RESUMO
Administration of plerixafor with granulocyte-colony stimulating factor (G-CSF) mobilizes CD34+ cells much more effectively than G-CSF alone, but cost generally limits plerixafor use to patients at high risk of insufficient CD34+ cell collection based on low peripheral blood (PB) CD34+ counts following 4 days of G-CSF. We analyzed costs associated with administering plerixafor to patients with higher day 4 CD34+ cell counts to decrease apheresis days and explored the use of a fixed split dose of plerixafor instead of weight-based dosing. We analyzed 235 patients with plasma cell disorders or non-Hodgkin's lymphoma who underwent progenitor cell mobilization and autologous hematopoietic cell transplantation (AHCT) between March 2014 and December 2017. Two hundred ten (89%) received G-CSF plus Plerixafor and 25 (11%) received G-CSF alone. Overall, 180 patients (77%) collected in 1 day, 53 (22%) in 2 days and 2 (1%) in 3 days. Based on our data, we present a probabilistic algorithm to identify patients likely to require more than one day of collection using G-CSF alone. CD34+ cell yield, ANC and platelet recovery were not significantly different between fixed and standard dose plerixafor. Plerixafor enabled collection in 1 day and with estimated savings of $5000, compared to patients who did not receive plerixafor and required collection for three days. While collection and processing costs and patient populations vary among institutions, our results suggest re-evaluation of current algorithms.
Assuntos
Mobilização de Células-Tronco Hematopoéticas/economia , Transplante de Células-Tronco Hematopoéticas/economia , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco/química , Adulto , Idoso , Algoritmos , Redução de Custos , Feminino , Filgrastim/farmacologia , Fator Estimulador de Colônias de Granulócitos , Custos de Cuidados de Saúde , Humanos , Linfoma não Hodgkin/economia , Transtornos Linfoproliferativos/economia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Risco , Células-Tronco/citologia , Transplante Autólogo , Adulto JovemRESUMO
PURPOSE OF REVIEW: The current review aims to highlight recent and important developments in the detection and value of minimal (measurable) residual disease (MRD) testing in patients with acute myeloid leukemia (AML) and the impact on the timing of allogeneic hematopoietic cell transplantation. RECENT FINDINGS: The European LeukemiaNet MRD Working Party recently published guidelines to help standardize testing, utilizing flow cytometry and molecular techniques. The timing of MRD assessments, choice of assay and cutoff of for reporting positive results are all important. Patients known to be MRD-positive pretransplantation have a poor prognosis and consideration should be given to selecting a myeloablative regimen over a reduced intensity regimen (if appropriate) and offering posttransplantation maintenance therapy. SUMMARY: It may be best to think of MRD as a dynamic variable, where a rising MRD result is more specific and highly predictive of relapse. It is unclear how MRD results should impact the timing of allogeneic hematopoietic cell transplantation, if at all. There are currently no published randomized studies to help guide the practitioner in this situation, hence decision-making should be individualized.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Neoplasia Residual/diagnóstico , Tomada de Decisão Clínica , Evolução Clonal/genética , Terapia Combinada , Gerenciamento Clínico , Citometria de Fluxo , Hematopoese/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Leucemia Mieloide Aguda/etiologia , Técnicas de Diagnóstico Molecular , Cuidados Pós-Operatórios , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do TratamentoRESUMO
BACKGROUND: Genomic fusions of the anaplastic lymphoma kinase gene (ALK) are a well-established therapy target in non-small cell lung cancer (NSCLC). From a survey of 114,200 clinical cases, we determined the prevalence of ALK rearrangements (rALK) in non-NSCLC tumors and report their responsiveness to therapies targeting ALK. MATERIALS AND METHODS: Comprehensive genomic profiling of 114,200 relapsed and metastatic malignancies, including both solid tumors and hematolymphoid cancers, was performed using a hybrid-capture, adaptor ligation-based next-generation sequencing assay. RESULTS: Of 114,200 clinical samples, 21,522 (18.8%) were NSCLC and 92,678 (81.2%) were other tumor types. Of the 876 (0.8%) cases with ALK fusions (fALK) or rALK, 675 (77.1%) were NSCLC and 201 (22.9%) were other tumor types. ALK fusions were significantly more frequent in NSCLC (3.1%) than non-NSCLC (0.2%; p < .0001). Patients with non-NSCLC tumors harboring fALK were significantly younger (p < .0001) and more often female (p < .0001) than patients with fALK-positive NSCLC. EML4 was more often the fusion partner in NSCLC (83.5%) versus non-NSCLC tumors (30.9%; p < .0001). CONCLUSION: ALK rearrangements can be