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The establishment of primary tumor cells in distant organs, termed metastasis, is the principal cause of cancer mortality and is a crucial therapeutic target in oncology. Thus, it is critical to establish a better understanding of metastatic progression for the future development of improved therapeutic approaches. Indeed, such development requires insight into the timing of tumor cell dissemination and seeding of distant organs resulting in occult lesions. Following dissemination of tumor cells from the primary tumor, they can reside in niches in distant organs for years or decades, following which they can emerge as an overt metastasis. This timeline of metastatic dormancy is regulated by interactions between the tumor, its microenvironment, angiogenesis, and tumor antigen-specific T-cell responses. An improved understanding of the mechanisms and interactions responsible for immune evasion and tumor cell release from dormancy would help identify and aid in the development of novel targeted therapeutics. One such mediator of dormancy is myeloid derived suppressor cells (MDSC), whose number in the peripheral blood (PB) or infiltrating tumors has been associated with cancer stage, grade, patient survival, and metastasis in a broad range of tumor pathologies. Thus, extensive studies have revealed a role for MDSCs in tumor escape from adoptive and innate immune responses, facilitating tumor progression and metastasis; however, few studies have considered their role in dormancy. We have posited that MDSCs may regulate disseminated tumor cells resulting in resurgence of senescent tumor cells. In this review, we discuss clinical studies that address mechanisms of tumor recurrence including from dormancy, the role of MDSCs in their escape from dormancy during recurrence, the development of occult metastases, and the potential for MDSC inhibition as an approach to prolong the survival of patients with advanced malignancies. We stress that assessing the impact of therapies on MDSCs versus other cellular targets is challenging within the multimodality interventions required clinically.
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Células Supresoras de Origen Mieloide , Humanos , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Microambiente TumoralRESUMEN
The third annual Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Myeloma Intergroup Workshop on Minimal Residual Disease and Immune Profiling was held on November 29, 2018, at the American Society of Hematology (ASH) annual meeting. This workshop featured the latest research focused on minimal residual disease (MRD) assessment and immune profiling (IP) in myeloma as well as discussion of the statistical and regulatory issues intrinsic to the development of MRD as a surrogate endpoint. In this report, we provide a summary of the workshop and focus on the integration of MRD and IP assessment into trial design and clinical practice.
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Mieloma Múltiple/terapia , Ensayos Clínicos como Asunto , Congresos como Asunto , Educación , Hematología , Humanos , Mieloma Múltiple/sangre , Neoplasia Residual , Sociedades Médicas , Estados UnidosRESUMEN
Aim: This study evaluated the overall survival (OS) of older patients (≥60 years) with acute myeloid leukemia based on the intensity of treatment. Methods: This single center, retrospective study included 211 patients diagnosed between 2000 and 2016, who received 10-day decitabine, low-intensity therapy or high-intensity therapy. Cox regression examined the impact of therapy on OS. Results: Younger patients were more likely to receive high-intensity therapy. Patients who received low-intensity therapy had worse OS compared with high-intensity therapy (median OS: 1.2 vs 8.5 months; p < 0.01). OS was similar with 10-day decitabine (median OS of 6.3 months) compared with either low-intensity therapy or high-intensity therapy. Conclusion: Ten-day decitabine is an effective alternative in older patients with newly diagnosed acute myeloid leukemia.
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Antimetabolitos Antineoplásicos/administración & dosificación , Decitabina/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Anciano , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Inducción de Remisión/métodos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
More than 90% of allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients receive red blood cell (RBC) or platelet transfusions in the peritransplantation period. We tested the hypothesis that transfusions are associated with the development of severe (grade III-IV) acute graft-versus-host disease (aGVHD) or mortality after allo-HSCT in a retrospective study of 322 consecutive patients receiving an allogeneic bone marrow or granulocyte colony-stimulating factor-mobilized blood stem cell graft for a hematologic malignancy. Counting transfused RBC and platelet units between day -7 pretransplantation and day +27 post-transplantation, but excluding transfusions administered after a diagnosis of aGVHD, yielded medians of 5 RBC units and 2 platelet units transfused. Sixty-three patients (20%) developed a maximal grade III-IV aGVHD with onset up to day +150 post-transplantation (median aGVHD onset of 28 days). HLA mismatch (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.2 to 4.7; P = .01), and transfusion of more than the median number of RBC units (HR, 2.1; 95% CI, 1.1 to 3.7; P = .02) were independently associated with greater risk of grade III-IV aGVHD in a multivariable analysis model. Disease risk strata (HR, 1.7; 95% CI, 1.2 to 2.4 for high risk versus low risk; P = .005) and transfusion of more than the median number of RBC units (HR, 1.4; 95% CI, 1.0 to 2.0; P = .054) were independently associated with inferior overall survival. These data support our hypothesis that peritransplantation RBC transfusions are associated with the risk of developing severe aGVHD and worse overall survival following allo-HSCT, and suggest that strategies to reduce routine RBC transfusion may favorably reduce the incidence and severity of GVHD.
