bluuebunny/crossref_metadata_2025 huggingface dataset:
Complete Arthroscopic Posterior Knee Capsulotomy in Patients With Knee Extension Deficit: Preliminary Results of a Clinical Trial
Authors: Malinowski Konrad , Mostowy Marcin , Koźlak Magdalena , Pękala Przemyslaw A. , Kennedy Nicholas I. , LaPrade Robert F.
Published: December 2023

Background:

Guided physiotherapy and surgical arthrolysis are effective in most patients with knee extension deficit. However, in refractory cases, posterior knee capsulotomy may be needed.

Purpose:

To assess extension restoration, pain reduction, and functional improvement after arthroscopic complete posterior knee capsulotomy in patients with extension deficit refractory to guided physiotherapy and surgical arthrolysis.

Study Design:

Case series; Level of evidence, 4.

Methods:

Included were patients with symptomatic asymmetric extension deficit >3° refractory to at least 6 months of guided physiotherapy and initial arthrolysis (15 patients with 12-month follow-up and 8 patients with 24-month follow-up). The mean duration of extension deficit was 24.6 months. An arthroscopic complete posterior knee capsulotomy was performed with transection of the posteromedial, posterolateral and central capsule, and the posterior septum. The primary outcome measure was knee extension, with hyperextension denoted as negative knee extension values. Secondary outcome measures included visual analog scale (VAS) for pain during maximum effort and exercise, International Knee Documentation Committee (IKDC) score, and Knee injury and Osteoarthritis Outcome Score (KOOS).

Results:

The mean patient age was 40.0 years (range, 26-70 years); 6 out of 15 patients had developed knee contracture after isolated anterior cruciate ligament reconstruction. The mean knee extension deficit decreased from 16.9° (range, 7° to 45°) preoperatively to -0.2° (range, -5° to 5°) at 12-month follow-up ( P = .003) and to -0.3° (range, -5° to 5°) at 24-month follow-up ( P = .035). The mean VAS pain score decreased from 3.5 (range, 1-6) preoperatively to 1.1 (range, 0-2) at 12-month follow-up ( P = .004) and to 1.5 (range, 0-4) at 24-month follow-up ( P = .005). The mean IKDC increased from 37.9 (range, 21-62) preoperatively to 63.9 (range, 46-87) at 12-month follow-up ( P < .001) and to 60.9 (range, 39-80) at 24-month follow-up ( P = .003). The mean KOOS increased from 45.0 (range, 30-62) preoperatively to 75.3 (range, 49-94) at 12-month follow-up ( P < .001) and to 72.3 (range, 49-92) at 24-month follow-up ( P = .003). There were no significant differences between 12- and 24-month follow-up in extension deficit or functional outcomes. One patient had a midcalf subcutaneous hematoma 5 weeks postoperatively, requiring evacuation.

Conclusion:

Arthroscopic complete posterior knee capsulotomy was able to restore knee extension, reduce pain, and improve function, with 12-month follow-up results sustained at 24-month follow-up.

Registration:

NCT05385393 (ClinicalTrials.gov identifier).
Site classification scheme based on geological age and genesis for Xinjiang and the Capital Metropolitan areas of China
Authors: Ren Yefei , Zhang Yuting , Ji Kun , Wen Ruizhi , Kishida Tadahiro , Yao Xinxin
Published: December 2023

The site classification map is one of the vital inputs in earthquake disaster scenario prediction and risk modeling that provides a perspective of proxy-based methods. In China, a systematic empirical relationship between geological age, genesis, and site class in the practice of site classification has yet to be established. In this study, data from 1:500,000 geological maps and thousands of engineering boreholes in the Xinjiang Uygur Autonomous Region and the Capital Metropolitan area in China were collected, and different types of geological unit were classified according to 10 types of geological age and 18 types of geological genesis. A site classification scheme was proposed on the basis of geological age, geological genesis, statistical properties of boreholes, and lithological descriptions. Borehole characteristics were investigated in terms of their proportions among the different site classes, and the mean and standard deviation of V S30. Accordingly, a chart correlating four site classes (B, C, D, and E) with each type of geological age and genesis was developed that could be used as a practical tool in regional site classification. Site classification maps were delineated in both areas using the proposed scheme and compared with those derived from the topographic slope-proxy method and another geology-proxy method, and the results showed that it is effective in identifying the site class, especially for class E sites, and probably class B that inferred by the qualitative evaluation. Moreover, the applicability of the method has also been confirmed in areas outside the study area. It is anticipated that it could provide a technical template for nationwide site classification using geological maps.
Benefit of TKI-Treatment in CML after Failing Molecular or Cytogenetic Milestones
Authors: Hehlmann Rüdiger , Lauseker Michael , Hochhaus Andreas , Saussele Susanne
Published: December 2023

No information is available on long-term survival of tyrosine kinase inhibitor (TKI)- treated patients failing the response milestones as defined by the European LeukemiaNet (ELN). Such information would help with decision making in failing patients when risks associated with comorbidities, drug toxicities or transplantation preclude switching to another TKI or other treatments.

To systematically analyze survival after reaching, or not reaching, ELN-response milestones, 1342 imatinib-treated patients from CML-study IV with newly diagnosed CML in chronic phase and regular molecular and cytogenetic tests were studied. Survival was analyzed by landmark analyses at 3, 6, 12 and 24 months and followed up to 14 years. In patients who failed the failure milestones (>10% BCR::ABL1 IS at 6 months, >1% BCR::ABL1 IS at 12 months), 10- to 12-year survival ranged around 70%, 10-20% less than in responding patients. An example is shown in Fig. 1a which depicts survival of patients reaching, or not reaching 1% BCR::ABL1 IS at 12 months. Similar survival curves were observed for the other landmarks that indicate failure. Inbetween response rates of >1%-10% BCR::ABL1 IS at 12 months indicated survival probabilities similar to those of patients failing 1% BCR::ABL1 IS, whereas patients reaching >1%-10% BCR::ABL1 IS at 24 months showed a survival similar to that of patients failing 10% BCR::ABL1 IS. Switching to alternative therapies, mostly to dasatinib and nilotinib, was observed in 372 patients (26.9%) and did not change the main results.

