Initial Remission Rate Research Articles

Cerebrovascular implications of takayasu arteritis: a review.

Takayasu arteritis (TA) is a rare, chronic, inflammatory large-vessel vasculitis that affects the aorta and its main branches, including the cerebrovascular system. This review analyzes current knowledge and patient outcomes concerning the cerebrovascular implications of TA. A literature search, with publications from 1994 to 2024, identified pertinent studies through PubMed. An illustrative case report details a 19-year-old female with Type 1 TA, illustrating the complex decision required in the absence of surgical or endovascular options. Our results offer a demographic analysis of 1,698 TA patients, highlighting a female predominance of 89.99% and a mean symptom onset at 33 years. The clinical spectrum of cerebrovascular involvement presented varied symptoms, most notably dizziness, with significant incidences of ischemic events and bilateral stenosis primarily affecting the carotid and subclavian arteries. The most common type of TA was Type V, affecting 40% of patients studied. Endovascular treatment had a 95% initial success rate, with a 67% restenosis rate. Surgical treatment was successful in 84% of cases, but 21% had notable post-operative complications. Similar to the endovascular population, those treated with stand-alone conservative therapy saw a 93% initial remission rate with 52% having relapsed. Assessing the disease activity of TA is crucial when planning vascular intervention due to its significant impact on treatment outcomes. Despite its greater initial invasiveness, surgical interventions showed lower restenosis rates compared to either endovascular interventions or standalone conservative management. We emphasize advancements in TA management and the pressing need for continued research into diagnostic and treatment protocols for improved patient outcomes.

A safety and efficacy study of allogeneic haematopoietic stem cell transplantation for refractory and relapsed T-cell acute lymphoblastic leukaemia/lymphoblastic lymphoma patients who achieved complete remission after autologous CD7 chimeric antigen receptor T-cell therapy.

CD7-targeted chimeric antigen receptor T-cell (CAR-T) therapy has shown promising initial complete remission (CR) rates in patients with refractory or relapsed (r/r) T-cell acute lymphoblastic leukaemia and lymphoblastic lymphoma (T-ALL/LBL). To enhance the remission duration, consolidation with allogeneic haematopoietic stem cell transplantation (allo-HSCT) is considered. Our study delved into the outcomes of 34 patients with r/r T-ALL/LBL who underwent allo-HSCT after achieving CR with autologous CD7 CAR-T therapy. These were compared with 124 consecutive T-ALL/LBL patients who received allo-HSCT in CR following chemotherapy. The study revealed that both the CAR-T and chemotherapy cohorts exhibited comparable 2-year overall survival (OS) (61.9% [95% CI, 44.1-78.1] vs. 67.6% [95% CI, 57.5-76.9], p = 0.210), leukaemia-free survival (LFS) (62.3% [95% CI, 44.6-78.4] vs. 62.0% [95% CI, 51.8-71.7], p = 0.548), non-relapse mortality (NRM) rates (32.0% [95% CI, 19.0-54.0] vs. 25.3% [95% CI, 17.9-35.8], p = 0.288) and relapse incidence rates (8.8% [95% CI, 3.0-26.0] vs. 15.8% [95% CI, 9.8-25.2], p = 0.557). Patients aged ≤14 in the CD7 CAR-T group achieved high 2-year OS and LFS rates of 87.5%. Our study indicates that CD7 CAR-T therapy followed by allo-HSCT is not only effective and safe for r/r T-ALL/LBL patients but also on par with the outcomes of those achieving CR through chemotherapy, without increasing NRM.

A systematic literature review of 74 Chinese blastic plasmacytoid dendritic cell neoplasm patients.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematological cancer. Due to its low incidence, researchers struggle to gather sufficient prospective data to inform clinical treatment. We sought to summarize the clinical characteristics and current treatment methods of BPDCN and provide more specific guidance on treatment options. A systematic literature review using data from 74 Chinese BPDCN patients. We retrospectively analyzed the clinical manifestations, treatment response, survival outcomes, and prognostic factors of six BPDCN patients treated at the First Affiliated Hospital of Zhengzhou University and 68 patients described in 28 articles published in the China Knowledge Network database since 2019. In Chinese patients, the disease occurred with a male-to-female ratio of 2.52 and a median age of onset of 50 years in adults and 10 years in pediatric patients. Immunohistochemical analysis revealed distinctive immune phenotypes of BPDCN cells, characterized by high expression levels of CD4, CD56, CD123, and HLA-DR, while showing minimal to no expression of myeloperoxidase (MPO), CD20, and CD79a. There was no significant difference in the initial complete remission (CR) rate, relapse rate, and the overall survival (OS) time of patients receiving acute myeloid leukemia-like, acute lymphocytic leukemia-like, or non-Hodgkin's lymphoma-like chemotherapy regimens. Univariate analysis identified CD3 expression, male gender, and central nervous system infiltration as hazardous factors. In multivariate analysis, age proved to be an independent prognostic indicator, indicating better prognosis and longer OS time in younger patients. Notably, hematopoietic stem cell transplantation (HSCT) emerged as a significant factor in improving the survival outcomes for individuals diagnosed with BPDCN. However, further investigation is needed to explore the role of HSCT and the best timing for its implementation in pediatric BPDCN patients. Administering HSCT during the initial CR state following inductive chemotherapy might extend the OS and improve the prognosis of patients with BPDCN.