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Transfusión de Eritrocitos/efectos adversos , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Adulto , Anciano , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Masculino , Persona de Mediana Edad , Atención Perioperativa/efectos adversos , Atención Perioperativa/métodos , Transfusión de Plaquetas , Estudios Retrospectivos , Riesgo , Análisis de Supervivencia , Trasplante Homólogo/efectos adversos , Adulto JovenRESUMEN
This phase Ib clinical trial evaluated whether pretargeting of CD20(+) clonogenic myeloma precursor cells (CMPCs) with anti-CD3 × anti-CD20 bispecific antibody-armed T cells (BATs) before autologous stem cell transplantation (SCT) in patients with standard-risk and high-risk multiple myeloma would induce antimyeloma immunity that could be detected and boosted after SCT. All 12 patients enrolled in this study received 2 BATs infusions before SCT, and 4 patients received a booster infusion of BATs after SCT. Pretargeting CD138(-)/CD20(+) CMPCs with BATs before SCT was safe and reduced levels of CMPCs by up to 58% in the postinfusion bone marrow in patients who remained in remission. Four of 5 patients who remained in remission had a >5-fold increase in IFN-γ enzyme-linked immunospot responses. SOX2 antibody increased after BATs infusions and persisted after SCT. The median anti-SOX2 level at 3 months after SCT was 28.1 ng/mL (range, 4.6 to 256 ng/mL) in patients who relapsed and 46 ng/mL (range, 28.3 to 73.3 ng/mL) in patients who remained in remission. The immune correlates suggest that infusions of targeted T cells given before SCT were able to reduce CMPC levels and induced cellular and humoral antimyeloma immunity that could be transferred and boosted after SCT.
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Anticuerpos Biespecíficos/administración & dosificación , Antígenos CD20/inmunología , Inmunidad Humoral , Mieloma Múltiple , Células Madre Neoplásicas/inmunología , Trasplante de Células Madre , Adulto , Anciano , Autoinjertos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/inmunología , Mieloma Múltiple/terapia , Sindecano-1RESUMEN
Gastrointestinal (GI) graft-versus-host disease (GVHD) is one of the most common causes of morbidity and mortality after allogeneic stem cell transplantation. In addition, cytomegalovirus (CMV) infection of the gastrointestinal tract can complicate the post-transplantation course of these patients and it can be difficult to differentiate the 2 diagnoses given that they can present with similar symptoms. We retrospectively analyzed 252 patients who were diagnosed with GI GVHD to evaluate the incidence, risk factors, and outcomes of CMV viremia and CMV gastroenteritis in these patients. The median age at the time of transplantation was 51 years, 35% were related donor transplantations, and 65% were unrelated donor transplantations. A total of 114 (45%) patients developed CMV viremia at a median of 34 days (range, 14 to 236 days) after transplantation. Only recipient CMV IgG serostatus was significantly associated with development of CMV viremia (P < .001). The incidence of CMV viremia with relation to donor (D) and recipient (R) CMV serostatus subgroups was as follows: D+/R+, 73%; D-/R+, 67%; D+/R-, 19%; and D-/R-, 0. A total of 31 patients were diagnosed with a biopsy-proven CMV gastroenteritis; 2 patients had evidence of CMV gastroenteritis and GVHD on the first biopsy and 29 on the second biopsy. Median time to development of CMV gastroenteritis was 52 days (range, 19 to 236 days) after transplantation. Using death as a competing risk, the cumulative incidence of CMV gastroenteritis at 1 year was 16.4%. The incidence of CMV gastroenteritis in relation to the donor/recipient serostatus was as follows: D+/R+, 22%; D-/R+, 31%; D+/R-, 12%; and D-/R-, 0. Median follow-up time for the 252 patients was 35.4 (95% CI 23.8 to 44.8) months. The estimated overall survival rate at 1 and 2 years was .45 (95% confidence interval [CI], .39 to .52) and .39 (95% CI, .33 to .46), respectively. Of the examined variables, those related to the overall survival were maximal clinical GVHD grade (P < .001) and development of CMV gastroenteritis (P = .008). Development of CMV viremia was not associated with increased mortality. In conclusion, CMV gastroenteritis is common complication in patients with GI GVHD and can adversely affect the prognosis.
