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Autologous anti-CD19 chimeric antigen receptor (CAR) T cells are now used in routine practice for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Severe (grade ≥ 3) cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are still the most concerning acute toxicities leading to frequent intensive care unit (ICU) admission, prolonging hospitalization, and adding significant cost to treatment. We report on the incidence of CRS and ICANS and the outcomes in a large cohort of 925 patients with LBCL treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) in France based on patient data captured through the DESCAR-T registry. CRS of any grade occurred in 778 patients (84.1%), with 74 patients (8.0%) with grade 3 CRS or higher, while ICANS of any grade occurred in 375 patients (40.5%), with 112 patients (12.1%) with grade ≥ 3 ICANS. Based on the parameters selected by multivariable analyses, two independent prognostic scoring systems (PSS) were derived, one for grade ≥ 3 CRS and one for grade ≥ 3 ICANS. CRS-PSS included bulky disease, a platelet count < 150 G/L, a C-reactive protein (CRP) level > 30 mg/L and no bridging therapy or stable or progressive disease (SD/PD) after bridging. Patients with a CRS-PSS score > 2 had significantly higher risk to develop grade ≥ 3 CRS. ICANS-PSS included female sex, low level of platelets (< 150 G/L), use of axi-cel and no bridging therapy or SD/PD after bridging. Patients with a CRS-PSS score > 2 had significantly higher risk to develop grade ≥ 3 ICANS. Both scores were externally validated in international cohorts of patients treated with tisa-cel or axi-cel.
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Antígenos CD19 , Síndrome de Liberación de Citoquinas , Inmunoterapia Adoptiva , Linfoma de Células B Grandes Difuso , Humanos , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Masculino , Femenino , Persona de Mediana Edad , Antígenos CD19/inmunología , Pronóstico , Linfoma de Células B Grandes Difuso/terapia , Linfoma de Células B Grandes Difuso/inmunología , Síndrome de Liberación de Citoquinas/etiología , Anciano , Adulto , Síndromes de Neurotoxicidad/etiología , Productos Biológicos/uso terapéutico , Productos Biológicos/efectos adversos , Francia , Anciano de 80 o más Años , Receptores de Antígenos de Linfocitos TRESUMEN
Tafasitamab plus lenalidomide (TAFA-LEN) treatment relevance pre- or post-anti-CD19 CAR T-cell is currently debated. We analyzed large B-cell lymphoma patients in the DESCAR-T registry treated with axi-cel or tisa-cel in ≥3rd line (L3+) and TAFA-LEN before (n=15, 'TL-pre-CAR-T' set) or directly after (n=52, 'TL-post-CAR-T' set) CAR T-cell. We compared TAFA-LEN v. other treatments using inverse probability weighting in the TL-post-CAR-T set. In the TL-post-CAR-T' set, the median follow-up duration (mFUD) was 7 months, and the median progression-free survival, overall survival and duration of response since the 1st treatment for progression (mPFS2/mOS2/mDOR2) were 3, 4.7 and 8.1 months, respectively. The best overall response rate (bORR) and best complete response rate (bCRR) after TAFA-LEN were 13.5% and 7.7%, respectively. Outcomes were better for patients who relapsed >6 months after CAR T-cell (mPFS2: 5.6 vs. 2 months, p=0.0138; mOS2: not reached vs. 3.8 months, p=0.0034). bORR and bCRR between TAFA-LEN and other treatments were 20.6% vs. 24.9% and 11.6% vs. 15.6%, respectively. Outcomes were similar between TAFA-LEN and other treatments (mPFS2: 2.9 [2-2.6] vs. 2.4 [1.5-4.2] months, p=0.91; mOS2: 3.3 [1.8-6.4] vs. 5.5 [4.4-6.3] months, p=0.06). In an exploratory analysis of the TL-pre-CAR-T set (mFUD since CAR T-cell: 2.8 months), the median TAFA-LEN treatment duration prior to CAR-T was 3.7 months and no patients were reported to become CD19 negative. The bORR, bCRR, 6-month PFS and OS rates after CAR T-cell infusion were 45.5%, 36.4%, 20.1% and 58.2%, respectively. Neither TAFA-LEN nor comparative salvage treatments improved outcomes of patients who relapsed after CAR T-cell.
