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Severe aplastic anemia (SAA) is a marrow failure disorder with high morbidity and mortality. It is treated with bone marrow transplantation (BMT) for those with fully matched donors, or immunosuppressive therapy (IST) for those who lack such a donor, which is often the case for underrepresented minorities. We conducted a prospective phase 2 trial of reduced-intensity conditioning HLA-haploidentical BMT and posttransplantation cyclophosphamide (PTCy)-based graft-versus-host (GVHD) prophylaxis as initial therapy for patients with SAA. The median patient age was 25 years (range, 3-63 years), and the median follow-up time was 40.9 months (95% confidence interval [CI], 29.4-55.7). More than 35% of enrollment was from underrepresented racial/ethnic groups. The cumulative incidence of grade 2 or 4 acute GVHD on day 100 was 7% (95% CI, not applicable [NA]-17), and chronic GVHD at 2 years was 4% (95% CI, NA-11). The overall survival of 27 patients was 92% (95% CI, 83-100) at 1, 2, and 3 years. The first 7 patients received lower dose total body irradiation (200 vs 400 cGy), but these patients were more likely to have graft failure (3 of 7) compared with 0 of 20 patients in the higher dose group (P = .01; Fisher exact test). HLA-haploidentical BMT with PTCy using 400 cGy total body irradiation resulted in 100% overall survival with minimal GVHD in 20 consecutive patients. Not only does this approach avoid any adverse ramifications of IST and its low failure-free survival, but the use of haploidentical donors also expands access to BMT across all populations. This trial was registered at www.clinicaltrials.gov as NCT02833805.
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Anemia Aplástica , Doença Enxerto-Hospedeiro , Humanos , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Transplante de Medula Óssea/efeitos adversos , Estudos Prospectivos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Ciclofosfamida/uso terapêuticoRESUMO
BACKGROUND: High-dose post-transplant cyclophosphamide allows safe and effective use of allografts from haploidentical relatives (siblings, parents and children) in patients undergoing allogeneic blood or marrow transplant (alloBMT). More recently, second- and third-degree relatives have also been shown to be safe allograft donors. An increasing number of older patients undergoing alloBMT have been receiving allografts from haploidentical donors. However, older patients are more likely to have older siblings and children, and older donor age is associated with worse outcomes. OBJECTIVE: In the current study, we report the safety and utility of grandchildren as haploidentical donors and compared with children as donors in patients undergoing alloBMT. METHODS: We compared characteristics and outcomes of alloBMT patients aged 55 years and older with children older than 30 years as donors (C group; n = 276) and those with grandchildren as donors (GC group; n = 40). Because many important baseline characteristics predict outcomes after alloBMT, we performed propensity score matched analysis based on recipient age, alloBMT year, disease, graft source and haematopoietic cell transplantation comorbidity index (HCT-CI). RESULTS: The median age of recipients was 67 years (range 55-79) in the C group and 73 years (range 57-78) in the GC group. More than 70% of recipients in the GC group were older than 70 years, compared with 27% in the C group. The median donor age was 37 years (range 31-52) in the C group and 20 years (range 14-34) in the GC group. More patients in the GC group had HCT-CI scores ≥3 than in the C group (32.5% vs. 23%, p = 0.27). Two-year overall survival did not differ between the two groups (GC 62% vs. C 60%, hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.53-1.75, p = 0.90) despite recipients of allografts from grandchildren being older. The 2-year RFS was 55% in the C group compared with 50% in the GC group (HR 1.05, 95% CI 0.62-1.77, p = 0.85). Non-relapse mortality subdistribution [SD] (SDHR 1.36, 95% 0.70-2.63, p = 0.36), relapse (SDHR 0.72, 95% CI 0.33-1.58, p = 0.42) or relapse-free survival (HR 1.05, 95% CI 0.62-1.77, p = 0.85). Propensity score matching analysis showed no significant differences in 2-year overall survival (GC 64% vs. C 53%; HR 0.77, 95% CI 0.42-1.42, p = 0.40), non-relapse mortality (SDHR 1.26, 95% 0.66-2.41, p = 0.48), relapse (SDHR 0.57, 95% CI 0.21-1.52, p = 0.26) or relapse-free survival (HR 0.94, 95% CI 0.57-1.54, p = 0.81). CONCLUSION: Our results indicate that outcomes of alloBMT patients with grandchild donors are similar to those with child donors, despite recipients' older age and higher comorbidities in the GC group. Grandchildren should be considered when selecting a donor for older alloBMT recipients.