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Anticuerpos Antivirales/sangre , Infecciones por Citomegalovirus/patología , Gastroenteritis/patología , Tracto Gastrointestinal/patología , Enfermedad Injerto contra Huésped/patología , Neoplasias Hematológicas/patología , Adulto , Enfermedad Crónica , Citomegalovirus/inmunología , Infecciones por Citomegalovirus/etiología , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Femenino , Gastroenteritis/etiología , Gastroenteritis/inmunología , Gastroenteritis/virología , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/virología , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Inmunoglobulina G/sangre , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Agonistas Mieloablativos/uso terapéutico , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia , Donantes de Tejidos , Acondicionamiento Pretrasplante , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Both acute and chronic graft-versus-host disease (GVHD) are major causes of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). The optimal pharmacological regimen for GVHD prophylaxis is unclear, but combinations of a calcineurin inhibitor (cyclosporin or tacrolimus [Tac]) and an antimetabolite (methotrexate or mycophenolate mofetil [MMF]) are typically used. We retrospectively evaluated the clinical outcomes of 414 consecutive patients who underwent AHSCT from sibling (SD) or unrelated donors (UD) with Tac/MMF combination, between January 2005 and August 2010. The median follow-up was 60 months. Less than one third of the patients received a reduced-intensity chemoregimen. The incidence of grades III and IV acute GVHD was 22.3% and 36.5% in SD and UD groups, respectively (P = .0007). The incidence of chronic GVHD was 47.1% and 52.7% in the SD and UD groups, respectively. Nonrelapse mortality (NRM) at 60 months was 33.3% and 46.5% in the SD and UD groups, respectively (P = .0016). The incidence of relapse was 22.4% for UD and 28.8% for SD. Five-year overall survival was 43% and 34% in the SD and UD groups, respectively (P = .0183). GVHD was the leading cause of death for the entire cohort. Multivariable analysis showed that 8/8 HLA match, patient's age < 60, and low-risk disease were associated with better survival. The use of Tac/MMF for GVHD prophylaxis was associated with a relatively high incidence of severe acute GVHD and NRM in AHSCT from sibling and unrelated donors.
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Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Inmunosupresores/uso terapéutico , Ácido Micofenólico/análogos & derivados , Tacrolimus/uso terapéutico , Acondicionamiento Pretrasplante/efectos adversos , Enfermedad Aguda , Adolescente , Adulto , Anciano , Estudios de Cohortes , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Ácido Micofenólico/uso terapéutico , Estudios Retrospectivos , Donantes de Tejidos , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo , Donante no Emparentado , Adulto JovenRESUMEN
We report our experience of collecting stem cells in patients who failed to mobilize sufficient hematopoietic stem cell (HSC) using plerixafor (P) in the initial mobilization attempt. Twenty four patients were identified who failed a first mobilization attempt using P. Of these, 22 patients received granulocyte colony stimulating factor (G-CSF) and two patients received cyclophosphamide (CY) + G-CSF in combination with P for the initial attempt. The agents used for second collection attempt were granulocyte macrophage colony stimulating factor (GM-CSF) + G-CSF (19 patients), G-CSF + P (three patients), CY + G-CSF (one patient), and bone marrow harvest (one patient). A median of 0.6 × 10(6) CD34(+) cells/kg (range 0-1.97) were collected in the initial attempt. A second collection was attempted at a median of 22 days (range 15-127) after the first failed mobilization. The median CD34(+) cell dose collected with the second attempt was 1.1 × 10(6) CD34(+) cells/kg (range 0-7.2). A third collection was attempted in six patients at median of 51 days (range 34-163) after the first failed mobilization. These patients collected a median of 1.1 × 10(6) CD34(+) cells/kg (range 0-6.5). Total of 16 patients (67%) collected sufficient cells to undergo autologous stem cell transplant and eight patients (33%) were able to collect ≥2 × 10(6) CD34(+) cells/kg in a single subsequent attempt. Our experience suggests that a majority of patients who fail primary mobilization despite use of P can collect sufficient HSC with a subsequent attempt using combination of G-CSF with either P or GM-CSF.
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Ciclofosfamida/farmacología , Factor Estimulante de Colonias de Granulocitos/farmacología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Movilización de Célula Madre Hematopoyética/métodos , Adulto , Anciano , Bencilaminas , Recuento de Células Sanguíneas , Ciclamas , Evaluación de Medicamentos , Sustitución de Medicamentos , Sinergismo Farmacológico , Femenino , Neoplasias Hematológicas/sangre , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas , Compuestos Heterocíclicos/farmacología , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Trasplante AutólogoRESUMEN
Relapse remains a major cause of treatment failure following allogeneic stem cell transplantation (allo-SCT) for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We retrospectively investigated low-dose decitabine and venetoclax (DEC/VEN) as post-transplant maintenance in 26 older patients with AML and MDS. The cumulative incidence of day 100 gIII-IV acute graft versus host disease (GVHD) and 1-year moderate-severe chronic GVHD was 5% and 26%, respectively. One patient relapsed 14 m after transplant. The 1-year non-relapse mortality and survival were 11% and 84%, respectively. DEC/VEN is a safe and potentially effective strategy to reduce the risk of post-transplant relapse.
