Summary Background Preclinical data and results from non-randomised trials suggest that the multikinase inhibitor sorafenib might be an effective drug for the treatment of acute myeloid leukaemia. We ...investigated the efficacy and tolerability of sorafenib versus placebo in addition to standard chemotherapy in patients with acute myeloid leukaemia aged 60 years or younger. Methods This randomised, double-blind, placebo-controlled, phase 2 trial was done at 25 sites in Germany. We enrolled patients aged 18–60 years with newly diagnosed, previously untreated acute myeloid leukaemia who had a WHO clinical performance score 0–2, adequate renal and liver function, no cardiac comorbidities, and no recent trauma or operation. Patients were randomly assigned (1:1) to receive two cycles of induction therapy with daunorubicin (60 mg/m2 on days 3–5) plus cytarabine (100 mg/m2 on days 1–7), followed by three cycles of high-dose cytarabine consolidation therapy (3 g/m2 twice daily on days 1, 3, and 5) plus either sorafenib (400 mg twice daily) or placebo on days 10–19 of induction cycles 1 and 2, from day 8 of each consolidation, and as maintenance for 12 months. Allogeneic stem-cell transplantation was scheduled for all intermediate-risk patients with a sibling donor and for all high-risk patients with a matched donor in first remission. Computer-generated randomisation was done in blocks. The primary endpoint was event-free survival, with an event defined as either primary treatment failure or relapse or death, assessed in all randomised patients who received at least one dose of study treatment. We report the final analysis. This trial is registered with ClinicalTrials.gov , number NCT00893373 , and the EU Clinical Trials Register (2008-004968-40). Findings Between March 27, 2009, and Nov 28, 2011, 276 patients were enrolled and randomised, of whom nine did not receive study medication. 267 patients were included in the primary analysis (placebo, n=133; sorafenib, n=134). With a median follow-up of 36 months (IQR 35·5–38·1), median event-free survival was 9 months (95% CI 4–15) in the placebo group versus 21 months (9–32) in the sorafenib group, corresponding to a 3-year event-free survival of 22% (95% CI 13–32) in the placebo group versus 40% (29–51) in the sorafenib group (hazard ratio HR 0·64, 95% CI; 0·45–0·91; p=0·013). The most common grade 3–4 adverse events in both groups were fever (71 53% in the placebo group vs 73 54% in the sorafenib group), infections (55 41% vs 46 34%), pneumonia (21 16% vs 20 14%), and pain (13 10% vs 15 11%). Grade 3 or worse adverse events that were significantly more common in the sorafenib group than the placebo group were fever (relative risk RR 1·54, 95% CI 1·04–2·28), diarrhoea (RR 7·89, 2·94–25·2), bleeding (RR 3·75, 1·5–10·0), cardiac events (RR 3·46, 1·15–11·8), hand-foot-skin reaction (only in sorafenib group), and rash (RR 4·06, 1·25–15·7). Interpretation In patients with acute myeloid leukaemia aged 60 years or younger, the addition of sorafenib to standard chemotherapy has antileukaemic efficacy but also increased toxicity. Our findings suggest that kinase inhibitors could be a useful addition to curative treatment for acute myeloid leukaemia. Overall survival after long-term follow-up and strategies to reduce toxicity are needed to determine the future role of sorafenib in treatment of this disease. Funding Bayer HealthCare.