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BACKGROUND: The bone/bone marrow is one of the most common sites for metastatic solid tumors. Moreover, the tumor microenvironment is an essential part of cancer homeostasis. Previously, it was shown that cytochrome P450 enzymes (CYPs) are present in the bone marrow (BM) microenvironment, particularly in the mesenchymal stroma cells, at levels comparable to those of hepatocytes. It was found that the CYPs play important roles in nurturing and maintaining normal hematopoietic stem cells as well as multiple myeloma and leukemia cells, including protecting them from toxic insults. It was hypothesized that the CYPs in the BM microenvironment might play a similar role in solid tumors metastatic to bone. METHODS: The interaction between the BM microenvironment and malignant cells that routinely metastasize to the bone (lung, breast, and prostate cancer) was modeled. Via genetic engineering and pharmacological approaches, the role of stromal cytochrome P450 3A4 (CYP3A4) in drug resistance promoted by the BM microenvironment in niche-cancer models in vitro and in vivo was interrogated. RESULTS: BM stroma protected prostate, breast, and lung cancer cells from cytotoxic chemotherapy. Stromal CYP3A4 was at least partially responsible for this protection in vitro and in vivo. Moreover, inhibiting CYP3A4 with clarithromycin overcame the stroma-mediated chemoresistance toward prostate, breast, and lung cancer cells. CONCLUSIONS: These results suggest that, similar to observations from hematologic malignancies, the BM microenvironment, through expression of CYPs, creates a sanctuary site from chemotherapy for metastatic solid tumors. Targeting these sanctuaries holds promise for eradicating bone metastasis in solid tumors.
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Citocromo P-450 CYP3A , Segunda Neoplasia Primária , Humanos , Medula Óssea/patologia , Células da Medula Óssea/metabolismo , Linhagem Celular Tumoral , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Segunda Neoplasia Primária/patologia , Microambiente Tumoral , Neoplasias/patologiaRESUMO
BACKGROUND: Older adults represent a large oncologic demographic and are under-represented within oncology research despite constituting nearly two-thirds of the oncologic population in the United States. Because many social factors influence research participation, those who enroll in research do not reflect the oncology population at large, introducing bias and creating issue with external validity of studies. The same factors that influence study enrollment may also impact cancer outcomes, meaning that those who enroll in studies may already have an improved chance of cancer survival, further skewing results of these studies. This study evaluates characteristics that influence study enrollment in older adults and explore to what degree these factors may influence survival after allogeneic blood or marrow transplantation. METHODS: This retrospective comparison study evaluates 63 adults aged 60 and above undergoing allogenic transplantation at one institution. Patients who elected and declined enrollment in a non-therapeutic observational study were evaluated. Demographic and clinical characteristics between groups were compared and assessed as predictors of transplant survival, including decision to enroll in the study. RESULTS: Participants who chose to enroll in the parent study were not different with regard to gender, race/ethnicity, age, insurance type, donor age, and neighborhood income/poverty level compared to patients who were invited to participate but declined enrollment. The research participant group had higher proportion assessed as being fully active (23.8% vs. 12.7%, p = 0.034) and lower mean comorbidity scores (1.0 vs 2.47, p = 0.008). Enrollment in an observational study independently predicted transplant survival (HR = 0.316, 95% CI 0.12-0.82, p = 0.017). When controlling for relevant confounders of disease severity, comorbidities, and transplant age, enrolling in the parent study was associated with a lower hazards of death following transplant (HR = 0.302, 95% CI 0.10-0.87, p = 0.027). CONCLUSIONS: Despite being demographically comparable, persons who enrolled in one non-therapeutic transplant study had significantly improved survivorship than those who did not participate in observational research. These findings suggest that there are unidentified factors that influence study involvement that may also impact disease survivorship, over-estimating outcomes from these studies. Results from prospective observational studies should be interpreted with the consideration that study participants have an improved chance of survival at baseline.
