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1.
N Engl J Med ; 390(11): 994-1008, 2024 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-38477987

RESUMEN

BACKGROUND: Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients. METHODS: In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. RESULTS: In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan. CONCLUSIONS: Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.).


Asunto(s)
Anemia Hemolítica , Factor B del Complemento , Inactivadores del Complemento , Hemoglobinas , Hemoglobinuria Paroxística , Humanos , Administración Oral , Anemia Hemolítica/complicaciones , Complemento C5/antagonistas & inhibidores , Factor B del Complemento/antagonistas & inhibidores , Inactivadores del Complemento/administración & dosificación , Inactivadores del Complemento/efectos adversos , Inactivadores del Complemento/uso terapéutico , Transfusión de Eritrocitos , Cefalea/inducido químicamente , Hemoglobinas/análisis , Hemoglobinuria Paroxística/tratamiento farmacológico , Hemoglobinuria Paroxística/etiología , Ensayos Clínicos Fase III como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto
2.
Cancer ; 130(5): 727-739, 2024 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-37897709

RESUMEN

BACKGROUND: This study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of 8-chloro-adenosine (8-Cl-Ado) in patients with relapsed/refractory acute myeloid leukemia (AML). METHODS: 8-Cl-Ado was administered daily for 5 days; the starting dose was 100 mg/m2 , the highest dose tested was 800 mg/m2 . The end points were toxicity, disease response, and PK/PD measurements. RESULTS: The predominant nonhematologic toxicity was cardiac with grade ≥3 toxicity. Plasma PK in all patients suggested heterogeneity among patients, yet, some dose-dependency for the accumulation of 8-Cl-Ado. Two 8-Cl-Ado metabolites accumulated at similar levels to 8-Cl-Ado. Cellular PK in eight patients indicated accumulation of 8-Cl-ATP, which was associated with AML blast cytoreduction in peripheral blood. The authors determined the RP2D of 8-Cl-Ado to be 400 mg/m2 . CONCLUSIONS: Given the cardiac adverse events observed, patients require monitoring for arrhythmias and QT interval during infusion. Although peripheral blood cytoreduction was observed, responses were transient, suggesting combination strategies will be required.


Asunto(s)
2-Cloroadenosina , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , 2-Cloroadenosina/análogos & derivados , 2-Cloroadenosina/farmacocinética , 2-Cloroadenosina/uso terapéutico
3.
Br J Haematol ; 205(1): 158-165, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38556836

RESUMEN

Therapy-related acute lymphoblastic leukaemia (tr-ALL) is a disease entity attributed to previous exposure to chemotherapy and/or radiation for antecedent malignancy. There is observed female predominance for tr-ALL, likely due to high prevalence and excellent curable rate for non-metastatic breast cancer as well as the frequent use of carcinogenic agents as part of adjuvant therapy. Here, we reviewed 37 women with diagnosis of ALL following breast cancer treatment with focus on cytogenetic categorization. Philadelphia chromosome positivity (Ph+), KMT2A alterations and other cytogenetic change groups were observed in 32%, 22% and 46% of patients respectively. Median overall survival (OS) and relapse-free survival (RFS) were 19.4 and 12.9 months, overall while both OS and RFS were superior in tr-ALL with Ph+ disease compared to KMT2Ar and other cytogenetics respectively. Seventeen (45.9%) patients underwent consolidative allogeneic haematopoietic cell transplantation (alloHCT) in CR1 out of which 4 (24%) relapsed following transplant. Both OS and RFS were superior in the KMT2Ar cytogenetics group following alloHCT. Ph chromosome represents the largest genetic entity of tr-ALL following breast cancer therapy, and it may be associated with superior survival outcomes while KMT2Ar may be associated with poorer outcomes that can perhaps be mitigated by alloHSCT.