Summary Background Routine prophylactic platelet transfusion is the standard of care for patients with severe thrombocytopenia. We assessed the effect of a new strategy of therapeutic platelet ...transfusion on the number of transfusions and safety in patients with hypoproliferative thrombocytopenia. Methods We did a multicentre, open-label, randomised parallel-group trial at eight haematology centres in Germany. Patients aged 16–80 years, who were undergoing intensive chemotherapy for acute myeloid leukaemia or autologous haemopoietic stem-cell transplantation for haematological cancers, were randomly assigned via a computer-generated randomisation sequence to receive either platelet transfusion when bleeding occurred (therapeutic strategy) or when morning platelet counts were 10×109 per L or lower (prophylactic strategy). Investigators undertaking interventions were not masked to group assignment. The primary endpoint was the number of platelet transfusions. Analysis was by intention to treat. This trial is registered, NCT00521664. Findings 197 patients were assigned the prophylactic strategy and 199 the therapeutic strategy. Of 391 patients analysed, the therapeutic strategy reduced the mean number of platelet transfusions by 33·5% (95% CI 22·2–43·1; p<0·0001) in all patients (2·44 2·22–2·67 in prophylactic group vs 1·63 1·42–1·83 in therapeutic group), 31·6% (18·6–42·6; p<0·0001) in those with acute myeloid leukaemia (2·68 2·35–3·01 vs 1·83 1·58–2·10), and 34·2% (6·6–53·7; p=0·0193) in those who had had autologous transplantation (1·80 1·45–2·15 vs 1·18 0·82–1·55. We noted no increased risk of major haemorrhage in patients who had undergone autologous transplantation. In those with acute myeloid leukaemia, risk of non-fatal grade 4 (mostly CNS) bleeding was increased. We recorded 15 cases of non-fatal haemorrhage: four retinal in each transfusion group, and one vaginal and six cerebral in the therapeutic group. 12 patients died in the study: two from fatal cerebral haemorrhages in the therapeutic group, and ten (five in each treatment group) unrelated to major bleeding. Interpretation The therapeutic strategy could become a new standard of care after autologous stem-cell transplantation; however, prophylactic platelet transfusion should remain the standard for patients with acute myeloid leukaemia. The new strategy should be used by some haematology centres only if the staff are well educated and experienced in the new approach and can react in a timely way to first signs of CNS bleeding. Funding Deutsche Krebshilfe eV (German Cancer Aid).
Extramedullary manifestations (EM) are rare in acute myeloid leukemia (AML) and their impact on clinical outcomes is controversially discussed.
We retrospectively analyzed a large multi-center cohort ...of 1583 newly diagnosed AML patients, of whom 225 (14.21%) had EM.
AML patients with EM presented with significantly higher counts of white blood cells (p < 0.0001), peripheral blood blasts (p < 0.0001), bone marrow blasts (p = 0.019), and LDH (p < 0.0001). Regarding molecular genetics, EM AML was associated with mutations of NPM1 (OR: 1.66, p < 0.001), FLT3-ITD (OR: 1.72, p < 0.001) and PTPN11 (OR: 2.46, p < 0.001). With regard to clinical outcomes, EM AML patients were less likely to achieve complete remissions (OR: 0.62, p = 0.004), and had a higher early death rate (OR: 2.23, p = 0.003). Multivariable analysis revealed EM as an independent risk factor for reduced overall survival (hazard ratio HR: 1.43, p < 0.001), however, for patients who received allogeneic hematopoietic cell transplantation (HCT) survival did not differ. For patients bearing EM AML, multivariable analysis unveiled mutated TP53 and IKZF1 as independent risk factors for reduced event-free (HR: 4.45, p < 0.001, and HR: 2.05, p = 0.044, respectively) and overall survival (HR: 2.48, p = 0.026, and HR: 2.63, p = 0.008, respectively).
Our analysis represents one of the largest cohorts of EM AML and establishes key molecular markers linked to EM, providing new evidence that EM is associated with adverse risk in AML and may warrant allogeneic HCT in eligible patients with EM.
Monitoring of measurable residual disease (MRD) in patients with advanced myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) who achieve a morphological complete remission can predict ...haematological relapse. In this prospective study, we aimed to determine whether MRD-guided pre-emptive treatment with azacitidine could prevent relapse in these patients.
The relapse prevention with azacitidine (RELAZA2) study is an open-label, multicentre, phase 2 trial done at nine university health centres in Germany. Patients aged 18 years or older with advanced MDS or AML, who had achieved a complete remission after conventional chemotherapy or allogeneic haemopoietic stem-cell transplantation, were prospectively screened for MRD during 24 months from baseline by either quantitative PCR for mutant NPM1, leukaemia-specific fusion genes (DEK–NUP214, RUNX1–RUNX1T1, CBFb–MYH11), or analysis of donor-chimaerism in flow cytometry-sorted CD34-positive cells in patients who received allogeneic haemopoietic stem-cell transplantation. MRD-positive patients in confirmed complete remission received azacitidine 75 mg/m2 per day subcutaneously on days 1–7 of a 29-day cycle for 24 cycles. After six cycles, MRD status was reassessed and patients with major responses (MRD negativity) were eligible for a treatment de-escalation. The primary endpoint was the proportion of patients who were relapse-free and alive 6 months after the start of pre-emptive treatment. Analyses were done per protocol. This trial is registered with ClincialTrials.gov, number NCT01462578, and finished recruitment on Aug 21, 2018.