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In a meta-analysis of 5 trials, the addition of gemtuzumab ozogamicin (GO) to intensive induction chemotherapy led to a survival benefit in patients with core-binding factor (CBF) acute myeloid leukemia (AML). Given the heterogeneous incorporation of GO in clinical trials, the ideal dose and schedule remains unclear. We conducted a single-center retrospective analysis to compare outcomes of patients with CBF-AML treated with intensive induction chemotherapy, with or without a single dose of GO 3â¯mg/m2, during induction only. We included 87 patients (GO=32, control=55). The composite complete remission (cCR) rate was higher in the control group (93%) compared to the GO group (82%) (p<0.001). The rate of measurable residual disease (MRD) negative cCR, by flow cytometry, was similar between both groups. There were no significant differences between the two groups in terms of toxicity. The 3-year relapse-free survival (RFS) for both groups was similar (71% vs 68%, p=0.5). The 3-year overall survival (OS) for the GO group was 68%, compared to 66% for the control group (p=0.9).In multivariable analysis, age and MRD positive status were risk factors for inferior outcomes. We find that survival of patients with CBF-AML is favorable in the real-world setting. The addition of single-dose GO, during induction, did not lead to a higher remission rate or survival benefit, when compared to intensive chemotherapy without GO. Further investigation into the incorporation of GO in the treatment algorithm for CBF-AML is needed.
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Anticuerpos Monoclonales Humanizados , Leucemia Mieloide Aguda , Humanos , Gemtuzumab/uso terapéutico , Quimioterapia de Inducción , Estudios Retrospectivos , Supervivencia sin Enfermedad , Citarabina , Aminoglicósidos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Respuesta Patológica Completa , Factores de Unión al Sitio PrincipalRESUMEN
BACKGROUND: One major limitation for broader applicability of allogeneic hematopoietic cell transplantation (allo-HCT) in the past was the lack of HLA-matched histocompatible donors. Preclinical mouse studies using T-cell depleted haploidentical grafts led to an increased interest in the use of ex vivo T-cell depleted (TCD) haploidentical allo-HCT. TCD grafts through negative (T-cell depletion) or positive (CD34+ cell selection) techniques have been investigated to reduce the risk of graft-versus-host disease (GVHD) given the known implications of alloreactive T cells. A more practical approach to deplete alloreactive T cells in vivo using high doses of cyclophosphamide after allografting has proved to be feasible in overcoming the HLA barrier. Such approach has extended allo-HCT feasibility to patients for whom donors could not be found in the past. Nowadays, haploidentical donors represent a common donor source for patients in need of an allo-HCT. The broad application of haploidentical donors became possible by understanding the importance of depleting alloreactive donor T cells to facilitate engraftment and reduce incidence and severity of GVHD. These techniques involve ex vivo graft manipulation or in vivo utilization of pharmacologic agents, notably post-transplant cyclophosphamide (PTCy). DISCUSSION: While acknowledging that no randomized controlled prospective studies have been yet conducted comparing TCD versus PTCy in haploidentical allo-HCT recipients, there are two advantages that would favor the PTCy, namely ease of application and lower cost. However, emerging data on adverse events associated with PTCy including, but not limited to cardiac associated toxicities or increased incidence of post-allograft infections, and others, are important to recognize.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Animales , Ratones , Estudios Prospectivos , Ciclofosfamida/uso terapéutico , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Donantes de TejidosRESUMEN
Melphalan 200 mg/m(2) is the standard conditioning regimen for patients with multiple myeloma (MM) with normal renal function (NRF) undergoing autologous stem cell transplant (ASCT). In an effort to escalate the dose of melphalan and to improve the efficacy, we designed a dose-escalation study of melphalan in conjunction with palifermin in patients with NRF, with the hope that a higher dose of melphalan can be administered with an acceptable degree of oral mucositis (OM). We enrolled 19 patients (18 evaluable) with NRF. Dose-escalation of melphalan administered on day -2 began at 200 mg/m(2) with palifermin administered at a fixed dose of 60 mcg/kg/day. Palifermin was given as an i.v. bolus on day -5, -4, and -3, and then on day +1, +2, and +3. Subsequent dose escalations of melphalan were done at 20 mg/m(2) increments up to a maximum dose of 280 mg/m(2). Of 18 evaluable patients, there were no treatment-related deaths by day 100. The median age was 48.5 years (range, 33-65 years). The most common adverse events related to palifermin included rash (18 events, no ≥ grade 3 events), elevation of amylase (10 events, 4 were grade 3 but asymptomatic), and lipase (5 events, 2 were grade 3 but asymptomatic), edema (11 events, no ≥ grade 3). The overall incidence of OM grade 3 was 44% (8/18) with a median duration of severe mucositis of 5 days (range, 3-6 days). Eleven patients (61%) required opioid analgesics. None of the patients received total parenteral nutrition (TPN)/nasogastric feeding. Two of 6 patients who were given melphalan 280 mg/m(2) did not develop OM. Cardiac dose-limiting toxicity (DLT) in the form of atrial fibrillation did occur in 1 of 6 patients treated with melphalan 280 mg/m(2). Palifermin has permitted safe dose escalation of melphalan up to 280 mg/m(2), thus reaching the cumulative dosage of melphalan administered in tandem ASCT. This higher dose of melphalan has the potential to improve the efficacy and, hopefully, outcomes of patients with MM with a single ASCT. A phase 2 trial is necessary to better delineate the antimyeloma efficacy of this regimen.
