ABSTRACT
FLT3 inhibitors combined with chemotherapy are the standard of care for newly diagnosed FLT3-mutated acute myeloid leukemia (AML). However, no head-to-head studies have established the superiority of one FLT3 inhibitor over another. We conducted a network meta-analysis (NMA) to evaluate overall survival (OS) among different FLT3 inhibitors. Three relevant randomized controlled trials (RCTs), involving 1.358 patients treated with midostaurin, quizartinib, and sorafenib, were included in our analysis. The hazard ratios (HRs) revealed no significant differences in OS between midostaurin and quizartinib (HR, 1.00; 95â¯% CI, 0.73-1.36), midostaurin and sorafenib (HR, 0.97; 95â¯% CI, 0.52-1.84), or quizartinib and sorafenib (HR, 0.97; 95â¯% CI, 0.51-1.85). This NMA, the first to explore this issue, found no OS differences among the different FLT3 inhibitors. In the absence of direct comparison trials, our findings provide practical insights for clinical decision-making.
ABSTRACT
INTRODUCTION: In patients with myelodysplastic syndromes (MDS), anemia is prevalent affecting 80%-85% of low-risk (LR-MDS) patients, with 40% eventually requiring red blood cell (RBC) transfusions. Except forlenalidomide, exclusively approved for those with deletion of chromosome 5q,erythropoiesis-stimulating agents (ESAs) are the primary treatment choice for low-risk patients. Those unresponsive to ESAs face limited alternatives, eventually necessitating long-term RBC transfusions, leading to secondary iron overload and adversely affecting quality of life (QoL). AREA COVERED: Luspatercept is a pioneering erythroid maturation agent. It received approval by both the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) for treating adults experiencing transfusion-dependent anemia associated with LR-MDS or ß-thalassemia. Recently, the FDA approved luspatercept as first- line therapy in patients with very low- to intermediate-risk MDS who require RBC transfusions and have not previously received ESAs. This review summarizes the historical impact of luspatercept intreating LR-MDS unresponsive to ESAs and illustrates its potential benefit asfrontline therapy in MDS and its employment in patients with myelofibrosis-induced anemia. EXPERT OPINION: Luspatercept has revolutionized the therapeutic paradigm of LR-MDS, for which there was a limited therapeutic arsenal, especially in the setting of patients who did not respond or fail after ESA treatment.
Subject(s)
Activin Receptors, Type II , Hematinics , Immunoglobulin Fc Fragments , Myelodysplastic Syndromes , Recombinant Fusion Proteins , Humans , Myelodysplastic Syndromes/drug therapy , Immunoglobulin Fc Fragments/therapeutic use , Immunoglobulin Fc Fragments/adverse effects , Hematinics/therapeutic use , Hematinics/adverse effects , Recombinant Fusion Proteins/therapeutic use , Recombinant Fusion Proteins/adverse effects , Activin Receptors, Type II/therapeutic use , Anemia/drug therapy , Erythrocyte Transfusion , Quality of LifeABSTRACT
In the last few years, molecularly targeted agents and immune-based treatments (ITs) have significantly changed the landscape of anti-cancer therapy. Indeed, ITs have been proven to be very effective when used against metastatic solid tumors, for which outcomes are extremely poor when using standard approaches. Such a scenario has only been partially reproduced in hematologic malignancies. In the context of acute myeloid leukemia (AML), as innovative drugs are eagerly awaited in the relapsed/refractory setting, different ITs have been explored, but the results are still unsatisfactory. In this work, we will discuss the most important clinical studies to date that adopt ITs in AML, providing the basis to understand how this approach, although still in its infancy, may represent a promising therapeutic tool for the future treatment of AML patients.
