Outcomes in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) have improved with the use of tyrosine kinase inhibitors. Molecular remission is a primary goal of ...treatment.
We conducted a phase 2 single-group trial of first-line therapy in adults with newly diagnosed Ph-positive ALL (with no upper age limit). Dasatinib plus glucocorticoids were administered, followed by two cycles of blinatumomab. The primary end point was a sustained molecular response in the bone marrow after this treatment.
Of the 63 patients (median age, 54 years; range, 24 to 82) who were enrolled, a complete remission was observed in 98%. At the end of dasatinib induction therapy (day 85), 29% of the patients had a molecular response, and this percentage increased to 60% after two cycles of blinatumomab; the percentage of patients with a molecular response increased further after additional blinatumomab cycles. At a median follow-up of 18 months, overall survival was 95% and disease-free survival was 88%; disease-free survival was lower among patients who had an
deletion plus additional genetic aberrations (
or
,
, or both i.e.,
).
mutations were detected in 6 patients who had increased minimal residual disease during induction therapy, and all these mutations were cleared by blinatumomab. Six relapses occurred. Overall, 21 adverse events of grade 3 or higher were recorded. A total of 24 patients received a stem-cell allograft, and 1 death was related to transplantation (4%).
A chemotherapy-free induction and consolidation first-line treatment with dasatinib and blinatumomab that was based on a targeted and immunotherapeutic strategy was associated with high incidences of molecular response and survival and few toxic effects of grade 3 or higher in adults with Ph-positive ALL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others; GIMEMA LAL2116 D-ALBA EudraCT number, 2016-001083-11; ClinicalTrials.gov number, NCT02744768.).
Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (
) infrequently have a response to salvage chemotherapy. Gilteritinib is an ...oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory
-mutated AML.
In a phase 3 trial, we randomly assigned adults with relapsed or refractory
-mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure i.e., relapse or lack of remission or death) and the percentage of patients who had complete remission.
Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval CI, 0.49 to 0.83; P<0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). In an analysis that was adjusted for therapy duration, adverse events of grade 3 or higher and serious adverse events occurred less frequently in the gilteritinib group than in the chemotherapy group; the most common adverse events of grade 3 or higher in the gilteritinib group were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%).
Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory
-mutated AML. (Funded by Astellas Pharma; ADMIRAL ClinicalTrials.gov number, NCT02421939.).
The GIMEMA LAL1509 protocol, designed for adult (≥18-60 years) de novo Ph+ acute lymphoblastic leukemia patients, was based on a dasatinib plus steroids induction - with central nervous system ...prophylaxis - followed by dasatinib alone in patients in complete molecular response or chemotherapy and/or allogeneic transplantation in patients not reaching a complete molecular response. Sixty patients (median age 41.9 years) were enrolled: 33 were p190+, 18 p210+ and 9 p190/p210+. At the end of induction (day +85), 58 patients (97%) achieved a complete hematologic remission. No deaths in induction were recorded. Eleven patients (18.3%) obtained a complete molecular response. Among non-complete molecular responders (n=47), 22 underwent an allogeneic transplant. Seventeen hematologic relapses occurred (median 7 months, range 3-40.1), 13 during consolidation and 4 post-transplant. ABL1 mutations (5 T315I, 3 V299L, 1 E281K and 1 G254E) were found in 10/13 relapsed cases. With a median follow-up of 57.4 months (range: 4.2-75.6), overall survival and disease-free survival are 56.3% and 47.2%. A better diseasefree survival was observed in patients who obtained a molecular response at day +85 compared to cases who did not. The presence of additional copy number aberrations - IKZF1 plus CDKN2A/B and/or PAX5 deletions - was the most important unfavorable prognostic factor on overall and disease-free survival (p=0.005 and p=0.0008). This study shows that in adult Ph+ ALL long-term survivals can be achieved with a total-therapy strategy based on a chemo-free induction and, in complete molecular responders, also without further systemic chemotherapy. Finally, the screening of additional copy number aberrations should be included in the diagnostic work-up. EudraCT 2010-019119-39.
Acute myeloid leukemia (AML) is a complex hematological disease characterized by genetic and clinical heterogeneity. Recent advances in the understanding of AML pathogenesis have paved the way for ...the development of new agents targeting specific molecules or mechanisms that contribute to finally move beyond the current standard of care, which is "3 + 7" regimen. In particular, new therapeutic options such as targeted therapies (midostaurin and enasidenib), monoclonal antibodies (gemtuzumab ozogamicin), and a novel liposomal formulation of cytarabine and daunorubicin (CPX-351) have been recently approved, and will be soon available for the treatment of adult patients with AML. In this review, we will present and describe these recently approved drugs as well as selected novel agents against AML that are currently under investigation, and show the most promising results as monotherapy or in combination with chemotherapy. The selection of these emerging treatments is based on the authors' opinion.