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Medula Óssea , Transplante de Células-Tronco Hematopoéticas , Humanos , Idoso , Estudos Retrospectivos , Etnicidade , Sobrevivência de EnxertoRESUMO
Multiple myeloma (MM) is a plasma cell neoplasm that commonly expresses CD38. Daratumumab (DARA), a human monoclonal antibody targeting CD38, has significantly improved the outcome of patients with relapsed or refractory MM, but the response is transient in most cases. Putative mechanisms of suboptimal efficacy of DARA include downregulation of CD38 expression and overexpression of complement inhibitory proteins on MM target cells as well as DARA-induced depletion of CD38high natural killer (NK) cells resulting in crippled antibody-dependent cellular cytotoxicity (ADCC). Here, we tested whether maintaining NK cell function during DARA therapy could maximize DARA-mediated ADCC against MM cells and deepen the response. We used the CRISPR/Cas9 system to delete CD38 (CD38KO) in ex vivo expanded peripheral blood NK cells. These CD38KO NK cells were completely resistant to DARA-induced fratricide, showed superior persistence in immune-deficient mice pretreated with DARA, and enhanced ADCC activity against CD38-expressing MM cell lines and primary MM cells. In addition, transcriptomic and cellular metabolic analysis demonstrated that CD38KO NK cells have unique metabolic reprogramming with higher mitochondrial respiratory capacity. Finally, we evaluated the impact of exposure to all-trans retinoic acid (ATRA) on wild-type NK and CD38KO NK cell function and highlighted potential benefits and drawbacks of combining ATRA with DARA in patients with MM. Taken together, these findings provide proof of concept that adoptive immunotherapy using ex vivo expanded CD38KO NK cells has the potential to boost DARA activity in MM.
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ADP-Ribosil Ciclase 1/deficiência , Anticorpos Monoclonais/farmacologia , Citotoxicidade Imunológica/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Glicoproteínas de Membrana/deficiência , Mieloma Múltiplo/patologia , ADP-Ribosil Ciclase 1/genética , Transferência Adotiva , Animais , Citotoxicidade Celular Dependente de Anticorpos , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Humanos , Imunoterapia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/transplante , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos NOD , NAD/metabolismo , Fosforilação Oxidativa , Organismos Livres de Patógenos Específicos , Tretinoína/farmacologia , Sequenciamento Completo do GenomaRESUMO
BACKGROUND: Patients with multiple myeloma (MM) were excluded from the original SARS-CoV-2 mRNA vaccine trials, which may influence vaccine hesitancy in this population. We prospectively characterized the safety and immunogenicity of two-dose SARS-CoV-2 mRNA vaccination in 44 patients with MM, who underwent vaccination from 12/17/2020 to 3/18/2021. RESULTS: Rates adverse reactions were low and consistent with those documented in vaccine trials. Among those on MM therapy, 93% developed detectable anti-receptor binding domain (RBD) antibodies after dose 2, while 94% of patients not on MM therapy seroconverted. CONCLUSIONS: Two-dose SARS-CoV-2 mRNA vaccination is mildly reactogenic and leads to high rates of seroconversion in patients with MM. These findings can provide reassurance to MM patients who are hesitant to receive SARS-CoV-2 mRNA vaccines.
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Vacina de mRNA-1273 contra 2019-nCoV/administração & dosagem , Anticorpos Antivirais/sangue , Vacina BNT162/administração & dosagem , COVID-19/prevenção & controle , Esquemas de Imunização , Mieloma Múltiplo/sangue , Vacina de mRNA-1273 contra 2019-nCoV/efeitos adversos , Idoso , Vacina BNT162/efeitos adversos , COVID-19/epidemiologia , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/efeitos adversos , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/epidemiologia , Estudos Prospectivos , Hesitação Vacinal , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Vacinas de mRNA/administração & dosagem , Vacinas de mRNA/efeitos adversosRESUMO
Transplant-associated thrombotic microangiopathy (taTMA) is a systemic vascular illness associated with significant morbidity and mortality, resulting from a convergence of risk factors after allogeneic blood or marrow transplantation (alloBMT). The diagnosis of taTMA has been a challenge, but most criteria include an elevated lactate dehydrogenase (LDH), low haptoglobin, and schistocytes on peripheral blood smear. We performed a retrospective review of the 678 consecutive adults who received high-dose post-transplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis between January 1, 2015, and August 31, 2018. In April 2016, we initiated a monitoring program of weekly LDH and haptoglobin measurements and blood smears when those 2 parameters were both abnormal on all of our adult patients undergoing alloBMT for hematologic malignancies. During the entire period, the 1-year cumulative incidence of taTMA was 1.4% (95% confidence interval, 0.5% to 2.3%). Eight patients were taking tacrolimus at the time of diagnosis, and 1 was not on any immunosuppression. Eight of 9 patients (89%) were hypertensive. Four patients had invasive infections at the time of diagnosis, 4 patients required renal replacement therapy, and 5 of 9 patients were neurologically impaired. Eculizumab was given to 6 patients (0.9%), of whom 2 died and 4 recovered with resolution of end-organ dysfunction. The paucity of events made the determination of risk factors difficult; however, the low incidence of taTMA in this cohort may be related to the limited use of myeloablative conditioning regimens, low incidence of severe GVHD, and use of PTCy. PTCy-based GVHD prophylaxis appears to be associated with a low incidence of severe taTMA.