ABSTRACT
The addition of cladribine, or sorafenib to standard chemotherapy have each demonstrated improved survival in patients with newly-diagnosed acute myeloid leukemia (AML). We studied the combination of cladribine, idarubicin, and intermediate-dose cytarabine (CLIA) in patients ≤65 years of age with newly diagnosed AML, fit to receive intensive therapy. Cladribine (5 mg/m2) IV was administered on days (D)1-5, cytarabine (1 g/m2) on D1-5, and idarubicin (10 mg/m2) on D1-3. Sorafenib was added to the CLIA backbone for patients with FLT3-ITD mutated AML. 80 patients were enrolled: 65 with newly diagnosed AML and 15 with AML arising from previously treated MDS (ts-AML). The median age was 55 years (range, 21-65). CR + CRi was 83% (54/65) and 27% in the untreated and ts-AML cohorts, respectively; 74% and 75% of responding patients, respectively, had undetectable measurable residual disease (MRD). Among patients with FLT3-ITD mutated AML receiving CLIA+sorafenib, the CR + CRi rate was 95%, with 81% negative for MRD. With a median follow-up of 76 months, the 2- and 4-year OS of 57% and 50% compared to 20%, and 13% for ts-AML, respectively. Patients treated with CLIA+sorafenib had 2- and 5-year OS rates of 63% and 59%, respectively. The most common Grade ≥3 adverse events were infection/fever, elevated bilirubin, rash, and nausea. CLIA was safe and effective in young, fit patients with newly diagnosed AML with inferior outcomes among patients with ts-AML. The addition of sorafenib to CLIA in FLT3-ITD mutated AML resulted in high rates of durable remission and excellent long-term survival.
Subject(s)
Idarubicin , Leukemia, Myeloid, Acute , Humans , Middle Aged , Sorafenib/therapeutic use , Cladribine/therapeutic use , Cytarabine/therapeutic use , Remission Induction , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/geneticsABSTRACT
Gilteritinib is currently approved for patients with relapsed/refractory AML with FLT3 mutations, based on the positive results of the pivotal ADMIRAL study. In ADMIRAL trial, no increased risk of bleeding was reported, but in the previous dose finding study, a single event of intracranial hemorrhage (ICH) was registered after exposure to subtherapeutic doses of gilteritinib. Here, we report the first case series on five ICHs diagnosed in patients with FLT3-mutated AML, occurred within the first month of exposure to gilteritinib. Our cohort included 24 patients treated in three Italian centers. Most of these ICH cases were non-severe and self-limiting, while one was fatal. This link with ICHs remains in any case uncertain for the presence of active AML. We further reported that an analysis of the post-marketing surveillance data (EudraVigilance) retrieved other 11 cases of ICHs present in the database after gilteritinib treatment. A causality assessment was performed according to the Dx3 method to evaluate the possibility that ICHs might be an actual side effect of gilteritinib. In conclusion, further research is needed to elucidate the potential role of gilteritinib in the pathogenesis of ICHs.
ABSTRACT
FMS-related tyrosine kinase 3 (FLT3) mutations, present in about 25%-30% of acute myeloid leukemia (AML) patients, constitute one of the most frequently detected mutations in these patients. The binding of FLT3L to FLT3 activates the phosphatidylinositol 3-kinase (PI3K) and RAS pathways, producing increased cell proliferation and the inhibition of apoptosis. Two types of FLT3 mutations exist: FLT3-ITD and FLT3-TKD (point mutations in D835 and I836 or deletion of codon I836). A class of drugs, tyrosine-kinase inhibitors (TKI), targeting mutated FLT3, is already available with 1st and 2nd generation molecules, but only midostaurin and gilteritinib are currently approved. However, the emergence of resistance or the selection of clones not responding to FLT3 inhibitors has become an important clinical dilemma, as the duration of clinical responses is generally limited to a few months. This review analyzes the insights into mechanisms of resistance to TKI and poses a particular view on the clinical relevance of this phenomenon. Has resistance been overlooked? Indeed, FLT3 inhibitors have significantly contributed to reducing the negative impact of FLT3 mutations on the prognosis of AML patients who are no longer considered at high risk by the European LeukemiaNet (ELN) 2022. Finally, several ongoing efforts to overcome resistance to FLT3-inhibitors will be presented: new generation FLT3 inhibitors in monotherapy or combined with standard chemotherapy, hypomethylating drugs, or IDH1/2 inhibitors, Bcl2 inhibitors; novel anti-human FLT3 monoclonal antibodies (e.g., FLT3/CD3 bispecific antibodies); FLT3-CAR T-cells; CDK4/6 kinase inhibitor (e.g., palbociclib).