Asunto(s)
Neoplasias de la Mama , Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Femenino , Neoplasias de la Mama/terapia , Neoplasias de la Mama/mortalidad , Persona de Mediana Edad , Adulto , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Anciano , Neoplasias Primarias Secundarias/etiología , Neoplasias Primarias Secundarias/terapia , Neoplasias Primarias Secundarias/epidemiología , Cromosoma Filadelfia , Proteína de la Leucemia Mieloide-Linfoide/genética , Estudios Retrospectivos , N-Metiltransferasa de Histona-Lisina
4.
Eur J Haematol ; 112(2): 236-247, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37772976

RESUMEN

Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated unprecedented success in the treatment of various hematologic malignancies including relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). Currently, there are two FDA-approved CD19-directed CAR-T cell products for the treatment of adults with R/R B-ALL. Despite high remission rates following CD19 CAR-T cell therapy in R/R B-ALL, remission durability remains limited in most adult patients, with relapse observed frequently in the absence of additional consolidation therapy. Furthermore, the burden of CAR-T cell toxicity remains significant in adults with R/R B-ALL and further limits the wide utilization of this effective therapy. In this review, we discuss patient and disease factors that are linked to CAR-T cell therapy outcomes in R/R B-ALL and strategies to optimize durability of response to reduce relapse and mitigate toxicity in the adult population. We additionally discuss future approaches being explored to maximize the benefit of CAR-T in adults with B-ALL.


Asunto(s)
Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores Quiméricos de Antígenos , Adulto , Humanos , Receptores Quiméricos de Antígenos/genética , Inmunoterapia Adoptiva/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Antígenos CD19 , Recurrencia , Tratamiento Basado en Trasplante de Células y Tejidos
6.
Am J Hematol ; 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38804599

RESUMEN

Allogeneic hematopoietic cell transplantation (HCT) offers a potential cure in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL); nonetheless, relapses are common and the major cause of mortality. One strategy to prevent relapse is tyrosine kinase inhibitor (TKI) maintenance post-HCT, but published clinical experience is primarily with the first-generation TKI imatinib while data with newer generation TKIs are limited. We conducted a retrospective analysis of 185 Ph+ ALL patients who underwent HCT followed by TKI maintenance from 2003 to 2021 at City of Hope. Initially, 50 (27.0%) received imatinib, 118 (63.8%) received a second-generation TKI (2G-TKI), and 17 (9.2%) received ponatinib. A total of 77 patients (41.6%) required a dose reduction of their initial TKI due to toxicity. Sixty-six patients (35.7%) did not complete maintenance due to toxicity; 69 patients (37.3%) discontinued 1 TKI, and 11 (5.9%) discontinued 2 TKIs due to toxicity. Initial imatinib versus 2G-TKI versus ponatinib maintenance was discontinued in 19 (38.0%) versus 68 (57.6%) versus 3 (17.6%) patients due to toxicity (p = .003), respectively. Patients on ponatinib as their initial TKI had a longer duration of TKI maintenance versus 2G-TKI: 576.0 days (range, 72-921) versus 254.5 days (range, 3-2740; p = .02). The most common reasons for initial TKI discontinuation include gastrointestinal (GI) intolerance (15.1%), cytopenia (8.6%), and fluid retention (3.8%). The 5-year overall survival and progression-free survival for the total population were 78% and 71%, respectively. Our findings demonstrate the challenges of delivering post-HCT TKI maintenance in a large real-world cohort as toxicities leading to TKI interruptions, discontinuation, and dose reduction were common.