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Microangiopatias Trombóticas , Adulto , Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Estudos Retrospectivos , Microangiopatias Trombóticas/etiologia , Condicionamento Pré-Transplante/efeitos adversosRESUMO
Inflammatory cytokines released by activated lymphocytes and innate cells in the context of cellular therapy can cause fever, vasodilatation, and end-organ damage, collectively known as cytokine release syndrome (CRS). CRS can occur after allogeneic blood or marrow transplantation, but is especially prevalent after HLA-haploidentical (haplo) peripheral blood transplantation (PBT). We reviewed charts of all patients who underwent haplo-PBT between October 1, 2013, and September 1, 2017 and graded CRS in these patients. A total of 146 consecutive patients who underwent related haplo-PBT were analyzed. CRS occurred in 130 patients (89%), with most cases of mild severity (grade 0 to 2). Severe CRS (grade 3 to 5) occurred in 25 patients (17%). In this group with severe CRS, 13 patients had encephalopathy, 12 required hemodialysis, and 11 were intubated. Death from the immediate complications of CRS occurred in 6 patients (24% of the severe CRS group and 4% of the entire haplo-PBT cohort). The cumulative probability of nonrelapse mortality (NRM) was 38% at 6 months for the patients with severe CRS and 8% (121 of 146) in patients without severe CRS. In conclusion, CRS occurs in nearly 90% of haplo-PBTs. Older haplo-PBT recipients (odds ratio [OR], 2.4; 95% confidence interval [CI], .83 to 6.75; P = .11) and those with a history of radiation therapy (OR, 3.85; 95% CI, 1.32 to 11.24; Pâ¯=â¯.01) are at increased risk of developing severe CRS. Although most recipients of haplo-PBT develop CRS, <20% experience severe complications. The development of severe CRS is associated with a significantly increased risk of NRM.
Assuntos
Síndrome da Liberação de Citocina/epidemiologia , Doença Enxerto-Hospedeiro/epidemiologia , Neoplasias Hematológicas/epidemiologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco de Sangue Periférico , Condicionamento Pré-Transplante , Idoso , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/etiologia , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante HaploidênticoRESUMO
Large alternative donor pools provide the potential for selecting a different donor for a second allogeneic (allo) bone or marrow transplant (BMT). As HLA disparity may contribute to the graft-versus-tumor effect, utilizing new mismatched haplotype donors may potentially improve the antitumor activity for relapsed hematologic malignancies despite a previous alloBMT. Data from patients who received a second alloBMT for relapsed hematologic malignancies at Johns Hopkins were analyzed. Outcomes were compared between patients who received a second allograft with the same MHC composition and those who received an allograft with a new mismatched haplotype. Loss of heterozygosity analysis was performed for patients with acute myeloid leukemia (AML) whose first allograft was haploidentical. Between 2005 and 2015, 40 patients received a second BMT for a relapsed hematologic malignancy. The median follow-up is 750 (range, 26 to 2950) days. The median overall survival (OS) in the cohort is 928 days (95% confidence interval [CI], 602 to not reached [NR]); median event-free survival (EFS) for the cohort is 500 days (95% CI, 355 to NR). The 4-year OS is 40% (95% CI, 25% to 64%), and the 4-year EFS is 36% (95% CI, 24% to 55%). The cumulative incidence of nonrelapsed mortality by 2 years was 27% (95% CI, 13% to 42%). The cumulative incidence of grade 3 to 4 acute graft-versus-host disease (GVHD) at 100 days was 15% (95% CI, 4% to 26%); the cumulative incidence of extensive chronic GVHD at 2 years was 22% (95% CI, 9% to 36%). The median survival was 552 days (95% CI, 376 to 2950+) in the group who underwent transplantation with a second allograft that did not harbor a new mismatched haplotype, while it was not reached in the group whose allograft contained a new mismatched haplotype (hazard ratio [HR], .36; 95% CI, .14 to .9; P = .02). EFS was also longer in the group who received an allograft containing a new mismatched haplotype, (NR versus 401 days; HR, .50; 95% CI, .22 to 1.14; P = .09). Although the allograft for this patient's second BMT contained a new mismatched haplotype, AML nevertheless relapsed a second time. Second BMTs are feasible and provide a reasonable chance of long-term survival. An allograft with a new mismatched haplotype may improve outcomes after second BMTs for relapsed hematologic malignancies.