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Autologous(auto-) and allogeneic(allo-) hematopoietic stem cell transplantation (HSCT) are key treatments for relapsed/refractory diffuse large B-cell lymphoma (DLBCL), although their roles are challenged by CAR-T-cells and other immunotherapies. We examined the transplantation trends and outcomes for DLBCL patients undergoing auto-/allo-HSCT between 1990 and 2021 reported to EBMT. Over this period, 41,148 patients underwent auto-HSCT, peaking at 1911 cases in 2016, while allo-HSCT saw a maximum of 294 cases in 2018. The recent decline in transplants corresponds to increased CAR-T treatments (1117 cases in 2021). Median age for auto-HSCT rose from 42 (1990-1994) to 58 years (2015-2021), with peripheral blood becoming the primary stem cell source post-1994. Allo-HSCT median age increased from 36 (1990-1994) to 54 (2015-2021) years, with mobilized blood as the primary source post-1998 and reduced intensity conditioning post-2000. Unrelated and mismatched allo-HSCT accounted for 50% and 19% of allo-HSCT in 2015-2021. Three-year overall survival (OS) after auto-HSCT improved from 56% (1990-1994) to 70% (2015-2021), p < 0.001, with a decrease in relapse incidence (RI) from 49% to 38%, while non-relapse mortality (NRM) remained unchanged (4%). After allo-HSCT, 3-year-OS increased from 33% (1990-1999) to 46% (2015-2021) (p < 0.001); 3-year RI remained at 39% and 1-year-NRM decreased to 19% (p < 0.001). Our data reflect advancements over 32 years and >40,000 transplants, providing insights for evaluating emerging DLBCL therapies.
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Trasplante de Células Madre Hematopoyéticas , Linfoma de Células B Grandes Difuso , Humanos , Trasplante de Células Madre Hematopoyéticas/métodos , Linfoma de Células B Grandes Difuso/terapia , Linfoma de Células B Grandes Difuso/mortalidad , Persona de Mediana Edad , Masculino , Femenino , Adulto , Anciano , Europa (Continente)/epidemiología , Adolescente , Adulto Joven , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo , Trasplante AutólogoRESUMEN
T-cell acute lymphoblastic leukemia (T-ALL) predominantly affects individuals in late childhood and young adulthood. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative modality particularly in the setting of poor risk genetics and/or persistent minimal residual disease. Limited studies have directly explored the impact of patient- and transplant-related factors on post-transplant outcomes in T-ALL. Using a large dataset from the European Society for Blood and Marrow Transplantation registry, we identified 1907 adult T-ALL patients (70% male) who underwent their first allo-HSCT in first complete remission (CR1) from matched sibling donors (MSD; 45%), unrelated donors (UD; 43%) or haploidentical donors (12%) between 2010 and 2021. The median age at transplant was 33.4 years (18.1-75). The median follow up was 2.9 years. Most patients underwent total body irradiation (TBI)-based myeloablative conditioning (69%). The 2-year overall survival (OS) was 69.4%, and leukemia -free survival (LFS) was 62.1%. In multivariate analysis, advanced age at transplant negatively affected LFS (for each 10-year increment, HR = 1.11, p = 0.004), GVHD-free, relapse-free survival (GRFS) (HR = 1.06, p = 0.04), OS (HR = 1.12, p = 0.002), and non-relapse mortality (NRM) (HR = 1.23, p < 0.001). More recent years of allo-HSCT were associated with improved GFRS (For each 3-year increment, HR = 0.89, p < 0.001), OS (HR = 0.9, p = 0.02), and decreased NRM (HR = 0.82, p = 0.008). TBI improved LFS. (HR = 0.79, p = 0.02), GRFS (HR = 0.83, p = 0.04), and relapse incidence (RI) (HR = 0.65, p < 0.001). Female-to-male transplant negatively affected GRFS (HR = 1.21, p = 0.02) and OS (HR = 1.23, p = 0.048). In vivo T-cell depletion significantly improved GFRS (HR = 0.74, p < 0.001). This large study identified prognostic factors, such as age at transplant conditioning regimen, in influencing post-transplant in adult T-ALL patients undergoing allo-HSCT. Importantly, a significant improvement over time was noted. These findings hold great promise for new adapted treatment strategies and can serve as a benchmark for future studies in that setting.