Between Oct 10, 2011, and Aug 20, 2015, we screened 198 patients with advanced MDS (n=26) or AML (n=172), of whom 60 (30%) developed MRD during the 24-month screening period and 53 (88%) were eligible to start study treatment. 6 months after initiation of azacitidine, 31 (58%, 95% CI 44–72) of 53 patients were relapse-free and alive (p<0·0001; one-sided binomial test for null hypothesis pexp≤0·3). With a median follow-up of 13 months (IQR 8·5–22·8) after the start of MRD-guided treatment, relapse-free survival at 12 months was 46% (95% CI 32–59) in the 53 patients who were MRD-positive and received azacitidine. In MRD-negative patients, 12-month relapse-free survival was 88% (95% CI 82–94; hazard ratio 6·6 95% CI 3·7–11·8, p<0·0001). The most common (grade 3–4) adverse event was neutropenia, occurring in 45 (85%) of 53 patients. One patient with neutropenia died because of an infection considered possibly related to study treatment.
Pre-emptive therapy with azacitidine can prevent or substantially delay haematological relapse in MRD-positive patients with MDS or AML who are at high risk of relapse. Our study also suggests that continuous MRD negativity during regular MRD monitoring might be prognostic for patient outcomes.
Celgene Pharma, José Carreras Leukaemia Foundation, National Center for Tumor Diseases (NCT), and German Cancer Consortium (DKTK) Foundation.
CONCLUSION Despite the development of new agents and the widespread use of hematopoietic cell transplantation (HCT), the prognosis of patients (pts) with multiple myeloma and extramedullary ...involvement (EMM) is rather unfavorable. Until now, there are no generally accepted standards for diagnosis and treatment of EMM. We performed a retrospective analysis of 130 pts with EMM treated at Klinikum Chemnitz between 2007 and 2022. Various demographic and clinical factors were recorded in a database and evaluated for their impact on response and survival. The data cut point was July 2022, and for follow-up a minimum of 3 months was required. One hundred and thirty pts (89 men, 41 women) with EMM at a median age of 68 years (range, 37-87 years) were included. In 78 pts extramedullary involvement was detected at the time of initial diagnosis (primary EMM), and in the remaining 52 pts a secondary EMM was diagnosed at the time of relapse (n=38) or refractory disease (n=14). In approximately two-thirds of pts EMM manifested exclusively in the paraskeleton (n=84), while roughly one-third of pts showed an extramedullary organ involvement (n=25), or both (n=21). Cytogenetic data were available in 125 pts, with 39 pts classified as high-risk EMM (including del17p in 11 pts). ISS could be evaluated in only 56 pts, of whom 22 pts had ISS III. Elevated serum LDH levels were observed in almost half of the pts (n=63) at the time of EMM diagnosis. Treatment regimens included mainly proteasome inhibitors (n=106), immunomodulatory drugs (n=74) and CD38 antibodies (n=42). Fifty-five pts (42.3%) received autologous (n=44), allogeneic (n=8) or autologous-allogeneic HCT (n=3). Serologic response to treatment (at least PR) according to IMWG criteria was 63.8% (83/130) and imaging response was 56.9% (74/130). With a median follow-up of 84.2 months, median progression-free survival was 10.3 months and median overall survival was 23.8 months. In univariate analysis for PFS and OS, we found significantly worse outcomes in patients with secondary EMM (vs. primary EMM), EMM with organ manifestation (vs. paraskeletal EMM only), ISS III (vs. ISS I +II), and elevated serum LDH (vs. not elevated). Furthermore, pts with del17p had significantly shorter PFS, while detection of ampl1q32 (n=14) was associated with significantly worse OS. For other tested factors lambda light chain involvement, t(14;16), dupl1q21 or tripl1q21, EMM diagnosis 2007-2013 vs. 2014-2022 we found no negative effects on PFS or OS. Multivariate Cox regression analysis confirmed secondary EMM as an independent negative factor for PFS (HR 3.62, p<0.0001) and OS (HR 2.95, p<0.0001), whereas detection of del17p was only associated with unfavorable PFS (HR 2.02, p=0.03). Our data show that the prognosis of pts with EMM remains poor. Despite the introduction of many innovative agents, outcomes have not improved significantly since 2013. There is an urgent need for diagnostic/therapeutic guidelines of EMM as well as risk-adapted therapeutic strategies (using modern immunotherapies and cell therapies).
