Diagnosis, prognostic factors, and assessment of ALL in adults: 2024 ELN recommendations from a European expert panel.

ABSTRACT: Working groups of the European LeukemiaNet have published several important consensus guidelines. Acute lymphoblastic leukemia (ALL) has many different clinical and biological subgroups and the knowledge on disease biology and therapeutic options is increasing exponentially. The European Working Group for Adult ALL has therefore summarized the current state of the art and provided comprehensive consensus recommendations for diagnostic approaches, biologic and clinical characterization, prognostic factors, and risk stratification as well as definitions of endpoints and outcomes. Aspects of treatment, management of subgroups and specific situations, aftercare, and supportive care are covered in a separate publication. The present recommendation intends to provide guidance for the initial management of adult patients with ALL and to define principles as a basis for future collaborative research.

Management of ALL in adults: 2024 ELN recommendations from a European expert panel.

ABSTRACT: Experts from the European Leukemia Net (ELN) working group for adult acute lymphoblastic leukemia have identified an unmet need for guidance regarding management of adult acute lymphoblastic leukemia (ALL) from diagnosis to aftercare. The group has previously summarized their recommendations regarding diagnostic approaches, prognostic factors, and assessment of ALL. The current recommendation summarizes clinical management. It covers treatment approaches, including the use of new immunotherapies, application of minimal residual disease for treatment decisions, management of specific subgroups, and challenging treatment situations as well as late effects and supportive care. The recommendation provides guidance for physicians caring for adult patients with ALL which has to be complemented by regional expertise preferably provided by national academic study groups.

NGS-based stratification refines the risk stratification in T-ALL and identifies a Very High-Risk subgroup of patients.

We previously reported a better outcome in adult and pediatric T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 mutations without alterations of K-N-RAS and PTEN genes. Availability of high-throughput next-generation sequencing strategies (NGS) led us to refine the outcome prediction in T-ALL. Targeted whole-exome sequencing of 72 T-ALL related oncogenes was performed in 198 adult T-ALLs in first remission (CR1) from the GRAALL-2003/2005 protocols (ClinicalTrial.gov, NCT00222027, NCT00327678) and 242 pediatric T-ALLs from the FRALLE2000T. This approach enabled the identification of the first NGS-based classifier in T-ALL categorizing low-risk patients as those with N/F, PHF6, or EP300 mutations, excluding N-K-RAS, PI3K pathway (PTEN, PIK3CA, and PIK3R1), TP53, DNMT3A, IDH1/2, and IKZF1 alterations, with a 5-year cumulative incidence of relapse (CIR) estimated at 21%. Conversely, the remaining patients were classified as high-risk, exhibiting a 5-year CIR estimated at 47%. We externally validated this stratification in the pediatric cohort. NGS-based classifier was highly prognostic, independently of minimal residual disease (MRD) and white blood cells counts (WBC), in both adult and pediatric cohorts. Integration of the NGS-based classifier into a comprehensive risk stratification model, including WBC count at diagnosis and MRD at the end of induction, enabled the identification of an adverse risk subgroup (25%) with a 5-year CIR estimated at 51%, and a favorable risk group (32%) with a 5-year CIR estimated at 12%. NGS-based stratification combined with WBC and MRD sharpens the prognostic classification in T-ALL and identifies a new subgroup of patients who may benefit from innovative therapeutic approaches.

Nilotinib with or without cytarabine for Philadelphia-positive acute lymphoblastic leukemia.