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Transplante de Medula Óssea/métodos , Complexo Principal de Histocompatibilidade/imunologia , Transplante Homólogo/métodos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Doadores de Tecidos , Adulto JovemRESUMO
Both clonal plasma cell and myeloid disorders occur more frequently with age. Patients with concurrent clonal plasma cell and myeloid disorders (CPCMD) can present clinical and therapeutic challenges. In this single-institution cohort of patients with CPCMD (n = 18), we abstracted clinically relevant themes. A majority of patients (12/18) were treated with clone-directed therapies and three received treatment targeting both clones. Treatment of clones with targetable genetic lesions or those causing end-organ complications should be prioritized. Simultaneous treatment of both clones can be safe but is best done in a stepwise manner. Further study of patients with dual clonal processes is warranted.
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The limited availability of molecularly targeted low-molecular-weight imaging agents for monitoring multiple myeloma (MM)-targeted therapies has been a significant challenge in the field. In response, a first-in-class peptide-based radiotracer, [68Ga]Ga-AJ206, is developed that can be seamlessly integrated into the standard clinical workflow and is specifically designed to noninvasively quantify CD38 levels and pharmacodynamics by positron emission tomography (PET). A bicyclic peptide, AJ206, is synthesized and exhibits high affinity to CD38 (KD: 19.1 ± 0.99 × 10-9 m) by surface plasmon resonance. Further, [68Ga]Ga-AJ206-PET shows high contrast within 60 min and suitable absorbed dose estimates for clinical use. Additionally, [68Ga]Ga-AJ206 detects CD38 expression in cell line-derived xenografts, patient-derived xenografts (PDXs), and disseminated disease models in a manner consistent with flow cytometry and immunohistochemistry findings. Moreover, [68Ga]Ga-AJ206-PET successfully quantifies CD38 pharmacodynamics in PDXs, revealing increased CD38 expression in the tumor following all-trans retinoic acid (ATRA) therapy. In conclusion, [68Ga]Ga-AJ206 exhibits the salient features required for clinical translation, providing CD38-specific high-contrast images in multiple models of MM. [68Ga]Ga-AJ206-PET could be useful for quantifying total CD38 levels and pharmacodynamics during therapy to evaluate approved and new therapies in MM and other diseases with CD38 involvement.
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ADP-Ribosil Ciclase 1 , Radioisótopos de Gálio , Mieloma Múltiplo , Tomografia por Emissão de Pósitrons , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/diagnóstico por imagem , Animais , ADP-Ribosil Ciclase 1/metabolismo , Camundongos , Humanos , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacocinética , Modelos Animais de Doenças , Peptídeos/metabolismo , Glicoproteínas de Membrana/metabolismo , Linhagem Celular TumoralRESUMO
ABSTRACT: Allogeneic blood and marrow transplantation (alloBMT) is increasingly being used in older patients with blood cancer. Aging is associated with an increasing incidence of clonal hematopoiesis (CH). Although the effects of donor CH on alloBMT has been reported, the impact of recipient CH on alloBMT outcomes is unknown. In this retrospective study, alloBMT recipients age 60 and older with lymphoid malignancies were included. Among 97 consecutive patients who received alloBMT between 2017 and 2022, CH was detected in 60 (62%; 95% confidence interval [CI], 51-72). CH was found in 45% (95% CI, 28-64) of patients aged 60 to 64, 64% (95% CI, 44-81) of patients aged 65% to 69%, and 73% (95% CI, 59-87) in those above 70. Pretransplant CH was associated with worse survival after alloBMT: 3-year overall survival (OS) was 78% (95% CI, 65-94) for patients without CH vs 47% (95% CI, 35-63) for those with CH, (unadjusted HR, 3.1; [95% CI, 1.4-6.8; P < .001]). Nonrelapse mortality (NRM) was higher in patients with CH; cumulative incidence of NRM at 1-year was 11% (95% CI, 1-22) vs 35% (95% CI, 23-48), (HR, 3.4; [95% CI, 1.4-8.5], P = .009]). Among CH patients, worse OS and NRM was associated with CH burden and number of mutations. Recipient CH had no effect on relapse. In conclusion, older patients with CH experience worse outcomes after alloBMT, almost exclusively attributable to increased NRM. CH is a strong, independent predictor of outcomes. Novel strategies to ameliorate the adverse impacts of patient CH on transplant outcomes are being evaluated.