Picalm::MLLT10 can Identify a New Subgroup of Acute Leukemias of Ambiguous Lineage with Unique Extramedullary Disease and Treatment Response

Background: Mixed-phenotype acute leukemias (MPAL), which is included in acute leukemias of ambiguous lineage (ALAL), can be classified as four different subtypes based on recurring genetic alterations including BCR::ABL, KMT2A and ZNF384 gene rearrangement as well as BCL11B activation. The 2022 WHO classification has already mentioned PICALM::MLLT10 fusions are also enriched in MPAL but need more data. In 2022 ELN classification, PICALM::MLLT10 was identified as acute myeloid leukemia (AML) with other rare recurring translocations but not ALAL. In addition, there is no separate classification for PICALM::MLLT10 in the new ICC classification. Therefore, it is still confused whether PICALM::MLLT10 corresponds to AML or acute lymphoblastic leukemia (ALL) or ALAL. Methods: Fourteen PICALM::MLLT10 positive patients of 390 AL patients (14/390, 3.6%) were identified by RNA sequencing (RNA-seq) in our center from 2020-2022, including 8 female and 6 male, with a median age of 33 years (16-50 years). These patients were newly diagnosed AL according to bone marrow morphology and immunology including 5 ALAL, 5 T-ALL [ 4 early T-cell precursor ALL (ETP-ALL), 1 cortical T-ALL], 2 AML, 1 B-ALL with aberrant expression of myeloid antigen, and 1 B/T MPAL. Results: The mean white blood cell counts of these patients was 8.25×10 9/L (2.34-51×10 9/L) and platelet counts was 168.5×10 12/L (39-429×10 12/L) individually. It should be mentioned that extramedullary disease (EMD) was found in 7 cases (7/14), including mediastinum, tonsil, and skin. In terms of immunotyping, CD7 was identified in all patients (14/14) and CD33 in 71.4% (10/14) patients. The major concurrence mutations were PHF6 mutation (8/14), JAK3 mutation (5/14), and SUZ12 mutation (4/14). Characteristic cytogenetic abnormality t(10;11)(p12.3;q14.2) was only found in three cases (3/14) (Table 1). The PICALM breakpoints are mainly concentrated in exon 17 (n=6) and exon 19 (n=8). Exon 4 (n=8), exon 6 (n=2), exon 9 (n=2) and exon 10 (n=2) are the most commonbreakpointsof MLLT10. To our knowledge, this is the first report about the breakpoints and fusion gene forms of PICALM::MLLT10. For initial treatment, these patients individually received standard ALL induction chemotherapy (VDPCP, vincristine, idarubicin, pegaspargase, cyclophosphamide, prednisone) and AML induction chemotherapy (3+7 IA regimen including idarubicin, cytarabine). The initial complete remission (CR) rate was only 35.7% (5/14), and 9 patients showing no remission (NR). These NR patients subsequently received salvage chemotherapy. It is worth mentioning that 6 of them received combined chemotherapy regimen including low doses of cytarabine (LDAC), granulocyte colony-stimulating factor (G-CSF) and anthracyclines such as aclarubicin or idarubicin or homoharringtonine (CAG or IAG or HAG), and 2 of 6 patients also further received combination therapy with venetoclax (CAG or IAG +VEN). Finally, 5 of them dramatically achieved CR (5/6). In the other 3 patients, 1 patient who was failure to initial Hyper-CVAD A/B regimen also dramatically achieved CR after the more Hyper-CVAD A regimen combined with venetoclax, and 1 patient achieved CR while another still NR with both receiving CLAG (cladribine, cytarabine, G-CSF) regimen. Subsequently 11 patients (9 CR, 2 with refractory disease) received allogenic hematopoietic stem cell transplantation (allo-HSCT), and all the CR patients survived well after HSCT (follow up 3-24 months, median 15 months) without relapse, while 2 NR patients died soon after transplantation because of severe complications (Table 2). Conclusions: Our data suggested PICALM::MLLT10 positive AL should be more appropriately recognized as an independent ALAL entity and may benefit from LDAC, G-CSF and anthracyclines combination chemotherapy as well as venetoclax. Sequential HSCT after chemotherapy combined with venetoclax may further improve long-term survival in AL patients with CR even MRD positive.

Comparative Effectiveness of Reinduction Approaches for Pediatric Relapsed Acute Myeloid Leukemia

