RESUMO
Posttransplant cyclophosphamide (PtCy) has been shown to decrease post-hematopoietic stem cell transplant acute and chronic graft-versus-host disease (GVHD). In this study, PtCy was used in 44 patients along with mycophenolate and tacrolimus with HLA matched (29) and mismatched (15) unrelated donors to determine the impact of graft content on outcome; thus, all patients had flow cytometric analysis of their graft content including the number of B cells, NK cells, and various T cell subsets. Higher γδ T cell dose was associated with the development of acute GVHD (p = .0038). For PtCy, further studies of the cell product along with further graft manipulation, such as selective γδ T cell depletion, could potentially improve outcomes.
Assuntos
Ciclofosfamida , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco de Sangue Periférico , Doadores não Relacionados , Humanos , Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Transplante de Células-Tronco de Sangue Periférico/métodos , Estudos Prospectivos , Imunossupressores/uso terapêutico , Linfócitos T/imunologia , Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Idoso , Adulto Jovem , Resultado do Tratamento , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/efeitos dos fármacos , Adolescente , Condicionamento Pré-Transplante/métodosRESUMO
The use of cyclophosphamide (CY) for bidirectional tolerization of recipient and donor T cells is associated with reduced rates of graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) after HLA-matched hematopoietic stem cell transplantation (HSCT). However, recurrent disease remains the primary barrier to long-term survival. We extended our 2-step approach to HLA-matched related HSCT using a radiation-based myeloablative conditioning regimen combined with a high dose of T cells in an attempt to reduce relapse rates while maintaining the beneficial effects of CY tolerization. After conditioning, patients received their grafts in 2 components: (1) a fixed dose of 2 × 108/kg T cells, followed 2 days later by CY, and (2) a CD34-selected graft containing a small residual amount of non-CY-exposed T cells, at a median dose of 2.98 × 103/kg. Forty-six patients with hematologic malignancies were treated. Despite the myeloablative conditioning regimen and use of high T cell doses, the cumulative incidences of grade II-IV acute GVHD, chronic GVHD, and NRM at 1 year and 5 years were very low, at 13%, 9%, and 4.3%, respectively. This contributed to a high overall survival of 89.1% at 1 year and 65.8% at 5 years. Relapse was the primary cause of mortality, with a cumulative incidence of 23.9% at 1 year and 45.7% at 5 years. In a post hoc analysis, relapse rates were significantly lower in patients receiving greater than versus those receiving less than the group median of non-CY-exposed residual T cells in the CD34 product (19.3% versus 58.1%; P = .009), without a concomitant increase in NRM. In its current form, this 2-step regimen was highly tolerable, but strategies to reduce relapse, potentially the addition of T cells not exposed to CY, are needed.
Assuntos
Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/terapia , Humanos , Recidiva Local de Neoplasia , Linfócitos T , Condicionamento Pré-TransplanteRESUMO
B-cell lymphoblastic lymphoma (B-LBL) is a malignant neoplasm of immature B cells that accounts for only 10% of all cases of lymphoblastic lymphoma. Most commonly, B-LBL presents as bony lesions, but in rare cases, the disease manifests cutaneously. We present a case of simultaneous cutaneous and systemic presentation of B-LBL in an otherwise healthy 28-year-old man in which the lymphoblastic infiltrate stained positive for CD79a, Tdt, CD10, and CD20. A diagnosis of cutaneous B-LBL was made, and systemic work-up revealed widespread involvement of the skin, bone, and lymph nodes. Review of all currently described cases of cutaneous B-LBL with or without systemic involvement revealed that the most frequently positive tumor markers were CD79a (92.3%), Tdt (90.6%), and CD10 (83.3%). Systemic involvement of B-LBL was found in nearly half of all cases with cutaneous presentation.
