allogeneic peripheral blood stem cells (PBSC) from related (n ¼ 11) or unrelated (n ¼ 15) donors following a fludarabine-based reduced-intensity regimen. Seventeen patients were not in remission before HSCT with a median marrow blast count of 34% (range 6-70). All patients achieved rapid engraftment and went into remission with complete myeloid and lymphatic chimerism. Grades II to IV acute GvHD occurred in 14 (56%) and extensive chronic GvHD was documented in 8 (35%) patients. The probability of disease-free survival was 61% with only three patients relapsing 5, 6 and 7 months after transplantation, respectively. Up-front allogeneic HSCT as part of primary induction therapy seems to be an effective strategy in highrisk AML patients and warrants further investigation.

SummaryPrimary central nervous system lymphomas (PCNSL) are usually diffuse large B-cell non-Hodgkin's lymphomas (NHL). Here we characterize the clinical presentation, course and outcome of patients with low-grade PCNSL. Records of 332 patients screened for inclusion in three multicentre prospective trials were reviewed. Ten patients (3%) with a median age of 59 years and a median Karnofsky performance status of 70% were identified. Seven patients had B-cell and three had T-cell lymphoma. The median growth fraction was 4%. The radiological morphology was unusual for PCNSL in eight patients. Three patients underwent complete tumour resection, combined with chemotherapy in one patient and with chemotherapy plus local radiotherapy in another. Four patients received chemotherapy and three received chemotherapy plus whole-brain irradiation, resulting in four complete remissions, two no-change situations and one progressive disease. Patients had an overall survival (OAS) of 2-58+ months with a 2-year OAS of 67%. Low-grade PCNSL may differ from classical high-grade PCNSL in its clinical features and radiological morphology. The clinical course may be variable and frequently more indolent than in classical PCNSL.

Background In newly diagnosed acute myeloid leukemia (AML), the general recommendation is to start treatment immediately after the diagnosis has been made. This paradigm is based both on the observation that untreated acute leukemia has a poor prognosis and on retrospective analyses demonstrating a shorter survival in younger AML patients (pts) in whom treatment was delayed by more than 5 days (Sekeres et al., 2009). A more recent single-center analysis came to a different conclusion, showing no prognostic effect for the time from diagnosis to treatment (TDT; Bertoli et al., 2013). We explored the relationship between TDT and prognosis on a large set of real-world data from the AML registry of the Study Alliance Leukemia (SAL) and compared it to the published cohorts. Methods The SAL runs a transregional AML registry in 46 treatment centers across Germany (NCT03188874). All registered patients with an intensive induction treatment, a minimum follow-up time of 12 months and no acute promyelocytic leukemia were selected (n=2,200). Treatment start was defined by the first day of cytarabine, whereas single agent hydroxyurea (HU) was labeled as pretreatment. We analyzed the influence of TDT on complete remission (CR), early death (ED) and overall survival (OS) in univariable analyses for each day of treatment delay, in groups of 0-5, 6-10, 11-15 and >15 days of TDT, and by using the restricted cubic spline (RCS) method for data modelling. In order to adjust for the influence of established prognostic variables on the outcomes, we used multivariable regression models and propensity score weighting. The influence of HU pretreatment on outcomes was investigated by introducing an interaction term between TDT and the presence of HU pretreatment. Results The median age was 59 years (y) (IQR 50-68), the proportion of pts with favorable, intermediate and adverse genetic risk according to ELN was 27%, 53%, and 20%; >95% of pts received induction treatment with standard 7+3. HU pretreatment was administered in 4% of pts. The median TDT was 3 days (IQR 2-6). Descriptive statistics after grouping of pts showed the highest median age and the lowest proportion of NPM1 mutated and favorable risk in the TDT group 11-15. Of all pts, 79% achieved a CR/CRi; unadjusted CR rates for the patient groups with TDT of 0-5, 6-10, 11-15 and >15 days were 80%, 77%, 74% and 76%, respectively (p=0.317). In multivariable analysis accounting for the influence of ELN risk, age, WBC, LDH, de novo versus secondary AML and ECOG, the OR for each additional day of TDT was 0.99 (95%-CI, 0.97-1.00; p=0.124). Four percent of pts died within the first 30 days from treatment start. The respective rates in the four TDT categories were 4.0%, 3.8%, 5.1% and 4.1% (p=0.960). In multivariable analysis, the OR for TDT was 1.01 (95%-CI, 0.98-1.05; p=0.549). After a median follow-up of 40 months, the 2-y OS of all pts was 51%. The unadjusted 2-y OS rates stratified by TDT of 0-5, 6-10, 11-15, >15 days were 52, 49, 46, and 51% (see Table 1 and Figure 1). The hazard ratio (HR) for each day of treatment delay was 1.00 (95%-CI; 0.99-1.01; p=0.317). In multivariable Cox regression analysis, the HR for TDT as continuous variable was 1.00 (95%-CI, 0.99-1.01; p=0.689). When OS was analyzed separately stratified for age ≤60 and >60 ys and for high versus lower initial WBC defined by a threshold of 50 x 109/L, no significant differences between TDT groups were observed. Multivariable models using TDT as a grouped variable or with RCS did not provide evidence for a significant influence of TDT on outcomes. Propensity score matching of pts in the four TDT groups did not reveal an influence on outcomes. The use of HU was not associated with CR, ED nor OS. Conclusion Our study on 2,200 newly diagnosed registry pts receiving consistent intensive induction with standard-dose cytarabine plus daunorubicin (7+3) suggests that TDT is not related to response or survival, neither in younger nor in older pts. Despite multivariable analyses, a bias towards longer TDT intervals in pts judged to be clinically stable by the treating physician cannot be excluded entirely. As treatment stratification in intensive first-line treatment of AML evolves, the TDT data suggests that it may be a safe and reasonable approach to wait for genetic and other laboratory test results in order to assign clinically stable pts to the best available treatment option before the start of intensive treatment. Disclosures Krämer: Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; BMS: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hänel:Roche: Honoraria; Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board. Jost:Daiichi: Honoraria; Sanofi: Honoraria; Gilead: Other: travel grants; Jazz Pharmaceuticals: Honoraria. Brümmendorf:Merck: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; University Hospital of the RWTH Aachen: Employment; Ariad: Consultancy. Krause:Siemens: Research Funding; Takeda: Honoraria; MSD: Honoraria; Gilead: Other: travel; Celgene Corporation: Other: Travel. Scholl:Novartis: Other: Project funding; Pfizer: Other: Advisory boards; Gilead: Other: Project funding; Daiichi Sankyo: Other: Advisory boards; AbbVie: Other: Advisory boards. Hochhaus:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding. Kiani:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Middeke:Sanofi: Research Funding, Speakers Bureau; Roche: Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Gilead: Consultancy; Janssen: Consultancy, Speakers Bureau; MSD: Consultancy. Thiede:AgenDix GmbH: Employment, Equity Ownership; Novartis: Research Funding, Speakers Bureau; Bayer: Research Funding; Daiichi-Sankyo: Speakers Bureau. Stoelzel:JAZZ Pharmaceuticals: Consultancy; Neovii: Other: Travel funding; Shire: Consultancy, Other: Travel funding. Platzbecker:Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding.

The dose escalation of cytarabine in induction therapy lead to improved remission rates in the elderly AML patients. This did not translate into a survival advantage, most likely due to differences in consolidation treatment. Thus, effective consolidation strategies need to be further explored. In combination with an effective consolidation strategy, the use of intermediate-dose cytarabine in induction may improve curative treatment for elderly AML patients.