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Transplante de Medula Óssea , Hematopoiese Clonal , Transplante Homólogo , Humanos , Pessoa de Meia-Idade , Masculino , Feminino , Idoso , Estudos Retrospectivos , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/mortalidadeRESUMO
Secondary hematologic malignancies, such as B-cell acute lymphoblastic leukemia/lymphoma (B-ALL), have been reported following multiple myeloma. Tyrosine kinase inhibitors have improved clinical outcomes of patients with Philadelphia-positive (Ph+) B-ALL. Therefore, recognition of the Ph chromosome in B-ALL patients is important for both prognosis and therapies. We present a case of a secondary Ph+ B-ALL following multiple myeloma that highlights a BCR::ABL1 fusion by a gene fusion assay to reveal a cryptic Ph chromosome, which may otherwise be missed by conventional cytogenetics and typical interphase fluorescence in situ hybridization.
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Linfoma de Burkitt , Linfoma , Mieloma Múltiplo , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Proteínas de Fusão bcr-abl/genética , Hibridização in Situ Fluorescente , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Cromossomo FiladélfiaRESUMO
PURPOSE: The limited availability of molecularly targeted low-molecular-weight imaging agents for monitoring multiple myeloma (MM)-targeted therapies has been a significant challenge in the field. In response, we developed [68Ga]Ga-AJ206, a peptide-based radiotracer that can be seamlessly integrated into the standard clinical workflow and is specifically designed to non-invasively quantify CD38 levels and pharmacodynamics by positron emission tomography (PET). EXPERIMENTAL DESIGN: We synthesized a high-affinity binder for quantification of CD38 levels. Affinity was tested using surface plasmon resonance, and In vitro specificity was evaluated using a gallium-68-labeled analog. Distribution, pharmacokinetics, and CD38 specificity of the radiotracer were assessed in MM cell lines and in primary patient-derived myeloma cells and xenografts (PDX) with cross-validation by flow cytometry and immunohistochemistry. Furthermore, we investigated the radiotracer's potential to quantify CD38 pharmacodynamics induced by all-trans retinoic acid therapy (ATRA). RESULTS: [68Ga]Ga-AJ206 exhibited high CD38 binding specificity (KD: 19.1±0.99 nM) and CD38-dependent In vitro binding. [68Ga]Ga-AJ206-PET showed high contrast within 60 minutes and suitable absorbed dose estimates for clinical use. Additionally, [68Ga]Ga-AJ206 detected CD38 expression in xenografts, PDXs and disseminated disease models in a manner consistent with flow cytometry and immunohistochemistry findings. Moreover, [68Ga]Ga-AJ206-PET successfully quantified CD38 pharmacodynamics in PDXs, revealing increased CD38 expression in the tumor following ATRA therapy. CONCLUSIONS: [68Ga]Ga-AJ206 exhibited the salient features required for clinical translation, providing CD38-specific high contrast images in multiple models of MM. [68Ga]Ga-AJ206-PET could be useful for quantifying total CD38 levels and pharmacodynamics during therapy to evaluate approved and new therapies in MM and other diseases with CD38 involvement.
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The use of post-transplantation cyclophosphamide (PTCy) for graft-versus host-disease (GVHD) prophylaxis has revolutionized allogeneic blood or marrow transplantation (alloBMT), but there is limited published experience in peripheral T cell lymphoma (PTCL). We sought to assess outcomes in patients with PTCL who underwent alloBMT with PTCy. We reviewed the charts of all adult patients age ≥18 years who underwent alloBMT with nonmyeloablative conditioning and PTCy-based GVHD prophylaxis at the Sidney Kimmel Comprehensive Cancer Center between January 2004 and December 2020. Sixty-five patients were identified. The median age was 59 years (range, 24 to 75 years). Lymphoma histology included PTCL not otherwise specified (n = 24), anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (n = 14), angioimmunoblastic T cell lymphoma (n = 7), enteropathy-associated T cell lymphoma (n = 6), hepatosplenic T cell lymphoma (n = 4), and others (n = 10). Eleven patients were in first complete remission (17%); the remaining patients were in first partial remission or underwent salvage therapy to at least PR prior to transplantation. Forty-eight patients underwent alloBMT from a haploidentical related donor (74%), 10 from a fully matched donor (15%), and 7 from a mismatched unrelated donor (11%). All patients received fludarabine, cyclophosphamide, and total body irradiation (TBI). The graft