Although cytogenetic tests were increasingly replaced by molecular tests in the course of the study, sufficient cytogenetic analyses were available for comparison with molecular analyses. Complete and partial cytogenetic remissions have been shown to be roughly equivalent to 1% and 10% BCR::ABL1 IS, respectively. Wheras reaching, or not reaching cytogenetic and molecular reponse markers at 6 and 12 months was equivalent, not reaching a complete or partial cytogenetic remission at 24 months identified a small subgroup of patients (5.9%) with inferior survival (Fig. 1b).

Age (more or less than 60 years) had no major impact on survival differences, but on hazard ratios for early death. Hazard ratios at 10% BCR::ABL1 IS by 6 months were 4.0 (95%CI:2.0-8.1) for the younger patients, but only 0.9 (95% CI: 0.4-1.8) for the elderly. The reasons for early death in the younger patients were mostly CML-related, whereas the elderly primarily died of other reasons.

The data show that TKI-treated patients not reaching failure milestones still may derive benefit from continuing TKI-treatment and provide a basis for individualized decisions, if failing patients are confronted with risks of alternative treatments.
A Novel PI3K γ/δ and DNA-PK Triple Inhibitor, BR101801, for r/r PTCL: A Phase 1a/b, Multi-Center, Open-Label Clinical Trial
Authors: Kim Bong-Seog , Kim Seok Jin , Yoon Dok Hyun , Kim Jin Seok , Kim Tae Min , Lee Eunyoung , Lee Jeong-Ok , Yang Deok-Hwan , Lee Won-Sik
Published: December 2023

Background

BR101801, a triple inhibitor of PI3Kγ/δ and DNA-PK, inhibits not only the signal affecting cell growth caused by PI3Kγ/δ but also efficiently induces cell cycle arrest and apoptosis through inhibition of DNA-PK activation, with this triple target inhibition it decreases the stability of oncogenic protein, c-Myc (AACR2020 abstract #655). BR101801 is currently being evaluated in a phase 1a/b study in advanced hematologic malignancies. In phase 1a study, BR101801 exhibited evidence of clinical activity and was established at 200mg orally once daily 28-day cycle (RP2D) in patients with r/r PTCL (ASCO2023 abstract #7551).

Methods

This is a phase 1, open-label, multi-center, dose escalation (1a), and expansion (1b) study of BR101801 in adult patients with advanced hematologic malignancies (NCT04018248). In the phase 1a study, Dose was escalated at 50, 100, 200 and 325 mg QD. PTCL-NOS, AITL, FTCL and Nodal PTCL with TFH phenotype were determined as target indications for phase 1b with the RP2D.

Results

As of Jul 19, 2023, a total of 26 patients were enrolled in dose-escalation phase (n=12) and dose-expansion phase (n=14). The median age was 66 years (range of 30-83). Histological subtypes include PTCL-NOS (n=11, 42%), AITL (n=11, 42%), DLBCL (n=2, 8%), MZL (n=1, 4%) and MF (n=1, 4%). The majority of patients had stage III or IV (92%). In the phase 1a study, Dose limiting toxicity (DLT) occurred at 325 mg; thus, 200 mg QD was determined as the maximum tolerated dose (MTD) and RP2D.

Of 19 evaluable patients with r/r PTCL (PTCL-NOS and AITL) in the phase 1 study. Patients' stage was III or IV (100%) with 47.4 % of patients having received three or more prior systemic therapies. The ORR was 31.6% (95% CI, 12.6-56.6) with 4 CRs (21.1%) and 2 PRs (10.5%), CBR was 47.4% (95% CI, 24.5-71.1). In median follow-up duration of 12.9 months, the median PFS was 7.5 months (95% CI, 1.7-NC), median OS and DoR (range of 1.9+-31.8+) has not reached. Currently, 5 patients still remain on treatment.

Safety analysis was conducted for the 26 patients; 23 patients (88.5%) experienced adverse events (AEs). The most common (≥ 20%) AEs were Rash (23.1%), AST increased (23.1%), ALT increased (23.1%) and Cough (23.1%). Grade 3/4 ADRs occurred in 12 patients (46.2%) and those were (≥ 10%, frequency) AST increased (19.2%), ALT increased (15.4%), Neutropenia (15.4%). There were no treatment related mortality observed.

Conclusion

BR101801, the triple inhibitor of PI3K γ/δ and DNA-PK, demonstrated as a promising therapeutic option for r/r PTCLs patients. Preliminary results showed the ORR of 31.6% and a CR rate of 21.1%. Phase 2 study is warranted further investigate the safety and efficacy of BR101801 in r/r PTCL and Nodal TFH cell lymphoma at 200 mg QD orally.
Mast Cell Leukemia Descriptors and Clinicopathologic Determinants of Survival: Analysis of a Pooled Database
Authors: Haddad Philip A , Chennapragada Suma Sri
Published: December 2023

Background

Mast cell leukemia (MstCL) is a rare but aggressive variant of systemic mastocytosis (SM) which is defined by the presence of >20% atypical mast cells in the bone marrow. It is further classified into leukemic and aleukemic variants based on the presence or absence of >10% atypical mast cells in the peripheral blood, respectively. There is a wide variation in treatment regimens used to treat MstCL. Despite this, the prognosis remains poor. The determinants of survival outcomes in this disease are not very well defined. Therefore, we conducted this pooled database analysis to identify the prognostic factors, clinicopathological characteristics, and therapeutic strategies that influence survival in this disease.

Methods

To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 144 cases that fit the diagnostic criteria for MstCL. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS).