Introduction: Intensive frontline chemotherapy achieves initial remission rates above 80% in pediatric acute myeloid leukemia (AML), however, approximately half of patients relapse, and overall survival (OS) after relapse is poor. There is a paucity of comparative effectiveness data on salvage regimens to inform selection of optimal post-relapse therapy. The objective of this analysis was to compare outcomes following relapse by prevalent reinduction regimens in a multi-center real-world dataset. Methods: Patients 18 years and younger who had received frontline chemotherapy for AML between 2011-2019 at 12 pediatric institutions were eligible for inclusion. Trained personnel completed manual chart abstraction to obtain demographics, diagnosis, treatment, and outcome information. The analysis included patients who achieved morphologic remission and then experienced disease relapse; patients with primary refractory AML and those who pursued palliative therapy only after relapse were excluded. Prevalent reinduction regimens were classified as (1) intensive without anthracycline [e.g. fludarabine/cytarabine and high-dose cytarabine-containing regimens], (2) intensive with anthracycline (e.g. CPX-351, mitoxantrone/cytarabine and cytarabine/daunorubicin/etoposide), and (3) non-intensive (including azacytidine or decitabine-based regimens). Primary outcomes were OS after relapse and end reinduction disease response defined by morphologic remission (<5% blasts) and measurable residual disease (MRD)-negative remission (<0.1% blasts). Covariate distributions were compared by reinduction regimen using chi-square tests. Survival analyses used Kaplan-Meier methods and multivariable cox proportional hazards models. End induction response was evaluated using logistic regression. Adjustment was made for covariates found to both differ by reinduction regimen and be associated with outcome, regardless of statistical significance. Results: Of 530 patients, 157 (29.6%) experienced a relapse at a median of 9.7 months (IQR 6.5-16.3) after initial diagnosis. Median post-relapse follow-up was 2.2 years (IQR 1.1-3.2). One- and 2-year OS rates from relapse were 44.9 ± 4.1% and 38.6 ± 4.1%, respectively. Of 157 patients with relapse, 129 from 9 institutions had available information on post-relapse treatment and pursued reinduction with curative intent. Patients were 48.8% female, 27.1% Hispanic, 14.7% non-Hispanic Black and had a median age of 7.1 years (IQR 2.70-14.2) at relapse. Most patients (89.2%) relapsed after completion of frontline therapy, and 24% had undergone hematopoietic cell transplantation (HCT) in first clinical remission. Reinduction regimens were as follows: 79 (61.2%) received intensive reinduction without anthracycline, 34 (26.4%) received intensive reinduction with anthracycline and 16 (12.4%) received non-intensive reinduction. Patients with a non-intensive reinduction were more likely to have relapsed within one year of initial diagnosis (50% versus 34%, p = 0.23) and undergone transplant prior to relapse (75.0% versus 16.8%, p < 0.001). Covariates were balanced across intensive induction regimens. One-year OS was 50.3 ± 4.6%, with 63 (40.1%) achieving morphologic remission and 40 (31.0%) achieving an MRD-negativity after first reinduction cycle. Seventy-three patients (56.9%) underwent HCT after relapse; 11 (15.1%) received a second transplant. OS curves and adjusted outcome comparisons by reinduction regimen are shown in the Figure and Table. One-year OS was 51.1 ± 5.8%, 60.2 ± 9.0% and 26.7 ± 11.4% for intensive therapy without anthracycline, with anthracycline and non-intensive, respectively. However, after adjustment hazard ratios (HRs) were not statistically significant [HR = 0.85 (p = 0.65) and 1.77 (p = 0.23) for intensive with anthracycline and non-intensive, compared to non-intensive without anthracycline, respectively]. Conclusions: After controlling for patient, disease and treatment characteristics, we did not identify a significant difference in remission rates or OS by reinduction approaches for pediatric relapsed AML. Although anthracycline-based reinduction did not improve OS, adjusted point estimates suggest that anthracyclines may improve end reinduction disease response. Ongoing cohort expansion will enable comparative effectiveness analyses of specific reinduction regimens.

Development and Clinical Validation of an Ultra-Fast CAR-T Manufacturing Platform Enabling Production of CAR-T Cells in Less Than 1 Day

Recently, the use of CAR-T cells has made a major impact on the therapy for a subset of hematologic malignancies including non-Hodgkin lymphoma (NHL) and multiple myeloma. In relapsed/refractory NHL where historically most patients did not respond to chemotherapy, CAR-T cell therapy can lead to initial remission rates >50%. Despite promising outcomes, there are major unmet needs to develop rapid, cost-effective, and scalable CAR-T manufacturing platforms that lead to efficacious and affordable autologous CAR-T cell products. Major barriers to widespread access to CAR-T cell therapy include weeks to months long delays from time of prescription to infusion that leads to disease progression in a significant subset of patients, very elevated costs that preclude access for a majority of patients world-wide, and high relapse rates (~estimated 30-60% within one year) in patients who initially achieve remission. To help address these barriers, we developed an ultra-fast CAR-T manufacturing platform (UF-CAR) that allows production of highly cost-effective CAR-T product in less than 24 hours. The manufacturing workflow was specifically designed to be simple, low cost and rapid to enable its formulation in healthcare facilities without sophisticated equipment or personnel expertise. In addition, we hypothesized that this manufacturing workflow would generate a product that demonstrates dramatically improved efficacy and CAR-T expansion in vivo. Using a BCMA CAR we manufactured CAR-T cell product using both our ultra-fast manufacturing workflow and a traditional 9-day CAR-T cell manufacture workflow. Both workflows led to nearly identical levels of CAR surface expression on the T cells (67% and 66% CAR expression on the UF-BCMA product and 9-day product respectively). To compare the activity of the products, we injected immunodeficient mice intravenously with luciferase labelled MM1.s cells followed by a single intravenous injection of CAR-T cells on day 0. As seen in figure 1A, both products demonstrated efficacy, but the UF-BCMA product induced durable disease control while disease progression started to occur with the 9-day product on day 29 after CAR-T injection. Consistent with the improved efficacy, circulating levels of the UF-BCMA CAR-T cells in the mouse blood were found to be up to 100x higher than the levels of the 9-day BCMA CAR-T product (Figure 1B). Similar increased potency and marked increases in circulating CAR-T cells were observed in a mouse model of human lymphoma when comparing a CD19 CAR manufactured using the UF-CAR workflow as compared to a standard CAR-T manufacturing process. To assess the safety and clinical potential of CAR-T products manufactured with the UF-CAR platform, a phase 1 trial was recently initiated using a CD19 CAR-T product (UF-Kure19). This trial that is open to patients with relapsed/refractory NHL completed treatment of its first patient who had relapsed mantle cell lymphoma. UF-Kure19 product was manufactured successfully in less than 1 day and demonstrated CAR expression of 41%. The product passed all release criteria for infusion and was administered to the patient after lymphodepletion with fludarabine 30mg/m2 and cyclophosphamide 500mg/m2 daily for 3 days. UF-Kure19 cells expanded robustly in the patient and peaked around day 10 (23% of circulating CD3) with a strong skewing of CD4/CD8 cells (93% CD8+ T cells on day 10). The patient was found to be in complete metabolic remission by day 28 and ongoing remission was confirmed on day 60. We have developed an ultra-fast CAR-T cell manufacturing platform that enables low-cost production in less than one day. In vitro and animal data suggest this fast-manufacturing platform leads to potent CAR-T cells. Early human testing indicates CAR-T cells generated using this novel system have clinical activity against hematologic malignancies.

