The initial molecular response predicts the deep molecular response but not treatment-free remission maintenance in a real-world chronic myeloid leukemia cohort

In chronic myeloid leukemia, the identification of early molecular predictors of stable treatment-free remission (TFR) after tyrosine kinase inhibitor (TKI) discontinuation is challenging. The predictive values of residual disease (BCR::ABL1 quantification) at months 3 and 6 and more recently, BCR::ABL1 transcript halving time (HT) have been described, but no study compared the predictive value of different early parameters. Using a real-world cohort of 408 patients, we compared the performance of the ELTS score, BCR::ABL1 HT, and residual disease at month 3 and 6 to predict the molecular response, achievement of the TKI discontinuation criteria, and TFR maintenance. The performances of BCR::ABL1 HT and residual disease at month 3 were similar. Residual disease at month 6 displayed the best performance for predicting the optimal response (area under the ROC curve between 0.81 and 0.92; cut-off values: 0.11% for MR4 at month 24 and 0.12% for MR4.5 at month 48). Conversely, no early parameter predicted reaching the TKI discontinuation criteria and TFR maintenance. We obtained similar results when patients were divided in subgroups by first-line treatment (imatinib vs second generation TKI, 2G-TKI). We identified a relationship between ELTS score, earlier milestones and TFR maintenance only in the 2G-TKI group. In conclusion, this first comparative study of early therapeutic response parameters showed that they are excellent indicators of TKI efficacy (BCR::ABL1 transcript reduction) and best responders. Conversely, they did not predict the achievement of the TKI discontinuation criteria and TFR maintenance, suggesting that other parameters are involved in TFR maintenance

A Phase 2 Study of Coltuximab Ravtansine (SAR3419) Monotherapy in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

International audienceBackground Long-term disease-free survival in adult patients with acute lymphoblastic leukemia (ALL) remains unsatisfactory, and treatment options are limited for those patients who relapse or fail to respond following initial therapy. We conducted a dose-escalation/expansion phase 2, multicenter, single-arm study to determine the optimal dose of coltuximab ravtansine (SAR3419), an anti-CD19 antibody-drug conjugate, in this setting. Patients and Methods The dose-escalation part of the study determined the selected dose of coltuximab ravtansine for evaluation of efficacy and safety in the dose-expansion phase. Patients received coltuximab ravtansine induction therapy (up to 8 weekly doses); responding patients were eligible for maintenance therapy (biweekly administrations for up to 24 weeks). Three dose levels of coltuximab ravtansine were examined: 55, 70, and 90 mg/m2. The primary endpoint was objective response rate (ORR). Secondary endpoints included duration of response (DOR) and safety. Results A total of 36 patients were treated: 19 during dose escalation; 17 during dose expansion. One dose-limiting toxicity was observed at 90 mg/m2 (grade 3 peripheral motor neuropathy), and therefore 70 mg/m2 was selected for the dose-expansion phase. Five patients discontinued therapy due to adverse events (AEs). The most common AEs were pyrexia, diarrhea, and nausea. Of 17 evaluable patients treated at the selected dose, 4 responded (estimated ORR using Bayesian methodology: 25.47% [80% confidence interval: 14.18-39.6%]); DOR was 1.94 (range: 1-5.6) months. Based on these results, the study was prematurely discontinued. Conclusions Coltuximab ravtansine is well tolerated but is associated with a low clinical response rate in patients with relapsed/refractory AL

High tumor burden before blinatumomab has a negative impact on the outcome of adult patients with B-cell precursor acute lymphoblastic leukemia. A real-world study by the GRAALL

