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1.
EJHaem ; 4(3): 639-646, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37601874

RESUMEN

The prognostic impact of t(11;14) in multiple myeloma (MM) needs to be better understood to inform future treatment decisions. The Australian Lymphoma Leukaemia Group embarked on a retrospective, observational cohort study using real-world data to interrogate treatment patterns and outcomes in 74 MM patients with t(11;14) [t(11;14)-MM] diagnosed over 10 years. This was compared to 159 and 111 MM patients with high-risk IgH translocations (IgH HR-MM) and hyperdiploidy (Hyperdiploid-MM), respectively, from the Australian Myeloma and Related Diseases Registry. No appreciable differences in age, gender, ISS, LDH levels, 1q21 or del(17p) status, or treatment patterns were observed between groups. Median PFS-1 was not different between groups but both t(11;14)-MM and IgH HR-MM had an inferior PFS-2 vs. Hyperdiploid-MM: median PFS-2 8.2 months, 10.0 months, and 19.8 months (p = 0.002), respectively. The 3-year OS were 69%, 71%, and 82% (p = 0.026), respectively. In the t(11;14)-MM group, gain or amplification of 1q21 at diagnosis predicted for poorer OS (HR 3.46, p = 0.002). Eleven patients had received venetoclax with 45% achieving better than a very good partial response. Results suggest that t(11;14) MM may confer an unfavorable risk profile and that the use of targeted therapies such as venetoclax earlier in the treatment algorithm should be explored.

2.
Cancer Discov ; 12(3): 774-791, 2022 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-34862195

RESUMEN

Cancer cell metabolism is increasingly recognized as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small-molecule ironomycin reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism. Ironomycin promotes the recruitment and activation of BAX/BAK, but the resulting mitochondrial outer membrane permeabilization (MOMP) does not lead to potent activation of the apoptotic caspases, nor is the ensuing cell death prevented by inhibiting the previously established pathways of programmed cell death. Consistent with the fact that ironomycin and BH3 mimetics induce MOMP through independent nonredundant pathways, we find that ironomycin exhibits marked in vitro and in vivo synergy with venetoclax and overcomes venetoclax resistance in primary patient samples. SIGNIFICANCE: Ironomycin couples targeting of cellular metabolism with cell death by reducing mitochondrial iron, resulting in the alteration of mitochondrial metabolism and the activation of BAX/BAK. Ironomycin induces MOMP through a different mechanism to BH3 mimetics, and consequently combination therapy has marked synergy in cancers such as acute myeloid leukemia. This article is highlighted in the In This Issue feature, p. 587.


Asunto(s)
Hierro , Proteína Destructora del Antagonista Homólogo bcl-2 , Apoptosis , Muerte Celular , Humanos , Hierro/metabolismo , Mitocondrias/metabolismo , Proteína Destructora del Antagonista Homólogo bcl-2/metabolismo , Proteína X Asociada a bcl-2/metabolismo
3.
Cancer Cell ; 40(10): 1190-1206.e9, 2022 10 10.
Artículo en Inglés | MEDLINE | ID: mdl-36179686

RESUMEN

There is increasing recognition of the prognostic significance of tumor cell major histocompatibility complex (MHC) class II expression in anti-cancer immunity. Relapse of acute myeloid leukemia (AML) following allogeneic stem cell transplantation (alloSCT) has recently been linked to MHC class II silencing in leukemic blasts; however, the regulation of MHC class II expression remains incompletely understood. Utilizing unbiased CRISPR-Cas9 screens, we identify that the C-terminal binding protein (CtBP) complex transcriptionally represses MHC class II pathway genes, while the E3 ubiquitin ligase complex component FBXO11 mediates degradation of CIITA, the principal transcription factor regulating MHC class II expression. Targeting these repressive mechanisms selectively induces MHC class II upregulation across a range of AML cell lines. Functionally, MHC class II+ leukemic blasts stimulate antigen-dependent CD4+ T cell activation and potent anti-tumor immune responses, providing fundamental insights into the graft-versus-leukemia effect. These findings establish the rationale for therapeutic strategies aimed at restoring tumor-specific MHC class II expression to salvage AML relapse post-alloSCT and also potentially to enhance immunotherapy outcomes in non-myeloid malignancies.


Asunto(s)
Proteínas F-Box , Leucemia Mieloide Aguda , Oxidorreductasas de Alcohol , Proteínas de Unión al ADN , Proteínas F-Box/genética , Antígenos HLA/genética , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Activación de Linfocitos , Proteína-Arginina N-Metiltransferasas/metabolismo , Recurrencia , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo
4.
Bone Marrow Transplant ; 56(10): 2582-2590, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34031553

RESUMEN

Identification of patients at risk of initial & recurrent cytomegalovirus (CMV) reactivation following allogeneic stem cell transplant (alloSCT) may help guide prophylactic strategies. T-cell receptor beta (TRB) deep sequencing was used to identify and enumerate the T-cell repertoire harbouring TRB sequences with annotated specificity to CMV (pubCMVrep), as well as the overall T-cell receptor (TCR) repertoire diversity at day +30 & day +60 post-alloSCT for 65 patients. T-cells harbouring TRB sequences with annotated specificity for CMV were identifiable in all patients. 56% of patients required CMV treatment and 23% of the cohort developed recurrent CMV. PubCMVrep size at day +30 was not associated with reactivation, however amongst patients with antecedent CMV viremia a low day +60 pubCMVrep was associated with a greater incidence of recurrent CMV (75% vs. 21%, HR 6.16, 95% CI 1.29-29.40, P = 0.0008). Moreover, patients with high pubCMVrep only developed recurrent CMV in the setting of GVHD. Low TCR diversity at day +30 was associated with a greater incidence of initial CMV reactivation (71% vs. 22%, HR 5.39, 95% CI 1.70-17.09, p = 0.0002). pubCMVrep and TCR diversity are promising biomarkers to identify patients at risk of initial & recurrent CMV who may benefit from novel prophylactic strategies.