Emergence of clones carrying point mutations in the BCR‐ABL1 kinase domain (KD) is a common mechanism of resistance to tyrosine kinase inhibitor (TKI)‐based therapies in Philadelphia ...chromosome‐positive (Ph+) acute lymphoblastic leukemia (ALL). Sanger sequencing (SS) is the most frequently used method for diagnostic BCR‐ABL1 KD mutation screening, but it has some limitations—it is poorly sensitive and cannot robustly identify compound mutations. Next‐generation sequencing (NGS) may overcome these problems. NSG is increasingly available and has the potential to become the method of choice for diagnostic BCR‐ABL1 KD mutation screening. A group discussion within an ad hoc constituted Panel of Experts has produced a series of consensus‐based statements on the potential value of NGS testing before and during first‐line TKI‐based treatment, in relapsed/refractory cases, before and after allo‐stem cell transplantation, and on how NGS results may impact on therapeutic decisions. A set of minimal technical and methodological requirements for the analysis and the reporting of results has also been defined. The proposals herein reported may be used to guide the practical use of NGS for BCR‐ABL1 KD mutation testing in Ph+ ALL.
This consensus paper presents the results of an initiative by an expert panel to define a set of indications for the practical use of next‐generation sequencing for BCR‐ABL1 kinase domain mutation screening in Philadelphia‐positive acute lymphoblastic leukemia patients receiving tyrosine kinase inhibitor‐based therapies. Minimal technical and methodological requirements for the analysis and the reporting of results have also been proposed.
The GIMEMA ALL 0288 trial was designed to evaluate the impact of a 7-day prednisone (PDN) pretreatment on complete remission (CR) achievement and length, the influence of the addition of ...cyclophosphamide (random I) to a conventional 4-drug induction on CR rate and duration, and whether an early post-CR intensification (random II) by an 8-drug consolidation could improve CR duration. Median follow-up of this study was 7.3 years. From January 1988 to April 1994, among 794 adult (> 12 but < 60 years) patients registered, 778 were eligible. Their median age was 27.5 years; 73% had B-lineage acute lymphoblastic leukemia (ALL) and 22% had T-lineage disease; 18% showed associated myeloid markers; 47 of 216 analyzed patients (22%) had Philadelphia chromosome–positive ALL. Response to PDN pretreatment was observed in 65% of cases. CR was achieved in 627 patients (82%). Resistant patients and induction death rates were 11% and 7%, respectively. Random II was applied to 388 patients with CR; 201 had maintenance alone and 187 had consolidation followed by maintenance. The relapse rate was 60%; isolated central nervous system relapses were 8% of all CRs and 13% of all relapses. Median survival (overall survival OS), continuous complete remission (CCR), and disease-free survival (DFS) were 2.2, 2.4, and 2 years, respectively. PDN pretreatment response resulted the main independent factor influencing CR achievement, OS, CCR, and DFS; the addition of cyclophosphamide in induction significantly influenced CR achievement in a multivariate analysis. Neither induction intensification nor early consolidation appeared to influence CCR and DFS duration. For the first time PDN pretreatment response proved to be a powerful factor predicting disease outcome in adult ALL patients.
Introduction: Management of Ph+ ALL has changed since the introduction of tyrosine kinase inhibitors (TKI). We previously reported the preliminary findings of the GIMEMA LAL 1509 total therapy ...protocol, based on dasatinib plus steroids administration as induction therapy (Chiaretti et al, ASH 2014). The updated results on overall survival (OS), disease-free survival (DFS) and the impact of a genetic-based prognostic stratification are hereby provided.
Methods: Steroids were administered from day -6 to day 31. Dasatinib (140 mg/day) was given between days 1 and 84. Patients reaching a complete molecular response (CMR, i.e. BCR/ABL1 to ABL1 ratio=0) at the end of induction (day 85) continued Dasatinib. Patients in complete hematologic remission (CHR), but not in CMR, underwent chemotherapy (clofarabine-cyclophosphamide) and/or an allogeneic transplant (HSCT), according to eligibility and donor availability. Dasatinib was administered until disease progression. Molecular testing was used to identify the presence of the BCR/ABL1 transcript on bone marrow samples, to define the fusion protein and to quantify BCR/ABL1 levels at baseline and follow-up (FU). Mutational screening was performed in relapsed cases, based on material availability. SNP array analysis was carried out using the Cytoscan HD arrays (Affymetrix, Santa Clara, CA) to identify genomic aberrations.