ABSTRACT
The traditionally dismal outcome of acute myeloid leukemia (AML) patients carrying the FMS-related tyrosine kinase 3 (FLT3) mutations has been mitigated by the recent introduction of tyrosine kinase inhibitors (TKI) into clinics, such as midostaurin and gilteritinib. The present work summarizes the clinical data that led to the use of gilteritinib in clinical practice. Gilteritinib is a second-generation TKI with deeper single-agent activity than first-generation drugs against both FLT3-ITD and TKD mutations in human studies. Moreover, the phase I/II dose-escalation, dose-expansion Chrysalis trial showed an acceptable safety profile of gilteritinib (diarrhea, elevated aspartate aminotransferase, febrile neutropenia, anemia, thrombocytopenia, sepsis, and pneumonia) and a 49% overall response rate (ORR) in 191 FLT3-mutated relapsed/refractory (R/R) AML patients. In 2019, the pivotal ADMIRAL trial showed that the median overall survival was significantly longer in patients treated with gilteritinib than among those receiving chemotherapy (9.3 vs. 5.6 months, respectively) and the ORR to gilteritinib was 67.6%, outperforming the 25.8% for chemotherapy arm and leading to the license for its clinical use by the US Food and Drug Administration. Since then, several real-world experiences have confirmed the positive results in the R/R AML setting. Finally, gilteritinib-based combinations currently under investigation, with several compounds (venetoclax, azacitidine, conventional chemotherapy, etc.) and some practical tips (maintenance after allogeneic transplantation, interaction with antifungal drugs, extramedullary disease, and onset of resistance), will be analyzed in detail in this review.
ABSTRACT
Chimeric antigen receptors (CAR)-T-cell therapy represents the most important innovation in onco-hematology in recent years. The progress achieved in the management of complications and the latest generations of CAR-T-cells have made it possible to anticipate in second-line the indication of this type of treatment in large B-cell lymphoma. While some types of B-cell lymphomas and B-cell acute lymphoid leukemia have shown extremely promising results, the same cannot be said for myeloid leukemias-in particular, acute myeloid leukemia (AML), which would require innovative therapies more than any other blood disease. The heterogeneities of AML cells and the immunological complexity of the interactions between the bone marrow microenvironment and leukemia cells have been found to be major obstacles to the clinical development of CAR-T in AML. In this review, we report on the main results obtained in AML clinical trials, the preclinical studies testing potential CAR-T constructs, and future perspectives.
ABSTRACT
The combination approach based on venetoclax (VEN) with azacytidine (AZA) has significantly improved outcomes for elderly patients with acute myeloid leukemia (AML). This innovative approach has led to higher rates of overall response, measurable residual disease (MRD)-negative remissions, and overall survival compared with AZA monotherapy. As a result, this combination has emerged as the gold-standard treatment for elderly or unfit patients with AML who are not eligible for intensive therapy. In younger, fit patients with AML, intensive induction and consolidation chemotherapy is commonly used as a first-line approach; however, relapse continues to be the main reason for treatment failure in approximately 30-40% of patients. Efforts to improve MRD-negative response rates and to facilitate the transition to allogeneic hematopoietic stem cell transplantation, particularly in high-risk AML, have inspired trials exploring the combination of intensive chemotherapy with targeted agents. VEN, a first-in-class anti-BCL2 agent, combined with intensive chemotherapy regimens has shown deep MRD-negative remissions, producing prolonged event-free survival and enhancing the transition to allogeneic transplant in first-complete-remission patients. These benefits support the incremental advantages of adding VEN to intensive chemotherapy approaches across ELN risk subcategories, and provides a robust benchmark to design future trials. In this review, we will discuss current studies assessing the efficacy of frontline regimens integrating VEN into intensive chemotherapy in younger patients with AML and specific molecularly defined subgroups.