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Citoprotección/efectos de los fármacos , Factor 7 de Crecimiento de Fibroblastos/administración & dosificación , Riñón/fisiopatología , Melfalán/administración & dosificación , Mieloma Múltiple , Agonistas Mieloablativos/administración & dosificación , Trasplante de Células Madre , Adulto , Anciano , Femenino , Factor 7 de Crecimiento de Fibroblastos/efectos adversos , Humanos , Masculino , Melfalán/efectos adversos , Persona de Mediana Edad , Mieloma Múltiple/sangre , Mieloma Múltiple/fisiopatología , Mieloma Múltiple/terapia , Agonistas Mieloablativos/efectos adversos , Estomatitis/sangre , Estomatitis/tratamiento farmacológico , Estomatitis/etiología , Estomatitis/fisiopatología , Trasplante AutólogoRESUMEN
A phase I trial of infusing anti-CD3 × anti-CD20 bispecific antibody (CD20Bi) armed activated T cells (aATC) was conducted in high-risk/refractory non-Hodgkin's lymphoma patients to determine whether aATC infusions are safe, affect immune recovery, and induce an antilymphoma effect. Ex vivo expanded ATC from 12 patients were armed with anti-CD20 bispecific antibody, cryopreserved, and infused after autologous stem cell transplantation (SCT). Patients underwent SCT after high-dose chemotherapy, and aATC infusions were started on day +4. The patients received 1 infusion of aATC per week for 4 weeks after SCT with doses of 5, 10, 15, and 20 × 10(9). aATC infusions were safe and did not impair engraftment. The major side effects were chills, fever, hypotension, and fatigue. The mean number of IFN-γ Enzyme-linked Immunosorbent Spots (ElSpots) directed at CD20 positive lymphoma cells (DAUDI, P = .0098) and natural killer cell targets (K562, P < .0051) and the mean specific cytotoxicity directed at DAUDI (P = .037) and K562 (P = .002) from pre-SCT to post-SCT were significantly higher. The increase in IFN-γ EliSpots from pre-SCT to post-SCT in patients who received armed ATC after SCT were significantly higher than those in patients who received SCT alone (P = .02). Serum IL-7, IL-15, Macrophage inflammatory protein (MIP)-1 beta, IP-10, MIP-1α, and Monokine induced by gamma interferone increased within hours after infusion. Polyclonal and specific antibodies were near normal 3 months after SCT. aATC infusions were safe and increased innate and specific antilymphoma cell immunity without impairing antibody recovery after SCT.
