RESUMO
Donor lymphocyte infusion (DLI) cures relapsed hematologic malignancies after allogeneic hematopoietic stem cell transplantation through the graft-versus-tumor (GVT) effect. Although the important role of magnesium in enhancing immunity has been mentioned in studies, limited clinical data have explored how magnesium affects the efficacy of DLI. Besides, although laboratory data demonstrate that magnesium can enhance CD8+ T cells effector function, whether magnesium regulates the tumor killing effect of peripheral blood mononuclear cells (PBMCs) remains to be explored. Here, for the retrospective study, we collected clinical data of relapsed patients receiving DLI and explored the relationship between different serum magnesium levels and patient outcomes. For in vitro studies, we investigated the effect of magnesium on the cytotoxicity of DLI cells which were PBMCs and preliminarily explored the mechanism. Eighty-one patients were enrolled in this study. It was found that the high post-DLI magnesium level was significantly associated with a higher incidence of complete remission (CR) or partial remission (CR/PR) and a higher possibility of survival. The magnesium level after DLI was an independent risk factor of overall survival. In vitro studies proved that increased magnesium enhanced the cytotoxic function of PBMCs on hematologic malignancies. Besides, magnesium modulated LFA-1 headpiece opening. When blocking the integrin-ligand interaction between LFA-1 and ICAM-1, the regulation effect of magnesium on PBMCs was weakened. Therefore, it was possible that magnesium regulated PBMCs effector function by stimulating LFA-1. These results show that serum magnesium levels affect immunological responses mediated by donor lymphocytes in hematologic malignancies.
Assuntos
Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Humanos , Magnésio , Linfócitos T CD8-Positivos , Leucócitos Mononucleares , Estudos Retrospectivos , Antígeno-1 Associado à Função Linfocitária , Doença Enxerto-Hospedeiro/etiologia , Recidiva Local de Neoplasia , Transplante de Células-Tronco Hematopoéticas/métodos , Transfusão de Linfócitos/métodosRESUMO
For relapsed acute myeloid leukemia (AML) patients who received allogeneic hematopoietic stem cell transplantation, donor lymphocyte infusion (DLI) is an effective therapy. However, the cell source of DLI remains a topic of debate. In this study, we aimed to compare the efficacy and safety of G-CSF mobilized cells (G-DLI) with conventionally collected DLI (C-DLI). A total of 81 patients (50 C-DLI vs. 31 G-DLI) were assessed for clinical outcomes. There were no statistically significant differences in the baseline characteristics between the two groups including AML risk, donor types, interval from relapse to DLI, and infused CD3+ cell count. Although not statistically significant, complete remission (CR) and chimerism conversion rates were higher in G-DLI than in C-DLI: 51.6% vs. 28.0%, P = 0.057 and 42.3% vs. 28.2%, P = 0.363, respectively. There was no difference in acute graft-versus-host disease (GVHD) incidence and severity of acute GVHD between the two groups. The median overall survival (OS) of the G-DLI and C-DLI groups was 139 days and 106 days, respectively (P = 0.58). In conclusion, G-DLI appears to be a safe and an equally efficacious substitute for C-DLI, which is more readily available.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mieloide Aguda/terapia , Transfusão de Linfócitos/efeitos adversos , Recidiva , Indução de Remissão , Transplante Homólogo/efeitos adversosRESUMO
Prophylactic donor lymphocyte infusion (DLI) starting at 6 months after T cell-depleted allogeneic stem cell transplantation (TCD-alloSCT) can introduce a graft-versus-leukemia (GvL) effects with low risk of severe graft-versus-host-disease (GvHD). We established a policy to apply low-dose early DLI at 3 months after alloSCT to prevent early relapse. This study analyzes this strategy retrospectively. Of 220 consecutive acute leukemia patients undergoing TCD-alloSCT, 83 were prospectively classified to have a high relapse risk and 43 were scheduled for early DLI. 95% of these patients received freshly harvested DLI within 2 weeks of the planned date. In patients transplanted with reduced intensity conditioning and an unrelated donor, we found an increased cumulative incidence of GvHD between 3 and 6 months after TCD-alloSCT for patients receiving DLI at 3 months compared to patients who did not receive this DLI (0.42 (95%Confidence Interval (95% CI): 0.14-0.70) vs 0). Treatment success was defined as being alive without relapse or need for systemic immunosuppressive GvHD treatment. The five-year treatment success in patients with acute lymphatic leukemia was comparable between high- and non-high-risk disease (0.55 (95% CI: 0.42-0.74) and 0.59 (95% CI: 0.42-0.84)). It remained lower in high-risk acute myeloid leukemia (AML) (0.29 (95% CI: 0.18-0.46)) than in non-high-risk AML (0.47 (95% CI: 0.42-0.84)) due to an increased relapse rate despite early DLI.