Results

A total of 144 patients with confirmed MstCL were identified. The median age was 58.5. There was a slight female preponderance with F:M of 1.2. The median duration of symptoms before diagnosis was 2 months. Involvement of lymph nodes, spleen, peripheral blood, skin, and CNS occurred in 17%, 44%, 23%, 13%, and 6%, respectively. Constitutional symptoms and hemophagocytosis occurred in 33% and 8% of the cases, respectively. The median OS and DFS of the whole group were 9 and 8 months, respectively. Patients younger than 55 had worse median OS (6 vs. 15 months, p=0.03). Hgb<10g/dl (p=0.0002), Platelets<100K (p=0.01), leukemic phase (p=0.02), and complex cytogenetics (p=0.02) were associated with worse OS. Furthermore, presence of hemophagocytosis had worse OS (p=0.06). Although the presence of constitutional symptoms, Tryptase>200, and KIT mutations other than D816V had numerically worse OS, they did not reach statistical significance. Sex, IHC phenotype, presence of concomitant malignancy, and type of organ involvement did not impact OS. Compared to no treatment, dose-intense chemotherapy, non-dose-intense chemotherapy, novel agents, and stem cell transplant had incrementally superior OS (2 vs. 7 vs. 15 vs. 15 vs. 23 months, p<0.0001). Patients who attained CR as their best response also had a superior median OS compared to responses less than CR and non-responders (NR vs. 29 vs. 8 months, p<0.0001).

Conclusion

This study presents updated clinicopathologic data from a large, pooled cohort of patients with MstCL. It identifies age, anemia, thrombocytopenia, leukemic presentation, complex cytogenetics, type of therapy, and quality of response to treatment as critical determinants of OS.
Potent in Vitro and In Vivo Efficacy of BYON4413, a Duba-Based Antibody-Drug Conjugate Targeting CD123 in Acute Myeloid Leukemia
Authors: van der Lee Miranda , van Achtenberg Tanja , Brouwers-Vos Annet , van der Vleuten Monique , Kappers Wendy , Verheijden Gijs , Huls Geert A. , van Wigcheren Glenn , Ubink Ruud , Sesink Aloys , MacInnes Alyson , Schuringa Jan Jacob , Dokter Wim
Published: December 2023

Acute myeloid leukemia (AML) and myelodysplasia (MDS) result from a differentiation impairment driving an accumulation of immature myeloid cells in the bone marrow and peripheral blood. A widely reported feature of these neoplastic myeloid cells is an increased cell surface expression of CD123, the IL3 receptor α subunit. This observation has established CD123 as an attractive target for precision therapy. Here, we describe BYON4413, a novel antibody-drug conjugate (ADC) that binds with high affinity to CD123. BYON4413 comprises a humanized IgG1 antibody directed at CD123 that is site-specifically conjugated to Byondis' proprietary duocarmazine linker-drug (LD) technology, ByonZine® and ByonShieLD®. This LD, when cleaved upon internalization and lysosomal routing, releases a potent duocarmycin payload that alkylates DNA, generating damage that results in replication stress and cell death. In vitro studies with AML cell lines demonstrate that BYON4413 is highly effective in eradicating CD123-positive cells while having little impact on CD123-negative cells. Similar results are observed when we test BYON4413 on AML patient-derived BMMCs/PBMCs in ex vivo assays (n=50), indicating that the specificity of BYON4413 cytotoxicity is largely limited to CD123-positive cells. Ex vivo experiments also reveal a stronger potency of BYON4413 in AML patient-derived blasts compared to healthy CD34 + hematopoietic stem/progenitor cells. In vivo PK/PD studies demonstrate that BYON4413 is remarkably efficient at reducing the tumor burden in multiple AML patient- and cell line-derived xenograft models. Studies in non-human primates suggest that BYON4413 has a favorable toxicity profile and a high maximum tolerable dose, features that should enable combination strategies with other oncolytics. In sum, BYON4413 shows great potential to be an effective targeted therapy against AML, MDS, and other CD123 + hematological malignancies such as blastic plasmacytoid dendritic cell neoplasm (BPDCN). Readied with these promising pre-clinical results, we have designed a first-in-human dose-escalation and expansion trial enrolling AML and high-risk MDS patients scheduled to begin in Q12024.
Differences in Clinical Outcomes between Hydroxyurea-Resistant and -Intolerant Polycythemia Vera Patients
Authors: Kim Sung-Yong , Lee Sung-Eun , Hong Junshik , Bang Soo-Mee , Park Jinny , Choi Chul Won , Bae Sung Hwa , Kim Min Kyoung , Yoon Seug Yun
Published: December 2023

Previous retrospective studies have revealed that a substantial portion of PV patients experience resistance to hydroxyurea (HU-R) and intolerance to HU (HU-I). Currently, the therapeutic options for both groups of patients do not differ, and most clinical trials investigating second-line therapies have enrolled patients with HU-R or HU-I without considering potential clinical distinctions between the two groups. Direct comparisons between patients with HU resistance and HU intolerance have not been conducted, and prognostic factors related to clinical outcomes, such as thrombosis, bleeding, disease progression, and survival, remain unclear for patients experiencing HU resistance or intolerance.

A total of 90 patients with HU-R/I were retrospectively anlyzed in this study. Among them, 44 and 46 patients fulfilled the ELN criteria defining resistance or intolerance to HU, respectively. Patients with HU-R were older at the time of diagnosis of PV (66.7 ± 13.2 years, vs. 59.8 ±11.2 years in the HU-I group, P = 0.016), had longer times to developing HU-R/I, and thus, were older at the time of HU-R/I development compared with those with HU-I. The majority of the study patients continued HU treatment with dose modification or intermittent discontinuation with anagrelide added to control platelet counts until disease progression or death because of limited second-line treatment options during the observed period.