7.
Am J Hematol ; 99(4): 615-624, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38343151

RESUMEN

Venetoclax-azacitidine is approved for treatment of patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive chemotherapy based on the interim overall survival (OS) analysis of the VIALE-A study (NCT02993523). Here, long-term follow-up is presented to address survival benefit and long-term outcomes with venetoclax-azacitidine. Patients with newly diagnosed AML who were ineligible for intensive chemotherapy were randomized 2:1 to receive venetoclax-azacitidine or placebo-azacitidine. OS was the primary endpoint; complete remission with/without blood count recovery (CR/CRi) was a key secondary endpoint. This final analysis was conducted when 100% of the predefined 360 OS events occurred. In VIALE-A, 431 patients were enrolled to venetoclax-azacitidine (n = 286) or placebo-azacitidine (n = 145). At 43.2 months median follow-up, median OS was 14.7 months (95% confidence interval [CI], 12.1-18.7) with venetoclax-azacitidine, and 9.6 months (95% CI, 7.4-12.7) with placebo-azacitidine (hazard ratio, 0.58 [95% CI, 0.47-0.72], p < .001); the estimated 24-month OS rate was 37.5% and 16.9%, respectively. Median OS for patients with IDH1/2 mutations and those with measurable residual disease responses was reached in this final analysis. CR/CRi rate was similar to interim analysis. Any-grade hematologic and gastrointestinal adverse events were most common in venetoclax-azacitidine and placebo-azacitidine arms, including thrombocytopenia (47% and 42%) and neutropenia (43% and 29%). No new safety signals were identified. Long-term efficacy and safety confirm venetoclax-azacitidine is an improvement in standard-of-care for patients with AML who are not eligible for intensive chemotherapy because of advanced age or comorbidities.


Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Mieloide Aguda , Neutropenia , Sulfonamidas , Humanos , Estudios de Seguimiento , Leucemia Mieloide Aguda/tratamiento farmacológico , Azacitidina/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos
8.
J Oncol Pharm Pract ; : 10781552231219995, 2024 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-38166462

RESUMEN

PURPOSE: This letter evaluated the impact of different management strategies, specifically the presence or absence of therapeutic anticoagulation, on clinical outcomes for central venous catheter (CVC)-associated deep vein thrombosis (DVT) in cancer patients. METHODS: One-hundred ninety-eight adult cancer patients with a confirmed CVC-associated DVT diagnosis from February 2013 and February 2021 were included. RESULTS: Incidence of symptomatic recurrent venous thromboembolism (VTE) was similar between patients who received therapeutic anticoagulation and those who did not (14% vs 16%, p = 0.807). In addition, therapeutic anticoagulation did not significantly alter the incidence of grade 3 and above bleeding events despite most patients having hematologic malignancies (9% vs 8%, p = 0.826). CONCLUSION AND RELEVANCE: Therapeutic anticoagulation was not associated with a reduction in the incidence of recurrent VTE or increase the incidence of bleeding in adult cancer patients following a CVC-associated DVT diagnosis.

9.
Oncologist ; 28(9): e843-e846, 2023 09 07.
Artículo en Inglés | MEDLINE | ID: mdl-37335880

RESUMEN

Trastuzumab emtansine and trastuzumab deruxtecan are widely used in breast cancer and other solid tumor malignancies. Thrombocytopenia is a common adverse event associated with the use of these agents that can lead to a treatment delay, reduction in dose intensity, and discontinuation. The role of thrombopoietin receptor agonists (TPO-RA) remains unknown in this setting. We report a case series of 6 individuals with breast cancer that experienced dose-reductions and therapy delays due to thrombocytopenia secondary to trastuzumab emtansine or trastuzumab deruxtecan therapy and received intervention with TPO-RA. All 6 were able to resume therapy with TPO-RA support.


Asunto(s)
Anemia , Neoplasias de la Mama , Inmunoconjugados , Trombocitopenia , Humanos , Femenino , Ado-Trastuzumab Emtansina/uso terapéutico , Receptores de Trombopoyetina/uso terapéutico , Receptor ErbB-2/genética , Receptor ErbB-2/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Trastuzumab/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Trombocitopenia/inducido químicamente , Trombocitopenia/tratamiento farmacológico , Anemia/inducido químicamente , Inmunoconjugados/uso terapéutico
10.
N Engl J Med ; 383(7): 617-629, 2020 08 13.
Artículo en Inglés | MEDLINE | ID: mdl-32786187

