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1.
Blood Cancer J ; 12(1): 5, 2022 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-35017466

RESUMO

Treatment with Menin inhibitor (MI) disrupts the interaction between Menin and MLL1 or MLL1-fusion protein (FP), inhibits HOXA9/MEIS1, induces differentiation and loss of survival of AML harboring MLL1 re-arrangement (r) and FP, or expressing mutant (mt)-NPM1. Following MI treatment, although clinical responses are common, the majority of patients with AML with MLL1-r or mt-NPM1 succumb to their disease. Pre-clinical studies presented here demonstrate that genetic knockout or degradation of Menin or treatment with the MI SNDX-50469 reduces MLL1/MLL1-FP targets, associated with MI-induced differentiation and loss of viability. MI treatment also attenuates BCL2 and CDK6 levels. Co-treatment with SNDX-50469 and BCL2 inhibitor (venetoclax), or CDK6 inhibitor (abemaciclib) induces synergistic lethality in cell lines and patient-derived AML cells harboring MLL1-r or mtNPM1. Combined therapy with SNDX-5613 and venetoclax exerts superior in vivo efficacy in a cell line or PD AML cell xenografts harboring MLL1-r or mt-NPM1. Synergy with the MI-based combinations is preserved against MLL1-r AML cells expressing FLT3 mutation, also CRISPR-edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1-r or mtNPM1.

2.
Cancer J ; 28(1): 43-50, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35072373

RESUMO

ABSTRACT: Immune checkpoint inhibitors have been investigated in acute myeloid leukemia (AML) with an intent to harness the immune microenvironment components to generate an immune response against leukemia. Anti-cytotoxic T-lymphocyte-associated antigen 4 and anti-programmed cell death 1/programmed cell death ligand 1 antibodies have been evaluated in combination with low-intensity therapy and cytotoxic chemotherapy, both in the pretransplant and posttransplant settings. Although the objective response rates with programmed cell death 1- and programmed cell death ligand 1-based therapies have been relatively low, durable stable disease and hematologic improvement were noted in a subset of patients, important endpoints in patients with limited therapeutic options. Novel AML and myelodysplastic syndrome-specific checkpoints such as TIM3 antibodies in combination with azacitidine are showing encouraging efficacy, especially durability of response, in ongoing studies. Anti-CD47/SIRPα therapy in combination with azacitidine has shown encouraging efficacy and safety in frontline AML, especially in TP53-mutated AML, a population of significant unmet need. Other T cell-based immune therapies are under investigation. T-cell and natural killer cell bispecific and trispecific engagers have shown modest activity in patients with relapsed and/or refractory AML albeit with frequent cytokine release syndrome. Chimeric antigen receptor T-cell therapy showed immense success in many lymphoid malignancies and is being evaluated in AML. Future trials should be designed to select patients based on markers of response and tailor therapies according to predictive biomarkers.

3.
Am J Hematol ; 2022 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-34981560

RESUMO

Gilteritinib is approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) with an FLT3-mutation (FLT3mut+ ). However, the gilteritinib phase 3 ADMIRAL study (Perl et al NEJM 2019) was conducted prior to widespread adoption of either midostaurin as a component of standard intensive induction and consolidation or posttransplant FLT3 inhibitor maintenance. We performed a retrospective analysis using data from 11 US centers and where we identified 113 patients who received gilteritinib alone or as combination therapy for the treatment of R/R FLT3mut+ AML. The composite complete remission (CR) rate (CRc, defined as CR + CRi + CR with incomplete platelet recovery [CRp]) was 48.7% (n = 55). The CRc rate after treatment with gilteritinib in patients who were treated with only prior 7+3 and midostaurin with or without consolidation was 58% with a median survival of 7.8 months. Survival was longest in patients who obtained a CR, particularly a cMRD (clinical minimal or measurable residual disease) negative response; this remained significant after censoring at the time of stem cell transplant. The mitogen-activated protein kinase pathway activating mutations that are known for gilteritinib resistance (NRAS, KRAS, and PTPN11) had lower CRc (35% vs. 60.5%) and lower median overall survival than patients' whose leukemia did not express these mutations (4.9 months vs. 7.8 months) (HR 2.4; 95% CI 1. 5.4) p value <.01.