Assuntos
Leucemia Linfoide/diagnóstico , Linfoma de Células B/diagnóstico , Neoplasias Cutâneas/diagnóstico , Adulto , Antígenos CD20/análise , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Biópsia , Antígenos CD79/análise , DNA Nucleotidilexotransferase/antagonistas & inibidores , Fracionamento da Dose de Radiação , Transplante de Células-Tronco Hematopoéticas , Humanos , Imuno-Histoquímica , Leucemia Linfoide/imunologia , Leucemia Linfoide/patologia , Leucemia Linfoide/terapia , Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Linfoma de Células B/terapia , Masculino , Neprilisina/análise , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Resultado do TratamentoRESUMO
Background Mammalian Target of Rapamycin Complex 1 (mTORC1) inhibitors enhance chemotherapy response in acute myelogenous leukemia (AML) cells in vitro. However whether inhibiting mTORC1 enhances clinical response to AML chemotherapy remains controversial. We previously optimized measurement of mTORC1's kinase activity in AML blasts during clinical trials using serial phospho-specific flow cytometry of formaldehyde-fixed whole blood or marrow specimens. To validate mTORC1 as a therapeutic target in AML, we performed two clinical trials combining an mTORC1 inhibitor (sirolimus) and MEC (mitoxantrone, etoposide, cytarabine) in patients with relapsed, refractory, or untreated high-risk AML. Methods Flow cytometric measurements of ribosomal protein S6 phosphorylation (pS6) were performed before and during sirolimus treatment to determine whether mTORC1 inhibition enriched for chemotherapy response. Results In 51 evaluable subjects, the overall response rate (ORR) to the combination regimen was 47% (95% confidence interval 33-61%, 33% CR, 2% CRi, 12% PR) and similar toxicity to historic experience with MEC alone. 37 subjects had baseline pS6 measured pre-sirolimus, of whom 27 (73%) exhibited mTORC1 activity. ORR was not significantly different between subjects with and without baseline mTORC1 activity (52% vs 40%, respectively, p = 0.20). The ORR among subjects with baseline target activation and mTORC1 inhibition during therapy was 71% (12/17) compared to 20% (2/10) in subjects without target inhibition. Conclusions Fixed, whole blood pS6 by flow cytometry may be a predictive biomarker for clinical response to mTORC1 inhibitor-based regimens. These data provide clinical confirmation that mTORC1 activation mediates chemotherapy resistance in patients with AML.
Assuntos
Leucemia Mieloide Aguda/tratamento farmacológico , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Sirolimo/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/uso terapêutico , Etoposídeo/uso terapêutico , Feminino , Humanos , Leucemia Mieloide Aguda/metabolismo , Masculino , Pessoa de Meia-Idade , Mitoxantrona/uso terapêutico , Fosforilação/efeitos dos fármacos , Projetos Piloto , Indução de Remissão/métodos , Transdução de Sinais/efeitos dos fármacosRESUMO
Haploidentical stem cell transplantation (SCT) offers a transplantation option to patients who lack an HLA-matched donor. We developed a 2-step approach to myeloablative allogeneic hematopoietic stem cell transplantation for patients with haploidentical or matched related (MR) donors. In this approach, the lymphoid and myeloid portions of the graft are administered in 2 separate steps to allow fixed T cell dosing. Cyclophosphamide is used for T cell tolerization. Given a uniform conditioning regimen, graft T cell dose, and graft-versus-host disease (GVHD) prophylaxis strategy, we compared immune reconstitution and clinical outcomes in patients undergoing 2-step haploidentical versus 2-step MR SCT. We retrospectively compared data on patients undergoing a 2-step haploidentical (n = 50) or MR (n = 27) peripheral blood SCT for high-risk hematological malignancies and aplastic anemia. Both groups received myeloablative total body irradiation conditioning. Immune reconstitution data included flow cytometric assessment of T cell subsets at day 28 and 90 after SCT. Both groups showed comparable early immune recovery in all assessed T cell subsets except for the median CD3/CD8 cell count, which was higher in the MR group at day 28 compared with that in the haploidentical group. The 3-year probability of overall survival was 70% in the haploidentical group and 71% in the MR group (P = .81), while the 3-year progression-free survival was 68% in the haploidentical group and 70% in the MR group (P = .97). The 3-year cumulative incidence of nonrelapse mortality was 10% in the haploidentical group and 4% in the MR group (P = .34). The 3-year cumulative incidence of relapse was 21% in the haploidentical group and 27% in the MR group (P = .93). The 100-day cumulative incidence of overall grades II to IV acute GVHD was higher in the haploidentical group compared with that in the MR group (40% versus 8%, P < .001), whereas the grades III and IV acute GVHD was not statistically different between both groups (haploidentical, 6%; MR, 4%; P = .49). The cumulative incidence of cytomegalovirus reactivation was also higher in the haploidentical group compared to the MR group (haploidentical, 68%; MR, 19%; P < .001). There were no deaths from GVHD in either group. Using an identical conditioning regimen, graft T cell dose, and GVHD prophylaxis strategy, comparable early immune recovery and clinical outcomes were observed in the 2-step haploidentical and MR SCT recipients.
Assuntos
Anemia Aplástica/terapia , Doadores de Sangue , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco de Sangue Periférico , Linfócitos T/transplante , Condicionamento Pré-Transplante , Doença Aguda , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
Haploidentical hematopoietic stem cell transplantation (HSCT) is an attractive alternative donor option based on the rapid availability of an acceptable donor for most patients and decreased cost compared with costs of other alternative donor strategies. The safety of haploidentical HSCT has increased in recent years, making it ethically feasible to offer to patients with earlier stage disease. We developed a 2-step approach to haploidentical HSCT that separates the lymphoid and myeloid portions of the graft, allowing fixed T cell dosing to improve consistency in outcome comparisons. In the initial 2-step trial, the subset of patients without morphologic disease at HSCT had high rates of disease-free survival. To confirm these results, 28 additional patients without evidence of their disease were treated and are now 15 to 45 (median, 31) months past HSCT. To date, the 2-year cumulative incidence of nonrelapse mortality is 3.6%, with only 1 patient dying of nonrelapse causes, confirming the safety of this approach. Based on low regimen toxicity, the probabilities of disease-free and overall survival at 2 years are 74% and 77%, respectively, consistent with the findings in the initial trial and supporting the use of this approach in earlier stage patients lacking a matched related donor.