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T-cell engagers (TCE) are cancer immunotherapies that have recently demonstrated meaningful benefit for patients with hematological malignancies and solid tumors. The anticipated widespread use of T cell engagers poses implementation challenges and highlights the need for guidance to anticipate, mitigate, and manage adverse events. By mobilizing T-cells directly at the contact of tumor cells, TCE mount an obligatory and immediate anti-tumor immune response that could result in diverse reactions and adverse events. Cytokine release syndrome (CRS) is the most common reaction and is largely confined to the first drug administrations during step-up dosage. Cytokine release syndrome should be distinguished from infusion related reaction by clinical symptoms, timing to occurrence, pathophysiological aspects, and clinical management. Other common reactions and adverse events with TCE are immune effector Cell-Associated Neurotoxicity Syndrome (ICANS), infections, tumor flare reaction and cytopenias. The toxicity profiles of TCE and CAR-T cells have commonalities and distinctions that we sum-up in this review. As compared with CAR-T cells, TCE are responsible for less frequently severe CRS or ICANS. This review recapitulates terminology, pathophysiology, severity grading system and management of reactions and adverse events related to TCE.
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Inmunoterapia Adoptiva , Neoplasias , Linfocitos T , Humanos , Neoplasias/inmunología , Neoplasias/terapia , Linfocitos T/inmunología , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/inmunología , Receptores Quiméricos de Antígenos/inmunologíaRESUMEN
INTRODUCTION: For the majority of patients with acute myeloid leukemia (AML) an allogeneic stem cell transplant (SCT) in first complete remission (CR) is preferred. However, whether the number of courses required to achieve CR has a prognostic impact is unclear. It is unknown which factors remain important in patients requiring more than one course of induction to attain remission. METHODS: This Acute Leukaemia Working Party study from the European Society for Blood and Marrow Transplantation identified adults who received an allograft in first CR from either a fully matched sibling or 10/10 or 9/10 human leucocyte antigen (HLA)-matched unrelated donor (HLA-A, HLA-B, HLA-C, HLA-DR, or HLA-DQ). Univariate and multivariate analyses were undertaken to identify the prognostic impact of one or two courses of induction to attain CR. RESULTS: A total of 4995 patients were included with 3839 (77%) patients attaining a CR following one course of induction chemotherapy (IND1), and 1116 patients requiring two courses (IND2) to attain CR. IND2 as compared to IND1 was a poor prognostic factor in a univariate analysis and remained so in a multivariate Cox model, resulting in an increased hazard ratio of relapse (1.38; 95% confidence interval [CI], 1.16-1.64; p = .0003) and of death (1.27; 95% CI, 1.09-1.47; p = .002). Adverse prognostic factors in a multivariate analysis of the outcomes of patients requiring IND2 included age, FLT3-ITD, adverse cytogenetics, and performance status. Pretransplant measurable residual disease retained a prognostic impact regardless of IND1 or IND2. CONCLUSION: Initial response to chemotherapy as determined by number of courses to attain CR, retained prognostic relevance even following SCT in CR.
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Antígenos HLA , Leucemia Mieloide Aguda , Inducción de Remisión , Hermanos , Donante no Emparentado , Humanos , Masculino , Persona de Mediana Edad , Adulto , Femenino , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/mortalidad , Pronóstico , Antígenos HLA/inmunología , Adolescente , Adulto Joven , Anciano , Trasplante de Células Madre Hematopoyéticas/métodos , Quimioterapia de Inducción/métodos , Trasplante HomólogoRESUMEN
Post-transplant cyclophosphamide plus calcineurin inhibitor (CNI)(tacrolimus or cyclosporine A) plus mycophenolate mofetil (PTCy/TAC or CSA/MMF) and anti-thymocyte globulin plus CNI (tacrolimus or cyclosporine A) plus methotrexate (ATG/TAC or CSA/MTX) are common graft-versus-host disease (GVHD) prophylaxis regimens. We compared the two regimens in patients with acute myeloid leukemia (AML) undergoing allogeneic transplantation from matched siblings or unrelated donors. 402 received PTCy/TAC or CSA/MMF and 5648 received ATG/TAC or CSA/MTX. Patients in the PTCy-based group were younger (48.7 vs. 51.5 years, p = 0.024) and there was a higher frequency of patient cytomegalovirus seropositivity and female donor to male patient combination in this group (77.8% vs. 71.8%, p = 0.009 and 18.4% vs. 14.4%, p = 0.029, respectively). More patients in the PTCy-based group received reduced-intensity conditioning (51.5% vs. 41%, p < 0.0001). No differences were observed in the incidence of acute GVHD grade II-IV and III-IV (21.2% vs. 20.4%, p = 0.92 and 8.1% vs. 6%, p = 0.1) or 2-year total and extensive chronic GVHD (33.7% vs. 30%, p = 0.09 and 10.7% vs. 11.2%, p = 0.81) between the groups. In the multivariate analysis, all transplant outcomes did not differ between the groups. PTCy/CNI/MMF and ATG/CNI/MTX are alternative regimens for GVHD prophylaxis in AML patients.