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Estudos Retrospectivos , Estudos de Viabilidade , Transfusão de Linfócitos/efeitos adversos , Linfócitos T , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/complicações , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Aguda , Doadores não Relacionados , Doença Crônica , RecidivaRESUMO
Therapeutic donor lymphocyte infusions (tDLI) are used to reinforce the graft-versus-leukemia (GvL) effect in relapse after allogeneic stem cell transplantation (alloSCT). In contrast, the role of prophylactic DLI (proDLI) in preventing leukemia relapse has been less clearly established, although supported by retrospective, case-control, and registry analyses. We report a prospective, monocentric, ten year cohort of patients with high risk acute leukemias (AL) or myelodysplasia (MDS) in whom proDLI were applied beyond day +120 post alloSCT to compensate for lack of GvL.272 consecutive allotransplanted AL or MDS patients in complete remission and off immunosuppression at day +120 were stratified according to the prior appearance of relevant GvHD (acute GvHD °II-IV or extensive chronic GvHD) as a clinical indicator for GvL. Escalating doses of unmodified proDLI were applied to 72/272 patients without prior relevant GvHD. Conversely, 157/272 patients with prior spontaneous GvHD did not receive proDLI, nor did 43/272 patients with contraindications (uncontrolled infections, patient refusal, DLI unavailability).By day 160-landmark analysis (median day of first DLI application), proDLI recipients had significantly higher five-year overall (OS) and disease free survival (DFS) (77% and 67%) than patients with spontaneous GvHD (54% and 53%) or with contraindications (46% and 45%) (p=0.003). Relapse incidence for patients with proDLI (30%) or spontaneous GvHD (29%) was significantly lower than in patients with contraindications (39%; p=0.021). With similar GvHD incidence beyond day +160, non-relapse mortality (NRM) was less with proDLI (5%) than without proDLI (18%; p=0.036).In conclusion, proDLI may be able to compensate for lack of GvL in alloSCT recipients with high risk AL or MDS.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Prevenção Secundária , Estudos Retrospectivos , Estudos Prospectivos , Transfusão de Linfócitos/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Leucemia Mieloide Aguda/complicações , Síndromes Mielodisplásicas/terapia , Síndromes Mielodisplásicas/complicações , Doença Crônica , LinfócitosRESUMO
BACKGROUND: Post-transplant cyclophosphamide (PTCy) has been recommended for prevention of graft-versus-host disease (GvHD) following haploidentical hematopoietic cell transplantation (haplo-HCT) for treatment of malignant blood diseases, but disease relapse remains a problem. Although donor lymphocyte infusion (DLI) is reported to be effective for treating post-transplantation relapse, the efficacy and safety of prophylactic-DLI (pro-DLI) post haplo-HCT, and PTCy in pediatric patients with hematological malignancies is unknown. METHODS: We retrospectively analyzed the outcomes of 54 pediatric patients with high-risk myeloid neoplasms who received a PTCy regimen for GvHD prophylaxis and pro-DLI after haploidentical peripheral blood stem cell transplantation. The high-risk myeloid neoplasms in this cohort included acute myeloid leukemia (n = 46) and myelodysplastic syndromes (n = 8). RESULTS: Median follow-up was for 19.7 (range: 3.4-46.6) months. The cumulative incidences of grade II-IV and III-IV acute GvHD were 37.0% (95% CI: 22.7%-48.7%) and 16.7% (95% CI: 6.1%-26.0%), respectively. There were no graft-failure events, and the 2-year rate of moderate/severe chronic GvHD was 8.1% (95% CI: 0%-16.7%). The 2-year non-relapse mortality, relapse, disease-free survival, GvHD-free relapse-free survival, and overall survival rates were 5.1% (95% CI: 0%-11.7%), 16.6% (95% CI: 5.3%-26.6%), 78.9% (95% CI: 68.0%-91.6%), 62.2% (95% CI: 49.4%-78.3%), and 87.3% (95% CI: 78.3%-97.4%), respectively. CONCLUSIONS: Prophylactic donor lymphocyte infusion in the setting of haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide appears to be effective and safe in pediatric patients with high-risk myeloid neoplasms.