Assuntos
Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Neoplasias Hematológicas/patologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Taxa de Sobrevida , Doadores de TecidosRESUMO
A single mismatch in highly expressed HLA-A, -B, -C, and -DRB1 loci (HEL) is associated with worse outcomes in hematopoietic stem cell transplantation, while less is known about the cumulative impact of mismatches in the lesser expressed HLA loci DRB3/4/5, DQ, and DP (LEL). We studied whether accumulation of LEL mismatches is associated with deleterious effects in 3853 unrelated donor transplants stratified according to number of matches in the HEL. In the 8/8 matched HEL group, LEL mismatches were not associated with any adverse outcome. Mismatches at HLA-DRB1 were associated with occurrence of multiple LEL mismatches. In the 7/8 HEL group, patients with 3 or more LEL mismatches scored in the graft-versus-host vector had a significantly higher risk of mortality (1.45 and 1.43) and transplant-related mortality (1.68 and 1.54) than the subgroups with 0 or 1 LEL mismatches. No single LEL locus had a more pronounced effect on clinical outcome. Three or more LEL mismatches are associated with lower survival after 7/8 HEL matched transplantation. Prospective evaluation of matching for HLA-DRB3/4/5, -DQ, and -DP loci is warranted to reduce posttransplant risks in donor-recipient pairs matched for 7/8 HEL.
Assuntos
Rejeição de Enxerto/imunologia , Antígenos HLA-DP/imunologia , Antígenos HLA-DQ/imunologia , Cadeias beta de HLA-DR/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Adulto , Feminino , Rejeição de Enxerto/mortalidade , Cadeias HLA-DRB3/imunologia , Cadeias HLA-DRB4/imunologia , Cadeias HLA-DRB5/imunologia , Histocompatibilidade , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Doadores de Tecidos , Adulto JovemRESUMO
There was an increase in the Clostridium difficile infection (CDI) rate in our bone marrow transplantation unit. To evaluate the role of unit-based transmission, C. difficile screening was performed on adult patients admitted for hematopoietic stem cell transplantation (HSCT) over a 2-year period, and C. difficile isolates were typed. C. difficile testing was performed using a 2-step C. difficile glutamate dehydrogenase antigen plus toxin A/B enzyme immunoassay (EIA) and cytotoxin assay (or molecular toxin assay). Multilocus sequence typing (MLST) was performed on toxin-positive whole stool samples. A retrospective chart review was performed on all patients with a positive toxin assay. Sixteen of 150 patients (10.7%) had toxigenic C. difficile colonization (CDC) on admission. The overall incidence of CDI within 100 days after HSCT was 24.7% (37 of 150). The median time to diagnosis of CDI was 3.5 days after HSCT. In an adjusted logistic regression model, CDC on admission was a significant risk factor for CDI (odds ratio, 68.5; 95% confidence interval, 11.4 to 416.2). MLST on 22 unit patient toxin-positive stool specimens revealed 15 distinct strain types. Further analysis identified at least 1 potential cross-transmission event; some events may have been missed because of incomplete typing from other specimens. Despite aggressive infection control interventions, there was no decline in the number of CDI cases during the study period. These data suggest that prior CDC plays a major role in CDI rates in this high-risk patient population. It remains unclear if CDI was cross-transmitted in the unit.