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Suero Antilinfocítico , Inhibidores de la Calcineurina , Ciclofosfamida , Enfermedad Injerto contra Huésped , Leucemia Mieloide Aguda , Metotrexato , Ácido Micofenólico , Hermanos , Donante no Emparentado , Humanos , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad Injerto contra Huésped/etiología , Masculino , Femenino , Persona de Mediana Edad , Suero Antilinfocítico/uso terapéutico , Ácido Micofenólico/uso terapéutico , Leucemia Mieloide Aguda/terapia , Adulto , Ciclofosfamida/uso terapéutico , Inhibidores de la Calcineurina/uso terapéutico , Metotrexato/uso terapéutico , Adolescente , Anciano , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Adulto Joven , Aloinjertos , Trasplante Homólogo/métodos , Inmunosupresores/uso terapéuticoRESUMEN
ABSTRACT: In this retrospective study, chimeric antigen receptor T cells remained effective in patients with relapsed/refractory large B-cell lymphoma after prior exposure to bispecific antibodies (BsAbs) targeting different antigens. These results are relevant to clinical practice, particularly given the increasing use of BsAbs in earlier treatment lines.
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Anticuerpos Biespecíficos , Inmunoterapia Adoptiva , Linfoma de Células B Grandes Difuso , Humanos , Anticuerpos Biespecíficos/uso terapéutico , Inmunoterapia Adoptiva/métodos , Estudios Retrospectivos , Linfoma de Células B Grandes Difuso/terapia , Linfoma de Células B Grandes Difuso/inmunología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Receptores Quiméricos de Antígenos/inmunología , Adulto , Resultado del TratamientoRESUMEN
There is an increased risk of GVHD and of non-relapse mortality (NRM) after allogeneic stem cell transplantations (alloSCT) when mismatched unrelated donors (MMUD) are used. In Europe, it is standard practice to use rabbit anti-thymocyte globulin (rATG) to reduce the high NRM and GVHD risks after MMUD alloSCT. As an alternative to rATG, post-transplantation Cyclophosphamide (PTCy) is in increasing clinical use. It is currently impossible to give general recommendations regarding preference for one method over another since comparative evidence from larger data sets is lacking. To improve the evidence base, we analyzed the outcome of rATG vs. PTCy prophylaxis in adult patients with hematologic malignancies undergoing first peripheral blood alloSCT from MMUD (9/10 antigen match) between Jan 2018 and June 2021 in the database of the European Society for Blood and Marrow Transplantation (EBMT). We performed multivariate analyses using the Cox proportional-hazards regression model. We included 2123 patients in the final analyses (PTCy, n = 583; rATG, n = 1540). p values and hazard ratios (HR) presented here are multivariate outcomes. Two years after alloSCT we found a lower NRM in the PTCy group of 18% vs. 24.9% in the rATG group; p = 0.028, HR 0.74. Overall survival in the PTCy cohort was higher with 65.7% vs. 55.7% in the rATG cohort; p < 0.001, HR 0.77. Progression-free survival was also better in the PTCy patients with 59.1% vs. 48.8% when using rATG; p = 0.001, 0.78. The incidences of chronic GVHD and acute GVHD were not significantly different between the groups. We found significantly lower NRM as well as higher survival in recipients of peripheral blood alloSCTs from MMUD receiving PTCy as compared to rATG. The results of the current analysis suggest an added value of PTCy as GVHD prophylaxis in MMUD alloSCT.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Adulto , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Ciclofosfamida/uso terapéutico , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Suero Antilinfocítico/uso terapéutico , Donante no Emparentado , Estudios RetrospectivosRESUMEN