Assuntos
Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Humanos , Criança , Estudos Retrospectivos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/terapia , Recidiva , LinfócitosRESUMO
INTRODUCTION: Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) remains the best curative option for high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Unfortunately, it is still associated with a significant risk of relapse due to mechanisms of escape from the control of alloreactive T cells. Repetitive adjuvant donor lymphocyte infusion (DLI), termed prophylactic DLI (proDLI), as an effective strategy in preventing relapse is still debated. METHODS: We performed a retrospective multicenter study to evaluate the efficacy of proDLI in allografted AML and MDS. We identified 56 patients treated with proDLI (DLI planned in full chimeras without any sign of disease relapse) and matched them to 167 patients in control group, (DLI performed for mixed chimerism or positive minimal residual disease) based on similar age, initial disease, cytogenetic prognosis, and conditioning intensity. RESULTS: In univariate analysis, the incidence of severe aGVHD at 100 days and incidence of all grades of chronic GVHD 1 year after allo-HSCT were similar in the two groups. We also observed a trend of higher 3-year RI (52.61% [95% confidence interval 25.99-79.23]) in the proDLI group versus the control group (29.31% [20.28-38.34], p = 0.067). However, 3-year overall survival (p = 0.892), progression-free survival (p = 0.239), and nonrelapse mortality (p = 0.343) were similar between the two groups. In multivariate analysis, the only factor influencing overall and progression-free survival was anti-thymocyte globulin administration during the conditioning regimen. CONCLUSION: The proDLI strategy had an acceptable toxicity profile but did not improve patient outcomes compared to the pre-emptive strategy.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Síndromes Mielodisplásicas/complicações , Linfócitos , Recidiva , Estudos Retrospectivos , Condicionamento Pré-Transplante/efeitos adversosRESUMO
Secondary graft failure (SGF) is a fatal complication of allogeneic hematopoietic stem cell transplantation without effective treatment methods, especially after haploidentical transplantation. This study aimed to analyze the efficacy of donor lymphocyte infusion (DLI) from a second donor in treating SGF and the underlying immune mechanisms. A second donor is a candidate donor who did not initially provide stem cells for HLA-matched sibling donor or HLA-haploidentical donor transplantation. We conducted a retrospective study of 237 patients with a median age of 38 years (range 9-56) for whom the degree of mixed chimerism (MC) and complete donor chimerism (CC), mRNA expression levels of Forkhead box P3 (Foxp3), and the proportion of regulatory T cells (Tregs) were regularly assessed. The median time to SGF was 62 days (range 41-117) after transplantation. Twenty-one patients with SGF received DLI, including 12 patients who initially received DLI from a second donor (i.e., a donor other than the transplantation [first] donor) and 9 patients who initially received DLI from the first donor but showed no response. Three of those 9 patients subsequently received DLI from a second donor. The incidence of acute GVHD and chronic GVHD induced by DLI from the second donor was significantly higher than that of DLI from the first donor (P = 0.006). Twenty-one patients with SGF exhibited synchronous MC, and the overall MC rate after transplantation was 65% (range 42%-85%).The proportion of Tregs significantly decreased in SGF patients, from a median of 2.61% ± 0.88% to 0.92% ± 0.23% at the indicated time point after transplantation (P = 0.03). Second-donor DLI resulted in a complete response (CR) in 13 patients, and MC gradually converted into CC; simultaneously, there was a significant increase in the mRNA level of Foxp3 and the proportion of Tregs (baseline, 0.92% ± 0.23% versus CR, 3.61% ± 0.82%; P = 0.01). For the patients who did not respond to DLI from either donor type, there was no significant change in donor chimerism, Foxp3 expression level or Treg proportion. Overall survival and disease-free survival 2 years after DLI were 66.7% ± 3.08% and 59.8% ± 4.11%, respectively. DLI from a second donor may be an effective treatment for SGF, and the mechanism is related to MC-to-CC conversion and activation of Foxp3 and Tregs.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Transfusão de Linfócitos , Adolescente , Adulto , Criança , Fatores de Transcrição Forkhead/genética , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Transfusão de Linfócitos/métodos , Pessoa de Meia-Idade , RNA Mensageiro , Estudos Retrospectivos , Linfócitos T Reguladores , Transplante Homólogo/efeitos adversos , Adulto JovemRESUMO