ABSTRACT: We previously demonstrated that a reduced-intensity chemotherapy schedule can safely replace hyper-CVAD (cyclophosphamide-vincristine-doxorubicin [Adriamycin]-dexamethasone) cycle 1 when combined with imatinib in adults with Philadelphia-positive acute lymphoblastic leukemia. In the present randomized GRAAPH-2014 trial, we used nilotinib and addressed the omission of cytarabine (Ara-C) in consolidation. The primary objective was the major molecular response (MMR) rate measured by BCR::ABL1 quantification after cycle 4 (end of consolidation). All patients were eligible for allogeneic stem cell transplant (SCT), whereas those in MMR could receive autologous SCT, followed by 2-year imatinib maintenance in both cases. After the enrollment of 156 of 265 planed patients, the data and safety monitoring board decided to hold the randomization because of an excess of relapse in the investigational arm. Among the 155 evaluable patients, 76 received Ara-C during consolidation (arm A) and 79 did not (arm B). Overall, 133 patients (85%) underwent SCT, 93 allogeneic and 40 autologous. The noninferiority end point regarding MMR was reached with 71.1% (arm A) and 77.2% (arm B) of patients reaching MMR. However, the 4-year cumulative incidence of relapse was higher in arm B compared with arm A (31.3% [95% confidence interval {CI}, 21.1%-41.9%] vs 13.2% [95% CI, 6.7%-21.9%]; P = .017), which translated to a lower relapse-free survival. With a median follow-up of 3.8 years, 4-year overall survival was 79.0% (95% CI, 70.6%-89.3%) in arm A vs 73.4% (95% CI, 63.9%-84.4%) in arm B (P = .35). Despite a noninferior rate of MMR, more relapses were observed when ARA-C was omitted without impact on survival. ClinicalTrials.gov ID, NCT02611492.

IL-7 receptor expression is frequent in T-cell acute lymphoblastic leukemia and predicts sensitivity to JAK inhibition.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a dismal prognosis related to refractory/relapsing diseases, raising the need for new targeted therapies. Activating mutations of interleukin-7-receptor pathway genes (IL-7Rp) play a proven leukemia-supportive role in T-ALL. JAK inhibitors, such as ruxolitinib, have recently demonstrated preclinical efficacy. However, prediction markers for sensitivity to JAK inhibitors are still lacking. Herein, we show that IL-7R (CD127) expression is more frequent (∼70%) than IL-7Rp mutations in T-ALL (∼30%). We compared the so-called nonexpressers (no IL-7R expression/IL-7Rp mutation), expressers (IL7R expression without IL-7Rp mutation), and mutants (IL-7Rp mutations). Integrative multiomics analysis outlined IL-7R deregulation in virtually all T-ALL subtypes, at the epigenetic level in nonexpressers, genetic level in mutants, and posttranscriptional level in expressers. Ex vivo data using primary-derived xenografts support that IL-7Rp is functional whenever the IL-7R is expressed, regardless of the IL-7Rp mutational status. Consequently, ruxolitinib impaired T-ALL survival in both expressers and mutants. Interestingly, we show that expressers displayed ectopic IL-7R expression and IL-7Rp addiction conferring a deeper sensitivity to ruxolitinib. Conversely, mutants were more sensitive to venetoclax than expressers. Overall, the combination of ruxolitinib and venetoclax resulted in synergistic effects in both groups. We illustrate the clinical relevance of this association by reporting the achievement of complete remission in 2 patients with refractory/relapsed T-ALL. This provides proof of concept for translation of this strategy into clinics as a bridge-to-transplantation therapy. IL7R expression can be used as a biomarker for sensitivity to JAK inhibition, thereby expanding the fraction of patients with T-ALL eligible for ruxolitinib up to nearly ∼70% of T-ALL cases.

Concurrent CDX2 cis-deregulation and UBTF::ATXN7L3 fusion define a novel high-risk subtype of B-cell ALL.

