RESUMO
The classification of haematological neoplasms recently underwent revision, generating two separate schemes-the International Consensus Classification and the fifth edition of the WHO classification. The new division into separate classification systems presents challenges for haematopathologists, haematologists/oncologists and patients. While it is too early to assess the full clinical impact, we sought to identify diagnostic discordance which may arise from applying separate classification schemes in myeloid neoplasia, and particularly in the challenging category of myelodysplastic syndrome/myeloproliferative neoplasms. A review of 64 such cases found 1 case with a significant discrepancy between the WHO and International Consensus Classification systems, and 9 cases with nominal discrepancies. Confusion from the use of conflicting diagnostic terms represents a potential source of patient harm, increased pathologist workload and burnout and erosion of clinician and patient trust.
Assuntos
Neoplasias Hematológicas , Síndromes Mielodisplásicas , Transtornos Mieloproliferativos , Humanos , Síndromes Mielodisplásicas/diagnóstico , Transtornos Mieloproliferativos/diagnóstico , Neoplasias Hematológicas/diagnóstico , Organização Mundial da SaúdeRESUMO
New therapies for multiple myeloma have improved outcomes, but are associated with therapy-related hematologic malignancies. We report eight patients with therapy-related B-lymphoblastic leukemias (t-B-ALL) in the setting of therapy for multiple myeloma, which included lenalidomide maintenance. A subset of patients had pancytopenia and low-level marrow involvement by acute leukemia, an unusual finding in de novo B-ALL. One patient died of chemotherapy complications; the other seven responded. No patient died of B-ALL (median follow up of 1.0 years). Our series suggests that t-B-ALL is clonally unrelated to myeloma, presents with diverse cytogenetic abnormalities, and responds well to B-ALL therapy.
RESUMO
Acute leukemias of ambiguous lineage (ALAL) are rare hematologic malignancies with poor outcomes. Retrospective studies have suggested that acute lymphoblastic leukemia (ALL) regimens are more effective than acute myeloid leukemia (AML) regimens. We retrospectively examined the effectiveness of the widely-used adult ALL regimen hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyperCVAD) as initial therapy in patients with ALAL at five academic institutions. Twenty-five patients were identified, including 23 with mixed phenotype acute leukemia (MPAL) and two with acute undifferentiated leukemia. Five of 8 tested (63%) had FLT3-ITD and 3 of 25 (12%) were Philadelphia chromosome-positive. The complete remission (CR) rate was 76%, with CR with incomplete count recovery (CRi) in an additional 8%, for an overall response rate of 84%. Median number of cycles to CR/CRi was 1. There were no deaths in the first 30 days. Of the 21 patients achieving CR or CRi, 14 (66%) proceeded to allogeneic hematopoietic stem cell transplantation. With a median follow-up time of 31.6 months, median overall survival for the entire cohort was not reached, and the estimated 2-year survival was 63%. HyperCVAD can be considered an effective and tolerable front-line regimen for patients with ALAL, and warrants further prospective study.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Aguda Bifenotípica/diagnóstico , Leucemia Aguda Bifenotípica/tratamento farmacológico , Adulto , Idoso , Estudos de Coortes , Ciclofosfamida/uso terapêutico , Dexametasona/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Vincristina/uso terapêutico , Adulto JovemAssuntos
Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Mieloma Múltiplo/complicações , Mieloma Múltiplo/tratamento farmacológico , Sulfonamidas/uso terapêutico , Adulto , Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Humanos , Masculino , Mieloma Múltiplo/patologia , Sulfonamidas/farmacologiaRESUMO
The day 14 bone marrow aspirate and biopsy (D14BM) is regularly used to predict achievement of complete remission (CR) with induction chemotherapy in acute myeloid leukemia (AML), however its utility has been questioned. Clearance of peripheral blood blasts (PBB) may serve as an early measure of chemosensitivity. PBB rate of clearance (PBB-RC) was calculated for treatment-naive AML patients (n = 164) undergoing induction with an anthracycline and cytarabine (7+3) and with detectable PBB at diagnosis. PBB-RC was defined as the percentage of the absolute PBB count on the day of diagnosis that was cleared with each day of therapy, on average, until D14 or day of PBB clearance. Each 5% increase in PBB-RC approximately doubled the likelihood of D14BM clearance (OR = 1·81; 95% CI: 1·24-2·64, P < 0·005). PBB-RC was also associated with improved CR rates (OR per 5% = 1·97; 95% CI: 1·27-3·01, P < 0·005) and overall survival (OS) [hazard ratio (HR) per 5% = 0·67; 95% CI: 0·52-0·87]. African American patients had poorer OS adjusted for PBB-RC (HR = 2·18; 95% CI: 1·13-4·23), while race was not associated with D14BM or CR rate. PBB-RC during induction chemotherapy is predictive of D14BM clearance, CR, and OS, and can therefore serve as a prognostic marker for clinical outcomes in AML.