Blinatumomab is a bispecific T-cell engager approved for B-cell precursor acute lymphoblastic leukemia (B-ALL) with persistent minimal residual disease (MRD) or in relapse. The prognostic impact of tumor load has been suggested before other immunotherapies but remains poorly explored before blinatumomab. We retrospectively analyzed the outcome of 73 patients who received blinatumomab either in first complete remission (CR) with MRD (n=35) or at relapse (n=38). Among MRD patients, 91% had MRD >0.01% before blinatumomab, and 89% achieved complete MRD response after blinatumomab. High pre-blinatumomab MRD levels were associated with shorter relapse-free survival (P=0.049) and overall survival (OS) (P=0.011). At 3 years, OS was 33%, 58% and 86% for pre-blinatumomab MRD >1%, between MRD 0.1- 1% and <0.1% respectively. Among relapsed patients, 23 received blinatumomab with overt relapse and 15 were in complete response (CR) after bridging chemotherapy. At 3 years, overall CR rate was 68% and complete MRD response rate was 84%. Patients who directly received blinatumomab had shorter relapse-free survival (P=0.033) and OS (P=0.003) than patients bridged to blinatumomab. Three-year OS was 66% in the latter group compared to 16% in the former group. Our observations suggest that pre-blinatumomab tumor burden should help to design more tailored strategies including tumor load reduction in relapsed patients

Kinetics of early and late molecular recurrences after first-line imatinib cessation in chronic myeloid leukemia: updated results from the STIM2 trial

Discontinuation of tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia is feasible in clinical practice based on recently published international recommendations. Nevertheless, factors predictive of molecular recurrence have not been fully elucidated and long-term follow-up of patients enrolled in clinical studies are required in order to update knowledge on discontinuation attempts particularly in terms of the safety and durability of treatment-free remission (TFR). In the current study, we updated results from the STIM2 study in the light of the consensual criterion of molecular recurrence reported in different international recommendations. Among the 199 patients included in the perprotocol study, 108 patients lost a major molecular response. With a median follow-up of 40.8 months (5.5-111 months), the probability of treatment-free remission was 43.4% [36.3-50.4] at 5 years, 40.9% [32.8-47.3] at 7 years and 34.5% [25.6- 43.3] at 9 years. Molecular recurrence occurred between 0 to 6 months, 6 to 24 months and after 24 months in 75 patients (69%), 15 patients (14%) and 18 patients (17%), respectively. Notably, the kinetics of molecular recurrence differed significantly between these three subgroups with a median time from loss of MR4 (BCR::ABL1 IS≤0.01%) to loss of major molecular response of 1, 7 and 22 months, respectively. Predictive factors of molecular recurrence differed according to the time of occurrence of the molecular recurrence. Durations of imatinib treatment and deep molecular response as well as BCR::ABL1/ABL1 levels at cessation of tyrosine kinase inhibitor treatment, as quantified by reverse transcriptase droplet digital polymerase chain reaction, are involved in molecular recurrence occurring up to 24 months but not beyond. (ClinicalTrial. gov Identifier NCT#0134373)

Spontaneous megakaryocytic colony formation does not discriminate between essential thrombocythemia and polycythemia vera.

International audienceLaboratory detection of spontaneous growth of colony-forming unit-megacaryocytes (CFU-MK), allowing us to distinguish essential thrombocythemia (ET) from reactive thrombocytosis, is therefore useful for the diagnostic of this myeloproliferative disorder. Whether CFU-MK assays allow us to discriminate at least partly between ET and other myeloproliferative disorders such as polycythemia vera (PV) remains, however, to be established. To gain insights about this point, we have performed CFU-MK cultures from bone marrow cells of patients diagnosed with ET (n = 42) or PV (n = 50) using a standardized collagen-based serum-free method. Spontaneous growth of CFU-MK was similarly detected in both 40/42 patients with ET and 47/50 patients with PV. These data suggest clearly that the CFU-MK assay is useful to detect not only ET, but also PV, but fails to discriminate, even partly, between these two myeloproliferative disorders

Induction-related cost of patients with acute myeloid leukaemia in France.