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Anticuerpos Biespecíficos/uso terapéutico , Antígenos CD20/inmunología , Complejo CD3/inmunología , Trasplante de Células Madre Hematopoyéticas , Linfoma no Hodgkin/terapia , Linfocitos T/inmunología , Anciano , Antígenos CD20/genética , Antineoplásicos/uso terapéutico , Complejo CD3/genética , Proliferación Celular , Citocinas/biosíntesis , Citocinas/inmunología , Citotoxicidad Inmunológica , Femenino , Expresión Génica , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/patología , Linfoma no Hodgkin/inmunología , Linfoma no Hodgkin/patología , Persona de Mediana Edad , Linfocitos T/trasplante , Trasplante Autólogo , Insuficiencia del TratamientoAsunto(s)
Suero Antilinfocítico/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Inmunosupresores/uso terapéutico , Tacrolimus/uso terapéutico , Adulto , Anciano , Aloinjertos , Supervivencia sin Enfermedad , Familia , Femenino , Enfermedad Injerto contra Huésped/etiología , Neoplasias Hematológicas/terapia , Humanos , Donadores Vivos , Transfusión de Linfocitos , Masculino , Persona de Mediana Edad , Insuficiencia del TratamientoRESUMEN
INTRODUCTION: Lenalidomide (LEN) is a relatively new and very effective therapy for multiple myeloma (MM). Prior LEN therapy is associated with an increased risk of peripheral blood stem cell collection (PBSC) failure, particularly with filgrastim (G-CSF) alone. We performed a retrospective chart review of 319 consecutive MM patients who underwent apheresis to collect PBSCs for the first autologous stem cell transplant (ASCT). RESULTS: The median number of PBSCs collected in the LEN (+) group was significantly less than the LEN (-) group (6.34 vs. 7.52 × 10(6) CD34(+) cells/kg; p = 0.0004). In addition, the median number of apheresis sessions required for adequate PBSCs collection were significantly more in the LEN (+) group as compared to LEN (-) group (2 vs. 1 sessions; p = 0.002). In the LEN (+) group, there was a negative correlation between PBSCs collected and prior number of cycles of LEN (p = 0.0001). Rate of PBSC collection failure was 9% in the LEN (+) group and 5% in the LEN (-) group (p = 0.16). Only six patients who failed PBSC collection with G-CSF were able to collect adequate PBSCs with G-CSF + plerixafor. LEN exposure had no effect on neutrophil or platelet recovery post-ASCT. CONCLUSIONS: Up to four cycles of LEN exposure have minimal negative impact on PBSC collection. Despite prolong exposure of LEN, PBSC collection was adequate for two ASCTs in the majority of patients and post-ASCT engraftment was not longer than expected; however, clinical relevance (complication rate, quality of life, cost) of prolonged LEN exposure on both PBSC and ASCT, should be evaluated in prospective clinical trials.
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Movilización de Célula Madre Hematopoyética/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Células Madre Hematopoyéticas/efectos de los fármacos , Mieloma Múltiple/terapia , Talidomida/análogos & derivados , Anciano , Antineoplásicos/uso terapéutico , Eliminación de Componentes Sanguíneos , Ácidos Borónicos/uso terapéutico , Bortezomib , Dexametasona/uso terapéutico , Femenino , Filgrastim , Glucocorticoides/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Células Madre Hematopoyéticas/citología , Humanos , Factores Inmunológicos/administración & dosificación , Lenalidomida , Masculino , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Pirazinas/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Estudios Retrospectivos , Talidomida/administración & dosificación , Trasplante AutólogoRESUMEN
Immunotherapy is an additional pillar when combined with traditional standards of care such as chemotherapy, radiotherapy, and surgery for cancer patients. It has revolutionized cancer treatment and rejuvenated the field of tumor immunology. Several types of immunotherapies, including adoptive cellular therapy (ACT) and checkpoint inhibitors (CPIs), can induce durable clinical responses. However, their efficacies vary, and only subsets of cancer patients benefit from their use. In this review, we address three goals: to provide insight into the history of these approaches, broaden our understanding of immune interventions, and discuss current and future approaches. We highlight how cancer immunotherapy has evolved and discuss how personalization of immune intervention may address present limitations. Cancer immunotherapy is considered a recent medical achievement and in 2013 was selected as the "Breakthrough of the Year" by Science. While the breadth of immunotherapeutics has been rapidly expanding, to include the use of chimeric antigen receptor (CAR) T-cell therapy and immune checkpoint inhibitor (ICI) therapy, immunotherapy dates back over 3000 years. The expansive history of immunotherapy, and related observations, have resulted in several approved immune therapeutics beyond the recent emphasis on CAR-T and ICI therapies. In addition to other classical forms of immune intervention, including human papillomavirus (HPV), hepatitis B, and the Mycobacterium bovis Bacillus Calmette-Guérin (BCG) tuberculosis vaccines, immunotherapies have had a broad and durable impact on cancer therapy and prevention. One classic example of immunotherapy was identified in 1976 with the use of intravesical administration of BCG in patients with bladder cancer; resulting in a 70 % eradication rate and is now standard of care. However, a greater impact from the use of immunotherapy is documented by the prevention of HPV infections that are responsible for 98 % of cervical cancer cases. In 2020, the World Health Organization (WHO) estimated that 341,831 women died from cervical cancer [1]. However, administration of a single dose of a bivalent HPV vaccine was shown to be 97.5 % effective in preventing HPV infections. These vaccines not only prevent cervical squamous cell carcinoma and adenocarcinoma, but also oropharyngeal, anal, vulvar, vaginal, and penile squamous cell carcinomas. The breadth, response and durability of these vaccines can be contrasted with CAR-T-cell therapies, which have significant barriers to their widespread use including logistics, manufacturing limitations, toxicity concerns, financial burden and lasting remissions observed in only 30 to 40 % of responding patients. Another, recent immunotherapy focus are ICIs. ICIs are a class of antibodies that can increase the immune responses against cancer cells in patients. However, ICIs are only effective against tumors with a high mutational burden and are associated with a broad spectrum of toxicities requiring interruption of administration and/or administration corticosteroids; both of which limit immune therapy. In summary, immune therapeutics have a broad impact worldwide, utilizing numerous mechanisms of action and when considered in their totality are more effective against a broader range of tumors than initially considered. These new cancer interventions have tremendous potential notability when multiple mechanisms of immune intervention are combined as well as with standard of care modalities.