The cumulative incidence of thrombosis after 7 years of HU-R/I was 21.4%, and the incidence of disease progression was 22.5%. Comparing the HU-R and HU-I groups, the HU-R group had a significantly higher rate of disease progression (36.7% vs. 0.56%, P = 0.009), while there was no significant difference in thrombosis incidence (19.0% vs. 22.9%, P = 0.463). The type of thrombosis did not differ between the two groups (P = 0.628). Multivariate analysis revealed that HU-R was an independent prognostic factor for progression-free survival (hazard ratio = 5.57, 95% CI: 1.22 - 25.54, P = 0.027).

The patients in the HU-R group had significantly lower PFS (40.2% vs. 66.1% in the HU- I group, P < 0.01). They also showed a trend toward lower TFS (51.0% vs. 62.1% in the HU-I group; P = 0.055) and lower OS (57.5% vs. 67.7% in the HU-I group; P = 0.060) compared to patients with HU-I. The mortality at seven years was 42.5% in the HU-R group and 32.3% in the HU-I group (P = 0.06). Higher LDH levels, multiple cardiovascular risk factors, and prior thrombosis were identified as unfavorable predictors of overall survival.

These findings suggest that HU-resistant patients have a higher risk of hematological transformation but a comparable risk of thrombosis to HU-intolerant patients. These distinctions should guide decisions on second-line treatment options and clinical trials involving these patients.
TP53 Aberrant B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) Are Uniquely Sensitive to a Combination of Pyrimidine De Novo Synthesis Blockade and Replication Checkpoint Inhibition
Authors: Stoll Gawin R. , Van Ingen Schenau Dorette , Cox Willem P. J. , Tang Ziqin , Wagener Emmely M. , van der Meer Laurens T. , van Leeuwen Frank N.
Published: December 2023

Background

Unlike most solid tumors, the incidence of TP53 aberrations in ALL is only 3% at diagnosis. However, in relapsed ALL this number increases to 12%. More importantly, at relapse, loss of p53 function is associated with therapy failure, with an overall survival of only 20%. Hence, there is a clear clinical need for more effective strategies to treat TP53 aberrant relapsed ALL. Owing to their high proliferative state, leukemic blasts show a high dependency on pyrimidines for DNA synthesis. A lack of pyrimidines leads to replication stress, causing activation of p53 and the DNA damage response pathway.

Results

We used CRISPR/Cas9 to generate TP53 deficient variants of the TP53 proficient BCP-ALL cell lines Nalm6 and RCH-ACV. We used these cell lines in a CRISPR screens and high throughput drug screen, and identified a strong synergy between the targeting of pyrimidine synthesis and DNA checkpoint kinase ATR and its downstream effectors Chk1 and Wee1 in TP53 deficient ALL. To validate these results, we tested the efficacy of a checkpoint inhibition together with Orludodstat (BAY-2402234), an inhibitor of Dihydroorotate Dehydrogenase (DHODH), a key enzyme in de novo pyrimidine biosynthesis. This clinical grade inhibitor was evaluated in either wild type or TP53 deficient BCP-ALL and T-ALL cell line models and patient derived xenografts (PDX).

A strong apoptotic response was observed when Orludodstat was combined with the ATR inhibitor Berzosertib, most notably in TP53 deficient ALL. This p53 dependency was confirmed using ex vivo cultures of patient derived xenografts (PDX) of diagnosis and relapse pairs, where each diagnostic sample was wild type for TP53, and the relapse carried a TP53 aberration. While little or no synergy was observed in the diagnostic samples, a strong efficacy of the combination was observed in the matched TP53 deficient relapsed samples (Figure 1 A).

Preliminary results from i n vivo experiments using p53 deficient patient derived xenografts indicate that the combination of Orludodstat and Berzosertib is well tolerated, while significantly delaying leukemic growth (Figure 1 B).

Conclusion

Together, our findings suggest that the combined targeting of de novo pyrimidine synthesis and ATR signaling may present a specific and non-genotoxic vulnerability for TP53 aberrant ALL.
ATG or Post-Transplant Cyclophosphamide to Prevent Gvhd in Matched Unrelated Stem Cell Transplantation? - a Registry Analysis By the EBMT Transplant Complications Working Party
Authors: Penack Olaf , Abouqateb Mouad , Peczynski Christophe , Boreland William , Kröger Nicolaus , Stelljes Matthias , Gedde-Dahl Tobias , Wolfgang Blau Igor , Schroeder Thomas , Salmenniemi Urpu , Kulagin Aleksandr , Peffault De Latour Regis , Mielke Stephan , Finke Jürgen , Moiseev Ivan Sergeevich , Schoemans Helene , Koenecke Christian , Peric Zinaida
Published: December 2023

T

There is a considerable risk of GVHD and non-relapse mortality (NRM) after allogeneic stem cell transplantations (alloSCT) when matched unrelated donors (MUD) are used. Prophylaxis with either rabbit anti-thymocyte globulin (rATG, also termed anti-T-lymphocyte globulin) or post-transplantation Cyclophosphamide (PTCy) is in standard clinical use. The unresolved question is whether to prefer PTCy or rATG in this setting. So far, two randomized trials, several retrospective studies and a meta-analysis comparing PTCy to rATG in MUD alloSCT gave contradictory results. Current data from large registry cohorts has not been published.

To improve the evidence base, we analyzed outcomes of rATG vs. PTCy prophylaxis in adult patients with hematologic malignancies undergoing peripheral blood alloSCT from 10/10 antigen MUD between Jan 2018 and June 2021 in the EBMT database. We performed multivariate analyses using Cox cause-specific hazard models, adjusting for known risk factors, and variables that showed significant difference between the two comparison groups.