Assuntos
Clostridioides difficile/isolamento & purificação , Infecções por Clostridium/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Condicionamento Pré-Transplante/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Allogeneic hematopoietic stem cell transplant (HSCT) remains the only potentially curative treatment for many hematologic malignancies (HM). We previously developed a two-step approach that separates the lymphoid and myeloid portions of the graft, allowing a consistent T cell dosing and sparing the stem cells from the effect of post-transplant cyclophosphamide (CY). The two-step approach demonstrated safety and efficacy in patients treated with myeloablative and reduced-intensity conditioning. Here, we extended our two-step platform to older and less fit patients and explored the effects of using a high dose of T cells on disease relapse and transplant outcomes. Thirty-four patients with HM were treated. Median age was 68 years old and included a minority population constituting 32%. Eighty-two percent had a hematopoietic cell transplantation comorbidity index score ≥3. Ninety-one percent were haploidentical, and the rest were matched-related donor HSCT. Following administration of fludarabine and 2 Gy total body irradiation (TBI) (13 patients) or 4 Gy TBI (21 patients) conditioning regimen, a fixed dose of 2 × 108/kg CD3+ T cells was given, followed 2 days later by CY, then infusion of CD34-selected stem cells. Overall survival (OS) was 70% at 1 year and 48% at 3 years. The cumulative incidence (CI) of non-relapse mortality (NRM) and relapse were 22% and 33% at 3 years. However, the CI of relapse was much lower for patients treated with 4 Gy TBI versus those treated with 2 Gy TBI (11% versus 54%, P = .045), while NRM was similar (23% versus 15%, P = .399). This contributed to a high OS of 64% in patients who received 4 Gy TBI-based conditioning at 3 years, with median OS not reached, although this was not statistically significant (P = .68). The median time to neutrophil and platelet recovery was 12 and 17 days, respectively. The CI of grade II acute graft-versus-host-disease (aGVHD) was 22% and 26% at 100 days and 6 months, respectively. The CI of chronic GVHD (cGVHD) was 7.5% at 3 years. There was no grade III or IV aGVHD, no severe cGVHD, and no deaths attributable to GVHD. In conclusion, the two-step approach HSCT demonstrated a low disease relapse rate and high survival in patients treated with 4 Gy TBI-based conditioning, despite a generally older and more medically compromised patient population.
RESUMO
ABSTRACT: Cytotoxic T lymphocytes (CTLs) destroy virally infected cells and are critical for the elimination of viral infections such as those caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Delayed and dysfunctional adaptive immune responses to SARS-CoV-2 are associated with poor outcomes. Treatment with allogeneic SARS-CoV-2-specific CTLs may enhance cellular immunity in high-risk patients providing a safe, direct mechanism of treatment. Thirty high-risk ambulatory patients with COVID-19 were enrolled in a phase 1 trial assessing the safety of third party, SARS-CoV-2-specific CTLs. Twelve interventional patients, 6 of whom were immunocompromised, matched the HLA-A∗02:01 restriction of the CTLs and received a single infusion of 1 of 4 escalating doses of a product containing 68.5% SARS-CoV-2-specific CD8+ CTLs/total cells. Symptom improvement and resolution in these patients was compared with an observational group of 18 patients lacking HLA-A∗02:01 who could receive standard of care. No dose-limiting toxicities were observed at any dosing level. Nasal swab polymerase chain reaction testing showed ≥88% and >99% viral elimination from baseline in all patients at 4 and 14 days after infusion, respectively. The CTLs did not interfere with the development of endogenous anti-SARS-CoV-2 humoral or cellular responses. T-cell receptor ß analysis showed persistence of donor-derived SARS-CoV-2-specific CTLs through the end of the 6-month follow-up period. Interventional patients consistently reported symptomatic improvement 2 to 3 days after infusion, whereas improvement was more variable in observational patients. SARS-CoV-2-specific CTLs are a potentially feasible cellular therapy for COVID-19 illness. This trial was registered at www.clinicaltrials.gov as #NCT04765449.
Assuntos
COVID-19 , SARS-CoV-2 , Linfócitos T Citotóxicos , Humanos , COVID-19/imunologia , COVID-19/terapia , Linfócitos T Citotóxicos/imunologia , Pessoa de Meia-Idade , Masculino , SARS-CoV-2/imunologia , Feminino , Idoso , Adulto , Estudos de Viabilidade , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Resultado do Tratamento , Antígeno HLA-A2/imunologiaRESUMO
Studies of haploidentical hematopoietic stem cell transplantation (HSCT) have identified threshold doses of T cells below which severe GVHD is usually absent. However, little is known regarding optimal T-cell dosing as it relates to engraftment, immune reconstitution, and relapse. To begin to address this question, we developed a 2-step myeloablative approach to haploidentical HSCT in which 27 patients conditioned with total body irradiation (TBI) were given a fixed dose of donor T cells (HSCT step 1), followed by cyclophosphamide (CY) for T-cell tolerization. A CD34-selected HSC product (HSCT step 2) was infused after CY. A dose of 2 × 10(8)/kg of T cells resulted in consistent engraftment, immune reconstitution, and acceptable rates of GVHD. Cumulative incidences of grade III-IV GVHD, nonrelapse mortality (NRM), and relapse-related mortality were 7.4%, 22.2%, and 29.6%, respectively. With a follow-up of 28-56 months, the 3-year probability of overall survival for the whole cohort is 48% and 75% in patients without disease at HSCT. In the context of CY tolerization, a high, fixed dose of haploidentical T cells was associated with encouraging outcomes, especially in good-risk patients, and can serve as the basis for further exploration and optimization of this 2-step approach. This study is registered at www.clinicaltrials.gov as NCT00429143.