Analysis benefits of a second Allo-HSCT after CAR-T cell therapy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia who relapsed after transplant.

Chimeric antigen receptor (CAR) T-cell therapy has demonstrated high initial complete remission (CR) rates in B-cell acute lymphoblastic leukemia (B-ALL) patients, including those who relapsed after transplant. However, the duration of remission requires improvements. Whether bridging to a second allogeneic hematopoietic stem cell transplant (allo-HSCT) after CAR-T therapy can improve long-term survival remains controversial. We retrospectively analyzed long-term follow-up data of B-ALL patients who relapsed post-transplant and received CAR-T therapy followed by consolidation second allo-HSCT to investigate whether such a treatment sequence could improve long-term survival. A single-center, retrospective study was performed between October 2017 and March 2022, involving 95 patients who received a consolidation second transplant after achieving CR from CAR-T therapy. The median age of patients was 22.8 years (range: 3.3-52.8) at the second transplant. After the first transplant, 71 patients (74.7%) experienced bone marrow relapse, 16 patients (16.8%) had extramedullary relapse, 5 patients (5.3%) had both bone marrow and extramedullary relapse and 3/95 patients (3.2%) had positive minimal residual disease (MRD) only. Patients received autologous (n=57, 60.0%) or allogeneic (n=28, 29.5%) CAR-T cells, while 10 patients (10.5%) were unknown. All patients achieved CR after CAR-T therapy. Before second HSCT, 86 patients (90.5%) were MRD-negative, and 9 (9.5%) were MRD-positive. All second transplant donors were different from the first transplant donors. The median follow-up time was 623 days (range: 33-1901) after the second HSCT. The 3-year overall survival (OS) and leukemia-free survival (LFS) were 55.3% (95%CI, 44.3-66.1%) and 49.8% (95%CI, 38.7-60.9%), respectively. The 3-year relapse incidence (RI) and non-relapse mortality (NRM) were 10.5% (95%CI, 5.6-19.6%) and 43.6% (95%CI, 33.9-56.2%), respectively. In multivariate analysis, the interval from CAR-T to second HSCT ≤90 days was associated with superior LFS(HR, 4.10, 95%CI,1.64-10.24; p=0.003) and OS(HR, 2.67, 95%CI, 1.24-5.74, p=0.012), as well as reduced NRM (HR, 2.45, 95%CI, 1.14-5.24, p=0.021). Our study indicated that CAR-T therapy followed by consolidation second transplant could significantly improve long-term survival in B-ALL patients who relapsed post-transplant. The second transplant should be considered in suitable patients and is recommended to be performed within 90 days after CAR-T treatment.

Recent advances and challenges in primary central nervous system lymphoma: a narrative review.

Primary central nervous system lymphoma (PCNSL) is a rare and highly invasive non-Hodgkin lymphoma that is challenging to diagnose and treat. It is typically confined to the brain, spinal cord, and eyes. The diagnosis of PCNSL lacks specificity, and the misdiagnosis and missed diagnosis rates of PCNSL are high. Traditional treatments for PCNSL, such as surgery, whole-brain radiation therapy, high-dose methotrexate-based chemotherapy, and rituximab (RTX), have been associated with higher initial remission rates. However, the duration of any remission is short, the recurrence rate is high, and treatment-related neurotoxicity is strong, which are challenges for medical researchers. This review provides an overview of and perspectives on the diagnosis, treatment, and evaluation of patients with PCNSL. The PubMed database was searched to retrieve articles published from January 1, 1991, to June 2, 2022 using the following Medical Subject Headings (MeSH) terms: "Primary central nervous system lymphoma" and "clinical trial". The American Society of Clinical Oncology and the National Comprehensive Cancer Network guidelines were also reviewed to obtain additional information. The search was limited to articles published in English, German, and French. In total, 126 articles were deemed eligible for inclusion in this study. In terms of the diagnosis of PCNSL, a combination of flow cytometry and cytology has been shown to improve the diagnostic accuracy of PCNSL. Additionally, interleukin 10 and chemokine C-X-C motif ligand 13 are promising biomarkers. In terms of the treatment of PCNSL, programmed death-1 (PD-1) blockage and chimeric antigen receptor T cell (CAR-T) therapy treatments have shown prospective efficacy, but more clinical trials need to be conducted to gather further evidence. We also reviewed and summarized prospective clinical trials on PCNSL. PCNSL is a rare and highly aggressive lymphoma. The treatment of PCNSL has progressed significantly, and while the survival of patients has improved, relapse and low long-term survival remain huge challenges. Continuous in-depth research is being conducted on new drug therapies and combination therapies for PCNSL. A combination of targeted drugs (e.g., ibrutinib, lenalidomide, and PD-1 monoclonal antibody) and traditional therapy represents the main research direction for future PCNSL treatments. CAR-T has also shown great potential in the treatment of PCNSL. With the development of these new diagnostic and therapeutic methods and further research into the molecular biology of PCNSL, patients with PCNSL should achieve a better prognosis.