Oncogenic alterations underlying B-cell acute lymphoblastic leukemia (B-ALL) in adults remain incompletely elucidated. To uncover novel oncogenic drivers, we performed RNA sequencing and whole-genome analyses in a large cohort of unresolved B-ALL. We identified a novel subtype characterized by a distinct gene expression signature and the unique association of 2 genomic microdeletions. The 17q21.31 microdeletion resulted in a UBTF::ATXN7L3 fusion transcript encoding a chimeric protein. The 13q12.2 deletion resulted in monoallelic ectopic expression of the homeobox transcription factor CDX2, located 138 kb in cis from the deletion. Using 4C-sequencing and CRISPR interference experiments, we elucidated the mechanism of CDX2 cis-deregulation, involving PAN3 enhancer hijacking. CDX2/UBTF ALL (n = 26) harbored a distinct pattern of additional alterations including 1q gain and CXCR4 activating mutations. Within adult patients with Ph- B-ALL enrolled in GRAALL trials, patients with CDX2/UBTF ALL (n = 17/723, 2.4%) were young (median age, 31 years) and dramatically enriched in females (male/female ratio, 0.2, P = .002). They commonly presented with a pro-B phenotype ALL and moderate blast cell infiltration. They had poor response to treatment including a higher risk of failure to first induction course (19% vs 3%, P = .017) and higher post-induction minimal residual disease (MRD) levels (MRD ≥ 10-4, 93% vs 46%, P < .001). This early resistance to treatment translated into a significantly higher cumulative incidence of relapse (75.0% vs 32.4%, P = .004) in univariate and multivariate analyses. In conclusion, we discovered a novel B-ALL entity defined by the unique combination of CDX2 cis-deregulation and UBTF::ATXN7L3 fusion, representing a high-risk disease in young adults.

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.

Involvement of the JAK-STAT pathway in the molecular landscape of tyrosine kinase fusion-negative hypereosinophilic syndromes: A nationwide CEREO study.

We investigated using a custom NGS panel of 149 genes the mutational landscape of 64 consecutive adult patients with tyrosine kinase fusion-negative hypereosinophilia (HE)/hypereosinophilic syndrome (HES) harboring features suggestive of myeloid neoplasm. At least one mutation was reported in 50/64 (78%) patients (compared to 8/44 (18%) patients with idiopathic HE/HES/HEUS used as controls; p < .001). Thirty-five patients (54%) had at least one mutation involving the JAK-STAT pathway, including STAT5B (n = 18, among which the hotspot N642H, n = 13), JAK1 (indels in exon 13, n = 5; V658F/L, n = 2), and JAK2 (V617F, n = 6; indels in exon 13, n = 2). Other previously undescribed somatic mutations were also found in JAK2, JAK1, STAT5B, and STAT5A, including three patients who shared the same STAT5A V707fs mutation and features consistent with primary polycythemia. Nearly all JAK-STAT mutations were preceded by (or associated with) myelodysplasia-related gene mutations, especially in RNA-splicing genes or chromatin modifiers. In multivariate analysis, neurologic involvement (hazard ratio [HR] 4.95 [1.87-13.13]; p = .001), anemia (HR 5.50 [2.24-13.49]; p < .001), and the presence of a high-risk mutation (as per the molecular international prognosis scoring system: HR 6.87 [2.39-19.72]; p < .001) were independently associated with impaired overall survival. While corticosteroids were ineffective in all treated JAK-STAT-mutated patients, ruxolitinib showed positive hematological responses including in STAT5A-mutated patients. These findings emphasize the usefulness of NGS for the workup of tyrosine kinase fusion-negative HE/HES patients and support the use of JAK inhibitors in this setting. Updated classifications could consider patients with JAK-STAT mutations and eosinophilia as a new "gene mutated-entity" that could be differentiated from CEL, NOS, and idiopathic HES.

Ponatinib vs Imatinib in Frontline Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Randomized Clinical Trial.