RESUMEN

BACKGROUND: Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine added to venetoclax had promising efficacy in a previous phase 1b study. METHODS: We randomly assigned previously untreated patients with confirmed AML who were ineligible for standard induction therapy because of coexisting conditions, because they were 75 years of age or older, or both to azacitidine plus either venetoclax or placebo. All patients received a standard dose of azacitidine (75 mg per square meter of body-surface area subcutaneously or intravenously on days 1 through 7 every 28-day cycle); venetoclax (target dose, 400 mg) or matching placebo was administered orally, once daily, in 28-day cycles. The primary end point was overall survival. RESULTS: The intention-to-treat population included 431 patients (286 in the azacitidine-venetoclax group and 145 in the azacitidine-placebo [control] group). The median age was 76 years in both groups (range, 49 to 91). At a median follow-up of 20.5 months, the median overall survival was 14.7 months in the azacitidine-venetoclax group and 9.6 months in the control group (hazard ratio for death, 0.66; 95% confidence interval, 0.52 to 0.85; P<0.001). The incidence of complete remission was higher with azacitidine-venetoclax than with the control regimen (36.7% vs. 17.9%; P<0.001), as was the composite complete remission (complete remission or complete remission with incomplete hematologic recovery) (66.4% vs. 28.3%; P<0.001). Key adverse events included nausea of any grade (in 44% of the patients in the azacitidine-venetoclax group and 35% of those in the control group) and grade 3 or higher thrombocytopenia (in 45% and 38%, respectively), neutropenia (in 42% and 28%), and febrile neutropenia (in 42% and 19%). Infections of any grade occurred in 85% of the patients in the azacitidine-venetoclax group and 67% of those in the control group, and serious adverse events occurred in 83% and 73%, respectively. CONCLUSIONS: In previously untreated patients who were ineligible for intensive chemotherapy, overall survival was longer and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone. The incidence of febrile neutropenia was higher in the venetoclax-azacitidine group than in the control group. (Funded by AbbVie and Genentech; VIALE-A ClinicalTrials.gov number, NCT02993523.).


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Azacitidina/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Sulfonamidas/administración & dosificación , Anciano , Anciano de 80 o más Años , Azacitidina/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Análisis de Intención de Tratar , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidad , Leucopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Neumonía/etiología , Recurrencia , Inducción de Remisión , Sulfonamidas/efectos adversos , Trombocitopenia/inducido químicamente
11.
Eur J Haematol ; 110(2): 213-216, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36335580

RESUMEN

Systemic mastocytosis (SM) results from clonal proliferation of neoplastic mast cells that infiltrate bone marrow and other organs. A major subset of patients with SM has a clonally related myeloid neoplasm and the SM itself (SM-AMN). We evaluated the efficacy of hypomethylating agent and venetoclax (HMA-VEN) to target both the myeloid neoplasm and mast cell infiltrate in a patient with SM associated with acute myeloid leukemia arising from myelodysplastic syndrome and illustrate complete elimination of bone marrow mast cells and complete remission of MDS/AML. This case illustrates the potent activity of HMA-VEN both against the AMN as well as the associated SM.


Asunto(s)
Leucemia Mieloide Aguda , Mastocitosis Sistémica , Síndromes Mielodisplásicos , Trastornos Mieloproliferativos , Humanos , Mastocitosis Sistémica/complicaciones , Mastocitosis Sistémica/diagnóstico , Mastocitosis Sistémica/tratamiento farmacológico , Mastocitos , Médula Ósea , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/tratamiento farmacológico , Trastornos Mieloproliferativos/complicaciones , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/tratamiento farmacológico , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico
12.
Am J Hematol ; 98(4): 588-597, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36594185