Second allogeneic stem cell transplantation (allo-SCT2) represents a rescue option for selected patients (pts) with relapsed/refractory (r/r) acute myeloid leukemia (AML). Still, relapse rates post-allo-SCT2 remain high and effective anti-relapse strategies and predictive biomarkers remain to be defined. We here analyzed a cohort of 41 AML patients (pts) undergoing allo-SCT2 in our center. Allo-SCT2 induced a third hematologic complete remission (CR) in 37 pts, at costs of a 36% non-relapse mortality rate. Furthermore, 19 pts eventually relapsed post allo-SCT2. Addressing relapse after allo-SCT2, 14 pts (74%) underwent cell-based anti-relapse strategies, including third allogeneic transplantation (allo-SCT3; 3/14), donor lymphocyte infusions (DLIs) combined with either 5-azacytidin and venetoclax (4/14) or chemotherapeutic agents (7/14). Notably, six of seven pts (86%) who received either allo-SCT3 or a combination therapy of DLIs, 5-azacytidine and venetoclax achieved CR despite poor cytogenetics post-allo-SCT2 (e.g., TP53). Finally, 11 of 41 pts were alive at the last follow-up (seven CR2, three CR3, one partial remission) resulting in estimated 2- and 5-year overall survival of 35% and 25%, respectively.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Azacitidina , Compostos Bicíclicos Heterocíclicos com Pontes , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Leucemia Mieloide Aguda/terapia , Recidiva , Estudos Retrospectivos , SulfonamidasRESUMO
Although haploidentical donor lymphocyte infusion (DLI) is a valid treatment option for relapsed acute myeloid leukemia (AML), the incidence and risk factors for graft-versus-host disease (GVHD) and the efficacy of haploidentical DLI have not been fully evaluated. We retrospectively analyzed the outcomes after haploidentical DLI for 84 patients with AML using a nationwide database and additional questionnaires. The median number of DLI cycles and infused CD3+ cell dose was 1 and 1.0 × 106/kg, respectively. The infused CD3+ cell count of 5.0 × 105/kg or higher was associated with acute GVHD (grade II-IV, 32.1% vs. 10.5%, p = 0.03; grade III-IV, 21.4% vs. 5.3%, p = 0.10). Patients who developed grade III-IV acute GVHD more frequently succumbed to treatment-related mortality (46.7% vs. 15.8% at 1 year, p = 0.002), although the relapse-related mortality was significantly low (40.0% vs. 72.2% at 1 year, p = 0.025). The overall response to DLI was significantly higher in the preemptive DLI group (47.4%) than in the therapeutic group (13.9%, p = 0.002). In the multivariate analysis, preemptive DLI was the predictive factor for overall response (odds ratio, 5.58; p = 0.003). Our results indicated the substantial risk of acute GVHD after haploidentical DLI with CD3+ cell count of 5.0×105/kg or higher and the favorable outcomes after preemptive DLI.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Transfusão de Linfócitos , Adolescente , Adulto , Doadores de Sangue , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
This study aimed to evaluate the efficacy and safety of venetoclax plus azacitidine and donor lymphocyte infusion (DLI) in treating patients with relapsed acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Twenty-six AML patients who relapsed after allo-HSCT were enrolled and treated with venetoclax plus azacitidine and DLI. Complete remission with incomplete recovery (CRi), partial remission (PR), and objective remission rate (ORR) were assessed, and then event-free survival (EFS) and overall survival (OS) were evaluated. Besides, adverse events were documented. Additionally, whole exome sequencing was performed in bone marrow samples. The CRi, PR, and ORR rates were 26.9%, 34.6%, and 61.5%, respectively. The median time of EFS and OS was 120 (95% CI: 71-610) days and 284.5 (95% CI: 81-610) days, respectively. The most common adverse events were hematologic system adverse