identified in a wide variety of epithelial and mesenchymal malignancies beyond NSCLC. Anti-ALK therapies can be effective in non-NSCLC tumors driven by fALK, and further study of therapies targeting ALK in clinical trials involving a wider variety of cancer types appears warranted. IMPLICATIONS FOR PRACTICE: Rearrangements involving the ALK gene have been detected in dozens of cancer types using next-generation sequencing. Patients whose tumors harbor ALK rearrangements or fusions respond to treatment with crizotinib and alectinib, including tumors not normally associated with ALK mutations, such as non-Langerhans cell histiocytosis or renal cell carcinoma. Comprehensive genomic profiling using next-generation sequencing can detect targetable ALK fusions irrespective of tumor type or fusions partner.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão Oncogênica/genética , Receptores Proteína Tirosina Quinases/genética , Quinase do Linfoma Anaplásico , Carbazóis/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Crizotinibe , Feminino , Humanos , Masculino , Terapia de Alvo Molecular , Mutação , Piperidinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Receptores Proteína Tirosina Quinases/antagonistas & inibidoresRESUMO
Cyclophosphamide (Cy) in combination with busulfan (Bu) or total body irradiation (TBI) is the most commonly used myeloablative conditioning regimen in patients with chronic myeloid leukemia (CML). We used data from the Center for International Bone Marrow Transplantation Research to compare outcomes in adults who underwent hematopoietic cell transplantation for CML in first chronic phase after myeloablative conditioning with Cy in combination with TBI, oral Bu, or intravenous (i.v.) Bu. Four hundred thirty-eight adults received human leukocyte antigen (HLA)-matched sibling grafts and 235 received well-matched grafts from unrelated donors (URD) from 2000 through 2006. Important differences existed between the groups in distribution of donor relation, exposure to tyrosine kinase inhibitors, and year of transplantation. In multivariate analysis, relapse occurred less frequently among patients receiving i.v. Bu compared with TBI (relative risk [RR], .36; P = .022) or oral Bu (RR, .39; P = .028), but nonrelapse mortality and survival were similar. A significant interaction was detected between donor relation and the main effect in leukemia-free survival (LFS). Among recipients of HLA-identical sibling grafts, but not URD grafts, LFS was better in patients receiving i.v. Bu (RR, .53; P = .025) or oral Bu (RR, .64; P = .017) compared with TBI. In CML in first chronic phase, Cy in combination with i.v. Bu was associated with less relapse than TBI or oral Bu. LFS was better after i.v. or oral Bu compared with TBI.
Assuntos
Bussulfano/administração & dosagem , Ciclofosfamida/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva , Agonistas Mieloablativos/administração & dosagem , Condicionamento Pré-Transplante , Administração Intravenosa , Administração Oral , Adolescente , Adulto , Aloenxertos , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Masculino , Pessoa de Meia-Idade , Irmãos , Taxa de Sobrevida , Irradiação Corporal TotalRESUMO
An unmet need exists for patients with relapsed/refractory (R/R) follicular lymphoma (FL) and high-risk disease features, such as progression of disease within 24 months (POD24) from first-line immunochemotherapy or disease refractory to both CD20-targeting agent and alkylator (double refractory), due to no established standard of care and poor outcomes. Chimeric antigen receptor (CAR) T cell therapy is an option in R/R FL after two or more lines of prior systemic therapy, but there is no consensus on its optimal timing in the disease course of FL, and there are no data in second-line (2L) treatment of patients with high-risk features. Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, 4-1BB CAR T cell product. The phase 2 TRANSCEND FL study evaluated liso-cel in patients with R/R FL, including 2L patients who all had POD24 from diagnosis after treatment with anti-CD20 antibody and alkylator ≤6 months of FL diagnosis and/or met modified Groupe d'Etude des Lymphomes Folliculaires criteria. Primary/key secondary endpoints were independent review committee-assessed overall response rate (ORR)/complete response (CR) rate. At data cutoff, 130 patients had received liso-cel (median follow-up, 18.9 months). Primary/key secondary endpoints were met. In third-line or later FL (n = 101), ORR was 97% (95% confidence interval (CI): 91.6â99.4), and CR rate was 94% (95% CI: 87.5â97.8). In 2L FL (n = 23), ORR was 96% (95% CI: 78.1â99.9); all responders achieved CR. Cytokine release syndrome occurred in 58% of patients (grade ≥3, 1%); neurological events occurred in 15% of patients (grade ≥3, 2%). Liso-cel demonstrated efficacy and safety in patients with R/R FL, including high-risk 2L FL. ClinicalTrials.gov identifier: NCT04245839 .