The Combination of Dopamine Agonist Treatment and Surgery May Be the Best Option in Challenging Prolactinoma Cases: A Single-Centre Experience

To investigate the initial and long-term remission rates, factors related to remission, secondary treatments, and outcomes for patients with prolactinoma who underwent endoscopic transsphenoidal surgery (ETSS). The medical files of the 45 prolactinoma patients who underwent ETSS between 2015 and 2022 were retrospectively reviewed. Relevant demographic and clinical data were obtained. Twenty-one (46.7%) patients were female. The median age of patients at ETSS was 35 (interquartile range, 22.5-50) years. The median clinical follow-up of patients was 28 (interquartile range 12-44) months. The initial surgical remission rate was 60%. Recurrence was detected in 7 patients (25.9%). Postoperative dopamine agonists were used in 25 patients, radiosurgery in 2, and second ETSS in 4 patients. After these secondary treatments, the long-term biochemical remission rate was 91.1%. The factors associated with failure in surgical remission are: male gender, older age, higher tumor size, advanced Knosp and Hardy stage, and elevated prolactin level at diagnosis. A prolactin level of <19ng/mL in the first postoperative week predicted surgical remission with a sensitivity of 77.8% and a specificity of 70.6% in patients who received preoperative dopamine agonist treatment. In macro adenomas and/or giant adenomas with cavernous sinus invasion, and significant suprasellar extension, which constitutes the difficult part of prolactinoma treatment, neither surgery nor medical treatment alone may be effective enough. Both treatment modalities should be carried out together by a team of neurosurgery and endocrinology in the management of these patients.

Low-rank fusion convolutional neural network for prediction of remission after stereotactic radiosurgery in patients with acromegaly: a proof-of-concept study.

Artificial intelligence approaches to analyze pathological images (pathomic) for outcome prediction have not been sufficiently considered in the field of pituitary research. A total of 5,504 hematoxylin & eosin-stained pathology image tiles from 58 acromegalic patients with a good or poor outcome were integrated with other clinical and genetic information to train a low-rank fusion convolutional neural network (LFCNN). The model was externally validated in 1,536 patches from an external cohort. The primary outcome was the time to the first endocrine remission after stereotactic radiosurgery (SRS). The median time of initial endocrine remission was 43 months (interquartile range [IQR]: 13-60 months) after SRS, and the 24-month initial cumulative remission rate was 57.9% (IQR: 46.4-72.3%). The patient-wise accuracy of the LFCNN model in predicting the primary outcome was 92.9% in the internal test dataset, and the sensitivity and specificity were 87.5 and 100.0%, respectively. The LFCNN model was a strong predictor of initial cumulative remission in the training cohort (hazard ratio [HR] 9.58, 95% confidence interval [CI] 3.89-23.59; p < 0.001) and was higher than that of established prognostic markers. The predictive value of the LFCNN model was further validated in an external cohort (HR 9.06, 95% CI 1.14-72.25; p = 0.012). In this proof-of-concept study, clinically and genetically useful prognostic markers were integrated with digital images to predict endocrine outcomes after SRS in patients with active acromegaly. The model considerably outperformed established prognostic markers and can potentially be used by clinicians to improve decision-making regarding adjuvant treatment choices. © 2022 The Pathological Society of Great Britain and Ireland.

A single institution cohort of patients with classical Hodgkin lymphoma treated with brentuximab vedotin plus nivolumab.

e18738 Background: Classical Hodgkin lymphoma (cHL) is a B-cell neoplasm which affects approximately 8,500 new patients annually. The initial remission rate is greater than 80%; however, 10-30% will have refractory or relapsed disease (R/R). Both Brentuximab vedotin (BV) and nivolumab (Nivo) have recently been approved for the treatment of R/R cHL. Previous studies have shown BV+Nivo to be well tolerated, with high response rates and progression free survival (PFS) in two prospective studies. However, no real-world data is available yet for this combination. Here we present clinical characteristics and outcomes of a single institution cohort of patients with cHL who received BV+Nivo. Methods: A retrospective chart review was completed of all patients with cHL who were treated with BV+Nivo at Moffitt Cancer Center between 2018 and 2021. Baseline characteristics and treatment details were obtained. PFS and overall survival (OS) were evaluated using the Kaplan-Meier curve. Results: A total of 29 patients were included in the cohort. Median follow up time was 3 months (range 1-21). 69% (n = 20) of patients were male. Histology types included unclassifiable 48.3% (n = 14), nodular sclerosis 27.6% (n = 8), lymphocyte depleted 13.8% (n = 4), and lymphocyte rich 10.3% (n = 3). 55.2% (n = 16) of patients had B symptoms at presentation. Initial stage included stage 2 (48.3%, n = 14), stage 3 (20.7%, n = 6), and stage 4 (24.1%, n = 7). 34% of the patients were primary refractory to their first line therapy. Median time from last chemo to BV+Nivo was 4.4 months (range 0.5-50 months). BV+Nivo was most often used as 2nd line therapy (51.7%, n = 15) followed by 3rd line therapy (20.7%, n = 6). One patient received BV+Nivo as first line therapy. Median number of cycles was 4 (range 1-15). The overall response rate was 65.5% (n = 19) (complete response 44.8%), and 17.2% (n = 5) had no response. Of the 15 patients receiving BV+Nivo as 2nd line therapy, 66% proceeded to autologous hematopoietic stem cell transplant. 4 patients did not proceed with transplant per their choice, and one patient could not proceed due to progressive disease. The median PFS was 21 months (95% CI: 9 months-non reached). OS was 100%. Conclusions: Here we describe the first real-world outcomes of BV+Nivo in classical Hodgkin lymphoma. In a high risk and refractory population, BV+Nivo showed excellent responses. Further studies are needed to focus on comparing the outcome to a more traditional chemotherapy based approach.