Management of Richter transformation (RT) is particularly challenging, with survival estimates <1 year. We report on outcomes of 66 RT patients undergoing allogeneic-HCT (allo-HCT) between 2008 and 2018 registered with the EBMT. Median age at allo-HCT was 56.2 years (interquartile range (IQR), 51.3-63.1). Median time from RT to allo-HCT was 6.9 months (IQR, 4.9-11) and 28 (42.4%) were in complete remission (CR). The majority underwent reduced intensity conditioning (66.2%) using peripheral blood derived stem cells. Eighteen (27.3%) patients had a matched sibling donor, 24 (36.4%) a matched unrelated donor and the remaining were mismatched. Median follow-up was 6.6 years; 1- and 3- year overall and progression free survival (PFS) (95% CI) was 65% (54-77) and 39% (27-51) and 53% (41-65) and 29% (18-40), respectively. Patients in CR at time of allo-HCT had significantly better 3-year PFS (39% vs. 21%, p = 0.032). Cumulative incidences of grade II-IV acute graft versus host disease (GVHD) at day +100 was 41% (95% CI 29-53) and chronic GVHD at 3 years was 53% (95% CI 41-65). High rates of non-relapse mortality (NRM) were observed; 38% (95% CI, 26-50) at 3 years. Although potentially curative, approaches to reduce considerable NRM and chronic GVHD rates are required.
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Trasplante de Células Madre Hematopoyéticas , Humanos , Persona de Mediana Edad , Trasplante de Células Madre Hematopoyéticas/métodos , Estudios Retrospectivos , Masculino , Femenino , Trasplante Homólogo/métodos , Acondicionamiento Pretrasplante/métodos , Enfermedad Injerto contra Huésped/mortalidad , Adulto , AloinjertosRESUMEN
Autoimmune diseases (ADs) are characterized by loss of immune tolerance, high chronicity, with substantial morbidity and mortality, despite conventional immunosuppression (IS) or targeted disease modifying therapies (DMTs), which usually require repeated administration. Recently, novel cellular therapies (CT), including mesenchymal stromal cells (MSC), Chimeric Antigen Receptors T cells (CART) and regulatory T cells (Tregs), have been successfully adopted in ADs. An international expert panel of the European Society for Blood and Marrow Transplantation and the International Society for the Cell and Gene Therapy, reviewed all available evidence, based on the current literature and expert practices, on use of MSC, CART and Tregs, in AD patients with rheumatological, neurological, and gastroenterological indications. Expert-based consensus and recommendations for best practice and quality of patient care were developed to support clinicians, scientists, and their multidisciplinary teams, as well as patients and care providers and will be regularly updated.
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ABSTRACT: Chimeric antigen receptor (CAR) T-cells targeting CD19 have been approved for the treatment of relapse/refractory large B-cell lymphoma. Hematotoxicity is the most frequent CAR T-cell-related adverse event. Transfusion support is a surrogate marker of severe cytopenias. Transfusion affects patients' quality of life, presents specific toxicities, and is known to affect immunity through the so-called transfusion-related immunomodulation that may affect CAR T-cell efficacy. We analyzed data from 671 patients from the French DESCAR-T registry for whom exhaustive transfusion data were available. Overall, 401 (59.8%) and 378 (56.3%) patients received transfusion in the 6-month period before and after CAR T-cell infusion, respectively. The number of patients receiving transfusion and the mean number of transfused products increased during the 6-month period before CAR T-cell infusion, peaked during the first month after infusion (early phase), and decreased over time. Predictive factors for transfusion at the early phase were age >60 years, ECOG PS ≥2, treatment with axicabtagene ciloleucel, pre-CAR T-cell transfusions, and CAR-HEMATOTOX score ≥2. Predictive factors for late transfusion (between 1 and 6 months after infusion) were pre-CAR T-cell transfusions, CAR-HEMATOTOX score ≥2, ICANS ≥3 (for red blood cells [RBC] transfusion), and tocilizumab use (for platelets transfusion). Early transfusions and late platelets (but not RBC) transfusions were associated with a shorter progression-free survival and overall survival. Lymphoma-related mortality and nonrelapse mortality were both increased in the transfused population. Our data shed light on the mechanisms of early and late cytopenia and on the potential impact of transfusions on CAR T-cell efficacy and toxicity.