ABSTRACT
INTRODUCTION: Acute myeloid leukemia (AML) is a genetically heterogeneous disease for which the treatment armamentarium has been historically restricted to chemotherapy. However, genomic and epigenomic alterations that contribute to AML initiation, maintenance, and relapse have disclosed new insights to the 5th update in WHO Classification of Haematolymphoid Tumours. AREAS COVERED: After four decades of intensive chemotherapy as a 'one-size-fits-all' concept, several targeted agents have been approved for the treatment of AML. Several compounds, directed against regulators of apoptotic, epigenetic, or micro-environmental pathways, and immune-system modulators, are currently in development and investigation in clinical trials. We review advances in target-based therapy for AML focusing on their mechanism of action, examining the intracellular events and pathways, and the results from published clinical trials. EXPERT OPINION: To improve patient clinical outcomes, find new biomarkers for therapeutic response, and pinpoint patients who might benefit from novel targeted medicines, next-generation sequencing is being used to evaluate AML-associated mutations. In fact, the new 5th edition of WHO classification has reaffirmed the importance of genetically defined entities that have a prognostic impact, but not all have a specific treatment available. New class of target drugs are in clinical development and could be beneficial to improve the therapeutic armamentarium available.
Subject(s)
Antineoplastic Agents , Leukemia, Myeloid, Acute , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Mutation , Prognosis , World Health OrganizationABSTRACT
Elderly patients represent the most challenging and hard-to-treat patient population due to dismal characteristics of the disease, such as secondary-acute myeloid leukemia (AML), enrichment of unfavorable molecular genes (TP53) and comorbidities. We conducted a multicentric retrospective study to evaluate activity and safety in a real-life setting of hypomethylating drugs (HMAs) in patients older than 75 years with AML. Between September 2010 and December 2021, 220 patients were treated, 164 (74.5%) received AZAcitidine and 56 DECitabine; most patients (57.8%), received more than four cycles of HMAs. The best response obtained was CR in 51 patients (23.2%), PR in 23 (10.5%) and SD in 45 (20.5%); overall transfusion independence was obtained in 47 patients (34%), after a median of 3.5 months. The median OS (mOs) was 8 months (95% CI 5.9-10.2), with 1- and 2-years OS of 39.4% (95% CI 32.7-46) and 17.4% (95% CI 11.7-23.1), respectively; similar mOS was observed according to HMA treatment (AZA 8.3 vs. DEC 7.8 months, p = 0.810). A subset of 57 long survivors (44 in AZA group and 13 in DEC group) received at least 12 cycles of HMAs, their mOS was 24.3 months. In multivariate analysis, age (≥80), Charlson comorbidity index (≥3), creatinine clearance and the type of best response (≥PR) during treatment maintained independent significance in predicting survival. Infectious complications, most frequently pneumonia (35) and septic shock (12), were lethal in 49 patients (22.2%). Our data show that HMAs have similar efficacy compared to pivotal trials and are well tolerated in a setting of very elderly patients with several co-comorbidities.