Assuntos
Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Agonistas Mieloablativos/uso terapêutico , Linfócitos T/citologia , Condicionamento Pré-Transplante/métodos , Adulto , Idoso , Calibragem , Contagem de Células , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Haplótipos , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/normas , Humanos , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/efeitos adversos , Condicionamento Pré-Transplante/efeitos adversos , Transplante Homólogo , Adulto JovemRESUMO
We established double-haploidentical (DH) hematopoietic stem cell transplantation (HSCT) murine models to explore competitive engraftment, graft-versus-graft effect and graft-versus-host disease (GVHD). T cell-depleted (TCD) bone marrow (BM) cells from B6SJF1 (donor 1 [D1]) and B6D2F1 (donor 2 [D2]) mice achieved >90% donor engraftment when transplanted into B6CBAF1 mice. B6CBAF1 recipients survived without evidence of GVHD when undergoing HSCT with TCD-BM from 2 haploidentical donors, D1 and D2. DH-HSCT recipients had significantly higher leukocyte and neutrophil counts than single-haploidentical HSCT recipients from either D1 or D2. DH recipients consistently showed successful mixed chimerism in both BM and spleen. Two other DH-HSCT models, B6D2F1 + C3D2F1âB6C3F1 and B6CBAF1 + B6SJLF1âB6D2F1, showed similar engraftment patterns. Low-dose T cell infusion from both D1 and D2 increased the degree of early engraftment of the respective donors in BM and spleen; however, this early engraftment pattern did not determine long-term engraftment dominance. In the long term, minimally engrafted D1 BM recovered and comprised >50% of all donor- derived B, T, and natural killer cells. We conclude that early BM engraftment is determined by donor T cell immunodominance, but long-term engraftment is related to the engraftment potential of stem cells after DH-HSCT.
Assuntos
Células da Medula Óssea/imunologia , Transplante de Medula Óssea/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Animais , Modelos Animais de Doenças , Feminino , Sobrevivência de Enxerto/imunologia , Haplótipos , Camundongos , Camundongos Endogâmicos C57BL , Doadores de TecidosRESUMO
The 2-step graft engineering approach has been the main platform for allogeneic hematopoietic cell transplantation (allo-HCT) at Thomas Jefferson University since 2005. We have previously described separating donor lymphocyte infusion followed by cyclophosphamide for bidirectional tolerization from CD34-selected hematopoietic grafts in haploidentical and matched related donors. Here we analyzed 60 patients with high-risk lymphoid malignancies who underwent a 2-step allo-HCT between 2008 and 2020. The majority of patients received haploidentical stem cell grafts (82%), and 20% of patients received matched related donor stem cell grafts. The patients underwent allo-HCT for diffuse large C cell lymphoma (n = 17; 28%), chronic lymphoblastic leukemia (n = 10; 17%), follicular lymphoma (n = 8; 13%), and Hodgkin lymphoma (n = 7; 12%). Eight patients (13%) had received prior high-dose chemotherapy. Thirty patients (50%) had a Hematopoietic Cell Transplantation Comorbidity Index ≥3, and 20 patients (33%) had a Center for International Blood & Marrow Transplant Research Revised Disease Risk Index of high risk or very high risk. The median patient age was 56 years (range, 24 to 75 years). Neutrophils engrafted at a median of 11 days (range, 9 to 16 days), and platelets engrafted at a median of 16 days (range, 13 to 37 days). With a median follow-up of 6 years, the 3-year probability of overall survival was 62.9% (95% confidence interval [CI], 49.3% to 73.8%), and that of disease-free survival was 60.2% (95% CI, 46.4% to 71.6%). The cumulative incidence of relapse at 3 years was 11.9% (95% CI, 5.2% to 21.6%). The cumulative incidence of nonrelapse mortality at 3 years was 30.1% (95% CI, 1.91% to 42.0%). The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) at 1 year was 45% (95% CI, 32.2% to 57.0%), and that of grade III-IV acute GVHD at 1 year was 5% (95% CI, 1.3% to 12.6%). The cumulative incidence of cGVHD at 3 years was 15.2% (95% CI, 7.5% to 25.4%). The 2-step approach achieved excellent outcomes in high-risk lymphoid malignancies, with rapid neutrophil and platelet recovery.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Linfocítica Crônica de Células B , Adulto , Idoso , Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia Linfocítica Crônica de Células B/complicações , Pessoa de Meia-Idade , Transplante de Células-Tronco/efeitos adversos , Adulto JovemRESUMO
Allogeneic hematopoietic stem cell transplantation (allo-SCT) remains the best curative option for the majority of patients with hematologic malignancies (HM); however, many elderly patients are excluded from transplant and outcome data in this population is still limited. The novel two-step graft engineering approach has been the main platform for allo-SCT at Thomas Jefferson University since 2006. Following administration of the preparative regimen, we infuse donor lymphocytes, followed by cyclophosphamide to induce bidirectional tolerance, then infusion of CD34-selected cells. A total of 76 patients ≥ 65 years old with HM underwent haploidentical (haplo) allo-SCT on the two-step transplant platform between 2007 and 2021. The median time to neutrophil engraftment was 11 days and platelet engraftment was 18 days. With a median follow up of 44 months, the 3-year overall survival (OS) and progression-free survival (PFS) were 36.3% and 35.6%, respectively. The cumulative incidences of non-relapse mortality (NRM) and relapse at 3 years were 43.5% and 21.0% at 3 years, respectively. The cumulative incidence of grade III-IV acute graft-versus-host-disease (GVHD) was 11.1% at 6 months, and chronic GVHD requiring treatment was 15.1% at 2 years. The two-step haplo allo-SCT is a novel alternative platform for high-risk older HM patients, achieving fast engraftment, low relapse rates and promising survival.