Importance: In newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), disease progression due to acquired resistance to first- or second-generation BCR::ABL1 tyrosine kinase inhibitors is common. Ponatinib inhibits BCR::ABL1 and all single-mutation variants, including T315I. Objective: To compare frontline ponatinib vs imatinib in adults with newly diagnosed Ph+ ALL. Design, Setting, and Participants: Global registrational, phase 3, open-label trial in adults aged 18 years or older with newly diagnosed Ph+ ALL. From January 2019 to May 2022, eligible patients at 77 sites were randomized 2:1 to ponatinib (30 mg/d) or imatinib (600 mg/d) with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after the cycle 20 phase of the trial. The last date of follow-up for this analysis was August 12, 2022. Intervention: Patients received ponatinib, 30 mg/d, or imatinib, 600 mg/d, with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after cycle 20. The ponatinib dose was reduced to 15 mg on achievement of minimal residual disease-(MRD) negative complete remission. Main Outcomes and Measures: The primary end point of this interim analysis was MRD-negative complete remission (≤0.01% BCR::ABL1 [MR4] centrally assessed by reverse transcriptase-quantitative polymerase chain reaction), with complete remission maintained for at least 4 weeks at the end of cycle 3. The key secondary end point was event-free survival. Results: Of 245 patients randomized (median age, 54 years; 133 [54.3%] female), 232 (ponatinib, n = 154; imatinib, n = 78) who had p190 or p210 dominant isoforms verified by the central laboratory were analyzed for the primary end point. The MRD-negative complete remission rate (primary end point) was significantly higher with ponatinib (34.4% [53/154]) vs imatinib (16.7% [13/78]) (risk difference, 0.18 [95% CI, 0.06-0.29]; P = .002). At the data cutoff, event-free survival had not met the prespecified number of events. Median event-free survival was not reached in the ponatinib group and was 29 months in the imatinib group. The most common adverse events were similar between treatment groups. Arterial occlusive events were infrequent and comparable between groups (ponatinib, 2.5%; imatinib, 1.2%). Conclusions and Relevance: Ponatinib demonstrated a superior rate of MRD-negative complete remission at the end of induction vs imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Ph+ ALL. The safety profile of ponatinib was comparable with imatinib. Trial Registration: ClinicalTrials.gov Identifier: NCT03589326.

Efficacy and safety of nilotinib in chronic myeloid leukaemia patients who failed to achieve a treatment-free remission period after imatinib discontinuation: Results of the French Nilo post-STIM study.

Molecular recurrence (MRec) occurs in about half of all patients with chronic myeloid leukaemia (CML) who discontinue tyrosine kinase inhibitors (TKI) in sustained deep molecular response. A second TKI discontinuation has been attempted in some patients who regain the discontinuation criteria after resuming treatment. Nilotinib treatment affords faster and deeper molecular responses than imatinib as first-line therapy. We prospectively evaluated the efficacy and safety of nilotinib (300 mg twice daily) in chronic-phase CML patients who experienced MRec, after imatinib discontinuation and analysed the probability of TFR after a new attempt in patients treated for 2 years with sustained MR4.5 for at least 1 year. A total of 31 patients were included in the study between 2013 and 2018. Seven (23%) patients experienced serious adverse events after a median of 2 months of nilotinib treatment leading to discontinuation of treatment. One patient was excluded from the study for convenience. Among the 23 patients treated for 2 years with nilotinib, 22 maintained their molecular response for at least 1 year (median: 22 months) and stopped nilotinib. The TFR rates at 24 and 48 months after nilotinib discontinuation were 59.1% (95% confidence interval [CI]: 41.7%-83.7%) and 42.1% (95% CI: 25%-71%) respectively (NCT #01774630).

Dasatinib plus Peg-Interferon alpha 2b combination in newly diagnosed chronic phase chronic myeloid leukaemia: Results of a multicenter phase 2 study (DASA-PegIFN study).

Superior rates of deep molecular response (DMR) have been reported with the combination of tyrosine kinase inhibitors and pegylated-interferon-alpha (Peg-IFN) in patients with newly diagnosed chronic phase-chronic myeloid leukaemia (CP-CML). In this setting, this study investigated the efficacy and safety of dasatinib combined to Peg-IFN-α2b (Dasa-PegIFN, NCT01872442). A total of 79 patients (age ≤65 years) started dasatinib; 61 were eligible for Peg-IFNα-2b add-on therapy at month 3 for a maximum 21-months duration. Dasatinib was continued thereafter. The primary endpoint was the cumulative rate of molecular response 4.5 log (MR4.5 ) by 12 months. The results are reported for the 5-year duration of the study. Grade 3 neutropenia was frequent with the combination but did not induce severe infection (one of grade 3). Other adverse events were generally low grade (4% of grade 3-4) and expected. Seventy-nine per cent and 61% of patients continued the Peg-IFN until months 12 and 24, respectively. Overall, at these time points, MR4.5 rates were 25% and 38%, respectively. Thereafter, 32% and 46% of patients achieved a sustained (≥2 years) MR4.5 or MR4 , respectively. This work established the feasibility and high rates of achievement of early and sustained DMR (a prerequisite for treatment-free-remission) with dasatinib and Peg-IFNα-2b combination as initial therapy.