Overall 8764 patients were included, treatment- and patient characteristics are shown in Table 1. Patients receiving PTCy (n=1039) were younger, had undergone alloSCT more recently, and had a lower disease risk compared to patients receiving rATG (n=7725). Median follow up was 2.1 years in both groups. Outcomes graphs are shown in figure 1. All outcomes are given starting from alloSCT (with 95% CI): NRM (fig 1A) was higher in the rATG arm (2-years NRM: PTCy 12.4% [10.2 - 14.7] vs. rATG 16.1% [15.3 - 17]; HR 0.72, p=0.016), same for Relapse incidence, (2-years RI: PTCy 22.8% [19.9 - 25.8] vs. rATG 26.6% [25.5 - 27.7]; HR 0.87, p=0.046), Overall survival (fig 1B) was better in the PTCy arm (2-years OS: PTCy 73.1% [70 - 76] vs. rATG 65.9% [64.7 - 67.1]; HR 0.82, p=0.001), same for Progression free survival (fig 1C) (2-years PFS: PTCy 64.9% [61.4 - 68.1] vs. rATG 57.2% [56 - 58.5]; HR 0.83, p<0.001), Chronic GVHD was lower in the PTCy arm (2-years cGVHD: PTCy 28.4% [25.2 - 31.7] vs. rATG 31.4% [30.3 - 32.6]; HR 0.77, p=0.012), whereas acute GVHD grades II-IV was not significantly different between the two arms (100-day aGVHD: PTCy 24.1% [21.3 - 27] vs. rATG 26.5% [25.5 - 27.6]; HR 0.85, p=0.11)

In conclusion, we found a lower NRM, lower incidence of chronic GVHD as well as higher survival outcomes in adult recipients of peripheral blood alloSCTs from MUD receiving PTCy compared to rATG. The current analysis improves the evidence basis for decision making on GVHD prophylaxis in MUD alloSCT.
Automatic Generation of Alloreactivity-Reduced Donor Lymphocytes and Hematopoietic Stem Cells from the Same Mobilized Apheresis Product
Authors: Wiercinska Eliza , Quade-Lyssy Patricia , Hümmer Christiane , Beifuß Josephine , Akarach Karima , Poppe Carolin , Olevska Valeriya , Lahnor Heike , Dzionek Julia , Bosio Andreas , Papanikolaou Eleni , Bonig Halvard
Published: December 2023

CONCLUSION

In vitro or in vivo depletion of alloreactive T cells can facilitate haplo-identical hematopoietic stem cell transplantation (HSCT). Very satisfactory transplant outcomes were thus reported for TCRαβ/CD19-depleted hematopoietic stem/progenitor cell (HSPC) grafts. However, the current semi-automatic manufacturing process, although robust, still requires a significant amount of time to be completed. Towards advancing and further facilitating large scale cell processing, a new TCRαβ/CD19 depletion module combined with a, previously described, CD45RA depletion module (to serve as allo-reactivity attenuated donor lymphocyte infusion) was established on the CliniMACS Prodigy.

We evaluated six apheresis products from G-CSF-mobilized volunteer donors which were split, one portion each depleted of CD45RA + or of TCRα/β + and CD19 + cells. Products were assessed for recovery of HSPCs and other mature subsets, as well as depletion of targeted cells using flow cytometry. Effects of apheresis and product age post 48 hours storage at 2-8 °C as well as freeze-thawing on product viability and recovery of WBC and HPSCs were assessed by flow cytometry.

Ten sequential depletions were technically uneventful, proceeding automatically with minimal hands-on time beyond tubing set installation. Depletion of CD45RA +, TCRα/β + and CD19 + cells was nearly complete, and at least equivalent to previous reports, achieving mean depletions of 4 log of targeted cells for both products. HSPC products retained TCRγ/δ + and NK cells. 48 hours storage of apheresis product was associated with the expected modest loss of HSPCs, but depletions proceeded efficiently. Depleted products were stable until at least 72 hours after apheresis with stem cell viabilities >90%. Freeze-thawing resulted in loss of NK cells; post-thaw recovery of viable CD45 + and HSPCs was >70% and in line with expectation.

The closed, GMP-compatible process generates two separate medicinal products from the same mobilized apheresis product. The CD45RA-depleted products contained functional memory T cells, whereas the TCRαβ/CD19-depleted products included HSPCs, TCRγ/δ + and NK cells . Both products are predicted to be effectively depleted of GvH-reactivity while providing immunological surveillance, in support of haplo-identical HSCT.
Daratumumab for Refractory Autoimmune Leukopenia: A Case Report
Authors: Wang Xiaoyang , Guo Michael , Seiter Karen , Steinberg Amir , Paracha Fauzia , Reilly Christopher R. , Shakil Fouzia Alam , Liu Delong
Published: December 2023

Autoimmune leukopenia is a rare disorder but may cause severe life-threatening infections. Here we report a case involving a 58-year-old male with a history of severe autoimmune leukopenia that was highly refractory to therapies targeting T and B linage cells but had a durable response to daratumumab. This case management suggested that targeting plasma cells may be considered for refractory autoimmune leukopenia.
Dual Co-Stimulation with CD28 and ICOS Enhances T Cell Activation and Optimizes CAR-T Cell Antitumor Activity
Authors: Wu Jianghua , Luo Wenjing , Tang Lu , Chen Zhaozhao , Zhou Jie , Li Chenggong , Xiong Wei , Mei Heng , Hu Yu
Published: December 2023

Background:

The Chimeric antigen receptor (CAR) T cell therapy for hematological malignancies has revolutionized anticancer therapy. CAR-T cell expansion and persistence are strikingly associated with the intrinsic programmes of T cells. However, the current process for CAR-T cells manufacturing resulted in high frequencies of exhausted and senescent CAR-T cells with reduced mitochondrial mass. T cell receptor (TCR) signaling cooperates with co-stimulatory signaling to regulate T cells activation and differentiation. Considering that ICOS has a well-defined role in T cell differentiation, especially with regard to the incorporation of ICOS into CAR to boost CAR-T cells antitumor activity, we therefore hypothesize that TCR activation in synergy with dual CD28 and ICOS co-stimulation rapidly triggers T cell activation and may be a potential approach to optimize CAR-T cells antitumor activity.