4.
Am J Hematol ; 2022 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-34981570

RESUMO

Mutations in fms-like tyrosine kinase 3 (FLT3) gene are common genomic alterations in acute myeloid leukemia (AML). FLT3 internal tandem duplication mutations (FLT3-ITD) have consistently been shown to be adversely prognostic, particularly those with high allelic ratio (AR). Current AML treatment strategies, including high dose cytarabine, purine analogs, FLT3 inhibitors (FLT3i), and with or without allogeneic stem cell transplant (SCT) have been shown to improve the outcomes in patients with FLT3 mutations. We analyzed a consecutive cohort of newly diagnosed patients with AML treated at a large academic medical center from January 2012 to January 2020. A total of 1576 patients with a new diagnosis of AML were reviewed. Among these, 1438 (91%) had molecular testing for FLT3 mutations and 21% (304/1438) had an FLT3 mutation, including 17% with an FLT3-ITD mutation. We show that FLT3-ITD high AR with NPM1 wild-type have significantly improved survival compared with other European LeukemiaNet (ELN) adverse risk disease. In multivariable cox proportional hazards model of patients receiving intensive or low-intensity induction regimens, FLT3 mutations did not have prognostic significance. The use of allogeneic SCT in CR1 for patients with FLT3 mutations appears to improve survival, particularly in those with ELN adverse risk disease. Overall, this data highlights the changing prognostic impact of FLT3 mutations in a contemporary era with appropriate use of induction therapy combined with targeted agents and allogenic SCT.

5.
Blood Adv ; 2022 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-35061885

RESUMO

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a clinically aggressive blood cancer, often involving skin, bone marrow, lymph nodes, as well as central nervous system (CNS) involvement in 20-30% of patients. Despite significant progress in CD123- and BCL-2-targeted therapy, most patients are not cured outside of hematopoietic stem cell transplant (HSCT), and CNS relapses are being observed quite frequently. Combination approaches with both targeted and chemotherapy agents plus incorporation of prophylactic CNS-directed therapy are urgently needed. In this setting, we sought to analyze outcomes of the cytotoxic chemotherapy backbone regimen hyperfractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone (HCVAD) in BPDCN. We conducted a retrospective analysis of patients with BPDCN (n=100), evaluating complete remission (CR) and median overall survival (OS) among three groups: those who received frontline HCVAD-based (n=35) vs SL-401 (n=37) vs other regimens (n=28). HCVAD-based regimens yielded higher CR (80% vs 59% vs 43%, p=0.01). There was no significant difference in OS (28.3 vs 13.7 vs 22.8 months p=0.41), nor significant difference in remission duration probability among treatment groups (38.6 vs NR vs 10.2 months; p=0.24). HSCT was performed in 51% vs 49% vs 38% respectively (p=0.455). These results suggest a continued important role for HCVAD-based chemotherapy for BPDCN, even in the modern targeted-therapy era, with high CR rates in the frontline setting. Further studies must establish the clinical activity, feasibility, and safety, of doublet/triplet combinations of targeted therapies plus cytotoxic agents and addition of CNS prophylaxis, with ultimate goal of durable long-term remissions for patients with BPDCN.