Hematopoietic Stem Cell Transplantation for Pediatric Acute Myeloid Leukemia - SBTMO/SOPOBE 2020 Consensus Guidelines

Acute myeloid leukemia (AML) represents 15%–20% of acute leukemias in children, and the risk of treatment failure is based on genetic risk and response to therapy1-4. Although the initial remission rate exceeds 90%, more than 30-40% of children with AML die of refractory/relapsed disease or treatment-related toxicity5. The best therapeutic results are achieved by integrating intensive chemotherapy, optimal supportive care, and hematopoietic stem cell transplant (HSCT) adapted to each patient’s risk of relapse6–9. In 2020, the Brazilian Group for Pediatric Bone Marrow Transplantation of the Brazilian Society of Bone Marrow Transplantation and Cellular Therapy (SBTMO) and the Brazilian Society for Pediatric Oncology (SOBOPE) convened a task force to provide general guidance on HSCT for childhood AML to provide evidence-based guidance for the appropriate management of this disease.

Impact of Allogeneic Hematopoietic Cell Transplantation (HCT) As Consolidation Following CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy for Treatment of Relapsed Acute Lymphoblastic Leukemia (ALL)

Impact of Allogeneic Hematopoietic Cell Transplantation (HCT) As Consolidation Following CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy for Treatment of Relapsed Acute Lymphoblastic Leukemia (ALL)

Acute Myeloid Leukemia Patients Requiring Two Cycles of Intensive Induction for Attainment of Remission Experience Inferior Survival Compared with Patients Requiring a Single Course of Induction Chemotherapy

Background: Achievement of initial remission remains the most important clinical factor predicting long term survival in acute myeloid leukemia (AML) patients treated with intensive chemotherapy. Yet, whether the patient subset in need of a second cycle of intensive induction chemotherapy to reach remission experiences inferior outcomes compared to patients reaching remission after a single cycle of therapy, remains uncertain with previous publication showing diverging outcomes with respect to patient survival and the risk for disease relapse (Rowe et al. Cancer 2010; Othus et al. Leukemia 2016). In this analysis we aimed to readdress this important clinical question in a uniform cohort of recently treated patients.Patients and Methods: Retrospective analysis of 302 consecutive AML patients treated with intensive induction chemotherapy in our institution in 2007-2020. Univariate analyses were performed using T-Test for continuous variables, and Fisher's Exact test and Pearson's chi-squared for assessment of categorical variables. Overall survival was assessed using the Kaplan-Meier method, and the log-rank test was used to compare overall survival between groups. Multivariate analyses using logistic regression were performed using year of diagnosis, patient age, follow-up duration, patient gender, white blood cell (WBC) count at diagnosis, MRC cytogenetic risk category, FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) and nucleophosmin 1 (NPM1) status, and ELN 2017 risk category, as covariates. All tests were two-sided with the type I error rate set at 0.05 for the determination of factors associated with time-to-event outcomes.Results: Median patient age was 55 years with a median follow-up duration of 23 months. In terms of European LeukemiaNet (ELN) 2017 classification, 122 patients (40%) were designated as favorable risk disease, 108 patients (36%) were intermediate risk, and 71 patients (24%) were adverse risk. A hundred and seventy-seven patients (60%) attained remission following initial chemotherapy while 58 patients (20%) required an additional cycle of intensive chemotherapy for remission. Patients requiring two cycles to reach remission were less likely to be NPM1 mutated (33% versus 51%; p=0.025) or be in the ELN 2017 favorable risk category (25% versus 57%; p<0.001). In multivariate analysis achievement of remission following 2 cycles of intensive compared with a single cycle resulted in significantly inferior survival [hazard ratio (HR)=1.68, 95% CI, 1.09-2.59; p=0.017] (figure 1) whereas leukemia-free survival was not significantly impacted (HR=1.26, 95% CI, 0.85-1.85) (p=0.23). Relapse rates also did not differ to a significant degree between groups (45% versus 47%, p=0.8).Conclusion: Our analysis reaffirms the indispensable clinical significance of attainment of an early remission following intensive induction chemotherapy for AML patients. The marked long term survival advantage conferred by an early remission speaks to the need to improve initial remission rates which with the recent introduction of novel targeted therapeutics seems to be an attainable goal. [Display omitted] DisclosuresAvigdor: Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Research Funding; Janssen: Research Funding; Takeda: Consultancy, Honoraria.

Surgical outcome of transsphenoidal surgery in Cushing's disease: a case series of 1106 patients from a single center over 30 years.

Transsphenoidal surgery (TSS) is the first-line treatment for patients with Cushing's disease (CD). However, the reported remission rates of patients who received TSS vary widely between different studies, and the predictors of surgical outcomes remain controversial. The present study analyzed the early outcome of TSS in a large population of patients with CD at a single center, and identified potential predictors of initial remission of TSS in patients with CD. The clinical features and surgical outcomes of CD patients who underwent TSS between 1988 and 2018 at Peking Union Medical College Hospital (PUMCH) were collected and analyzed from their medical records. Of the 1604 CD patients who underwent TSS at PUMCH between February 1988 and October 2018, 1106 patients had complete medical data and pathological results. After surgery, the overall postoperative initial remission rate was 72.5, and 27.5% of patients maintained persistent hypercortisolism. The initial remission rate of patients with preoperative noninvasive adenoma based on MRI (77.1%), intraoperative noninvasiveness (72.5%), microadenoma (74.3%), pathological confirmation (76.4%), and first TSS (73.9%) was significantly higher than that in patients with preoperative invasive adenoma (53.0%), intraoperative invasiveness (60.7%), macroadenomas (65.9%), pathologically negative (49.7%), and repeat TSS (56.0%), respectively (all P < 0.05). The initial remission rate in patients with pseudocapsule-based extracapsular resection (88.1%), MRI-visible adenoma (74.2%) was higher than that in patients without pseudocapsule-based extracapsular resection (77.1%), and with MRI-negative results (64.5%), respectively, but did not reach statistical significance (All P > 0.05). Striking, there was no significant differences in initial remission rates between patients who underwent selective adenomectomy and enlarged adenomectomy (P > 0.05). Whereas, the initial remission rates in patients who underwent partial hypophysectomy only was 51.0%, which was much lower than that in patients underwent selective adenomectomy and enlarged adenomectomy (P < 0.05). The TSS is a safe and effective procedure for the treatment of CD. Whereas, preoperative invasiveness based on MRI, intraoperative invasiveness, macroadenomas pathologically negative, and repeat TSS are related to lower initial remission rates.