Methods: In this study, we established a culture system using plate-coated CD3 in combination with CD28 and ICOS mAbs to simultaneously stimulate T cells, and further studied whether dual CD28 and ICOS co-stimulation could reprogram the transcriptional, epigenetic and proteomic states of T cells and optimize CAR-T cells antitumor activity. In vitro CAR-T cell phenotype and cytotoxicity were detected via flow cytometry, co-culture killing assay and degranulation assay. NSG mice were inoculated with Raji cells to establish xenograft mouse model, and the tumor load and survival time were dynamically monitored after treatment with CAR-T cells.

Results: As expected, dual co-stimulation potently enhanced T cells activation and expansion via reprogramming their transcriptome, epigenome and proteome. Mechanistically, dual CD28 and ICOS co-stimulation rapidly upregulated the pathways such as ribosome, citrate cycle (TCA cycle) and oxidative phosphorylation (OXPHOS) to drive T cells exiting from quiescence. Moreover, metabolic pathways are rewired in CD28 and ICOS-stimulated T cells to guarantee sufficient energy for cell proliferation. Meaningfully, dual co-stimulation confers CAR-T cells with high lentiviral transfection efficiency, possibly correlating with highly open chromatin accessibility in CD28 and ICOS-stimulated T cells. CAR-T cells manufactured with dual CD28 and ICOS co-stimulation demonstrated significantly enhanced OXPHOS and mitochondrial biogenesis, resulting in a superior expansion and being more effective at killing tumor cells in immunodeficient animals.

Conclusions: Collectively, our data indicated that activating CD28 and ICOS signaling during CAR-T cells preparation is a potential strategy for optimizing CAR-T cells antitumor activity.
Estimation of Relapsed/Refractory Follicular Lymphoma Patients on Therapy in the United States
Authors: Johnston Karissa , Bennett Mark , Bains Chawla Savreet , Yang Shibing , Wang Anthony , Yu Junhua , Jun Monika
Published: December 2023

Background: Follicular lymphoma (FL) represents approximately 20-25% of non-Hodgkin lymphomas (NHL). In contrast to patients with more aggressive NHL, patients with FL have a heterogenous course of disease in which some can spend extended periods in an initial watch-and-wait state and/or within a single line of treatment. As such, these patients may have multiple relapses and a variety of clinical features that may impact disease course (eg, double-refractory disease, increased Follicular Lymphoma International Prognostic Index (FLIPI) scores, high Ann Arbor disease stage, older age, etc.). The objective of this study was to estimate the number of treated patients with FL in each line of therapy (LOT) to better understand the proportion with relapsed or refractory (R/R) disease in the US while accounting for distributions of LOTs within a baseline prevalent population and annual trends in treatment initiation by LOT.

Methods: Two companion models were developed from a US perspective: 1) an epidemiologic model that utilized FL incidence and survival data from the Surveillance, Epidemiology, and End Results (SEER) program to project the size of the prevalent population; and 2) a state-transition model describing the proportion of patients with FL initiating treatment and time on treatment by line of therapy. Within the state-transition model, hypothetical incident cohorts were simulated annually to follow FL treatment patterns and survival trajectories until a “steady-state” was reached regarding the distribution of LOTs in the prevalent population. Model inputs were based on data from published literature. Several published sources were identified regarding estimates of treatment rates by line of therapy, with base-case values based on physician survey: 51% for first LOT, 32% for second LOT, and 31% for third and successive LOTs. This distribution was then applied to a baseline prevalent population and subsequent incident cohorts were modeled annually over a 3-year time horizon.

Results: In 2022, the estimated FL prevalent population in the US was 154,922. Over a subsequent 3-year period combining the prevalent patients with newly incident patients, the model projected 10,399 patients initiating first-line treatment, 3197 initiating second-line treatment, and 975 initiating third-line treatment.

Conclusions: While incidence of FL initial diagnosis in the US is well reported, there are limited data describing prevalence or population makeup with respect to LOT. While many patients can benefit from long remissions after first-line therapy, a portion of patients experience R/R disease and require further treatment. Estimation of the R/R FL population can support with planning of treatment needs as novel therapies emerge in the US.
Sorafenib Plus Triplet Therapy with Venetoclax, Azacitibine and Homoharringtonine for Refractory/Relapsed Acute Myeloid Leukemia with FLT3-ITD: A Multicentre, Phase 2 Study
Authors: Yu Sijian , Liu Qifa , Zhang Yu , Yu Guopan , Wang Yu , Shao Ruoyang , Liu Qiong
Published: December 2023

Abstract

Background

Patients with relapsed or refractory acute myeloid leukemia (R/R AML) with FLT3 internal tandem duplication (FLT3-ITD) have an infrequent response to salvage chemotherapy. We aimed to investigate the activity of sorafenib plus triplet therapy with venetoclax, azacitidine, and homoharringtonine (VAH) as salvage therapy for this population.

Methods and findings

This multicentre, single-arm, phase 2 study was done at twelve hospitals in China, to investigate the activity and safety of sorafenib plus VAH. Eligible patients were R/R AML with FLT3-ITD (aged 18-65 years) with an Eastern Cooperative Oncology Group performance status of 0-2. Patients received venetoclax (100mg on day 1, 200mg on day 2, and 400mg on days 3-14) and azacitidine (75 mg/m² on days 1-7) and homoharringtonine (1 mg/m² on days 1-7). Sorafenib (400 mg twice daily) was given on 1-14 during each course and continuously during maintenance.The primary endpoint was composite complete remission (CRc) after 2 cycles. Secondary outcomes included overall response rate (ORR), safety and survival.Between July 9, 2020, and March 19, 2022, 58 patients were assessed for eligibility, 51 of whom enrolled. Median age was 47 years (IQR 31-57). CRc was 76.5% with ORR of 82.4%. At a median follow-up of 10.3 months (IQR, 6.6-16.5), median duration of CRc was not reached (NR) overall survival was 18.1 months (95% CI, 12.2-NR) and event-free survival was 13.2 months (95% CI, 7.3-NR). The grade 3 or 4 adverse events occurring in ≥10% of patients included neutropenia in 47 (92·2%), thrombocytopenia in 41 (80.4%), anemia in 35 (68.6%), febrile neutropenia in 29 (56.9%), pneumonia in 13 (25.5%) and sepsis in 6 (11.8%) patients. Treatment-related death occurred in 2 (3.9%) patients.