Asunto(s)
Mycobacterium bovis , Infecciones por Papillomavirus , Neoplasias de la Vejiga Urinaria , Neoplasias del Cuello Uterino , Humanos , Femenino , Vacuna BCG , Neoplasias del Cuello Uterino/tratamiento farmacológico , Inmunoterapia/métodos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
Acute graft-versus-host disease (aGVHD) is a major cause of morbidity and mortality in patients undergoing unrelated hematopoietic stem cell transplantation. We prospectively evaluated the efficacy of intermediate-dose rabbit anti-thymocyte globulin (Thymoglobulin® a total of 4.5 mg/kg given over days -3, -2, and -1) in combination with tacrolimus and sirolimus for the prevention of aGVHD. We enrolled 47 recipients who underwent unrelated hematopoietic stem cell transplantation. Patients received daily granulocyte colony-stimulating factor starting on day +6 until neutrophil engraftment (median duration, 11 days; range, 9-15 days). Twenty-two patients received HLA 8/8 and 25 received 7/8 matched grafts, respectively. The median follow-up duration was 23.6 months (range, 18.8-27.9 months). The cumulative incidence of grade II to IV aGVHD was 23.4% (95% confidence interval, 12.4-36.3). At 2-year follow-up, the cumulative incidence of nonrelapse mortality was 31.9%, cumulative incidence of relapse was 24.6%, and cumulative incidence of chronic GVHD was 33%. Progression-free survival at 1 year was 54%, with a median of 17.7 months. Overall survival at 1 year was 65%, with no median reached. These results suggest that the combination of Thymoglobulin, tacrolimus, and sirolimus in patients undergoing unrelated hematopoietic stem cell transplantation is well tolerated and associated with a low incidence and severity of aGVHD and chronic graft-versus-host disease.
Asunto(s)
Suero Antilinfocítico/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Agonistas Mieloablativos/uso terapéutico , Sirolimus/uso terapéutico , Tacrolimus/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Enfermedad Aguda , Adulto , Anciano , Enfermedad Crónica , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Antígenos HLA/inmunología , Trasplante de Células Madre Hematopoyéticas/mortalidad , Prueba de Histocompatibilidad , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Recurrencia , Índice de Severidad de la Enfermedad , Tasa de Supervivencia , Trasplante Homólogo , Donante no EmparentadoRESUMEN
UNLABELLED: High-dose melphalan 140 mg/m2 is the standard of care for patients with multiple myeloma (MM) with renal insufficiency (RI). Palifermin as a cytoprotective agent has demonstrated efficacy in reducing the intensity and duration of oral mucositis (OM) in patients who receive intensive chemotherapy/radiotherapy. There is no prospective data on the use of palifermin in patients with MM with RI. ELIGIBILITY CRITERIA: creatinine clearance ≤60 mL/minute/1.73 m2, age >18 years, no dialysis, no active OM, and a suitable candidate for autologous stem cell transplant (ASCT). Melphalan dose ranged from 140 to 200 mg/m2 and escalated at the increment of 20 mg/m2. Six dosages of palifermin 60 mcg/kg/day were given intravenously between day -5 to day +3. Dose escalations were to stop if dose-limiting toxicities (DLTs) occurred at melphalan dose in ≥2 of 3 patients, with that dose declared as the maximal administered dose and the level below where ≤1 of 6 patients had DLTs was considered the maximally tolerated dose (MTD). Nineteen patients were enrolled from June 2007 to June 2011. Data on 15 evaluable patients is reported as 4 patients were removed. Median age was 59 years (range, 36-67 years). The overall incidence of OM ≥ grade 3 was 53% (8 of 15) and a median duration of ≥grade 3 OM was 6.5 days (range, 3-42 days). One patient in L2 (melphalan 160 mg/m2) developed atrial fibrillation on day +9. Two patients in L4 (melphalan 200 mg/m2) developed grade 4 OM, hence reaching DLT. No DLT was observed in 6 patients enrolled in L3 (melphalan 180 mg/m2). Palifermin has permitted safe dose escalation of melphalan up to 180 mg/m(2) in patients with RI.