6.
Blood ; 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34780598

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that may complicate hematologic malignancies (HM). The appropriateness of current criteria for diagnosing HLH in the context of HMs is unknown because they were developed for children with familial HLH (HLH-2004) or derived from adult patient cohorts in which HMs were underrepresented (HScore). Moreover, many features of these criteria may directly reflect the underlying HM rather than an abnormal inflammatory state. To improve and potentially simplify HLH diagnosis in patients with HMs, we studied an international cohort of 225 adult patients with various HMs both with and without HLH and for whom HLH-2004 criteria were available. We used classification and regression tree and receiver operating curve analysis to identify the most useful diagnostic and prognostic parameters and optimize laboratory cutoff values. Combined elevation of soluble CD25 (>3,900 U/ml) and ferritin (>1,000 ng/ml) best identified HLH-2004 defining features (sensitivity 84%, specificity 81%). Moreover, this combination, which we term the 'optimized HLH inflammatory' (OHI) index, was highly predictive of mortality (hazard ratio 4.3; confidence interval 3.0-6.2) across diverse HMs. Furthermore, the OHI index identified a large group of patients with high mortality risk that were not defined as having HLH by HLH-2004/HScore. Finally, the OHI demonstrates diagnostic and prognostic value when used for routine surveillance of patients with newly diagnosed HMs as well as those with clinically suspected HLH. Thus, we conclude that the OHI index identifies HM patients with an inflammatory state associated with a high mortality risk and warrants further prospective validation.

7.
Artigo em Inglês | MEDLINE | ID: mdl-34810120

RESUMO

BACKGROUND: The incidence and spectrum of infections in acute myeloid leukemia (AML) patients treated with immune checkpoint inhibitors (CPIs) in combination with a hypomethylating agents (HMAs) is not known. Nivolumab is a PD-1 checkpoint inhibitor approved in many solid tumors and lymphoma. MATERIALS/METHODS: We performed a retrospective cohort study of 75 adult patients at MD Anderson Cancer Center with relapsed/refractory AML treated with azacitidine and nivolumab or with nivolumab and ipilimumab from March 2016 through March 2020 and described the infectious complications that occurred during their treatment. RESULTS: Sixty-four (85%) patients developed an infection during the study period, and bacterial infections were by far the most common type of infection. A comparison of risk factors and characteristic between the 75 patients on CPIs who developed infection and those who did not found that corticosteroid use (odds ratio [OR], 28; 95% confidence interval [CI], 1.6-490; P =.02) and lymphopenia (OR, 4; 95% CI, 1-15.5; P =.04) were significantly associated with infections. CONCLUSION: Patient with relapsed/refractory AML treated with salvage CPI-based therapy were more likely to develop infections when treated with corticosteroids in the setting of an immune-related adverse event, compared to those who were not.

8.
Am J Hematol ; 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34716921

RESUMO

The progress with intensive chemotherapy and supportive care measures has improved survival in patients with newly diagnosed acute myeloid leukemia (AML). Given the recent development of effective low intensity therapies, an optimal decision on the therapy intensity may improve survival through the avoidance of early mortality. We reviewed the outcome of 3728 patients with newly diagnosed AML who received intensive chemotherapy between August 1980 and May 2020. Intensive chemotherapy was defined as a cumulative cytarabine dose ≥ 700 mg/m2 during induction therapy. We divided the whole cohort into a training and validation group at a 3:1 ratio. The population was divided into a training (2790 patients) and a validation cohort (938 patients). The median age was 55 years (range, 15-99). Among them, 442 patients (12%) had core-binding factor AML. Binary logistic regression identified older age, worse performance status, hyperbilirubinemia, elevated creatinine, hyperuricemia, cytogenetic abnormalities other than CBF and -Y, and pneumonia as adverse prognostic factors for an early 4-week mortality. This risk classification for early mortality was verified in the validation cohort of patients. In the validation cohort of more recently treated patients from 2000 to 2017, the 4-week mortality rates with intensive chemotherapy were 2%, 14%, and 50% in the low-, high-, and very high-risk group, respectively. The mortality rates with low intensity therapies were 3%, 9%, and 20%, respectively. The risk classification guides treatment intensity by the assessment of age, frailty, organ dysfunction, cytogenetic abnormality, and infection to avoid early mortality.