Therapy for Children and Adults with EGIL- or WHO2008-Defined Mixed Phenotype Acute Leukemia: A Systematic Review and Meta-Analysis

The rarity of Mixed-Phenotype Acute Leukemia (MPAL) and competing definitions has resulted in diffuse literature reporting small case series and precluded a consensus treatment approach. We therefore conducted a meta-analysis and systematic review to investigate the association of treatment type (acute lymphoblastic leukemia [ALL], acute myeloid leukemia [AML], or “hybrid” regimens) and disease response. We searched seven databases from inception through 2017 without age or language restriction. Included studies reported sufficient treatment detail for de novo MPAL classified according to the European Group for Immunological Characterization of Acute Leukemias (EGIL) or World Health Organization (WHO2008). Meta-analyses were performed for the endpoints of complete remission (CR) and overall survival (OS). A compiled case series for multivariable analysis was established from patients with data from time of diagnosis.We identified 92 reports meeting criteria, resulting in 1,265 unique patients included in at least one quantitative analysis. Using either definition of MPAL, meta-analyses revealed that AML Induction was less likely to achieve a CR as compared to ALL regimens, (WHO2008 Odds Ratio [OR] = 0.34, 95% Confidence interval [95%CI] 0.18-0.65; EGIL, OR=0.22, 95%CI 0.09-0.53). Multivariable analysis of the compiled case-series supported poorer efficacy for AML Induction (Table 1). Meta-analyses found better OS with ALL therapy (WHO2008 OR=0.48, 95%CI 026-0.89; EGIL, OR=0.45, 95%CI 0.22-0.93) but multivariable analysis of the compiled case series showed only adult age as predictive of lower survival (Table 1). MPAL definition did not impact trends within each endpoint. Examination of presenting features of MPAL revealed hyperleukocytosis and central nervous system involvement to be uncommon (<25%). For either classification system of MPAL, ALL-directed therapy is associated with higher initial remission rates and is at least equivalent to more intensive AML therapy for long-term survival. Prospective trials are urgently needed to establish a uniform approach to this heterogeneous disease. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Bone Marrow Stroma Protects FLT3 Acute Myeloid Leukemia (AML) through CYP3A4-Mediated Drug Metabolization of FLT3 Tyrosine Kinase Inhibitors (TKIs)

IntroductionFms-like tyrosine kinase 3 internal tandem duplications (FLT3/ITD) are among the most common mutations found in AML patients. Interestingly, although initial remission rates of FLT3/ITD AML are similar to standard-risk AMLs, these AML have a high relapse rate and poor overall survival. Moreover, FLT3 TKIs have been much more successful in eliminating peripheral FLT/ITD blasts, than eradicating marrow disease and generating durable responses clinically. Studies have addressed several mechanisms underlying the FLT3 TKI resistance, including a protective role for the bone marrow (BM) microenvironment. However, the mechanisms underlying this protection remain unknown. We previously showed that human bone marrow stromal cells (BMSCs) highly express most cytochrome P450 (CYP) enzymes, and these enzymes are a major means of chemoprotection within the BM niche (Alonso et al. Oncotarget 2015). Among them, CYP3A4 is a key enzyme responsible for hepatic inactivation of many chemotherapy agents, including many FLT3 TKIs used clinically. Therefore, we hypothesized that BM stromal CYP3A4 contributes to BM microenvironment mediated FLT3 TKI resistance by FLT3/ITD AML.Methods and ResultsTo test our hypothesis in vitro, FLT3/ITD AML cell lines (MV4-11 and Molm14) were co-cultured with FLT3 TKIs with or without BMSCs (F/STRO), and their clonogenic activity was assessed. We found that 3 different clinically active FLT3 TKIs (sorafenib, quizartinib, and gilteritinib), while active against the FLT3/ITD AML in liquid culture, had little activity when co-cultured with BMSCs (Figure 1A). Moreover, when FLT3/ITD AMLs were co-cultured with BMSCs with short hairpin (sh) RNA knockdown of CYP3A4 (shCYP3A4), the activity of the FLT3 TKIs was restored (Figure 1A). To test the hypothesis in vivo, we investigated the growth of FLT3/ITD AML tumors containing control or shCYP3A4 human primary BMSCs upon FLT3 TKI treatments in a xenograft mouse model. We observed that the tumors with shCYP3A4 BMSCs were significantly more sensitive to FLT3 TKI treatments compared to those with control BMSCs.To further examine the role of CYP3A4 in BMSCs, we examined the inhibitory effects of FLT3 TKIs in the absence of stromal cellular contact with FLT3/ITD AML cells. FLT3 TKI-containing media was incubated with and without control BMSCs and shCYP3A4 BMSCs, and then incubated with FLT3/ITD AML cells. Western blot performed on the FLT3/ITD AML cells showed that FLT3 TKI media conditioned with BMSCs blocked the inhibition of FLT3 phosphorylation, and this was reversed by CYP3A4 knockdown in the BMSCs. These results demonstrated that stromal CYP3A4 protected against FLT3 TKIs even in the absence of stromal cell contact.We next studied if combining a clinically active CYP3A4 inhibitor with FLT3 TKIs would increase the FLT3/ITD AML cells' sensitivities to FLT3 TKIs in the presence of BMSCs. Clarithromycin, a clinically active CYP3A4 inhibitor, significantly reversed the protective effects of BMSCs to 3 different FLT3 TKIs (Figure 1B).ConclusionsThese data confirm the protective effects of stroma for FLT3/ITD AML against FLT3 TKIs. Further, we found for the first time that CYP3A4 expressed in BMSCs contributes to BMSC mediated FLT3/ITD AML protection against FLT3 TKIs both in vitro and in vivo mouse model. Our results also demonstrated that combining FLT3 TKIs with clinically available CYP3A4 inhibitors may become a promising strategy to overcome drug resistance in FLT3/ITD AML treatment. [Display omitted] DisclosuresLevis:Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo, Inc.: Consultancy, Honoraria; Astellas Pharma Us: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; FujiFilm: Research Funding.