Assuntos
Crise Blástica/fisiopatologia , Leucemia Mieloide Aguda/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia Mieloide Aguda/complicações , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto JovemRESUMO
OBJECTIVE: The diagnostic criteria for secondary hemophagocytic lymphohistiocytosis (HLH) have not been validated in the critically ill adult population. We set out to evaluate the performance of diagnostic criteria and determine the ferritin cutoff in critically ill adults. DESIGN: A retrospective single-center study. SETTING AND PATIENTS: Patients admitted to intensive care unit between 2008 and March 2010. Data were collected on consecutive patients who had ferritin measured. Charts were reviewed for the diagnostic criteria of HLH and components of Hscore. MEASUREMENTS AND MAIN RESULTS: A total of 445 patients had a ferritin level measured during the study period. A diagnosis of HLH was made for 10 patients. Having 5 of 6 criteria had a specificity of 97% and a sensitivity of 70%. Hemophagocytosis was found in 41 (47.1%) of 87 bone marrow biopsies. Two hundred thirty-one patients had a ferritin level above 500 ng/dL. When determining the odds of HLH being clinically diagnosed, the optimal cut point for ferritin was 1197 ng/dL. When determining the odds of HLH based on the Hscore, the best cutoff was 143.5 (sensitivity of 90% and specificity of 90%) and patients who had HLH in our study population had an Hscore of 203.8 ± 64.9. CONCLUSION: In this cohort of critically ill patients, the HLH criteria are specific for HLH but not sensitive. Critically ill patients can have a higher incidence of hemophagocytosis without HLH. A higher ferritin cutoff in combination with 5 other clinical criteria is comparable to the Hscore for the recognition of HLH in the critically ill population.
Assuntos
Linfo-Histiocitose Hemofagocítica , Adulto , Estado Terminal , Ferritinas/metabolismo , Humanos , Unidades de Terapia Intensiva , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/metabolismo , Estudos RetrospectivosAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mieloide/mortalidade , Mieloma Múltiplo/terapia , Síndromes Mielodisplásicas/mortalidade , Transtornos Mieloproliferativos/mortalidade , Segunda Neoplasia Primária/mortalidade , Idoso , Terapia Combinada , Feminino , Seguimentos , Humanos , Leucemia Mieloide/etiologia , Leucemia Mieloide/patologia , Masculino , Mieloma Múltiplo/patologia , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/patologia , Transtornos Mieloproliferativos/etiologia , Transtornos Mieloproliferativos/patologia , Segunda Neoplasia Primária/etiologia , Segunda Neoplasia Primária/patologia , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) treated with conventional chemotherapy have dismal outcomes. Novel immunotherapies targeting CD19, including the bispecific T-cell engager blinatumomab and chimeric antigen-receptor T (CAR-T) cells, have revolutionized the treatment of R/R B-ALL. Robust response rates to CAR-T cell therapy after blinatumomab have recently been reported, but it is unknown whether blinatumomab can be effective following failure of anti-CD19 CAR-T cell therapy. Herein, we describe a patient with Philadelphia chromosome-positive B-ALL who relapsed after CD19-directed CAR-T therapy, but subsequently responded to the combination of blinatumomab and the tyrosine kinase inhibitor ponatinib, with the achievement of a complete remission lasting 12 months.