Novel precision medicine approaches and treatment strategies in hematological malignancies.

Genetic testing has been applied for decades in clinical routine diagnostics of hematological malignancies to improve disease (sub)classification, prognostication, patient management, and survival. In recent classifications of hematological malignancies, disease subtypes are defined by key recurrent genetic alterations detected by conventional methods (i.e., cytogenetics, fluorescence in situ hybridization, and targeted sequencing). Hematological malignancies were also one of the first disease areas in which targeted therapies were introduced, the prime example being BCR::ABL1 inhibitors, followed by an increasing number of targeted inhibitors hitting the Achilles' heel of each disease, resulting in a clear patient benefit. Owing to the technical advances in high-throughput sequencing, we can now apply broad genomic tests, including comprehensive gene panels or whole-genome and whole-transcriptome sequencing, to identify clinically important diagnostic, prognostic, and predictive markers. In this review, we give examples of how precision diagnostics has been implemented to guide treatment selection and improve survival in myeloid (myelodysplastic syndromes and acute myeloid leukemia) and lymphoid malignancies (acute lymphoblastic leukemia, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia). We discuss the relevance and potential of monitoring measurable residual disease using ultra-sensitive techniques to assess therapy response and detect early relapses. Finally, we bring up the promising avenue of functional precision medicine, combining ex vivo drug screening with various omics technologies, to provide novel treatment options for patients with advanced disease. Although we are only in the beginning of the field of precision hematology, we foresee rapid development with new types of diagnostics and treatment strategies becoming available to the benefit of our patients.

PRC2 loss of function confers a targetable vulnerability to BET proteins in T-ALL.

T-cell acute lymphoblastic leukemia (T-ALL) is a group of aggressive hematological cancers with dismal outcomes that are in need of new therapeutic options. Polycomb repressor complex 2 (PRC2) loss-of-function alterations were reported in pediatric T-ALL, yet their clinical relevance and functional consequences remain elusive. Here, we extensively analyzed PRC2 alterations in a large series of 218 adult T-ALL patients. We found that PRC2 genetic lesions are frequent events in T-ALL and are not restricted to early thymic precursor ALL. PRC2 loss of function associates with activating mutations of the IL7R/JAK/STAT pathway. PRC2-altered T-ALL patients respond poorly to prednisone and have low bone marrow blast clearance and persistent minimal residual disease. Furthermore, we identified that PRC2 loss of function profoundly reshapes the genetic and epigenetic landscapes, leading to the reactivation of stem cell programs that cooperate with bromodomain and extraterminal (BET) proteins to sustain T-ALL. This study identifies BET proteins as key mediators of the PRC2 loss of function-induced remodeling. Our data have uncovered a targetable vulnerability to BET inhibition that can be exploited to treat PRC2-altered T-ALL patients.

Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial.

In PACE (Ponatinib Ph+ ALL and CML Evaluation), a phase 2 trial of ponatinib that included patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to multiple prior tyrosine kinase inhibitors (TKIs), ponatinib showed deep and durable responses, but arterial occlusive events (AOEs) emerged as notable adverse events. Post hoc analyses indicated that AOEs are dose dependent. We assessed the benefit/risk ratio across 3 ponatinib starting doses in the first prospective study to evaluate a novel, response-based, dose-reduction strategy for TKI treatment. Adults with CP-CML resistant to or intolerant of at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1 T315I mutation were randomly assigned 1:1:1 to 3 cohorts receiving ponatinib 45, 30, or 15 mg once daily. In patients who received 45 or 30 mg daily the dose was reduced to 15 mg upon response (BCR-ABL1IS transcript levels ≤1%). The primary end point was response at 12 months. From August 2015 through May 2019, 283 patients were randomly assigned to the cohorts: 282 (94 per dose group) received treatment (data cutoff, 31 May 2020). The primary end point (98.3% confidence interval) was achieved in 44.1% (31.7-57.0) in the 45-mg cohort, 29.0% (18.4-41.6) in the 30-mg cohort, and 23.1% (13.4-35.3) in the 15-mg cohort. Independently confirmed grade 3 or above treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 45-, 30-, and 15-mg cohorts, respectively. All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit/risk outcomes occurred with the 45-mg starting dose, which was decreased to 15 mg upon achievement of a response. This trial is registered on www.clinicaltrials.gov as NCT02467270.