9.
Blood ; 2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34601571

RESUMO

Majority of RUNX1 mutations in AML are missense or deletion-truncation and behave as loss-of-function mutations. Following standard therapy, AML patients expressing mtRUNX1 exhibit inferior clinical outcome than those without mutant RUNX1. Studies presented here demonstrate that as compared to AML cells lacking mtRUNX1, their isogenic counterparts harboring mtRUNX1 display impaired ribosomal biogenesis and differentiation, as well as exhibit reduced levels of wild-type RUNX1, PU.1 and c-Myc. Compared to AML cells with only wild-type RUNX1, AML cells expressing mtRUNX1 were also more sensitive to the protein translation inhibitor homoharringtonine (omacetaxine) and BCL2 inhibitor venetoclax. HHT treatment repressed enhancers and their BRD4 occupancy, as well as was associated with reduced levels of c-Myc, c-Myb, MCL1 and Bcl-xL. Consistent with this, co-treatment with omacetaxine and venetoclax or BET inhibitor induced synergistic in vitro lethality in AML expressing mtRUNX1. Compared to each agent alone, co-treatment with omacetaxine and venetoclax or BET inhibitor also displayed improved in vivo anti-AML efficacy, associated with improved survival of immune depleted mice engrafted with AML cells harboring mtRUNX1. These findings highlight superior efficacy of omacetaxine-based combination therapies for AML harboring mtRUNX1.

10.
Lancet Haematol ; 8(12): e922-e933, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34687602

RESUMO

Research has resulted in regulatory approval of nine agents for acute myeloid leukaemia indications by the US Food and Drug Administration since 2017: the Bcl-2 inhibitor, venetoclax; two FLT3 inhibitors, midostaurin and gilteritinib; two IDH inhibitors, ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor); the anti-CD33 antibody-drug conjugate, gemtuzumab ozogamicin; the oral, poorly absorbable hypomethylating agent, azacitidine; the liposomal formulation of cytarabine and daunorubicin (5:1 ratio), CPX-351; and the hedgehog signalling pathway inhibitor, glasdegib. A 100% absorbable oral formulation of the hypomethylating agent decitabine was approved for the treatment of myelodysplastic syndrome and chronic myelomonocytic leukaemia, and might be used as an alternative to parenteral hypomethylating agents. Several of the approvals are as single-agent therapies or in specific combinations for narrow indications, thus offering poor treatment value. In this Review, we discuss ongoing research into combinations containing these commercially available targeted therapies for acute myeloid leukaemia.

11.
Artigo em Inglês | MEDLINE | ID: mdl-34602371

RESUMO

The treatment landscape for acute myeloid leukemia has expanded significantly in the past 5 years with the approval of several therapeutic small molecules. While agents such as FLT3 inhibitors and IDH inhibitors are restricted for patients with specific mutations, the selective BCL-2 inhibitor venetoclax combined with a hypomethylating agent or low-dose cytarabine was approved after demonstrating frontline efficacy across a molecularly heterogenous group of patients. Currently, venetoclax is being investigated in combination with multiple other therapies as the role of the intrinsic apoptotic pathway in acute myeloid leukemia continues to be explored.

12.
Leuk Lymphoma ; : 1-4, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34668451

RESUMO

Acute promyelocytic leukemia (APL) is characterized by the chromosomal translocation t(15;17) and the resulting gene PML-RARA, used for measurable residual disease (MRD) monitoring. Despite highly effective therapy for APL, MRD monitoring practices are not fully established. We aimed to assess the value of MRD monitoring by RT-qPCR in patients with APL treated with ATRA and arsenic trioxide +/- GO. We reviewed 223 patients with APL treated with this regimen. RT-qPCR for PML-RARA was measured every 3 months, and at 12, 18, and 24 months after therapy. Seven patients relapsed. Time to relapse was 7.9-12.4 months in 6 patients, and one patient relapsed after 79.5 months. These data show that MRD monitoring may be important for the detection of relapse in patients treated with this regimen within one year after completing therapy, however, since late molecular relapse is rare, our data suggest a low value of MRD monitoring beyond that first year.