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 ...time from diagnosis to treatment start (TDT) and prognosis in a large real-world data set from the German Study Alliance Leukemia–Acute Myeloid Leukemia (SAL-AML) registry. All registered non–acute promyelocytic leukemia patients with intensive induction treatment and a minimum 12 months of follow-up were selected (n = 2263). We analyzed influence of TDT on remission, early death, and overall survival (OS) in univariable analyses for each day of treatment delay, in groups of 0 to 5, 6 to 10, 11 to 15, and >15 days of TDT, adjusted for influence of established prognostic variables on outcomes. Median TDT was 3 days (interquartile range, 2-7). Unadjusted 2-year OS rates, stratified by TDT of 0 to 5, 6 to 10, 11 to 15, and >15 days, were 51%, 48%, 44%, and 50% (P = .211). In multivariable Cox regression analysis accounting for established prognostic variables, the TDT hazard ratio as a continuous variable was 1.00 (P = .617). In OS analyses, separately stratified for age ≤60 and >60 years and for high vs lower initial white blood cell count, no significant differences between TDT groups were observed. Our study suggests that TDT is not related to survival. As stratification in intensive first-line AML treatment evolves, TDT data suggest that it may be a feasible approach to wait for genetic and other laboratory test results so that clinically stable patients are assigned the best available treatment option. This trial was registered at www.clinicaltrials.gov as #NCT03188874.
•Analyses of time from diagnosis of AML to start of intensive treatment indicate that a treatment delay has no negative prognostic impact.
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Early results of the randomized placebo-controlled SORAML trial showed that, in patients with newly diagnosed acute myeloid leukaemia (AML), sorafenib led to a significant improvement in event-free ...(EFS) and relapse-free survival (RFS). In order to describe second-line treatments and their implications on overall survival (OS), we performed a study after a median follow-up time of 78 months. Newly diagnosed fit AML patients aged ≤60 years received sorafenib (n = 134) or placebo (n = 133) in addition to standard chemotherapy and as maintenance treatment. The 5-year EFS was 41 versus 27% (HR 0.68; p = 0.011) and 5-year RFS was 53 versus 36% (HR 0.64; p = 0.035). Allogeneic stem cell transplantation (allo SCT) was performed in 88% of the relapsed patients. Four years after salvage allo SCT, the cumulative incidence of relapse was 54 versus 35%, and OS was 32 versus 50%. The 5-year OS from randomization in all study patients was 61 versus 53% (HR 0.82; p = 0.282). In conclusion, the addition of sorafenib to chemotherapy led to a significant prolongation of EFS and RFS. Although the OS benefit did not reach statistical significance, these results confirm the antileukaemic activity of sorafenib.
Purpose
The aim of this study was to prospectively compare the MIFAP protocol, which had been shown to be effective in patients with relapsed and refractory Hodgkin’s lymphoma (HL) or aggressive ...non-Hodgkin’s lymphoma (NHL), to an established regimen like Dexa-BEAM.
Methods
Seventy-three adult patients with HL (
N
= 25) or aggressive NHL (
N
= 48) suffering from relapse or refractory disease were randomly allocated to receive two cycles of Dexa-BEAM (dexamethasone, carmustine, etoposide, cytarabine, melphalan;
N
= 37) or MIFAP (mitoxantrone, fludarabine, cytarabine, cisplatin;
N
= 36) prior to a consolidating high-dose therapy and hematopoietic cell transplantation (HCT). Primary endpoint was the overall response rate (ORR) complete response (CR) and partial response (PR) after two courses of salvage chemotherapy.
Results
The ORR was 51% (CR 38%) and 53% (CR 36%) in the Dexa-BEAM arm and in the MIFAP arm (both not significant), respectively. There was a significantly higher grade 3–4 toxicity after MIFAP compared to Dexa-BEAM. Thirty-five patients were consolidated by autologous (
N
= 29), allogeneic (
N
= 1) or sequential autologous/allogeneic (
N
= 5) HCT. No significant differences were found in progression-free survival (PFS) and overall survival (OS) between the Dexa-BEAM and the MIFAP arms.
Conclusion
Compared to Dexa-BEAM, MIFAP is associated with a higher toxicity and does not improve the outcome of patients with recurrent HL or aggressive NHL. For those patients, innovative treatment concepts like recently developed immunotherapies are necessary.
Trial registration number
EudraCT number 2021-001937-38.
Date of registration
7 April 2021, retrospectively registered.
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