Conclusions

Sorafenib plus VAH regimen is well tolerated and highly active for R/R AML with FLT3-ITD. This regimen might be a suitable therapeutic option for this population, and larger population trials are needed to be explored.
Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Acute Myeloid Leukemia Harboring KMT2A Rearrangement and Its Prognostic Factors
Authors: Jiang Bingqian , Zhao Yanmin , Luo Yi , Yu Jian , Chen Yi , Ye Baodong , Fu Huarui , Lai Xiaoyu , Liu Lizhen , Ye Yishan , Zheng Weiyan , Sun Jie , He Jingsong , Zhao Yi , Wei Guoqing , Cai Zhen , Huang He , Shi Jimin
Published: December 2023

Background: KMT2A rearrangement ( KMT2A-r) in patients with acute myeloid leukemia (AML) is associated with poor outcomes; the prognostic factors after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear.

Methods: We investigated 364 adults with AML who underwent allo-HSCT between April 2016 and May 2022, and 45 had KMT2A-r among them. Propensity score analysis with 1:1 matching and the nearest neighbor matching method identified 42 patients in KMT2A-r and non- KMT2A-r cohorts respectively.

Results: The 2-year overall survival (OS), relapse-free survival (RFS), cumulative incidence of relapse (CIR), and non-relapsed mortality (NRM) rates of patients with KMT2A-r were 59.1%, 49.6%, 41.5%, and 8.9%, respectively. With propensity score matching, the 2-year OS rate of KMT2A-r patients was lower than in those without KMT2A-r (56.1% vs. 88.1%, P=0.003), and in patients who achieved first complete remission (CR1), flow cytometry-based measurable residual disease (FCM-MRD) <1% and KMT2A-r negative before HSCT, the difference in the 2-year OS rate was reduced (71.5% vs. 93.9%, P=0.065). Patients with KMT2A-r exhibited the prognostic advantage from transplantation while in CR1 with FCM-MRD <1% and KMT2A-r negative which was reflected in OS, RFS, and CIR ( P<0.001, P<0.001, P=0.002, respectively). Besides, there were differences in OS, RFS, and CIR depending on KMT2A-r subtypes ( P=0.032, P=0.001, P=0.001, respectively). However, there was no difference regardless of the presence of mutations (all P>0.05). Univariate and multivariate analyses demonstrated that achieving CR1, FCM-MRD <1% and KMT2A-r negative before HSCT was a protective factor for OS (HR=0.242, P=0.007), RFS (HR=0.350, P=0.036), and CIR (HR=0.271, P=0.021), while AF6 was a risk factor for RFS (HR=2.985, P=0.028) and CIR (HR=4.675, P=0.004).

Conclusion: The poor prognosis of patients with KMT2A-r AML is associated with KMT2A-r subtypes, but not the presence of mutations. These patients can benefit from achieving CR1, FCM-MRD <1% and KMT2A-r negative before HSCT.
Double-Negative T Cells Attenuate Acute Graft-Versus-Host Disease By Modulating CD4 + T Cell Activation Post-Allo-HSCT
Authors: Pan Tianzhong , Huang Aijie , Tang Baolin , Song Kaidi , Sun Guangyu , Wu Yue , Wang Dongyao , Zhu Xiaoyu
Published: December 2023

Background: Acute graft-versus-host disease (aGVHD) is a major and life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Double-negative T cells (DNTs) have demonstrated potent cytotoxicity against various hematological tumors, and emerging evidence from animal experiments and clinical studies suggests their potential in predicting and treating aGVHD. Thus, DNTs may be a novel and versatile immunotherapy for aGVHD and relapse management post-allo-HSCT due to the function of harnessing the anti-leukemic effects and immune regulation. Nevertheless, the precise mechanisms underlying DNT-mediated aGVHD prevention remain unclear.

Results: In vitro, DNTs inhibited the proliferation of CD4 + T cells in a dose-dependent manner, and significantly inhibited the expression of CD25 on CD4 + T cells. CD4 + T cells inhibited by DNTs displayed decreased interleukin-2 secretion, reduced cell volume, nuclear condensation, and diminished mitochondrial number and volume. Transcriptome sequencing analysis verified significant downregulation of DNA replication, cell cycle, mitochondrial matrix metabolism, JAK-STAT, interleukin-17, and mitosis signaling pathways in CD4 + T cells co-cultured with DNTs. In addition, we found DNTs arrested CD4 + T cells at the G0/G1 phase, hindering their transition to the S phase, and inhibited CD4 + T cell proliferation by the CD25-JAK-STAT pathway. However, DNTs had no adverse effects on the activity and colony-forming capacity of allogeneic hematopoietic progenitor cells in vitro. Importantly, DNT infusion significantly improved the survival of mice in aGVHD model, reduced splenomegaly, downregulated CD25 expression on CD4 + T cells, and attenuated CD4 + T cell infiltration into host lungs, liver, and spleen, and effectively ameliorated organ damage (Figure 1).