Results: 60/63 enrolled patients were eligible. Median age was 41.9 years (range 18.7-59.1), 34 were males and 26 females; median WBC count was 12.5 x 109/l (range 1.4-178.0); the p190 fusion product was detected in 33 patients, p210 in 18 and p190/p210 in 9. Median FU is 28.4 months (range 4.2-43.7). After the steroid pre-phase, 38 patients (63%) had a blast reduction ≥75%. At day 85, 58 patients were in CHR (97%), while 2, in CHR at day 57, lost it: both harbored the p210 fusion transcript. They both returned into CHR following chemotherapy. A sustained CMR was obtained in 11 patients (18.6%): 72% had a p190 fusion transcript. No deaths in induction occurred. Among the CMR patients, only 1 experienced a hematologic relapse, which carried a T315I mutation. Of the 46 non-CMR cases, 14 relapses occurred, 8 of which in p210+ patients. Overall, there have been 12 deaths in CHR. OS is 58.3% (95%CI: 44.4-76.3) at 36 months and DFS at 30 months is 48.9% (95%CI: 36.8.0-64.9). A better DFS was observed in patients who obtained a CMR compared to cases with minimal residual disease (MRD) at day 85 (75% vs 44%, p=0.06), and in p190+ vs p210+ patients (57.1% vs 39.6%, p=ns). Mutational screening, performed in 7/15 cases at hematologic relapse detected mutations in 5: 3 T315I and 2 V299L, of which 1 with a concomitant F317I and F317L. SNP array analysis, performed in 39 cases with available DNA, showed that the most frequent aberrations were deletions of IKZF1 (85%), PAX5 (38%), CDKN2A/B (33%), MLLT3 (33%), RB1 (28%) and JAK2 (28%). While IKZF1 deletions alone did not impact on CHR or CMRachievement and DFS, a significantly worse DFS (p=0.01) and increased cumulative incidence of relapse (CIR, p=0.024) were observed in cases harboring deletions of IKZF1 plus CDKN2A/B and PAX5 (DFS: 40% vs 65% at 18 months; CIR: 40% vs 14% at 18 months (Fig. 1A and B). The relevance of this finding was further refined by stratifying patients according to the fusion protein: the impact of IKZF1 plus CDKN2A/B and PAX5 deletions is prognostically relevant in p190+, but not in p210+ patients, possibly because of the worse outcome of the latter group (Fig. 2). Finally, this analysis identified a set of genes specifically deleted in CMR cases; investigations are ongoing on additional cases to validate their potential role in predicting response to TKI.
Conclusions: In this updated analysis of the GIMEMA 1509 trial, we confirm the effectiveness of a chemo-free induction in inducing CHR in almost all adult Ph+ ALL patients (97%) and CMR in a subgroup of cases (18.6%). OS and DFS at 36 months and 30 months, approaching 60% and 50%, are encouraging. More importantly, CMR achievement at day 85 is associated with extremely promising results, being 75% at 30 months, underlying that CMR should be regarded as a primary endpoint in Ph+ ALL. We confirm that p210+ patients may require an intensified approach, given the lower rate of CMR achievement and the higher relapse rate. Finally, we provide evidence that a broader genetic characterization at diagnosis allows a more refined prognostic stratification of Ph+ ALL patients.
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Martinelli:Pfizer: Consultancy; Ariad: Consultancy; AMGEN: Consultancy; BMS: Consultancy, Speakers Bureau; ROCHE: Consultancy; MSD: Consultancy; Novartis: Consultancy, Speakers Bureau. Foà:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
Deletion at 22q11.2 responsible for Di George syndrome (DGs) is a risk factor for early-onset Parkinson’s disease (EOPD). To date, all patients reported with 22q11.2 deletions and parkinsonian ...features are negative for a family history of PD, and possible mutations in PD-related genes were not properly evaluated. The goal of this paper was to identify variants in PD genes that could contribute, together with 22q11.2 del, to the onset of parkinsonian features in patients affected by Di George syndrome. To this aim, sequencing analysis of 4800 genes including 17 PD-related genes was performed in a patient affected by DGs and EOPD. The analysis identified mutation p.Gly399Ser in OMI/HTRA2 (PARK13). To date, the mechanism that links DGs with parkinsonian features is poorly understood. The identification of a mutation in a PARK gene suggests that variants in PD-related genes, or in genes still not associated with PD, could contribute, together with deletion at 22q11.2, to the EOPD in patients affected by DGs. Further genetic analyses in a large number of patients are strongly required to understand this mechanism and to establish the pathogenetic role of p.Gly399Ser in OMI/HTRA2.
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