RESUMEN

To enhance protective cytomegalovirus (CMV)-specific T cells in immunosuppressed recipients of an allogeneic hematopoietic cell transplant (HCT), we evaluated post-HCT impact of vaccinating healthy HCT donors with Triplex. Triplex is a viral vectored recombinant vaccine expressing three immunodominant CMV antigens. The vector is modified vaccinia Ankara (MVA), an attenuated, non-replicating poxvirus derived from the vaccinia virus strain Ankara. It demonstrated tolerability and immunogenicity in healthy adults and HCT recipients, in whom it also reduced CMV reactivation. Here, we report feasibility, safety, and immunological outcomes of a pilot phase 1 trial (NCT03560752 at ClinicalTrials.gov) including 17 CMV-seropositive recipients who received an HCT from a matched related donor (MRD) vaccinated with 5.1 × 108 pfu/ml of Triplex before cell harvest (median 15, range 11-28 days). Donor and recipient pairs who committed to participation in the trial resulted in exceptional adherence to the protocol. Triplex was well-tolerated with limited adverse events in donors and recipients, who all engrafted with full donor chimerism. On day 28 post-HCT, levels of functional vaccinia- and CMV-specific CD137+ CD8+ T cells were significantly higher (p < .0001 and p = .0174, respectively) in recipients of Triplex vaccinated MRD than unvaccinated MRD (control cohort). Predominantly, central and effector memory CMV-specific T-cell responses continued to steadily expand through 1-year follow-up. CMV viremia requiring antivirals developed in three recipients (18%). In summary, this novel approach represents a promising strategy applicable to different HCT settings for limiting the use of antiviral prophylaxis, which can impair and delay CMV-specific immunity, leading to CMV reactivation requiring treatment.


Asunto(s)
Infecciones por Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Vaccinia , Adulto , Humanos , Citomegalovirus , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Linfocitos T CD8-positivos , Vaccinia/tratamiento farmacológico , Vaccinia/etiología , Infecciones por Citomegalovirus/prevención & control , Antivirales/uso terapéutico , Vacunación
13.
Am J Hematol ; 98(6): 848-856, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36880203

RESUMEN

Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is associated with a poor response to standard chemotherapy. However, outcomes with novel antibody and cellular therapies in relapsed/refractory (r/r) Ph-like ALL are largely unknown. We conducted a single-center retrospective analysis of adult patients (n = 96) with r/r B-ALL and fusions associated with Ph-like who received novel salvage therapies. Patients were treated with 149 individual novel regimens (blinatumomab = 83, inotuzumab ozogamicin [InO] = 36, and CD19CAR T cells = 30). The median age at first novel salvage therapy was 36 years (range; 18-71). Ph-like fusions were IGH::CRLF2 (n = 48), P2RY8::CRLF2 (n = 26), JAK2 (n = 9), ABL-class (n = 8), EPOR::IGH (n = 4) and ETV6::NTRK2 (n = 1). CD19CAR T cells were administered later in the course of therapy compared to blinatumomab and InO (p < .001) and more frequently in recipients who relapsed after allogeneic hematopoietic cell transplantation (alloHCT) (p = .002). Blinatumomab was administered at an older age compared to InO and CAR T-cells (p = .004). The complete remission (CR)/CR with incomplete hematologic recovery (CRi) rates were 63%, 72%, and 90% following blinatumomab, InO and CD19CAR, respectively, among which 50%, 50%, and 44% of responders underwent consolidation with alloHCT, respectively. In multivariable analysis, the type of novel therapy (p = .044) and pretreatment marrow blasts (p = .006) predicted the CR/CRi rate, while the Ph-like fusion subtype (p = .016), pretreatment marrow blasts (p = .022) and post-response consolidation with alloHCT (p < .001) influenced event-free survival. In conclusion, novel therapies are effective in inducing high remission rates in patients with r/r Ph-like ALL and successfully transitioning the responders to alloHCT.


Asunto(s)
Anticuerpos Biespecíficos , Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Humanos , Estudios Retrospectivos , Inotuzumab Ozogamicina/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Inducción de Remisión , Anticuerpos Biespecíficos/uso terapéutico
14.
Curr Oncol Rep ; 25(1): 51-61, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36449117

RESUMEN

PURPOSE OF REVIEW: This review aims to help oncologists who predominantly treat adults better understand and manage asparaginase associated toxicities and prevent unnecessary discontinuation or reluctance of its use. RECENT FINDINGS: Given the data supporting the benefit of incorporating multiple doses of asparaginase in pediatric type regimens, it is prudent to promote deeper understanding of this drug, particularly its toxicities, and its use so as to optimize treatment of ALL. Although asparaginase is associated with a variety of toxicities, the vast majority are not life threatening and do not preclude repeat dosing of this important drug. Understanding the pharmacology and toxicity profile of asparaginase is critical to dosing asparaginase appropriately in order to minimize these toxicities.