events including agranulocytosis, anemia, and thrombocytopenia, while the adverse events of other systems were relatively less and milder. In addition, no serious adverse events existed. Of note, there were 6 (23.1%) patients who developed GVHD. As for gene mutation, 49 mutated genes were found, which were categorized as first-, second-, and third-class mutations, and then further analysis revealed that the first-class mutations were not correlated with EFS or OS. Additionally, the most frequent mutated genes were FLT3, CEBPA, DNMT3A, KIT, KRAS, and NRAS. Venetoclax plus azacitidine and DLI is efficient and tolerant in treating patients with relapsed AML after allo-HSCT, implying this combined therapy as a potential treatment option in the studied patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azacitidina/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Leucemia Mieloide Aguda/terapia , Transfusão de Linfócitos , Sulfonamidas/uso terapêutico , Adulto , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/terapia , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
Donor lymphocyte infusion (DLI) can (re-)induce durable remission in relapsing patients after allogeneic hematopoietic stem-cell transplantation (alloHSCT). However, DLI harbors the risk of increased non-relapse mortality due to the co-occurrence of graft-versus-host disease (GVHD). GVHD onset may be caused or accompanied by changes in the clonal T-cell receptor (TCR) repertoire. To investigate this, we analyzed T cells in a cohort of 21 patients receiving DLI after alloHSCT. We performed deep T-cell receptor ß (TRB) sequencing of sorted CD4+CD25+CD127low regulatory T cells (Treg cells) and CD4+ conventional T cells (Tcon cells) in order to track longitudinal changes in the TCR repertoire. GVHD following DLI was associated with less diverse but clonally expanded CD4+CD25+CD127low Treg and CD4+ Tcon TCR repertoires, while patients without GVHD exhibited healthy-like repertoire properties. Moreover, the diversification of the repertoires upon GVHD treatment was linked to steroid-sensitive GVHD, whereas decreased diversity was observed in steroid-refractory GVHD. Finally, the unbiased sample analysis revealed that the healthy-like attributes of the CD4+CD25+CD127low Treg TCR repertoire were associated with reduced GVHD incidence. In conclusion, CD4+CD25+CD127low Treg and CD4+ Tcon TRB repertoire dynamics may provide a helpful real-time tool to improve the diagnosis and monitoring of treatment in GVHD following DLI.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Transfusão de Linfócitos/efeitos adversos , Receptores de Antígenos de Linfócitos T alfa-beta , Linfócitos T ReguladoresRESUMO
Essential thrombocythemia gradually developed into secondary myelofibrosis and progressed to leukemia eight months later in a 53-year-old man. After remission induction therapy, he achieved remission by undergoing allogeneic hematopoietic stem cell transplantation from unrelated patients in non-remission. However, peripheral blood WT-1 mRNA gradually increased, and the disease relapsed three years and six months after transplantation. He was taking prednisolone (7.5 mg) and tacrolimus (5 mg) for chronic pulmonary graft-versus-host disease (GVHD) and was reluctant to reduce or discontinue immunosuppressive drugs; therefore, donor lymphocyte infusion (DLI) was performed for a total of five times. Four months after the fifth DLI, cutaneous GVHD appeared, a slow decrease in WT-1 mRNA was observed, and blasts in the peripheral blood disappeared. One year and three months after the last DLI, he achieved complete remission. Although DLI for post-transplant relapse in patients with secondary myelofibrosis or leukemia is rare, it can be beneficial for post-relapse therapy.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Mielofibrose Primária , Masculino , Humanos , Pessoa de Meia-Idade , Mielofibrose Primária/etiologia , Mielofibrose Primária/terapia , Transplante Homólogo , Transfusão de Linfócitos , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/terapia , Doença Crônica , Doença Enxerto-Hospedeiro/terapia , Doença Enxerto-Hospedeiro/genética , Linfócitos , RecidivaRESUMO