Assuntos
Anticorpos Biespecíficos/uso terapêutico , Antígenos CD19/metabolismo , Antineoplásicos/uso terapêutico , Imidazóis/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Piridazinas/uso terapêutico , Adulto , Terapia Baseada em Transplante de Células e Tecidos , Quimioterapia Combinada , Humanos , Masculino , Cromossomo Filadélfia , Receptores de Antígenos de Linfócitos T/uso terapêutico , RecidivaAssuntos
Cromotripsia , Rearranjo Gênico , Doenças Mieloproliferativas-Mielodisplásicas/genética , Proteínas de Fusão Oncogênica/genética , Translocação Genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 12 , Cromossomos Humanos Par 5 , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Humanos , Cariótipo , Doenças Mieloproliferativas-Mielodisplásicas/diagnóstico , Doenças Mieloproliferativas-Mielodisplásicas/terapiaAssuntos
Anticorpos Biespecíficos/uso terapêutico , Antígenos CD19/análise , Antineoplásicos Imunológicos/uso terapêutico , Leucemia Aguda Bifenotípica/tratamento farmacológico , Terapia de Alvo Molecular , Adulto , Antígenos CD19/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem da Célula , Terapia Combinada , Citarabina/administração & dosagem , Dasatinibe/administração & dosagem , Daunorrubicina/administração & dosagem , Substituição de Medicamentos , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunofenotipagem , Leucemia Aguda Bifenotípica/patologia , Leucemia Aguda Bifenotípica/terapia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Células-Tronco Neoplásicas/química , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/patologia , Indução de RemissãoRESUMO
We describe two patients with acute promyelocytic leukemia (APL) with an unusual immunophenotype with co-expression of myeloperoxidase (MPO) with cytoplasmic CD3 (cCD3) representing myeloid and T-lineage differentiation. Both harbored FLT3-ITD mutations. One additionally had a deletion in the PML gene affecting the primer binding site, thus limiting measurable residual disease (MRD) analysis during follow-up. Both patients achieved durable remission with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO)-based therapy, thus mitigating the need for repetitive conventional chemotherapy cycles and allogeneic stem cell transplantation. Our report highlights the complexity and challenge of diagnosis and management of APL due to the variant immunophenotype and genetics, and underscores the importance of synthesizing information from all testing modalities. The association of the unusual immunophenotype and FLT3-ITD mutation illustrates the plasticity of the hematopoietic stem cell and the pathobiology of leukemia with mixed lineage or lineage infidelity.
Assuntos
Exoftalmia/etiologia , Exoftalmia/patologia , Leucemia Mieloide Aguda/complicações , Sarcoma Mieloide/complicações , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Citarabina/administração & dosagem , Citarabina/uso terapêutico , Exoftalmia/terapia , Feminino , Humanos , Idarubicina/administração & dosagem , Idarubicina/uso terapêutico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Radioterapia , Sarcoma Mieloide/diagnóstico , Sarcoma Mieloide/patologiaRESUMO
We report a NUMA1-PDGFRB fusion in a myeloproliferative neoplasm with eosinophilia in a 61-year old man, with response to imatinib mesylate therapy. A t(5;11) chromosome translocation involving bands 5q32 and 11q13.4 was identified by metaphase chromosome analysis, and rearrangement of the platelet-derived growth factor receptor beta (PDGFRB) gene on 5q32 was demonstrated by FISH using a PDGFRB break-apart probe set. Bacterial artificial chromosome (BAC) FISH mapping of the PDGFRB fusion partner gene narrowed the breakpoint at 11q13.4 to a 150 kb genomic region containing three genes, including NUMA1. Mate pair sequencing analysis demonstrated NUMA1-PDGFRB fusion. The fusion protein includes coiled-coil domains of nuclear mitotic apparatus protein 1 (NuMA1, involved in protein homodimerization and heteroassociation) and tyrosine kinase domains of PDGFRB. Diverse rearrangements involving the PDGFRB gene have been identified in myeloid and lymphoid neoplasms with eosinophilia, but rearrangement of the nuclear mitotic apparatus protein 1 (NUMA1) gene has previously been reported in a human malignancy in only one instance, a NUMA1-RARA fusion caused by a t(11;17) translocation in a patient with acute promyelocytic leukemia. The NUMA1-PDGFRB fusion is the second instance of rearrangement of NUMA1, encoding an element of the mitotic apparatus, in human cancer.
Assuntos
Antígenos Nucleares/genética , Eosinofilia/tratamento farmacológico , Mesilato de Imatinib/uso terapêutico , Transtornos Mieloproliferativos/tratamento farmacológico , Proteínas Associadas à Matriz Nuclear/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Proteínas de Ciclo Celular , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 5/genética , Eosinofilia/genética , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/genética , Proteínas de Fusão Oncogênica/genética , Translocação Genética , Resultado do TratamentoRESUMO
Poly (ADP-ribose) polymerase inhibitors (PARPis) are clinically effective predominantly for BRCA-mutant tumors. We introduce a mechanism-based strategy to enhance PARPi efficacy based on DNA damage-related binding between DNA methyltransferases (DNMTs) and PARP1. In acute myeloid leukemia (AML) and breast cancer cells, DNMT inhibitors (DNMTis) alone covalently bind DNMTs into DNA and increase PARP1 tightly bound into chromatin. Low doses of DNMTis plus PARPis, versus each drug alone, increase PARPi efficacy, increasing amplitude and retention of PARP1 directly at laser-induced DNA damage sites. This correlates with increased DNA damage, synergistic tumor cytotoxicity, blunting of self-renewal, and strong anti-tumor responses, in vivo in unfavorable AML subtypes and BRCA wild-type breast cancer cells. Our combinatorial approach introduces a strategy to enhance efficacy of PARPis in treating cancer.