13.
Nat Commun ; 12(1): 6071, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34663807

RESUMO

In contrast to the curative effect of allogenic stem cell transplantation in acute myeloid leukemia via T cell activity, only modest responses are achieved with checkpoint-blockade therapy, which might be explained by T cell phenotypes and T cell receptor (TCR) repertoires. Here, we show by paired single-cell RNA analysis and TCR repertoire profiling of bone marrow cells in relapsed/refractory acute myeloid leukemia patients pre/post azacytidine+nivolumab treatment that the disease-related T cell subsets are highly heterogeneous, and their abundance changes following PD-1 blockade-based treatment. TCR repertoires expand and primarily emerge from CD8+ cells in patients responding to treatment or having a stable disease, while TCR repertoires contract in therapy-resistant patients. Trajectory analysis reveals a continuum of CD8+ T cell phenotypes, characterized by differential expression of granzyme B and a bone marrow-residing memory CD8+ T cell subset, in which a population with stem-like properties expressing granzyme K is enriched in responders. Chromosome 7/7q loss, on the other hand, is a cancer-intrinsic genomic marker of PD-1 blockade resistance in AML. In summary, our study reveals that adaptive T cell plasticity and genomic alterations determine responses to PD-1 blockade in acute myeloid leukemia.


Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Azacitidina/uso terapêutico , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Resistencia a Medicamentos Antineoplásicos/genética , Granzimas/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/imunologia , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico , Receptores de Antígenos de Linfócitos T/genética , Análise de Célula Única , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transcriptoma/efeitos dos fármacos
14.
Blood Adv ; 5(23): 5415-5419, 2021 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-34525185

RESUMO

Acute lymphoblastic leukemia (ALL) with t(4;11)(q21;q23)-KMT2A-AFF1 is associated with a poor prognosis. The impact of KMT2A rearrangements other than t(4;11) is uncertain, and the benefit of allogeneic stem cell transplantation (HSCT) is unclear. We reviewed adult patients with ALL treated at our institution from 1984 to 2019 and identified 50 out of 1102 (5%) with KMT2A rearrangement, including 42 (84%) with t(4;11)/KMT2A-AFF1 and 8 (16%) with other gene partners. The median age was 45 years (range, 18-78 years); median white blood cell count was 109.0 3 109/L (range, 0.5-1573.0). The complete remission (CR) rate was 88%, and the rate of measurable residual disease negativity by flow cytometry at CR was 41% (76% overall during follow-up). At the last follow-up, 14 patients were alive. The 5-year overall survival (OS) rate was 18% (95% confidence interval [CI], 9% to 35%), with no difference between t(4;11) and other KMT2A rearrangements (P 5 .87). In a 4-month landmark analysis, the 5-year OS rate was 32% (95% CI, 14% to 70%) in patients who underwent HSCT vs 11% (95% CI, 3-39) in others (P 5 .10). Our study confirms the poor prognosis of ALL with any KMT2A rearrangement and the role of HSCT in these patients.

16.
Blood Adv ; 5(22): 4569-4574, 2021 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-34555853

RESUMO

Acute myeloid leukemia (AML) remains a difficult disease to treat disease. In a phase 2 clinical trial in patients with relapsed/refractory AML, combining the hypomethylating agent, azacitidine, with the PD-1 checkpoint inhibitor, nivolumab, demonstrated encouraging response rates (33%), median event-free, and overall survival, compared with a historical cohort of contemporary patients treated with azacitidine-based therapies, with an acceptable safety profile. Biomarkers of response are yet to be determined. In this study, we leveraged a multiplexed immune assay to assess the functional states of CD4+ and CD8+ cells at a single-cell level in pretherapy bone marrows in 16 patients with relapsed/refractory AML treated with azacitidine/nivolumab. Effector CD4+ but not CD8+ cells had distinct polyfunctional groups and were associated with responses and better outcomes. Further evaluation of the polyfunctional strength index composition across cell types revealed that interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) were the major drivers of enhanced polyfunctionality index of pretherapy CD4+ subset, whereas Granzyme B, IFN-γ, MIP-1b, and TNF-α drove the nonsignificantly enhanced pretreatment Polyfunctional Strength Index of CD8+ subset in the responders. Single-cell polyfunctional assays were predictive of response in AML and may have a potential role as a biomarker in the wider sphere of immunotherapy.