Conclusion: Our findings suggest that DNTs attenuate acute aGVHD by affecting the proliferation and activation of CD4 +T cells via the CD25-JAK-STAT pathway, which is important to the prevention and management of aGVHD.
Retail Price of Imatinib Negotiated By Medicare Part D Plans with National or Regional Coverage at Large Chain and Mail Order Pharmacies
Authors: Kim Myung Sun (Sunny)
Published: December 2023

Title

Retail price of imatinib negotiated by Medicare Part D plans with national or regional coverage at large chain and mail order pharmacies

Background

Direct-to-consumer pharmacies or websites such as Cost Plus or GoodRx has made imatinib more affordable even without prescription drug coverage. Wholesale acquisition cost (WAC) or list price is often used to compare drug prices. However, the pharmacy retail price negotiated by prescription drug plans and pharmacies is more relevant to patient as it directly impacts out-of-pocket costs and affects decisions on how to acquire oral cancer medications. The price of imatinib for Medicare beneficiaries through different Part D prescription drug plans is variable and not well known.

Methods

Part D Plan Finder was used to identify Medicare drug' plans offered in Portland, OR at zip code 97239. The monthly retail price of imatinib 400 mg was compared for all available Part D plans for a representative list of nationwide and regional large chain pharmacies (Walgreens, CVS, Rite Aid, Safeway) and for mail order pharmacy. The premium and deductible for each drug plan was extracted. The highest and lowest retail price available for each drug plan and the drug cost for first, second and third fill for each retail price was extracted. This drug cost of imatinib was compared to the out-of-pocket cost of imatinib available from Cost Plus pharmacy and GoodRx in zip code 97239.

Results

Nine insurance companies offered 24 drug plans in July, 2023. The premium ranged from $1.6 to $113 and the deductible was $0 to $505. All insurance companies offered 2-3 plans with low premium/high deductible or high premium/low deductible. Plans were categorized to low deductible plans (less than $100), medium deductible plans ($100 to $300) and high deductible plans (more than $300). There were 19 high deductible plans. The median retail price was $4340 (IQR 945-5467). The median drug cost for the patient at first fill was $1464 (IQR 583-1745). There were 4 low deductible plans with median retail price of $823 (IQR 187-6419) and median drug cost at first fill of $275 (IQR 61-1971). There was one medium deductible plan and the retail price was $4374 and patient drug cost at first fill was $1425. The lowest retail price was $77 for Asuris Medicare Script Enhanced (PDP) if prescription was filled at Safeway. The highest retail price was $8881 for Elixir RxPlus (PDP) if prescription was filled at Safeway, CVS or Rite Aid. The monthly imatinib from Cost Plus is $33 (+$5 shipping). GoodRx offered coupons for Walgreens at $150, Rite Aid at $64, CVS at $789 and Safeway $90.

Conclusions

The retail price of imatinib for patients with Medicare Part D drug plan is highly variable depending on the drug plan and filling pharmacy and the out-of-pocket drug cost is often higher than the cost of buying imatinib at Cost Plus by mail order or at the same pharmacy using a GoodRx coupon.
Radiotherapy Consolidation Reduces Risk of Relapse in Diffuse Large B-Cell Lymphoma Patients with Bulky Disease in Complete Response after Frontline Immunochemotherapy: Results from a Retrospective Single Center Study
Authors: Benevolo Savelli Corrado , Novo Mattia , Vassallo Francesco , Evangelista Andrea , Bisio Matteo , Legato Luca , Peri Veronica , Clerico Michele , Levis Mario , Bartoncini Sara , Cavallin Chiara , Nicolosi Maura , Boccomini Carola , Orsucci Lorella , Cavallo Federica , Bruno Benedetto , Freilone Roberto , Ricardi Umberto , Botto Barbara
Published: December 2023

INTRODUCTION: The role of radiotherapy (RT) consolidation upfront in patients with diffuse large B-cell lymphoma (DLBCL) and bulky disease at diagnosis is controversial, especially in those in complete response (CR) after immunochemotherapy.

METHODS: All patients with DLBCL diagnosed between January 2010 and June 2021 at AOU Città della Salute e della Scienza di Torino and treated frontline with RCHOP-like regimens were retrospectively selected. Patients with primary mediastinal lymphoma were excluded. Clinical and biological features as well as treatment and survival data for the whole population were collected. All patients with bulky disease (defined as ≥6 cm) at diagnosis who obtained CR (defined as PET/TC Deauville score ≤ 3) at the end of systemic treatment were further selected. Progression free survival (PFS) and overall survival (OS) were compared between patients receiving consolidative RT on initial bulky mass and those who did not.

RESULTS: A total of 453 patients with DLBCL were identified. Median age was 68 years (IQR 58-77), 56% were males, 74% stage ≥3, 52% IPI ≥3. 140/451 (31%) had bulky disease at diagnosis. Median follow-up was 5 years. 5-year PFS and OS for the whole cohort were 59% and 66%, respectively. Bulky disease correlated with a significantly lower 5-year PFS (bulky 50% vs no bulky 64%, p = 0.0005) and OS (bulky 68% vs no bulky 60%, p = 0.01). 82 out of 140 patients with bulky disease (68/82 with a bulky ≥7 cm) were in CR after immunochemotherapy: 19/82 (23%) received RT (16/19 on bulky ≥7 cm), 63/82 (77%) did not (55/63 with a bulky ≥7 cm). There were no significant differences between the two groups regarding age, stage, ECOG PS, LDH levels, extranodal involvement and IPI. RT dose was 30 Gy in most patients (17/19); two patients received 36 Gy and 40 Gy. The 5-year PFS was 95% in the RT cohort and 58% in the no-RT cohort (p = 0.004); the 5-y OS was 95% in the RT cohort and 69% in the no-RT cohort (p = 0.038) (figure 1). A propensity score matching analysis confirmed the benefit of RT on PFS (HR 0.1, 95% CI 0.01-0.68, p = 0.019), and showed a non-statistically significant trend of better OS (p = 0.06). 14/24 relapses in the no-RT cohort occurred on the site of bulky disease.

CONCLUSIONS: With the limit of a non-randomized retrospective study, our data showed a benefit of RT consolidation on bulky disease in patients with DLBCL in RC after frontline immunochemotherapy, significantly prolonging PFS and with a trend of improved OS in a propensity score matching analysis.