Genetic identification of patients with AML older than 60 years achieving long-term survival with intensive chemotherapy.

To design a simple and reproducible classifier predicting the overall survival (OS) of patients with acute myeloid leukemia (AML) ≥60 years of age treated with 7 + 3, we sequenced 37 genes in 471 patients from the ALFA1200 (Acute Leukemia French Association) study (median age, 68 years). Mutation patterns and OS differed between the 84 patients with poor-risk cytogenetics and the 387 patients with good (n = 13), intermediate (n = 339), or unmeasured (n = 35) cytogenetic risk. TP53 (hazards ratio [HR], 2.49; P = .0003) and KRAS (HR, 3.60; P = .001) mutations independently worsened the OS of patients with poor-risk cytogenetics. In those without poor-risk cytogenetics, NPM1 (HR, 0.57; P = .0004), FLT3 internal tandem duplications with low (HR, 1.85; P = .0005) or high (HR, 3.51; P < 10-4) allelic ratio, DNMT3A (HR, 1.86; P < 10-4), NRAS (HR, 1.54; P = .019), and ASXL1 (HR, 1.89; P = .0003) mutations independently predicted OS. Combining cytogenetic risk and mutations in these 7 genes, 39.1% of patients could be assigned to a "go-go" tier with a 2-year OS of 66.1%, 7.6% to the "no-go" group (2-year OS 2.8%), and 3.3% of to the "slow-go" group (2-year OS of 39.1%; P < 10-5). Across 3 independent validation cohorts, 31.2% to 37.7% and 11.2% to 13.5% of patients were assigned to the go-go and the no-go tiers, respectively, with significant differences in OS between tiers in all 3 trial cohorts (HDF [Hauts-de-France], n = 141, P = .003; and SAL [Study Alliance Leukemia], n = 46; AMLSG [AML Study Group], n = 223, both P < 10-5). The ALFA decision tool is a simple, robust, and discriminant prognostic model for AML patients ≥60 years of age treated with intensive chemotherapy. This model can instruct the design of trials comparing the 7 + 3 standard of care with less intensive regimens.

Differential inhibition of T-cell receptor and STAT5 signaling pathways determines the immunomodulatory effects of dasatinib in chronic phase chronic myeloid leukemia.

Dasatinib is a multi-kinase inhibitor with activity against the SRC kinase LCK, which plays a critical role in T-cell receptor signaling. Dasatinib, initially developed as an immunosuppressive agent, is by contrast, also noted to result in enhanced tumor immunity in a subset of patients. We studied the impact of dasatinib in chronic myeloid leukemia patients and compared it with patients taking other tyrosine kinase inhibitors (TKI) and healthy controls. We found that patients on dasatinib showed inhibition of both T-cell receptor (TCR) and STAT5 signaling pathways, and reduced expression of Teffector pro-inflammatory cytokines. In addition, dasatinib induced selective depletion of regulatory T cells (Tregs) and effector Tregs, particularly in patients with clonal expansion of effector CD8+ T cells, who demonstrated greater and preferential inhibition of Treg TCR intracellular signaling. In addition, we show that dasatinib selectively reduces Treg STAT5 phosphorylation via reduction of IL-2, in relation with the marked reduction of plasma IL-2 levels in patients taking dasatinib. Finally, patients on other TKI had significantly increased TCR signaling in TIM3+ cells compared to patients taking dasatinib, suggesting that chronic SRC kinase inhibition by dasatinib may play a role in preventing TIM-3-mediated T-cell exhaustion and preserve anti-tumor immunity. These data provide further insight into the selective immunomodulatory effects of dasatinib and its potential use for pharmacologic control of immunotherapies.