Assuntos
Leucemia Mieloide Aguda , Proteômica , Azacitidina/uso terapêutico , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico
18.
Clin Cancer Res ; 27(21): 5739-5741, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34470774

RESUMO

Cellular therapies have demonstrated limited efficacy thus far in acute myeloid leukemia (AML). A recent study shows that mTOR complex 1 activation downregulated CXCR4 reducing marrow infiltration of EpCAM-targeting chimeric antigen receptor (CAR) T-cells in AML. Abrogating mTOR signaling by cotreatment with mTOR inhibitors during IL2-mediated ex vivo expansion upregulated CXCR4 and bolstered bone marrow migration and AML elimination by CAR T-cells.See related article by Nian et al., p. 6026.

19.
Blood Cancer J ; 11(9): 162, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34588432

RESUMO

Acute myeloid leukemia (AML) with rearrangement of the lysine methyltransferase 2a gene (KMT2Ar) has adverse outcomes. However, reports on the prognostic impact of various translocations causing KMT2Ar are conflicting. Less is known about associated mutations and their prognostic impact. In a retrospective analysis, we identified 172 adult patients with KMT2Ar AML and compared them to 522 age-matched patients with diploid AML. KMT2Ar AML had fewer mutations, most commonly affecting RAS and FLT3 without significant impact on prognosis, except for patients with ≥2 mutations with lower overall survival (OS). KMT2Ar AML had worse outcomes compared with diploid AML when newly diagnosed and at relapse, especially following second salvage (median OS of 2.4 vs 4.8 months, P < 0.0001). Therapy-related KMT2Ar AML (t-AML) had worse outcomes compared with de novo KMT2Ar AML (median OS of 0.7 years vs 1.4 years, P < 0.0001). Allogeneic hematopoietic stem cell transplant (allo-HSCT) in first remission was associated with improved OS (5-year, 52 vs 14% for no allo-HSCT, P < 0.0001). In a multivariate analysis, translocation subtypes causing KMT2Ar did not predict survival, unlike age and allo-HSCT. In conclusion, KMT2Ar was associated with adverse outcomes regardless of translocation subtype. Therefore, AML risk stratification guidelines should include all KMT2Ar as adverse.

20.
Leuk Lymphoma ; : 1-9, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34380367

RESUMO

Myeloid sarcoma (MS) in the setting of concomitant medullary AML is relatively well described, while much less is known about patients presenting with MS with <20% bone marrow blasts. We conducted a retrospective analysis of 56 patients with MS with <20% marrow blasts seen at MD Anderson between 2005 and 2020. The prevalence of MS without medullary AML was 1.4% among all newly diagnosed AML patients. The majority (75%) of patients had a single known anatomic site involved, with the skin (34%) being the most frequent. The most common histologic subtype was monocytic, and 11% of patients had a known history of an antecedent hematologic disorder. The majority of patients (70%) received frontline intensive chemotherapy induction, with 75% of those evaluable attaining complete or partial responses. The median overall survival (OS) and event-free survival (EFS) were 3.41 and 3.07 years, respectively. Patients with bone marrow blasts of ≥5% or medullary relapse had inferior outcomes, while age (>60 years) was not associated with outcomes. There was a suggestion that patients with isolated leukemia cutis may have had better outcomes compared to patients with other organ involvement, but this did not reach statistical significance. Most patients who had cytogenetic analysis had a diploid karyotype within their MS and bone marrow. RAS pathway mutations were enriched in MS at diagnosis, and at time of medullary relapse. Our study provides a large dataset summarizing the clinical and molecular analysis of patients with MS with <20% BM blasts and suggests that monitoring for medullary leukemia is important for early detection of relapse.

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