International audienceOBJECTIVE: The economic profile of acute myeloid leukaemia (AML) is badly known. The few studies published on this disease are now relatively old and include small numbers of patients. The purpose of this retrospective study was to evaluate the induction-related cost of 500 patients included in the AML 2001 trial, and to determine the explanatory factors of cost. SETTING: "Induction" patient's hospital stay from admission for "induction" to discharge after induction. METHOD: The study was performed from the French Public Health insurance perspective, restrictive to hospital institution costs. The average management of a hospital stay for "induction" was evaluated according to the analytical accounting of Besançon University Teaching Hospital and the French public Diagnosis-Related Group database. Multiple linear regression was used to search for explanatory factors. MAIN OUTCOME MEASURE: Only direct medical costs were included: treatment and hospitalisation. RESULTS: Mean induction-related direct medical cost was estimated at €41,852 ± 6,037, with a mean length of hospital stay estimated at 36.2 ± 10.7 days. After adjustment for age, sex and performance status, only two explanatory factors were found: an additional induction course and salvage course increased induction-related cost by 38% (± 4) and 15% (± 1) respectively, in comparison to one induction. These explanatory factors were associated with a significant increase in the mean length of hospital stay: 45.8 ± 11.6 days for 2 inductions and 38.5 ± 15.5 if the patient had a salvage course, in comparison to 32.9 ± 7.7 for one induction (P < 10⁻⁴). This result is robust and was confirmed by sensitivity analysis. CONCLUSION: Consideration of economic constraints in health care is now a reality. Only the control of length of hospital stay may lead to a decrease in induction-related cost for patients with AML

Longer treatment duration and history of osteoarticular symptoms predispose to tyrosine kinase inhibitor withdrawal syndrome

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Evaluation of a new rapid D-dimer assay for clinically suspected deep venous thrombosis (Liatest D-dimer).

International audienceIn previous studies, enzyme-linked immunosorbent assays (ELISA) for plasma D-dimer analysis have demonstrated high sensitivity, suggesting their potential usefulness in excluding deep venous thrombosis (DVT). We evaluated the usefulness of a new D-dimer test (Liatest D-dimer) for suspected DVT in a prospective study of patients admitted to the hospital because of recent (not exceeding 1 week before admission) clinical signs. Contrast venography or compression ultrasonography or both were performed within 24 hours of admission. A new quantitative determination of D-dimer concentration using a suspension of microlatex particles coated with specific antibodies was tested. A standard plasma D-dimer ELISA measurement was also performed. Of 464 patients, 276 had a proven DVT (distal, 74; proximal, 202). For a cutoff level of 400 ng/mL, sensitivity of the Liatest method in the diagnosis of overall DVT was 94.6% (95% confidence interval, 92.0%-97.0%), and the specificity was 35% (95% confidence interval, 28%-42%). The sensitivity and negative predictive value were 98.5% and 95.6%, respectively, in the diagnosis of proximal DVT, but only 83.8% and 84.6%, respectively, in the diagnosis of distal DVT. This new rapid Liatest D-dimer assay seems to be highly sensitive and could replace the ELISA method in excluding patients with proximal DVT. Both methods provide lower sensitivity for distal DVT

Evaluation of a new rapid D-dimer assay for clinically suspected deep venous thrombosis (Liatest D-dimer).

International audienceIn previous studies, enzyme-linked immunosorbent assays (ELISA) for plasma D-dimer analysis have demonstrated high sensitivity, suggesting their potential usefulness in excluding deep venous thrombosis (DVT). We evaluated the usefulness of a new D-dimer test (Liatest D-dimer) for suspected DVT in a prospective study of patients admitted to the hospital because of recent (not exceeding 1 week before admission) clinical signs. Contrast venography or compression ultrasonography or both were performed within 24 hours of admission. A new quantitative determination of D-dimer concentration using a suspension of microlatex particles coated with specific antibodies was tested. A standard plasma D-dimer ELISA measurement was also performed. Of 464 patients, 276 had a proven DVT (distal, 74; proximal, 202). For a cutoff level of 400 ng/mL, sensitivity of the Liatest method in the diagnosis of overall DVT was 94.6% (95% confidence interval, 92.0%-97.0%), and the specificity was 35% (95% confidence interval, 28%-42%). The sensitivity and negative predictive value were 98.5% and 95.6%, respectively, in the diagnosis of proximal DVT, but only 83.8% and 84.6%, respectively, in the diagnosis of distal DVT. This new rapid Liatest D-dimer assay seems to be highly sensitive and could replace the ELISA method in excluding patients with proximal DVT. Both methods provide lower sensitivity for distal DVT