Assuntos
Imunoterapia Adotiva , Linfoma Folicular , Humanos , Linfoma Folicular/terapia , Linfoma Folicular/imunologia , Linfoma Folicular/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Adulto , Antígenos CD19/imunologia , Antígenos CD19/uso terapêutico , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/uso terapêuticoRESUMO
Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of organ transplantation. Although PTLD typically has a B-cell histology, an uncommon variant, plasmacytic PTLD can present as a monoclonal plasma cell proliferation similar to plasmacytomas seen in multiple myeloma. A retrospective analysis was performed on nine patients at our center with plasmacytic PTLD as characterized by plasmacytic histology with the presence of CD138 and lack of CD20. Of the 210 adult solid organ transplant PTLD patients diagnosed between 1988 and 2012, 9 (4%) had a histological appearance consistent with plasmacytic PTLD. The median time from transplant to diagnosis was 3.7 years (range 8 months-24 years). All patients presented with extranodal and often subcutaneous solid tumors. Laboratory features included elevated LDH and beta-2 microglobulin levels, monoclonal gammopathy, and EBV positivity of the tumor. Unlike conventional multiple myeloma, patients had normal calcium levels and only mild anemia. Six patients who have completed treatment achieved complete responses with radiation therapy and/or reduction in immunosuppression with two patients now greater than 5 years in continuous complete response. Plasmacytic PTLD, despite its plasmacytic histology, is responsive to conventional therapies used for B-cell PTLD including reduction in immunosuppression and radiation therapy.
Assuntos
Infecções por Vírus Epstein-Barr/complicações , Terapia de Imunossupressão/efeitos adversos , Linfoma/complicações , Transtornos Linfoproliferativos/etiologia , Transplante de Órgãos/efeitos adversos , Plasmocitoma/etiologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Plasmócitos/patologia , Estudos RetrospectivosAssuntos
Etoposídeo/farmacologia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/efeitos dos fármacos , Linfoma não Hodgkin/terapia , Feminino , Humanos , MasculinoRESUMO
Purpose T-cell-replete HLA-haploidentical donor hematopoietic transplantation using post-transplant cyclophosphamide was originally described using bone marrow (BM). With increasing use of mobilized peripheral blood (PB), we compared transplant outcomes after PB and BM transplants. Patients and Methods A total of 681 patients with hematologic malignancy who underwent transplantation in the United States between 2009 and 2014 received BM (n = 481) or PB (n = 190) grafts. Cox regression models were built to examine differences in transplant outcomes by graft type, adjusting for patient, disease, and transplant characteristics. Results Hematopoietic recovery was similar after transplantation of BM and PB (28-day neutrophil recovery, 88% v 93%, P = .07; 100-day platelet recovery, 88% v 85%, P = .33). Risks of grade 2 to 4 acute (hazard ratio [HR], 0.45; P < .001) and chronic (HR, 0.35; P < .001) graft-versus-host disease were lower with transplantation of BM compared with PB. There were no significant differences in overall survival by graft type (HR, 0.99; P = .98), with rates of 54% and 57% at 2 years after transplantation of BM and PB, respectively. There were no differences in nonrelapse mortality risks (HR, 0.92; P = .74) but relapse risks were higher after transplantation of BM (HR, 1.49; P = .009). Additional exploration confirmed that the higher relapse risks after transplantation of BM were limited to patients with leukemia (HR, 1.73; P = .002) and not lymphoma (HR, 0.87; P = .64). Conclusion PB and BM grafts are suitable for haploidentical transplantation with the post-transplant cyclophosphamide approach but with differing patterns of treatment failure. Although, to our knowledge, this is the most comprehensive comparison, these findings must be validated in a randomized prospective comparison with adequate follow-up.