Assuntos
Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Humanos , Idoso , Doença Enxerto-Hospedeiro/etiologia , Recidiva Local de Neoplasia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Ciclofosfamida , Condicionamento Pré-Transplante/efeitos adversosRESUMO
Contemporary, prospective data regarding the impact of granulocyte-colony stimulating factor (G-CSF) on outcomes after autologous hematopoietic stem cell transplantation (Auto-HSCT) in an era when stem cell grafts are more qualitatively robust are limited. Recent retrospective analyses have not supported a beneficial effect of post-transplantation G-CSF use on major outcomes after Auto-HSCT leading to strategies to delay or eliminate the use of G-CSF altogether in this context. To test the hypothesis that the infusion of consistently higher doses of stem cells (defined as ≥4 × 106/kg) in Auto-HSCT will obviate the need for post-transplantation G-CSF. If so, the impact of withholding G-CSF will be noninferior to the use of G-CSF in terms of length of stay (LOS). The specific objectives were to conduct a prospective, randomized clinical trial primarily examining the impact of post-transplantation G-CSF on LOS, and secondarily on engraftment, infectious complications, antibiotic usage, and incidence of engraftment syndrome after Auto-HSCT in patients receiving versus not receiving G-CSF after Auto-HSCT. Patients with multiple myeloma or non-Hodgkin lymphoma (NHL) who underwent Pegfilgrastim plus Plerixafor-primed stem cell collection followed by Auto-HSCT were randomized to the G-CSF group (receive G-CSF starting at day 3 after Auto-HSCT) or the no G-CSF group (G-CSF withheld after Auto-HSCT). Seventy patients per arm were planned to demonstrate the primary endpoint of noninferiority in LOS between the G-CSF and the no G-CSF groups. Patient outcomes in the two groups were followed up and compared after Auto-HSCT, and an interim analysis for futility was planned when accrual reached 50%.The primary finding of this study was that despite only a 2-day longer median absolute neutrophil count (ANC) recovery in the no G-CSF arm (median 11 versus 13 days; P = .001), LOS was 4 days longer in patients not treated with G-CSF (median 11 days versus 15 days; P = .001). G-CSF use was associated with more robust incremental daily increases in ANC once recovered (P = .001), fewer days of febrile neutropenia (P = .001), and fewer days on antibiotics (P = .001), potentially contributing to this disproportionate finding. Inferiority in LOS in the no G-CSF group was demonstrated on the interim analysis, and the study was closed at the half-way point. There were no significant group differences in platelet recovery, documented infections, hospital readmissions, or overall survival at 1 year. Engraftment syndrome occurred in 54.3% of patients and was not related to G-CSF use. These results suggest that the increased LOS associated with the omission of G-CSF is largely due to concerns regarding the potential for infection in patients without a stable, recovered ANC in a hospital setting. Engraftment syndrome represented a significant source of febrile neutropenia further contributing to patient safety concerns and requires strategies to decrease its incidence. Infectious complications and death were not affected by the omission of G-CSF supporting a carefully monitored outpatient approach to Auto-HSCT in which white blood cell growth factor is eliminated or given as needed for documented infection. © 2023 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Assuntos
Neutropenia Febril , Compostos Heterocíclicos , Humanos , Transplante Autólogo , Mobilização de Células-Tronco Hematopoéticas/métodos , Estudos Retrospectivos , Estudos Prospectivos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neutropenia Febril/tratamento farmacológicoRESUMO
The molecular mechanisms governing breast tumor cellular self-renewal contribute to breast cancer progression and therapeutic resistance. The ErbB2 oncogene is overexpressed in approximately 30% of human breast cancers. c-Jun, the first cellular proto-oncogene, is overexpressed in human breast cancer. However, the role of endogenous c-Jun in mammary tumor progression is unknown. Herein, transgenic mice expressing the mammary gland-targeted ErbB2 oncogene were crossed with c-jun(f/f) transgenic mice to determine the role of endogenous c-Jun in mammary tumor invasion and stem cell function. The excision of c-jun by Cre recombinase reduced cellular migration, invasion, and mammosphere formation of ErbB2-induced mammary tumors. Proteomic analysis identified a subset of secreted proteins (stem cell factor (SCF) and CCL5) induced by ErbB2 expression that were dependent upon endogenous c-Jun expression. SCF and CCL5 were identified as transcriptionally induced by c-Jun. CCL5 rescued the c-Jun-deficient breast tumor cellular invasion phenotype. SCF rescued the c-Jun-deficient mammosphere production. Endogenous c-Jun thus contributes to ErbB2-induced mammary tumor cell invasion and self-renewal.