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).

Ponatinib after failure of second-generation tyrosine kinase inhibitor in resistant chronic-phase chronic myeloid leukemia.

Ponatinib, the only third-generation pan-BCR::ABL1 inhibitor with activity against all known BCR::ABL1 mutations including T315I, has demonstrated deep and durable responses in patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to prior second-generation (2G) TKI treatment. We present efficacy and safety outcomes from the Ponatinib Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and CML Evaluation (PACE) and Optimizing Ponatinib Treatment in CP-CML (OPTIC) trials for this patient population. PACE (NCT01207440) evaluated ponatinib 45 mg/day in CML patients with resistance to prior TKI or T315I. In OPTIC (NCT02467270), patients with CP-CML and resistance to ≥2 prior TKIs or T315I receiving 45 or 30 mg/day reduced their doses to 15 mg/day upon achieving ≤1% BCR::ABL1IS or received 15 mg/day continuously. Efficacy and safety outcomes from patients with CP-CML treated with ≥1 2G TKI (PACE, n = 257) and OPTIC (n = 93), 45-mg starting dose cohort, were analyzed for BCR::ABL1IS response rates, overall survival (OS), progression-free survival (PFS), and safety. By 24 months, the percentages of patients with ≤1% BCR::ABL1IS response, PFS, and OS were 46%, 68%, and 85%, respectively, in PACE and 57%, 80%, and 91%, respectively, in OPTIC. Serious treatment-emergent adverse events and serious treatment-emergent arterial occlusive event rates were 63% and 18% in PACE and 34% and 4% in OPTIC. Ponatinib shows high response rates and robust survival outcomes in patients whose disease failed prior to 2G TKIs, including patients with T315I mutation. The response-based dosing in OPTIC led to improved safety and similar efficacy outcomes compared with PACE.

Successful mRNA SARS-Cov-2 vaccine rechallenge after a first episode of immune thrombocytopenic purpura.

In 2021, the world experienced the most extensive vaccination campaign to defeat COVID-19. Many cases of idiopathic thrombocytopenia have been reported following injections of SARS-Cov-2 mRNA vaccine. We present the case of a 73-year-old woman with de novo ITP after a first injection of SARS-Cov-2 mRNA vaccine (Moderna vaccine) who experienced a successful rechallenge of SARS-Cov-2 mRNA vaccine (Pfizer vaccine) a few months later.

Dasatinib dose optimisation based on therapeutic drug monitoring reduces pleural effusion rates in chronic myeloid leukaemia patients.

Dasatinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor approved for patients with chronic myeloid leukaemia (CML). Dasatinib 100 mg per day is associated with an increased risk of pleural effusion (PlEff). We randomly evaluated whether therapeutic drug monitoring (TDM) may reduce dasatinib-associated significant adverse events (AEs) by 12 months (primary endpoint). Eligible patients started dasatinib at 100 mg per day followed by dasatinib (C)min assessment. Patients considered overdosed [(C)min ≥ 3 nmol/l) were randomised between a dose-reduction strategy (TDM arm) and standard of care (control arm). Out of 287 evaluable patients, 80 patients were randomised. The primary endpoint was not met due to early haematological AEs occurring before effective dose reduction. However, a major reduction in the cumulative incidence of PlEff was observed in the TDM arm compared to the control arm (4% vs. 15%; 11% vs. 35% and 12% vs. 39% at one, two and three years, respectively (P = 0·0094)). Molecular responses were superimposable in all arms. Dasatinib TDM during treatment initiation was feasible and resulted in a significant reduction of the incidence of PlEff in the long run, without impairing molecular responses. (NCT01916785; https://clinicaltrials.gov).