4K 3-dimensional video microscope system (orbeye) for transsphenoidal pituitary surgery

BackgroundIn previous reports on experiences with an exoscope, this new technology was not found to be applicable for transsphenoidal pituitary surgery. As a specialized center for pituitary surgery, we were using a 4K 3D video microscope (Orbeye, Olympus) to evaluate the system for its use in transsphenoidal pituitary surgery in comparison to conventional microscopy.MethodWe report on 296 cases performed with the Orbeye at a single institution. An observational study was conducted with standardized subjective evaluation by the surgeons after each procedure. An objective measurement was added to compare the exoscopic and microscopic methods, involving surgery time and the initial postoperative remission rate in matched cohorts.ResultsThe patients presented with a wide range of pathologies. No serious events or minor complications occurred based on the usage of the 4K 3D exoscope. There was no need for switching back to the microscope in any of the cases. Compared to our microsurgically operated collective, there was no significant difference regarding duration of surgery, complications, or extent of resection. The surgeons rated the Orbeye beneficial in regard to instrument size, positioning, surgeon’s ergonomics, learning curve, image resolution, and high magnification.ConclusionsThe Orbeye exoscope presents with optical and digital zoom options as well as a 4K image resolution and 3D visualization resulting in better depth perception and flexibility in comparison to the microscope. Split screen mode offers the complementary benefit of the endoscope which may increase the possibilities of lateral view but has to be evaluated in comparison to endoscopic transsphenoidal procedures in the next step.

Single-cell profiling identifies pre-existing CD19-negative subclones in a B-ALL patient with CD19-negative relapse after CAR-T therapy

Chimeric antigen receptor T cell (CAR-T) targeting the CD19 antigen represents an innovative therapeutic approach to improve the outcome of relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). Yet, despite a high initial remission rate, CAR-T therapy ultimately fails for some patients. Notably, around half of relapsing patients develop CD19 negative (CD19neg) B-ALL allowing leukemic cells to evade CD19-targeted therapy. Herein, we investigate leukemic cells of a relapsing B-ALL patient, at two-time points: before (T1) and after (T2) anti-CD19 CAR-T treatment. We show that at T2, the B-ALL relapse is CD19 negative due to the expression of a non-functional CD19 transcript retaining intron 2. Then, using single-cell RNA sequencing (scRNAseq) approach, we demonstrate that CD19neg leukemic cells were present before CAR-T cell therapy and thus that the relapse results from the selection of these rare CD19neg B-ALL clones. In conclusion, our study shows that scRNAseq profiling can reveal pre-existing CD19neg subclones, raising the possibility to assess the risk of targeted therapy failure.

Outcomes of Transsphenoidal Microsurgery for Prolactinomas - A Contemporary Series of 162 Cases.

Renewed interest in transsphenoidal surgery (TSS) as a therapeutic option for prolactinomas has emerged. This study is aimed at defining the current role of pituitary surgery in the management of prolactinomas. In this retrospective, consecutive single-center study, 162 patients who underwent primary microscopic TSS for prolactinomas between 2006 and 2019 were analyzed regarding surgical indication, previous dopamine-agonist (DA) treatment, early remission rates (3 months postoperatively), surgical complications and pituitary function. Seventy-four microprolactinomas and 88 macroprolactinomas were operated by TSS. 62.3% of the patients had received prior DA treatment. For microprolactinomas, the predominant indication for surgery was patient's wish (41.9%), while indications for macroprolactinomas varied. For enclosed microprolactinomas, the initial remission rate was 92.1%, while for macroprolactinomas, the rate was 70.4%. No significant difference of remission rates was found between DA-pretreated (65.3%) and non-pretreated (72.1%) patients (p=0.373).None of the patients suffered a significant complication. Re-operation for a postoperative cerebrospinal fluid leak was required in one patient (0.6%). Permanent postoperative deterioration of pituitary function was only observed in one of 158 patients with surgery for a prolactinoma (0.6%). Improvement of pituitary function was observed in 8 of 25 patients (32%) with preoperative deficits. Transsphenoidal microsurgery is safe and efficient for treatment of prolactinomas. It is particularly suitable for enclosed prolactinomas. The patient should be well informed of the pros and cons of the treatment options, which include DA medication and TSS, and the patient's preference should be taken into account during decision-making.