Assuntos
Neoplasias da Mama/patologia , Neoplasias da Mama/fisiopatologia , Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , Animais , Neoplasias da Mama/genética , Divisão Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Quimiocina CCL5/metabolismo , Células Epiteliais/patologia , Células Epiteliais/fisiologia , Feminino , Humanos , Camundongos , Camundongos Transgênicos , Invasividade Neoplásica/patologia , Invasividade Neoplásica/fisiopatologia , Fenótipo , Proto-Oncogene Mas , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Fator de Células-Tronco/metabolismoRESUMO
The association between HLA matching and outcome in unrelated-donor peripheral blood stem cell (PBSC) transplantation has not yet been established. In the present study, a total of 1933 unrelated donor-recipient pairs who underwent PBSC transplantation between 1999 and 2006 for acute myelogenous leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myelogenous leukemia and received high-resolution HLA typing for HLA-A, -B, -C, -DRB1, -DQA1, and -DQB1 were included in the analysis. Outcomes were compared between HLA-matched and HLA-mismatched pairs, adjusting for patient and transplant characteristics. Matching for HLA-A, -B, -C, and -DRB1 alleles (8/8 match) was associated with better survival at 1 year compared with 7/8 HLA-matched pairs (56% vs 47%). Using 8/8 HLA-matched patients as the baseline (n = 1243), HLA-C antigen mismatches (n = 189) were statistically significantly associated with lower leukemia-free survival (relative risk [RR], 1.36; 95% confidence interval [CI], 1.13-1.64; P = .0010), and increased risk for mortality (RR, 1.41; 95% CI, 1.16-1.70; P = .0005), treatment-related mortality (RR, 1.61; 95% CI, 1.25-2.08; P = .0002), and grade III-IV graft-versus-host disease (RR, 1.98; 95% CI, 1.50-2.62; P < .0001). HLA-B antigen or allele mismatching was associated with an increased risk for acute GVHD grade III-IV. No statistically significant differences in outcome were observed for HLA-C allele (n = 61), HLA-A antigen/allele (n = 136), HLA-DRB1 allele (n = 39), or HLA-DQ antigen/allele (n = 114) mismatches compared with 8/8 HLA-matched pairs. HLA mismatch was not associated with relapse or chronic GVHD. HLA-C antigen-mismatched unrelated PBSC donors were associated with worse outcomes compared with 8/8 HLA-matched donors. The study's limited power due to small sample size precludes conclusions about other mismatches.
Assuntos
Doença Enxerto-Hospedeiro/imunologia , Histocompatibilidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Leucemia Mieloide Aguda/imunologia , Síndromes Mielodisplásicas/imunologia , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Alelos , Doadores de Sangue , Feminino , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/mortalidade , Antígenos HLA-A/genética , Antígenos HLA-A/imunologia , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Antígenos HLA-C/genética , Antígenos HLA-C/imunologia , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/imunologia , Antígenos HLA-DR/genética , Antígenos HLA-DR/imunologia , Cadeias HLA-DRB1 , Histocompatibilidade/genética , Histocompatibilidade/imunologia , Teste de Histocompatibilidade/métodos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Transplante , Resultado do TratamentoRESUMO
Few treatment decision support interventions (DSIs) are available to engage patients diagnosed with late-stage non-small cell lung cancer (NSCLC) in treatment shared decision making (SDM). We designed a novel DSI that includes care plan cards and a companion patient preference clarification tool to assist in shared decision making. The cards answer common patient questions about treatment options (chemotherapy, chemotherapy plus immunotherapy, targeted therapy, immunotherapy, clinical trial participation, and supportive care). The form elicits patient treatment preference. We then conducted interviews with clinicians and patients to obtain feedback on the DSI. We also trained oncology nurse educators to implement the prototype. Finally, we pilot tested the DSI among five patients with NSCLC at the beginning of an office visit scheduled to discuss treatment with an oncologist. Analyses of pilot study baseline and exit survey data showed that DSI use was associated with increased patient awareness of the alternatives' treatment options and benefits/risks. In contrast, patient concern about treatment costs and uncertainty in treatment decision making decreased. All patients expressed a treatment preference. Future randomized controlled trials are needed to assess DSI implementation feasibility and efficacy in clinical care.