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Factor 7 de Crecimiento de Fibroblastos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Melfalán/uso terapéutico , Mieloma Múltiple/terapia , Insuficiencia Renal Crónica/terapia , Acondicionamiento Pretrasplante , Adulto , Anciano , Creatinina/sangre , Citoprotección , Esquema de Medicación , Quimioterapia Combinada , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Mieloma Múltiple/inmunología , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/inmunología , Estomatitis/complicaciones , Estomatitis/inmunología , Estomatitis/terapia , Trasplante AutólogoRESUMEN
This is a phase II trial evaluating efficacy and safety of aprepitant (AP) in combination with 5-HT3 antagonist and adjusted dose dexamethasone in patients receiving high-dose cyclophosphamide (CY) and filgrastim for stem cell mobilization. We used Simon's optimal two-stage design constrained to fewer than 40 patients with 10% type I error and 85% statistical power. The first stage of the study required accrual of 18 response-evaluable patients. The primary endpoint was the control of vomiting without the use of any rescue anti-emetics at 24 h after the administration of high dose CY (4 g/m(2)). If emesis was controlled in ≥9 patients, an additional cohort of 17 patients would be enrolled. The null hypothesis would be rejected if there were ≥20 responses among 35 patients. Forty patients were enrolled, five of whom were not evaluable for response. Eighteen evaluable patients were enrolled in the first stage. Acute emesis was controlled in 10 patients; therefore, enrollment proceeded to stage 2. An additional 17 patients were enrolled; 20/35 response-evaluable patients (57%) did not develop acute vomiting or require rescue anti-emetics, thus achieving the goal of the study. A total of 22/35 response-evaluable patients (63%) met the secondary endpoint of delayed emesis control (days 2-5). Thirty-three out of 35 patients underwent successful stem cell mobilization. No ≥ grade 3 AP-related adverse events were noted. The AP regimen can effectively control acute and delayed emesis in the majority patients receiving high-dose CY.
Asunto(s)
Antieméticos/uso terapéutico , Antineoplásicos/efectos adversos , Ciclofosfamida/efectos adversos , Morfolinas/uso terapéutico , Náusea/prevención & control , Trasplante de Células Madre , Vómitos/prevención & control , Adulto , Antieméticos/administración & dosificación , Antineoplásicos/administración & dosificación , Aprepitant , Ciclofosfamida/administración & dosificación , Dexametasona/administración & dosificación , Femenino , Filgrastim , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Morfolinas/administración & dosificación , Náusea/inducido químicamente , Proteínas Recombinantes/administración & dosificación , Vómitos/inducido químicamente , Adulto JovenRESUMEN
Innate immune cells [Natural killer (NK) and gamma-delta (γδ) T-cells] have the advantage of mediating graft versus leukemia (GVL) without graft versus host disease (GVHD). Therefore, the infusion of activated innate immune cells post allogenic hematopoietic stem transplant (AHSCT) is a promising adoptive immunotherapy strategy for relapsed and/or refractory myeloid malignancies. Microbead depletion of T-cells and B-cells has been used as a graft manipulation method to prevent GVHD post haploidentical AHSCT. These grafts are enriched for NK and γδ T-cell receptor (TCR+) cells. Brief ex vivo activation of purified NK cells with interleukin (IL)-12, IL-18, and IL-15 [triple cytokines (TC)] has been shown to produce cells with a memory like function and significantly enhanced leukemia cytotoxicity. In our studies we depleted αß TCR+ and CD19+ B-cells from healthy donors' peripheral blood mononuclear cells (PBMC) using microbeads; enriching the frequency of NK and γδ TCR+ cells. Following overnight TC incubation, we observed that these innate immune cells were activated based on phenotypic expression of CD69 and CD25. Further, we observed increased cytotoxicity of TC activated innate immune cells against NK sensitive and NK refractory leukemic cell targets. Further, the presence or absence of monocytes did not alter activation marker expression or in vitro cytotoxicity of innate immune cells. Additionally, we observed correlation between target cytotoxicity and mature activated NK phenotypes (CD56dim or CD56dim with co-expression of the activation markers CD69+ and/or CD25+). This approach of depleting T- and B-cells from PBMCs, combined with overnight TC activation, provides a novel cell population for donor lymphocyte infusion (DLI) post AHSCT.