Asunto(s)
Antineoplásicos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Humanos , Niño , Asparaginasa/efectos adversos , Antineoplásicos/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico
15.
Cancer ; 128(3): 529-535, 2022 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-34633671

RESUMEN

BACKGROUND: Blinatumomab has demonstrated encouraging activity in relapsed/refractory (r/r) and minimal residual disease-positive (MRD+) acute lymphoblastic leukemia (ALL). Extramedullary disease (EMD) relapse or relapse with CD19- disease has been observed after blinatumomab therapy in patients with r/r or MRD+ ALL. However, the pathophysiology and risk factors of treatment failure are not fully understood. METHODS: This study retrospectively reviewed the outcomes of adult patients with B-cell ALL treated with blinatumomab (n = 132) for either r/r (n = 103) or MRD+ disease (n = 29) at the authors' center (2013-2021) and analyzed factors associated with treatment response and EMD failure. RESULTS: The overall response rate was 64%. A lower marrow blast burden before blinatumomab (P = .049) and no history of previous EMD (P = .019) were significantly associated with a higher response. Among the patients who responded to blinatumomab, 56% underwent consolidation with allogeneic transplantation. Blinatumomab failure was observed in 89 patients; 43% of these patients (n = 38) either progressed or relapsed at extramedullary sites. A history of extramedullary involvement (53% vs 24%; P = .005) and retention of CD19 expression at the time of relapse/progression (97% vs 74%; P = .012) were associated with a higher risk for extramedullary failure. Central nervous system (CNS) failure after blinatumomab was encountered in 39% of the patients with EMD. CONCLUSIONS: A history of EMD predicted an inferior response to blinatumomab therapy with a higher risk for relapse/progression at extramedullary sites (particularly CNS). Consolidation with allogenic transplantation in patients who primarily responded to blinatumomab did not abrogate the risk of extramedullary relapse. The incorporation of extramedullary assessment and the intensification of CNS prophylaxis may help in addressing extramedullary failure. LAY SUMMARY: Extramedullary failure is common during blinatumomab therapy for relapsed/refractory acute lymphoblastic leukemia. A history of extramedullary disease predicts an inferior response to blinatumomab therapy and a higher risk for relapse/progression at extramedullary sites. Most extramedullary failure cases retain CD19 expression.


Asunto(s)
Anticuerpos Biespecíficos , Progresión de la Enfermedad , Leucemia-Linfoma Linfoblástico de Células Precursoras , Anticuerpos Biespecíficos/uso terapéutico , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recurrencia , Estudios Retrospectivos
16.
Curr Opin Oncol ; 34(5): 531-539, 2022 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-35855507

RESUMEN

PURPOSE OF REVIEW: Venetoclax in combination with nucleoside analogs such as hypomethylating agents (HMA) and low-dose cytarabine (LDAC) has led to unprecedented response and survival outcomes in patients with acute myeloid leukemia (AML). This has spurred the development of regimens combining venetoclax with other nucleoside analogs with distinct mechanisms of action. Here, we review older and newer nucleoside analogs, the rationale for their combination with venetoclax, and clinical evidence for the combination when available. RECENT FINDINGS: Venetoclax with HMA prolonged survival in a phase 3 study. Additionally, biologic correlates of response and resistance to venetoclax with HMA have been identified. The addition of venetoclax to standard intensive regimens containing higher doses of cytarabine and purine nucleoside analogs are safe and induce very high rates of remission and measurable residual disease negativity (MRD) negativity in newly diagnosed and relapsed/refractory AML. Investigational nucleoside analogs aim to improve upon the safety, bioavailability, or efficacy of approved venetoclax combinations and are currently being evaluated in clinical studies. SUMMARY: The development of venetoclax with HMA has transformed care for elderly adults with AML and opened the door for novel combinations of venetoclax with other nucleoside analogs. Further clinical studies are needed to see if these novel combinations further improve outcomes in AML particularly for patients with high-risk disease.