source was bone marrow (BM) in 46 patients (71%) and peripheral blood (PB) in 19 patients (29%); all patients in the BM cohort received 200 cGy TBI, and most patients in the PB cohort (15 of 19) received 400 cGy TBI. GVHD prophylaxis comprised PTCy, mycophenolate mofetil, and a calcineurin inhibitor or sirolimus. With a median follow-up of 2.8 years (range, 290 days to 14.2 years), the 2-year progression-free survival (PFS) for the entire cohort was 49% (95% confidence interval [CI], 38% to 64%), and the 2-year overall survival (OS) was 55% (95% CI, 44% to 69%). Outcomes were significantly improved in those receiving PB compared to those receiving BM, including a 2-year PFS of 79% (95% CI 63% to 100%) versus 39% (95% CI, 27% to 56%), 2-year OS of 84% (95% CI, 69% to 100%) versus 46% (95% CI, 33% to 63%), and 1-year cumulative incidence of relapse of 5% (95% CI, 0 to 16%) versus 33% (95% CI, 19% to 46%), with no difference in GVHD and nonrelapse mortality. AlloBMT with PTCy is safe and well-tolerated in patients with PTCL. Our data suggest that increasing the TBI dose to 400 cGy and using PB allografts may offer improved disease control and better survival outcomes, though additional studies are needed to confirm these findings.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Linfoma de Células T Periférico , Adulto , Humanos , Pessoa de Meia-Idade , Adolescente , Linfoma de Células T Periférico/complicações , Linfoma de Células T Periférico/tratamento farmacológico , Medula Óssea , Ciclofosfamida/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doadores não RelacionadosRESUMO
Patients age ≥55 years with acute lymphoblastic leukemia (ALL) fare poorly with conventional chemotherapy, with a 5-year overall survival (OS) of â¼20%. Tyrosine kinase inhibitors and novel B cell-targeted therapies can improve outcomes, but rates of relapse and death in remission remain high. Allogeneic blood or marrow transplantation (alloBMT) provides an alternative consolidation strategy, and post-transplantation cyclophosphamide (PTCy) facilitates HLA-mismatched transplantations with low rates of nonrelapse mortality (NRM) and graft-versus-host disease (GVHD). The transplantation database at Johns Hopkins was queried for patients age ≥55 years who underwent alloBMT for ALL using PTCy. The database included 77 such patients. Most received reduced-intensity conditioning (RIC) (88.3%), were in first complete remission (CR1) (85.7%), and had B-lineage disease (90.9%). For the entire cohort, 5-year relapse-free survival (RFS) and overall survival (OS) were 46% (95% confidence interval [CI], 34% to 57%) and 49% (95% CI, 37% to 60%), respectively. Grade III-IV acute GVHD occurred in only 3% of patients, and chronic GVHD occurred in 13%. In multivariable analysis, myeloablative conditioning led to worse RFS (hazard ratio [HR], 4.65; P = .001), whereas transplantation in CR1 (HR, .30; P = .004) and transplantation for Philadelphia chromosome-positive (Ph+) ALL versus T-ALL (HR, .29; P = .03) were associated with improved RFS. Of the 54 patients who underwent RIC alloBMT in CR1 for B-ALL, the 5-year RFS and OS were 62% (95% CI, 47% to 74%) and 65% (95% CI, 51% to 77%), respectively, with a 5-year relapse incidence of 16% (95% CI, 7% to 27%) and an NRM of 24% (95% CI, 13% to 36%). RIC alloBMT with PTCy in CR1 represents a promising consolidation strategy for B-ALL patients age ≥55 years.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Pessoa de Meia-Idade , Medula Óssea , Ciclofosfamida/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Doença Enxerto-Hospedeiro/tratamento farmacológico , Recidiva , Doença AgudaRESUMO
The clinical course of chronic lymphocytic leukemia (CLL) is highly variable. Immunoglobulin heavy chain variable region (IgHV) mutation status is among the most important prognostic factors, with unmutated IgHV associated with inferior outcomes. CLL presumably arises from mature B cells. However, we hypothesized that IgHV unmutated CLL could arise early in B cell differentiation. We prospectively studied 29 patients with mutated and 88 with unmutated IgHV CLL for the presence of CD34+CD19+ cells harboring CLL chromosomal abnormalities. CD34+CD19+ cells were never detected in mutated CLL. In contrast, a small but distinct population of CD34+CD19+ cells harboring the CLL chromosomal abnormality was present in 86/88 patients with unmutated IgHV across all cytogenetic subtypes. Moreover, the CD34+CD19+ cells generated a 3.8 ± 0.7 fold CLL cell expansion over 3-4 weeks in cultures containing IL-3 and IL-2. Unmutated IgHV CLL appears to arise in CD34+ B cells, which perhaps contributes to its poorer prognosis.