Acute myeloid leukemia (AML) relapse after allogeneic stem cell transplant (alloSCT) remains a major therapeutic challenge. While patients with longer remission after initial alloSCT are recommended to receive cell therapy (CT) such as 2ndalloSCT or donor lymphocyte infusion (DLI), survival for patients who relapse within 6 months of alloSCT has been dismal. We evaluated the outcomes of AML relapse after alloSCT to assess the impact of different treatments on long-term survival. One hundred and seventy-two patients with AML underwent alloSCT at the Penn State Cancer Institute from January 2014 to August 2019. Sixty-nine patients relapsed (median age, 60 years; range, 10-75). Of these, 4 patients underwent 2ndalloSCT, and 26 received DLI. One-year overall survival (OS) in all cases was 20.3% (95% CI: 11.8-30.4%). Patients with ECOG performance status (PS) 0-2 at relapse showed a better 1-year OS than those with PS 3-4. Median OS for patients who received chemotherapy only or chemotherapy with CT was 74 or 173.5 days, respectively (p < 0.001). Relapsed patients receiving conventional re-induction chemotherapy were categorized as the high-intensity chemotherapy (H) group, while those receiving treatments such as hypomethylating agents or targeted agents were categorized as the low-intensity chemotherapy (L) group. The H group showed a better 1-year OS compared with the L group. Patients who received H + CT showed a better 1-year OS of 52.9% than the other 3 groups (p < 0.001). Even for patients with post-alloSCT remission duration of less than 6 months, the statistical significance was preserved. Factors including age, donor source at 1stalloSCT, time to relapse, blast counts, PS at relapse, and treatment type after post-alloSCT relapse were used for a multivariate analysis, and matched or mismatched related donor and H + CT after alloSCT were identified as independent factors associated with OS. These findings support the use of H + CT as the treatment option of choice for AML patients who relapse after alloSCT when feasible.
Assuntos
Leucemia Mieloide Aguda/terapia , Recidiva Local de Neoplasia/terapia , Adolescente , Adulto , Idoso , Antineoplásicos/uso terapêutico , Criança , Feminino , Humanos , Transfusão de Linfócitos , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
The prognosis of 11q23/KMT2A-rearranged (KMT2A-r) acute leukemia (AL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is poor. Minimal residual disease (MRD) is an important prognostic factor for relapse. Thus, we aimed to identify the evolution of KMT2A before and after allo-HSCT and the efficacy of preemptive immunotherapies for KMT2A-r AL patients receiving allo-HSCT. KMT2A expression was determined through TaqMan-based RQ-PCR technology. Preemptive immunotherapies included interferon-α and donor lymphocyte infusion. We collected 1751 bone marrow samples from 177 consecutive KMT2A-r AL patients. Pre-HSCT KMT2A positivity was correlated with post-HSCT KMT2A positivity (correlation coefficient=0.371, P<0.001). The rates of achieving KMT2A negativity after allo-HSCT were 96.6%, 92.9%, and 68.8% in the pre-HSCT low-level group (>0, <0.1%), intermediate-level group (≥ 0.1%, <1%), and high-level group (≥1%), respectively. The rates of regaining KMT2A positivity after allo-HSCT were 7.7%, 35.7%, 38.5%, and 45.5% for the pre-HSCT KMT2A-negative, low-level, intermediate-level, and high-level groups, respectively (P<0.001). The 4-year cumulative incidence of relapse after allo-HSCT was as high as 53.7% in the pre-HSCT KMT2A expression ≥ 0.1% group, which was compared to the KMT2A-negative group (15.1%) and KMT2A <0.1% group (31.2%). The clinical outcomes of patients with post-HSCT KMT2A positivity were poorer than those of patients with persistent KMT2A negativity. Although post-HSCT preemptive immunotherapies might help to achieve KMT2A negativity, the long-term efficacy was unsatisfactory. Thus, pre-HSCT KMT2A positivity was significantly associated with post-HSCT KMT2A positivity. The clinical outcomes of patients with post-HSCT KMT2A positivity were poor, which might not be overcome by commonly used immunotherapies.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/diagnóstico , Proteína de Leucina Linfoide-Mieloide/genética , Neoplasia Residual/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Rearranjo Gênico , Humanos , Imunoterapia , Lactente , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/genética , Neoplasia Residual/terapia , Prognóstico , Transplante Homólogo , Adulto JovemRESUMO