Asunto(s)
Infecciones por Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Citomegalovirus , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Receptores de Antígenos de Linfocitos T/genética , Trasplante de Células Madre/efectos adversos , Trasplante Homólogo , Activación Viral
5.
Pathology ; 53(5): 608-612, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-33618863

RESUMEN

We reviewed haematological investigations for 43 patients treated at a single centre with alectinib, an inhibitor of anaplastic lymphoma kinase (ALK) which is considered standard first-line treatment for patients with ALK-rearranged advanced non-small cell lung cancer. Ninety-five percent of patients developed marked acanthocytosis, echinocytosis and/or spheroacanthocytosis, not observable with prior treatment with other ALK-inhibitors. Anaemia developed in 73% of patients (38% <100 g/L, 8% <80 g/L), though definite new haemolysis was present in only 11%. Eosin-5-maleimide binding was reduced in all assessed patients, and increased membrane cholesterol was identified in one patient assessed with lattice light sheet microscopy. We have identified a previously undescribed phenomenon whereby alectinib induces red cell membrane abnormalities in nearly all patients through an unclear, but likely ALK-independent, mechanism, resulting in mild anaemia without universal haemolysis.


Asunto(s)
Abetalipoproteinemia/patología , Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Carbazoles/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Piperidinas/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Abetalipoproteinemia/inducido químicamente , Quinasa de Linfoma Anaplásico/metabolismo , Anemia/inducido químicamente , Anemia/patología , Carbazoles/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Hemólisis/efectos de los fármacos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Maleimidas/metabolismo , Piperidinas/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Estudios Retrospectivos
6.
Blood Adv ; 5(23): 5107-5111, 2021 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-34555849

RESUMEN

Monitoring of NPM1 mutant (NPM1mut) measurable residual disease (MRD) in acute myeloid leukemia (AML) has an established role in patients who are treated with intensive chemotherapy. The European LeukemiaNet has defined molecular persistence at low copy number (MP-LCN) as an MRD transcript level <1% to 2% with a <1-log change between any 2 positive samples collected after the end of treatment (EOT). Because the clinical impact of MP-LCN is unknown, we sought to characterize outcomes in patients with persistent NPM1mut MRD after EOT and identify factors associated with disease progression. Consecutive patients with newly diagnosed NPM1mut AML who received ≥2 cycles of intensive chemotherapy were included if bone marrow was NPM1mut MRD positive at the EOT, and they were not transplanted in first complete remission. One hundred patients were followed for a median of 23.5 months; 42% remained free of progression at 1 year, either spontaneously achieving complete molecular remission (CRMRD-; 30%) or retaining a low-level NPM1mut transcript (12% for ≥12 months and 9% at last follow-up). Forty percent met the criteria for MP-LCN. Preemptive salvage therapy significantly prolonged relapse-free survival. Risk factors associated with disease progression were concurrent FLT3-internal tandem duplication at diagnosis and suboptimal MRD response (NPM1mut reduction <4.4-log) at EOT.


Asunto(s)
Leucemia Mieloide Aguda , Proteínas Nucleares , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Mutación , Neoplasia Residual , Proteínas Nucleares/genética , Inducción de Remisión
7.
Leuk Lymphoma ; 60(14): 3417-3425, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31304820

RESUMEN

We present an analysis of 98 consecutive patients with peripheral T-cell lymphoma (PTCL) treated over a 10-year period within Western Australia. The most common frontline therapies were CHO(E)P (47%), HyperCVAD (21%), and reduced intensity therapy or supportive care alone (19%). Median and 4-year overall survival (OS) for the whole cohort were 1.59 years and 34%. Amongst CHO(E)P and HyperCVAD-treated patients, elevated LDH, advanced stage, IPI >1, and non-ALK + ALCL histology predicted inferior progression-free survival (PFS). Inferior OS was predicted by elevated LDH, age >60, IPI >1, and non-ALK + ALCL histology. Response rates and PFS were not significantly different between patients treated with CHO(E)P or HyperCVAD. OS was longer in the HyperCVAD group, however this was not significant on multivariable analysis and appears to relate to the younger age and more aggressive therapy at relapse in this group. Our data confirmed the prognostic utility of the IPI in patients with PTCL and do not demonstrate a clear benefit of HyperCVAD.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma Anaplásico de Células Grandes/mortalidad , Linfoma de Células T Periférico/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Trasplante de Células Madre/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Linfoma Anaplásico de Células Grandes/patología , Linfoma Anaplásico de Células Grandes/terapia , Linfoma de Células T Periférico/patología , Linfoma de Células T Periférico/terapia , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Australia Occidental , Adulto Joven
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