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Inmunoterapia Adoptiva , Linfoma de Células B Grandes Difuso , Humanos , Persona de Mediana Edad , Inmunoterapia Adoptiva/efectos adversos , Calidad de Vida , Recurrencia Local de Neoplasia , Linfoma de Células B Grandes Difuso/patología , Biomarcadores , Antígenos CD19RESUMEN
The use of peripheral blood (PB) or bone marrow (BM) stem cells graft in haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis remains controversial. Moreover, the value of adding anti-thymoglobulin (ATG) to PTCy is unknown. A total of 1344 adult patients received an unmanipulated haploidentical transplant at 37 centers from 2012 to 2019 for hematologic malignancy. We compared the outcomes of patients according to the type of graft, using a propensity score analysis. In total population, grade II-IV and III-IV acute GVHD (aGVHD) were lower with BM than with PB. Grade III-IV aGVHD was lower with BM than with PB + ATG. All outcomes were similar in PB and PB + ATG groups. Then, in total population, adding ATG does not benefit the procedure. In acute leukemia, myelodysplastic syndrome and myeloproliferative syndrome (AL-MDS-MPS) subgroup receiving non-myeloablative conditioning, risk of relapse was twice greater with BM than with PB (51 vs. 22%, respectively). Conversely, risk of aGVHD was greater with PB (38% for aGVHD II-IV; 16% for aGVHD III-IV) than with BM (28% for aGVHD II-IV; 8% for aGVHD III-IV). In this subgroup with intensified conditioning regimen, risk of relapse became similar with PB and BM but risk of aGVHD III-IV remained higher with PB than with BM graft (HR = 2.0; range [1.17-3.43], p = 0.012).
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Adulto , Humanos , Médula Ósea , Estudios Retrospectivos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Ciclofosfamida/uso terapéutico , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Recurrencia , Células Madre HematopoyéticasRESUMEN
B-cell acute lymphoblastic leukemia (B-ALL) is the most common subtype of acute leukemia in the pediatric population. The prognosis and treatment of B-ALL have dramatically improved over the past decade with the adoption of intensive and prolonged combination chemotherapy regimens. The advent of novel immunologic agents such as blinatumomab and inotuzumab has changed the treatment landscape of B-ALL. However, patients have continued to relapse, raising the need for novel therapies. Chimeric antigen receptor (CAR) T-cells have achieved a milestone in the treatment of B-ALL. Two CD19-targeting CAR T-cells were approved by the Food and Drug Administration and the European Medicines Agency for the treatment of relapsed and/or refractory B-ALL. In this review, we review the available data regarding CD19-targeting CAR T-cells with their safety profile as well as the mechanism of resistance to these agents and the way to overcome this resistance.
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CD19 chimeric antigen receptor (CAR) T cells can induce prolonged remissions and potentially cure a significant proportion of patients with relapsed/refractory large B-cell lymphomas. However, some patients may die of causes unrelated to lymphoma after CAR T-cell therapy. To date, little is known about the nonrelapse mortality (NRM) after CAR T-cell therapy. Using the French DESCAR-T registry, we analyzed the incidence and causes of NRM and identified risk factors of NRM. We report on 957 patients who received standard-of-care axicabtagene ciloleucel (n = 598) or tisagenlecleucel (n = 359) between July 2018 and April 2022, in 27 French centers. With a median follow-up of 12.4 months, overall NRM occurred in 48 patients (5.0% of all patients): early (before day 28 after infusion) in 9 patients (0.9% of all patients and 19% of overall NRM), and late (on/after day 28 after infusion) in 39 patients (4.1% of all patients and 81% of overall NRM). Causes of overall NRM were distributed as follows: 56% infections (29% with non-COVID-19 and 27% with COVID-19), 10% cytokine release syndromes, 6% stroke, 6% cerebral hemorrhage, 6% second malignancies, 4% immune effector cell associated neurotoxicities, and 10% deaths from other causes. We report risk factors of early NRM and overall NRM. In multivariate analysis, both diabetes and elevated ferritin level at lymphodepletion were associated with an increased risk of overall NRM. Our results may help physicians in patient selection and management in order to reduce the NRM after CAR T-cell therapy.