RESUMO
PURPOSE: An important obstacle to cancer research is that nearly all academic cancer centers maintain substantial collections of highly duplicative, poorly quality-assured, nonintercommunicating, difficult-to-access data repositories. It is inherently clear that this state of affairs increases costs and reduces quality and productivity of both research and nonresearch activities. We hypothesized that designing and implementing a multipurpose cancer information system on the basis of the Biomedical Research Integrated Domain (BRIDG) model developed by the National Cancer Institute and its collaborators might lessen the duplication of effort inherent in capturing, quality-assuring, and accessing data located in multiple single-purpose systems, and thereby increases productivity while reducing costs. METHODS: We designed and implemented a core data structure on the basis of the BRIDG model and incorporated multiple entities, attributes, and functionalities to support the multipurpose functionality of the system. We used the resultant model as a foundation upon which to design and implement modules for importing preexisting data, capturing data prospectively, quality-assuring data, exporting data to analytic files, and analyzing the quality-assured data to support multiple functionalities simultaneously. To our knowledge, our system, which we refer to as the Cancer Informatics Data System, is the first multipurpose, BRIDG-harmonized cancer research information system implemented at an academic cancer center. RESULTS: We describe the BRIDG-harmonized system that simultaneously supports patient care, teaching, research, clinical decision making, administrative decision making, mandated volume-and-outcomes reporting, clinical quality assurance, data quality assurance, and many other functionalities. CONCLUSION: Implementation of a highly quality-assured, multipurpose cancer information system on the basis of the BRIDG model at an academic center is feasible and can increase access to accurate data to support research integrity and productivity as well as nonresearch activities.
Assuntos
Pesquisa Biomédica , Transplante de Células-Tronco Hematopoéticas , Humanos , Sistemas de Informação , National Cancer Institute (U.S.) , Estados UnidosRESUMO
Previous analyses of the effects of race and socioeconomic status (SES) on outcomes after hematopoietic stem cell transplantation (HSCT) have suggested that minority populations and those in disadvantaged groups have inferior outcomes. However, the results of these studies have been inconsistent, potentially due to a multitude of factors, both medical and nonmedical, that have confounded results. In haploidentical (HI) HSCT, an expanding approach with the potential to enfranchise more minority patients, data on the effect of race and SES on outcomes are very limited. To identify and potentially correct factors that negatively impact outcomes after HI HSCT in disadvantaged groups at our institution, we performed a retrospective, multivariable analysis of the impact of race and SES as single and combined variables on HI HSCT outcomes of relapse, transplantation-related mortality, acute and chronic graft-versus-host disease (GVHD), and overall survival (OS). In addition to controlling for race and SES, all patients had HI donors and were treated with the same 2-step approach, with consistent T cell dosing and GVHD prophylaxis to further reduce the impact of confounders in this complex area. The study cohort of 239 patients was 71% Caucasian, 19.7% African American, 4.6% Hispanic, and 4.2% Asian. The majority of minority patients were in areas of higher deprivation (P = .001) and had the highest incidence of cytomegalovirus (CMV) seropositivity (P = .001) and the lowest likelihood of possessing a CMV immunodominant (IMD) allele (P = .001), which was previously associated with an OS benefit. Positive CMV serostatus was highly linked to post-transplantation CMV reactivation (P = .001) which was associated with higher relapse rates (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.06 to 2.30; P = .026), higher TRM (HR, 2.10; 95% CI, 1.09 to 4.05; P = .027), and lower OS (HR, 1.77; 95% CI, 1.18 to 2.65; P = .006). The lack of a CMV IMD allele largely replicated the results of CMV reactivation on HSCT results. Although race and SES did not directly correlate with either OS or relapse incidence, non-Caucasians in a more disadvantaged group had a higher incidence of chronic GVHD (HR, 2.55; 95% CI, 1.08 to 6.01; P = .033) compared with Caucasians and minorities in less disadvantaged groups. Regardless of SES, minorities had a lower incidence of acute GVHD than Caucasians in a more advantaged SES group (HR, 0.52; 95% CI, 0.30 to 0.90; P = .020). The primary finding of this study is that CMV reactivation was the major driver of mortality after HI HSCT. CMV reactivation may have be associated with poor HSCT outcomes in HI HSCT recipients in disadvantaged areas, most of whom were minorities. The data suggest that the prevention of post-transplantation CMV reactivation possibly could have a major impact on HI HSCT outcomes, especially in minority recipients. The finding of different GVHD manifestations between races are intriguing and merits further study.