Assuntos
Transplante de Medula Óssea/métodos , Ciclofosfamida/administração & dosagem , Neoplasias Hematológicas/terapia , Mobilização de Células-Tronco Hematopoéticas/métodos , Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Seleção do Doador , Feminino , Haplótipos , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/cirurgia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Linfócitos T/citologia , Condicionamento Pré-Transplante/métodos , Adulto JovemRESUMO
PURPOSE: To develop a system prognostic of outcome in those undergoing allogeneic hematopoietic cell transplantation (allo HCT) for myelodysplastic syndrome (MDS). PATIENTS AND METHODS: We examined 2,133 patients with MDS undergoing HLA-matched (n = 1,728) or -mismatched (n = 405) allo HCT from 2000 to 2012. We used a Cox multivariable model to identify factors prognostic of mortality in a training subset (n = 1,151) of the HLA-matched cohort. A weighted score using these factors was assigned to the remaining patients undergoing HLA-matched allo HCT (validation cohort; n = 577) as well as to patients undergoing HLA-mismatched allo HCT. RESULTS: Blood blasts greater than 3% (hazard ratio [HR], 1.41; 95% CI, 1.08 to 1.85), platelets 50 × 10(9)/L or less at transplantation (HR, 1.37; 95% CI, 1.18 to 1.61), Karnofsky performance status less than 90% (HR, 1.25; 95% CI, 1.06 to 1.28), comprehensive cytogenetic risk score of poor or very poor (HR, 1.43; 95% CI, 1.14 to 1.80), and age 30 to 49 years (HR, 1.60; 95% CI, 1.09 to 2.35) were associated with increased hazard of death and assigned 1 point in the scoring system. Monosomal karyotype (HR, 2.01; 95% CI, 1.65 to 2.45) and age 50 years or older (HR, 1.93; 95% CI, 1.36 to 2.83) were assigned 2 points. The 3-year overall survival after transplantation in patients with low (0 to 1 points), intermediate (2 to 3), high (4 to 5) and very high (≥ 6) scores was 71% (95% CI, 58% to 85%), 49% (95% CI, 42% to 56%), 41% (95% CI, 31% to 51%), and 25% (95% CI, 4% to 46%), respectively (P < .001). Increasing score was predictive of increased relapse (P < .001) and treatment-related mortality (P < .001) in the HLA-matched set and relapse (P < .001) in the HLA-mismatched cohort. CONCLUSION: The proposed system is prognostic of outcome in patients undergoing HLA-matched and -mismatched allo HCT for MDS.
Assuntos
Transplante de Células-Tronco Hematopoéticas/mortalidade , Síndromes Mielodisplásicas/terapia , Adolescente , Adulto , Idoso , Feminino , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Transplante HomólogoRESUMO
UNLABELLED: Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (non-LCH), respectively. The discovery of BRAF(V600E) mutations in approximately 50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of patients with BRAF(V600E)-wild-type non-LCH are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole-exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in patients with BRAF(V600E)-wild-type non-LCH. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of patients with MAP2K1- and ARAF-mutated non-LCH using MEK and RAF inhibitors, respectively, resulted in clinical efficacy, demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders. SIGNIFICANCE: We provide the first description of kinase fusions in systemic histiocytic neoplasms and activating ARAF and MAP2K1 mutations in non-Langerhans histiocytic neoplasms. Refractory patients with MAP2K1- and ARAF-mutant histiocytoses had clinical responses to MEK inhibition and sorafenib, respectively, highlighting the importance of comprehensive genomic analysis of these disorders.
Assuntos
Perfilação da Expressão Gênica/métodos , Histiocitose de Células de Langerhans/enzimologia , Histiocitose de Células não Langerhans/enzimologia , Mutação , Análise de Sequência de DNA/métodos , Quinase do Linfoma Anaplásico , Histiocitose de Células de Langerhans/tratamento farmacológico , Histiocitose de Células de Langerhans/genética , Histiocitose de Células não Langerhans/tratamento farmacológico , Histiocitose de Células não Langerhans/genética , Humanos , MAP Quinase Quinase 1/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Receptores Proteína Tirosina Quinases/genética , Receptor trkA/genéticaRESUMO
Lenalidomide is an immunomodulatory agent that has been approved by the US Food and Drug Administration for treatment of multiple myeloma, deletion 5q myelodysplastic syndrome, and mantle cell lymphoma. In addition, it has clinical activity in lymphoproliferative disorders and acute myeloid leukemia. The mode of action includes immunomodulatory, anti-inflammatory, antiangiogenic, and antiproliferative mechanisms. The antitumor effect is a result of direct interference of key pathways in tumor cells and indirect modulation of the tumor microenvironment. There has been no recent collective review on lenalidomide in multiple myeloma, myelodysplastic syndrome/acute myeloid leukemia, and lymphoma. This review summarizes the results of current clinical studies of lenalidomide, alone and in combination with other agents, as a therapeutic option for various hematologic malignancies.