Minimal residual disease (MRD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) heralds high risk of relapse. Whether preemptive recombinant interleukin-2 (pre-IL2) is effective for patients with late-onset MRD (LMRD) remains unknown. We retrospectively compared the efficacy and safety of pre-IL2 (n = 30) and pre-DLI (n = 25) for LMRD in patients receiving allo-HSCT for acute leukemia or myelodysplastic syndrome. The 1-year overall survival (OS) and disease-free survival (DFS) rates were 86.7% and 78.4% (P = 0.267), 83.3% and 75.6% (P = 0.329), the cumulative incidence of grades III-IV acute graft-versus-host disease (aGVHD) at 100 days post-preemptive intervention was 3.3% and 12.0% (P = 0.226) in the pre-IL2 group and pre-DLI group, respectively. The 1-year cumulative incidence of moderate/severe chronic GVHD (cGVHD), relapse (CIR), and non-relapse mortality (NRM) were 7.7% and 27.9% (P = 0.018), 13.6% and 20.0% (P = 0.561) and 3.3% and 5.5% (P = 0.321) in the two groups, respectively. No remarkable differences in CIR, OS, and DFS between the two intervention groups were found in multivariate analysis. The GVHD-free and relapse-free survival (GRFS) were better in the pre-IL2 group than in the pre-DLI group (HR = 0.31, 95% confidence interval (CI), 0.12-0.76; P = 0.011). In conclusion, preemptive low-dose IL2 and preemptive DLI yield comparable outcomes for patients with LMRD receiving allo-HSCT, in terms of aGVHD, NRM, relapse, OS, and DFS. However, preemptive low-dose IL2 has a lower incidence of moderate/severe cGVHD and a higher CRFS. Preemptive low-dose IL2 may be an alternative method for patients who develop LMRD after allo-HSCT, particularly for patients who cannot receive preemptive DLI.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Interleucina-2/administração & dosagem , Leucemia , Transfusão de Linfócitos , Síndromes Mielodisplásicas , Doença Aguda , Adolescente , Adulto , Aloenxertos , Criança , Doença Crônica , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Incidência , Leucemia/sangue , Leucemia/mortalidade , Leucemia/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/terapia , Neoplasia Residual , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Advanced systemic mastocytosis is a relatively rare entity where allogeneic stem cell transplantation can lead to the cure of the disease in selected patients. Delayed incomplete responses with graft-versus-mastocytosis effect were published in a few cases. In this particular patient's report, we describe the direct evidence and potency of graft-versus-mastocytosis effect of donor lymphocyte infusions in a patient with systemic mastocytosis with associated hematological neoplasm (SM-AHN). In a 53-year-old female patient, an allogeneic stem cell transplantation after conventional induction treatment was performed for transformed acute myeloid leukemia (AML) during the course of polycythemia vera. After 6 years of remission period of AML and PV, the patient developed aleukemic mast cell leukemia and JAK2-positive myeloproliferative neoplasm (SM-AHN). We were able to achieve a sustained complete remission of SM-AHN lasting for 6 years with only donor lymphocyte infusions in a status of mixed chimerism. The patient is in a good clinical condition and remission. The potent graft-versus-mastocytosis effect in this patient resembles the favorable effect of donor lymphocyte infusions in relapsing chronic myeloid leukemia patients after transplantation. This patient is, to our knowledge, the first case showing the proof of principle of graft-versus-mastocytosis effect.
Assuntos
Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transfusão de Linfócitos/efeitos adversos , Mastocitose Sistêmica/diagnóstico , Mastocitose Sistêmica/etiologia , Biópsia , Medula Óssea/patologia , Feminino , Humanos , Imuno-Histoquímica , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Transplante HomólogoRESUMO
Allogeneic transplantation still remains as standard of care for patients with high-risk hematological malignancies at diagnosis or after relapse. However, GvHD remains yet as the most relevant clinical complication in the early post-transplant period. TCD allogeneic transplant is now considered a valid option to reduce severe GvHD and to provide a platform for cellular therapy to prevent relapse disease or to treat opportunistic infections.