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Inmunoterapia Adoptiva , Linfoma de Células B Grandes Difuso , Humanos , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Linfoma de Células B Grandes Difuso/patología , Factores de Riesgo , Antígenos CD19RESUMEN
Chimeric antigen receptor (CAR) T-cell therapy is currently approved for the treatment of B-cell non-Hodgkin lymphomas and B-cell acute lymphoblastic leukemia. Prolonged hematological toxicity is an emergent concern following CAR T cells and occurred in 30% of patients with unknown mechanism. Few cases of myelodysplastic syndrome (MDS) following CAR T-cell therapy were reported and attributed to previous chemotherapies in heavily pretreated patients. The authors report the case of a patient with diffuse large B-cell lymphoma treated with axicabtagene ciloleucel who developed prolonged hematological toxicity by day 28. During the follow-up, the diagnosis of MDS was made. The patient underwent allogenic hematological stem cell transplantation. The patient remains in complete remission of his lymphoma and MDS 19 months after hematological stem cell transplantation.
Chimeric antigen receptor (CAR) T cell is a new type of immunotherapy that was recently validated for the treatment of some types of B-cell lymphoma and leukemia. One of the most recently reported side effects of CAR T cells is the appearance of anemia, thrombocytopenia and/or neutropenia lasting for a long duration. The authors report the case of a patient treated with CAR T cells for non-Hodgkin lymphoma who developed prolonged hematological toxicity. During follow-up, the diagnosis of myelodysplastic syndrome was made and the patient underwent allogenic bone marrow transplantation and remains in complete remission at last follow-up.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Linfoma de Células B Grandes Difuso , Síndromes Mielodisplásicos , Receptores Quiméricos de Antígenos , Humanos , Inmunoterapia Adoptiva/efectos adversos , Antígenos CD19/uso terapéutico , Receptores de Antígenos de Linfocitos TRESUMEN
Allogeneic hematopoietic stem cell transplantation remains the best curative option for higher-risk myelodysplastic syndrome. The presence of monosomal karyotype and/or complex karyotype abnormalities predicts inferior survival after allo-SCT in MDS patients. Haploidentical allo-SCT has been increasingly used in acute leukemia (AL) and has similar results as using HLA-matched donors, but data on higher-risk MDS is sparse. We compared outcomes in 266 patients with higher-risk MDS after HLA-matched sibling donor (MSD, n = 79), HLA-matched unrelated donor (MUD, n = 139) and HLA haploidentical donor (HID, n = 48) from 2010 to 2019. Median donor age differed between the three groups (p < 0.001). The overall survival was significantly different between the three groups with a better OS observed in the MUD group (p = 0.014). This observation could be explained by a higher progression-free survival with MUD (p = 0.014). The cumulative incidence of grade 2-4 acute GvHD was significantly higher in the HID group (p = 0.051). However, in multivariable analysis, patients transplanted using an HID had comparable mortality to patients transplanted using a MUD (subdistribution hazard ratio [sHR]: 0.58 [0.32-1.07]; p = 0.080) and a MSD ([sHR]: 0.56 [0.28-1.11]; p = 0.094). MUD do not remain a significant positive predictor of survival, suggesting that beyond the donor-recipient HLA matching, the donor age might impact recipient outcome.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/complicaciones , Donantes de Tejidos , Enfermedad Aguda , Trasplante Homólogo/métodos , Enfermedad Injerto contra Huésped/etiología , Acondicionamiento Pretrasplante/métodos , Donante no Emparentado , Estudios Retrospectivos , HermanosRESUMEN
The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 12th workshop on hematopoietic stem cell transplantation clinical practices harmonization procedures on September 2021 in Lille, France. In the absence of specific national or international recommendation, the French working group for autologous stem Cell transplantation in Auto-immune Diseases (MATHEC) proposed guidances for vaccinations of patients undergoing autologous hematopoietic stem cell transplantation for autoimmune disease, including in the context of SARS-Cov-2 pandemic.
Asunto(s)
Enfermedades Autoinmunes , COVID-19 , Trasplante de Células Madre Hematopoyéticas , Humanos , Trasplante de Médula Ósea , Trasplante Autólogo , COVID-19/prevención & control , SARS-CoV-2 , Enfermedades Autoinmunes/terapia , Sociedades Médicas , Vacunación , FranciaRESUMEN
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.