ABSTRACT
Therapy-related acute myeloid leukemia (t-AML) and acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) represent aggressive diseases characterized by a dismal prognosis if compared with de novo acute myeloid leukemia, especially in older patients. In these AML subsets, standard chemotherapy regimens produce poor response rates and unsatisfactory outcomes. Historically, conventional approaches consisted of an anthracycline combined with continuous infusion of cytarabine for 7 days, the "3+7" regimen. Several attempts have been conducted to ameliorate this combination regimen but inconsistent improvements in response rates and no significant changes in overall survival have been observed, until the recent introduction of targeted molecules. A liposomal formulation of traditional chemotherapy agents cytarabine and daunorubicin, termed CPX-351, enhances pharmacodynamics and synergistic effects through the maintenance of the optimal 5:1 molar ratio, which extends the treatment's half-life and increases the bone marrow tropism of the drug. The use of CPX-351 in newly diagnosed AML-MRC and t-AML patients aged 60-75 years has demonstrated superior remission rates compared to conventional chemotherapy and improvements in event-free and overall survival. Recently, published data from a 5-year follow-up highlighted evidence that CPX-351 has the ability to produce and contribute to long-term remission and survival in older patients with newly diagnosed high-risk/secondary AML. Future perspectives include evaluation of dose intensification with CPX-351 in high-risk settings, combining this agent with targeted therapies, and better understanding the mechanism of improved responses in t-AML and AML-MRC. In this review, we will examine the role of CPX-351 inside the new AML therapeutic scenario and how its employment could potentially modify the treatment algorithm of high-risk and elderly patients with AML.
ABSTRACT
INTRODUCTION: Until the late 1980s, acute promyelocytic leukemia (APL) was the most rapidly fatal leukemia; however, nowadays, it is a curable disease with survival rates exceeding 90-95%. The improvement of APL outcome is mainly due to two agents, which target the typical translocation t(15;17) and its fusion transcript PML-RARα responsible for initiating and maintaining the disease: all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). The story of APL represents a pioneering model for the development of precision medicine and curative chemotherapy-free approaches for acute leukemia. AREA COVERED: The authors examine the major advances in the treatment of patients with APL focusing on three different eras: 1) the pre-ATRA era; 2) the ATRA era; 3) the ATO era. EXPERT OPINION: The combination of ATRA and ATO is effective and curative for the majority of APL patients. It has been approved for low/intermediate risk cases while an experimental trial with a minimal addition of chemotherapy for high-risk ones is ongoing. Disease relapse is infrequent and can be cured with ATRA-ATO rechallenging, with or without subsequent transplantation depending on the interval between complete remission and relapse. New therapeutic landscapes contemplate the use of an oral chemo-free ATRA-ATO combination, implementing treatment as outpatient care, thus increasing quality of life and decreasing medical costs.
Subject(s)
Arsenicals , Leukemia, Promyelocytic, Acute , Pharmaceutical Preparations , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Arsenicals/therapeutic use , Humans , Leukemia, Promyelocytic, Acute/drug therapy , Leukemia, Promyelocytic, Acute/genetics , Oxides/therapeutic use , Quality of Life , Treatment OutcomeABSTRACT
Acute myeloid leukemia (AML), the most frequent acute leukemia in adults, has been historically treated with infusional cytarabine (ara-c) + daunorubicin (3 + 7) for at least 40 years. The first "target therapy" to be introduced was the monoclonal anti-CD33 gemtuzumab ozogamicin (GO) in 2004. Unfortunately, in 2010 it was voluntarily withdrawn from the market both for safety reasons related to potential liver toxicity and veno-occlusive disease (VOD) and because clinical studies failed to confirm the clinical benefit during induction and maintenance. Seven years later, GO was re-approved based on new data, including insights into its mechanism of action on its target receptor CD33 expressed on myeloid cells. The present review focuses on current biological information and clinical data from several studies investigating GO. Cytogenetic, molecular, and immunophenotypic data are now able to predict the potential positive advantages of GO, with the exception of high-risk AML patients who do not seem to benefit. GO can be considered a 'repurposed drug' that could be beneficial for some patients with AML, mostly in combination with new drugs already approved or currently in testing.