Assuntos
Neoplasias Hematológicas/terapia , Hematologia/tendências , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante Homólogo/efeitos adversos , Antígenos CD34/biossíntese , Doença Enxerto-Hospedeiro , Hematologia/métodos , Humanos , Células Matadoras Naturais/citologia , Antígenos Comuns de Leucócito/biossíntese , Depleção Linfocítica , Recidiva Local de Neoplasia , Recidiva , Linfócitos T/citologia , Resultado do TratamentoRESUMO
Initial treatment with the monoclonal anti-CD52 antibody alemtuzumab induces responses in the majority of patients with T-cell prolymphocytic leukemia (T-PLL). In eligible patients, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an option to consolidate hematological remissions. Here, we report our experience with 10 patients who received allo-HSCT against T-PLL. Notably, 3 patients with complete remission at transplantation and durable full-donor chimerism relapsed at months 12, 59, and 84 after transplantation, respectively. This relapse was associated with rapid progressive leukemia in 1 patient and extralymphatic lymphoma growth in the other 2. Despite CD52 positivity at relapse, alemtuzumab retreatment, donor lymphocyte infusions, and/or chemotherapy including salvage therapy, allo-HSCT yielded a transient partial response, only. Alemtuzumab induction and consolidative allo-HSCT enabled prolonged disease-free survival in these patients but failed to procure cure.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Prolinfocítica de Células T/diagnóstico , Leucemia Prolinfocítica de Células T/terapia , Terapia Combinada , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunofenotipagem , Leucemia Prolinfocítica de Células T/mortalidade , Masculino , Prognóstico , Recidiva , Quimeras de Transplante , Condicionamento Pré-Transplante , Transplante Homólogo , Resultado do TratamentoRESUMO
Among haematological parameters of patients seriously ill with the coronavirus infectious disease 2019 (COVID-19), leucocytosis, lymphocytopenia, and the abnormal release of circulating cytokines, termed cytokine storm syndrome (CSS, also known as cytokine release syndrome or CRS), were found associated with disease severity. In particular, according to the serum cytokine profiling, pro-inflammatory interleukin 6 (IL-6) and anti-inflammatory interleukin 10 (IL-10) were observed to be considerably higher in patients experiencing respiratory distress, septic shock and/or multi-organ failure, namely "critical cases" requiring intensive care unit (ICU) admission, very often resulting in death. Interestingly, the production of these cytokines from human lymphocytes was found to be modulated by exposure of 24 h to a 554.2-553.8 mT inhomogeneous static magnetic field (SMF), which elicits IL-10 and suppresses IL-6. Thus, herein, with the aim of restoring lymphocyte count and physiological serum levels of IL-6 and IL-10, the infusion of human leukocyte antigen (HLA)-matched and SMF-exposed allogenic lymphocytes is proposed for the first time as an easy and affordable treatment option for COVID-19 patients. Even if the count of lymphocytes in COVID-19 patients is very low, SMF exposure may be a valuable tool for reprogramming autologous lymphocytes towards physiological conditions. Furthermore, the same procedure could be extended to include the whole autologous or allogenic white blood cells (WBCs). Time-varying/pulsed magnetic fields exerting comparable cell effects could also be employed.
Assuntos
COVID-19/complicações , Síndrome da Liberação de Citocina/terapia , Antígenos HLA/imunologia , Linfócitos/citologia , Linfopenia/terapia , Campos Magnéticos , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Humanos , Imunoterapia , Interleucina-6/química , Interleucina-6/metabolismo , Linfócitos/imunologia , Linfopenia/complicações , Linfopenia/imunologia , Linfopenia/patologia , Modelos Moleculares , Conformação Proteica , Transdução de Sinais/imunologiaRESUMO
In this cross-sectional study, we retrospectively evaluated the files of 227 patients with myelofibrosis who underwent transplantation between 1994 and 2015 for relapse later than 5 years after allogeneic stem cell transplantation (SCT). A total of 94 patients who were alive and in remission at 5 years were identified with follow-up of at least 5 years (median, 9.15 years) after SCT. Thirteen patients (14%) experienced late molecular (n = 6) or hematologic (n = 7) relapse at a median of 7.1 years while 81 patients did not experience relapse. Relapse patients received either donor lymphocyte infusion (DLI) (n = 7) and/or second transplantation (n = 4). Of those, 72.7% achieved again full donor cell chimerism and molecular remission, and after a median follow-up of 45 months, the 3-year overall survival rates for patients with or without relapse were 90.9% (95% confidence interval [CI], 77% to 100%) and 98.8% (95% CI, 96% to 100%), respectively (P = .13). We conclude that late relapse occurs in about 14% of the patients and the majority can be successfully salvaged with DLI and/or second allograft. All patients with molecular relapse are alive and support the long-time molecular monitoring in myelofibrosis patients after allogeneic SCT.