Asunto(s)
Leucemia Mieloide Aguda , Nucleósidos , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes , Citarabina/efectos adversos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Nucleósidos/uso terapéutico , Sulfonamidas
17.
Hematol Oncol ; 40(1): 105-110, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34766363

RESUMEN

Acute Lymphocytic Leukemia (ALL) is a malignancy that originates from immature lymphoid cells and is clinically established with flow cytometry through disease-specific markers. Variation between ethnic groups is an epidemiological aspect of ALL. Higher incidence rates have been observed in Latin American patients and ALL in Latinos carries a dismal prognosis. The cell of origin in ALL is derived from immature cells of either the B or T lineage. Most reported data among Latinos either exclusively looks at B cell precursor ALL or do not distinguish between subtypes. We used the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database to delineate the differences in incidence rates of B-ALL and T-ALL across ethnic groups in the United States. Data from SEER-18 was used to compare incidence rates of T-ALL and B-ALL. Due to the utilization of cytogenetics and subsequent changes in ICD coding over the years examined the most recent data reported from 2002 to 2017. We compared rates in Non-Hispanic Whites (NHWs), Latinos, Blacks and Asian-Pacific Islanders (API). Age-adjusted incidence rates per 100,000 person-years were calculated. The incidence rate of B-ALL in the Latino population was consistently higher than other race/ethnicities throughout the years, ranging from 1.0 per 100,000 in 2002 to 2.5 per 100,000 in 2017. Blacks had the lowest age adjusted incidence rate (AAIR) of B-ALL overall, with rates approximately one third of those found in Latinos and the highest AAIR of T-ALL with an AAIR of 0.5 per 100,000.


Asunto(s)
Inmunofenotipificación/métodos , Grupos Minoritarios/estadística & datos numéricos , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Programa de VERF/estadística & datos numéricos , Adolescente , Adulto , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Lactante , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Estados Unidos/epidemiología , Adulto Joven
18.
Am J Hematol ; 97(3): 256-266, 2022 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-34748664

RESUMEN

Thrombosomes are trehalose-stabilized, freeze-dried group O platelets with a 3-year shelf life. They can be stockpiled, rapidly reconstituted, and infused regardless of the recipient's blood type. Thrombosomes thus represent a potential alternative platelet transfusion strategy. The present study assessed the safety and potential early signals of efficacy of Thrombosomes in bleeding thrombocytopenic patients. We performed an open-label, phase 1 study of single doses of allogeneic Thrombosomes at three dose levels in three cohorts, each consisting of eight patients who had hematologic malignancies, thrombocytopenia, and bleeding. Adverse events, dose-limiting toxicities (DLTs), World Health Organization (WHO) bleeding scores, and hematology values were assessed. No DLTs were reported. The median age was 59 years (24-71). Most patients had AML (58%) or ALL (29%), followed by MDS (8%) and myeloproliferative neoplasm (4%). The WHO scores of 22 patients who were actively bleeding at a total of 27 sites at baseline either improved (n = 17 [63%]) or stabilized (n = 10 [37%]) through day 6. Twenty-four hours after infusion, 12 patients (50%) had a clinically significant platelet count increase. Of eight patients who received no platelet transfusions for 6 days after Thrombosomes infusion, 5 had a clinically significant increase in platelet count of ≥5000 platelets/µL and 2 had platelet count normalization. Thrombosomes doses up to 3.78 × 108 particles/kg demonstrated safety in 24 bleeding, thrombocytopenic patients with hematological malignancies. Thrombosomes may represent an alternative to conventional platelets to treat bleeding. A phase 2 clinical trial in a similar patient population is underway.