Assuntos
Cadeias Pesadas de Imunoglobulinas , Leucemia Linfocítica Crônica de Células B , Mutação , Células Precursoras de Linfócitos B , Animais , Antígenos CD19 , Antígenos CD34 , Aberrações Cromossômicas , Citometria de Fluxo , Xenoenxertos , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Leucemia Linfocítica Crônica de Células B/genética , Camundongos , Células Precursoras de Linfócitos B/imunologia , PrognósticoRESUMO
INTRODUCTION: Mutations in the IDH1 or IDH2 genes are detected in approximately 20% of cases of acute myeloid leukemia (AML). Few studies have examined the impact of IDH mutations in AML on allogeneic bone marrow transplant (alloBMT) outcomes. PATIENTS AND METHODS: In this single center study, alloBMT outcomes for 61 patients with IDH-mutated (mIDH) AML were compared to those for 146 patients with IDH-wildtype (wtIDH) AML. RESULTS: Patients with mIDH AML had a 2-year overall survival (OS) of 85% (95% CI 76%-95%), 2-year relapse free survival (RFS) of 71% (95% CI 59%-85%), 1-year cumulative incidence of relapse (CIR) of 14% (95% CI 5%-23%) and a 1-year cumulative incidence of transplant related mortality (CITRM) of 3% (95% CI 0%-8%). Patients with wtIDH had a 2-year OS of 61% (95% CI 53%-70%), 2-year RFS of 58% (95% CI 50%-67%), 1-year CIR of 27% (95% CI 20%-35%), and a 1-year CITRM of 9% (95% CI 5%-14%). In a univariate analysis cox-proportional hazard model, mIDH was associated with significantly better OS (HR 0.52, 95% CI 0.29-0.96) and a trend toward better RFS (HR 0.60, 95% CI 0.35-1.01). After controlling for donor age, diagnosis, and ELN risk category, mIDH was associated with a nonsignificantly improved OS (HR 0.54, 95% CI 0.29-1.01) and RFS (HR 0.67, 95% CI 0.39-1.15). CONCLUSION: Among patients with mIDH AML, patients who received a peritransplant IDH inhibitor had improved OS (P = .03) compared to those who did not, but there was no detectable difference for RFS (P = .29).
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Ciclofosfamida , Humanos , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutação , Prognóstico , Transplante HomólogoRESUMO
We describe outcomes after post-transplantation cyclophosphamide and nonmyeloablative conditioning-based allogeneic blood or marrow transplantation for myelofibrosis using matched or mismatched related or unrelated donors. The conditioning regimen consisted of fludarabine, cyclophosphamide, and total body irradiation. Forty-two patients were included, with a median age of 63 years, of whom 19% had Dynamic International Prognostic Scoring System (DIPSS)-plus intermediate-1 risk, 60% had intermediate-2 risk, and 21% had high-risk disease, and 60% had at least 1 high-risk somatic mutation. More than 90% of patients engrafted neutrophils, at a median of 19.5 days, and 7% experienced graft failure. At 1 year and 3 years, respectively, overall survival was 65% and 60%, relapse-free survival was 65% and 31%, relapse was 5% and 40%, and nonrelapse mortality was 30% and 30%. Acute graft-versus-host disease grade 3-4 was seen in 17% of patients at 1 year, and chronic graft-versus-host disease requiring systemic therapy in occurred in 12% patients. Spleen size ≥17 cm or prior splenectomy was associated with inferior relapse-free survival (hazard ratio [HR], 3.50; 95% confidence interval [CI], 1.18 to 10.37; P = .02) and higher relapse rate (subdistribution HR [SDHR] not calculable; P = .01). Age >60 years (SDHR, 0.26; 95% CI, 0.08 to 0.80, P = .02) and receipt of peripheral blood grafts (SDHR, 0.34; 95% CI, 0.11 to 0.99; P = .05) were associated with a lower risk of relapse. In our limited sample, the presence of a high-risk mutation was not statistically significantly associated with an inferior outcome, although ASXL1 was suggestive of inferior survival (SDHR, 2.36; 95% CI, 0.85 to 6.6; P = .09). Overall, this approach shows outcomes comparable those of to previously reported approaches and underscores the importance of spleen size in the evaluation of transplantation candidates.