ABSTRACT
Relapses of acute promyelocytic leukemia (APL) beyond 7 years from the first molecular remission are exceptional, and it is unclear whether these relapses represent a new, therapy-related leukemia rather than a delayed relapse of the original leukemic clone. The increase extra-medullary relapses (ER) in the era of all-trans retinoic acid (ATRA) therapy suggests a potential correlation between ATRA therapy and ER, and several potential explanations have been proposed. The gold standard post-remission approach, particularly for patients in late relapse, has not yet been established. The benefit of a transplant approach has been questioned in this setting because continuing ATRA-arsenic trioxide (ATO) might be curative. Here we report on the case of an APL patient who relapsed 9 years after achieving her first molecular complete remission (mCR) and who showed an atypical isolated localization at nodal sites, including the into- and peri-parotid glands. Genomic PML/RARa breakpoint analysis detected the same bcr3 PML/RARa hybrid gene in DNA purified from bone marrow and lymph nodes, suggesting that the relapse was because of the reemergence of the initial clone. This case shows that APL, treated with ATRA and cytotoxic drugs, may still emerge in extra-medullary sites even after a very prolonged mCR and could be salvaged with an ATO-based protocol, not including a transplant approach.
ABSTRACT
An unmet clinical need currently exists for elderly patients with relapsed/resistant (R/R) Philadelphia (Ph) positive acute lymphoblastic leukemia (ALL), nearly all who have a very poor prognosis. This includes patients already exposed to the first or second generation tyrosine kinase inhibitors (TKIs) and therefore has few treatment options available. New immunotherapies and targeted agents have shown encouraging activity in R/R ALL irrespective of age. Inotuzumab (InO), a humanized anti-CD22 monoclonal antibody, has potentially beneficial clinical effects in patients with resistant and difficult-to-treat disease in whom prior TKIs have failed. However, InO, as a single agent, did not show durable response and longer progression free survival and overall survival in R/R Ph positive ALL patients compared with those treated with standard chemotherapy. We observed a durable molecular remission (7 months) in an elderly patient affected by Ph'+ ALL with T315I and concomitant p190 and p210 expression achieved by concomitant therapy of InO (for 4 cycles) and ponatinib (15 mg/daily) followed by ponatinib (15 mg/daily) only as maintenance therapy. These findings suggest that elderly R/R Ph positive patients who cannot proceed to the transplant might benefit by concomitant immunotherapy and TKIs aimed to deepen the responses and prolong CR and outcomes.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Fusion Proteins, bcr-abl/genetics , Imidazoles/therapeutic use , Philadelphia Chromosome , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyridazines/therapeutic use , Aged , Fusion Proteins, bcr-abl/metabolism , Humans , Male , Polymorphism, Single Nucleotide , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Recurrence , Treatment OutcomeABSTRACT
BACKGROUND: According to 2008/2016 classification of the World Health Organization (WHO), a platelet (PLT) count ≥ 450 × 109/L, reduced from the previously published WHO 2001 indicated level ≥ 600 × 109/L, was considered the new PLT threshold for the diagnosis of essential thrombocythemia (ET). PATIENTS AND METHODS: To validate this important diagnostic change in a setting of current clinical practice, we retrospectively analyzed clinical and hematologic features at diagnosis and during follow-up of 162 patients with ET, diagnosed in our center from January 2008 to December 2017. We subdivided patients according to PLT value at baseline into Group A (PLT ≥ 600 × 109/L) (124 patients; 76.5%) and Group B (PLT ≥ 450 × 109/L < 600 × 109/L) (38 patients; 23.5%). RESULTS: Among clinical features, only the median value of leukocytes (P < .001) was significantly higher in Group A. Cytostatic treatment was administered in 103 patients, with a significantly higher rate in patients of group A (P < .001). After a median follow-up of 42.4 months (interquartile range, 22.1-70.6 months), 8 thrombotic events were recorded in the entire cohort, without differences between the 2 groups (P = .336). The 5-year overall survival (OS) of the entire cohort was 96.9% (95% confidence interval, 92.6%-100%), without differences between the 2 groups (P = .255). CONCLUSIONS: Our data indicate a substantial homogeneity among patients with ET regardless of the PLT count at diagnosis, thus confirming the usefulness of the 2008/2016 WHO diagnostic criteria.