Asunto(s)
Plaquetas , Conservación de la Sangre , Neoplasias Hematológicas/terapia , Hemorragia/terapia , Transfusión de Plaquetas , Trombocitopenia/terapia , Adulto , Anciano , Femenino , Liofilización , Humanos , Masculino , Persona de Mediana Edad
19.
Int J Mol Sci ; 23(12)2022 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-35743010

RESUMEN

Venetoclax (VEN) in combination with hypomethylating agents induces disease remission in patients with de novo AML, however, most patients eventually relapse. AML relapse is attributed to the persistence of drug-resistant leukemia stem cells (LSCs). LSCs need to maintain low intracellular levels of reactive oxygen species (ROS). Arsenic trioxide (ATO) induces apoptosis via upregulation of ROS-induced stress to DNA-repair mechanisms. Elevated ROS levels can trigger the Nrf2 antioxidant pathway to counteract the effects of high ROS levels. We hypothesized that ATO and VEN synergize in targeting LSCs through ROS induction by ATO and the known inhibitory effect of VEN on the Nrf2 antioxidant pathway. Using cell fractionation, immunoprecipitation, RNA-knockdown, and fluorescence assays we found that ATO activated nuclear translocation of Nrf2 and increased transcription of antioxidant enzymes, thereby attenuating the induction of ROS by ATO. VEN disrupted ATO-induced Nrf2 translocation and augmented ATO-induced ROS, thus enhancing apoptosis in LSCs. Using metabolic assays and electron microscopy, we found that the ATO+VEN combination decreased mitochondrial membrane potential, mitochondria size, fatty acid oxidation and oxidative phosphorylation, all of which enhanced apoptosis of LSCs derived from both VEN-sensitive and VEN-resistant AML primary cells. Our results indicate that ATO and VEN cooperate in inducing apoptosis of LSCs through potentiation of ROS induction, suggesting ATO+VEN is a promising regimen for treatment of VEN-sensitive and -resistant AML.


Asunto(s)
Antineoplásicos , Arsenicales , Leucemia Mieloide Aguda , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antioxidantes/farmacología , Apoptosis , Trióxido de Arsénico/farmacología , Trióxido de Arsénico/uso terapéutico , Arsenicales/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Óxidos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Recurrencia , Sulfonamidas
20.
Blood ; 133(1): 7-17, 2019 01 03.
Artículo en Inglés | MEDLINE | ID: mdl-30361262

RESUMEN

Older patients with acute myeloid leukemia (AML) respond poorly to standard induction therapy. B-cell lymphoma 2 (BCL-2) overexpression is implicated in survival of AML cells and treatment resistance. We report safety and efficacy of venetoclax with decitabine or azacitidine from a large, multicenter, phase 1b dose-escalation and expansion study. Patients (N = 145) were at least 65 years old with treatment-naive AML and were ineligible for intensive chemotherapy. During dose escalation, oral venetoclax was administered at 400, 800, or 1200 mg daily in combination with either decitabine (20 mg/m2, days 1-5, intravenously [IV]) or azacitidine (75 mg/m2, days 1-7, IV or subcutaneously). In the expansion, 400 or 800 mg venetoclax with either hypomethylating agent (HMA) was given. Median age was 74 years, with poor-risk cytogenetics in 49% of patients. Common adverse events (>30%) included nausea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased appetite, and decreased white blood cell count. No tumor lysis syndrome was observed. With a median time on study of 8.9 months, 67% of patients (all doses) achieved complete remission (CR) + CR with incomplete count recovery (CRi), with a CR + CRi rate of 73% in the venetoclax 400 mg + HMA cohort. Patients with poor-risk cytogenetics and those at least 75 years old had CR + CRi rates of 60% and 65%, respectively. The median duration of CR + CRi (all patients) was 11.3 months, and median overall survival (mOS) was 17.5 months; mOS has not been reached for the 400-mg venetoclax cohort. The novel combination of venetoclax with decitabine or azacitidine was effective and well tolerated in elderly patients with AML (This trial was registered at www.clinicaltrials.gov as #NCT02203773).


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Azacitidina/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Estudios de Cohortes , Decitabina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/patología , Masculino , Dosis Máxima Tolerada , Pronóstico , Sulfonamidas/administración & dosificación , Tasa de Supervivencia
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