Compassionate Basis Research Articles

État des lieux de la prise en charge de l’orbitopathie dysthyroidïenne modérée à sévère active en France à partir de 28 centres experts métropolitains

Introduction: This study investigates the management of Graves’orbitopathy (GO) in France, at 26 university medical centers (CHU) as well as the Rothschild Foundation and the Quinze-Vingts national eye hospital in Paris.Methods: The 28 metropolitan university medical centers were contacted by telephone or e-mail. The authors devised a 5-item questionnaire that explored the scheduling of multidisciplinary meetings, the existence or lack of a dedicated Graves’ consultation service, the place of hospitalization, and first- and second-line treatments.Results: 89% of hospital departments had a dedicated service for patients with GO, with 36% organizing multidisciplinary meetings. Intravenous corticosteroid therapy is still used as first-line treatment, while mycophenolate is used much less (14.3%), despite the new EUGOGO (European Group on Graves' orbitopathy) 2021 recommendations. For second-line treatment, tocilizumab is most commonly used (64%). Teprotumumab is available in France only on a compassionate basis, and its use is limited (18%).Conclusion: This study highlights the variability in practices and the importance of a multidisciplinary approach, while calling for national standardization of practices. Despite disparities in the application of recommendations, the emergence of second-line treatments such as tocilizumab and teprotumumab indicates a steady evolution in therapeutic options, although obstacles in terms of accessibility and cost remain.

Efficacy and Safety of Low-Dose Nivolumab in Treatment of Advanced Solid Tumors: A Retrospective Audit from Resource-Constrained Settings

Background Immunotherapy has improved outcomes in many advanced solid tumors. In resource-constrained settings, less than 2% of patients can afford standard dose immunotherapy. A recent phase II study showed the efficacy of low-dose immunotherapy in this setting. We used low-dose immunotherapy on a compassionate basis in patients who had progressed on available standard treatment options and standard dose immunotherapy was not feasible. Patients and Methods We retrospectively collected data from the medical oncology department for consecutive patients who had initially received standard lines of therapy followed by low-dose immunotherapy (nivolumab 40 mg) on a compassionate basis. The demographic details, histology, prior treatment, clinical and radiological response, date of disease progression, date of death, and toxicity data were collected. Results A total of 54 consecutive patients, who received low-dose immunotherapy with nivolumab from January 1, 2018 to February 14, 2020, were included in this analysis; 4 patients were not radiologically evaluable. The median age was 50.4 years (range 35–74 years), male:female ratio was 6:1. The most common comorbidities were hypertension and diabetes seen in 12 (22.2%) and 6 (11.1%) patients, respectively. The majority of the patients (70.4%) were of head and neck cancer. The median follow-up was 4.5 months (range 0.5–11.7). Clinical benefit was observed in 18 (33.3%) patients. Partial response and stable disease were achieved in 9 (16.7%) and 5 (9.3%) patients, respectively. Median survival was not reached for these patients. Six months progression-free survival and overall survival were 100 versus 8.7% (hazard ratio [HR] 0.05, 95% confidence interval [CI]: 0.01–0.36; p = 0.003) and 100 versus 29.7% (HR 0.03, 95% CI: 0.00–0.95; p = 0.047), respectively, for responders and nonresponders. The side effects were manageable. Conclusion In resource-constrained settings, low-dose immunotherapy with nivolumab seems to be an effective treatment option. Further studies are warranted to evaluate this approach.

Transcatheter Myotomy to Reduce Left Ventricular Outflow Obstruction

BackgroundLeft ventricular outflow tract (LVOT) obstruction is a source of morbidity in hypertrophic cardiomyopathy (HCM) and a life-threatening complication of transcatheter mitral valve replacement (TMVR) and transcatheter aortic valve replacement (TAVR). Available surgical and transcatheter approaches are limited by high surgical risk, unsuitable septal perforators, and heart block requiring permanent pacemakers. ObjectivesThe authors report the initial experience of a novel transcatheter electrosurgical procedure developed to mimic surgical myotomy. MethodsWe used septal scoring along midline endocardium (SESAME) to treat patients, on a compassionate basis, with symptomatic LVOT obstruction or to create space to facilitate TMVR or TAVR. ResultsIn this single-center retrospective study between 2021 and 2023, 76 patients underwent SESAME. In total, 11 (14%) had classic HCM, and the remainder underwent SESAME to facilitate TMVR or TAVR. All had technically successful SESAME myocardial laceration. Measures to predict post-TMVR LVOT significantly improved (neo-LVOT 42 mm2 [Q1-Q3: 7-117 mm2] to 170 mm2 [Q1-Q3: 95-265 mm2]; P < 0.001; skirt-neo-LVOT 169 mm2 [Q1-Q3: 153-193 mm2] to 214 mm2 [Q1-Q3: 180-262 mm2]; P < 0.001). Among patients with HCM, SESAME significantly decreased invasive LVOT gradients (resting: 54 mm Hg [Q1-Q3: 40-70 mm Hg] to 29 mm Hg [Q1-Q3: 12-36 mm Hg]; P = 0.023; provoked 146 mm Hg [Q1-Q3: 100-180 mm Hg] to 85 mm Hg [Q1-Q3: 40-120 mm Hg]; P = 0.076). A total of 74 (97.4%) survived the procedure. Five experienced 3 of 76 (3.9%) iatrogenic ventricular septal defects that did not require repair and 3 of 76 (3.9%) ventricular free wall perforations. Neither occurred in patients treated for HCM. Permanent pacemakers were required in 4 of 76 (5.3%), including 2 after concomitant TAVR. Lacerations were stable and did not propagate after SESAME (remaining septum: 5.9 ± 3.3 mm to 6.1 ± 3.2 mm; P = 0.8). ConclusionsWith further experience, SESAME may benefit patients requiring septal reduction therapy for obstructive hypertrophic cardiomyopathy as well as those with LVOT obstruction after heart valve replacement, and/or can help facilitate transcatheter valve implantation.

Therapeutic advances in neuroinfectious diseases.

There have been several major advances in therapeutic options for the treatment of neurological infections over the past two decades. These advances encompass both the development of new antimicrobial therapies and the repurposing of existing agents for new indications. In addition, advances in our understanding of the host immune response have allowed for the development of new immunomodulatory strategies in the treatment of neurological infections. This review focuses on the key advances in the treatment of neurological infections, including viral, bacterial, fungal, and prion diseases, with a particular focus on immunomodulatory treatment options. This review also highlights the process by which clinicians can request access to therapeutic agents on a compassionate or emergency basis when they may not be commercially available. While many therapeutic advances have been achieved in the past several years, there remains a pressing need for the continued development of additional therapeutic agents in the treatment of neurological infections.

Emergency and Compassionate Use of a Novel Ascending Endograft for Ascending and Arch Aortic Pathology.

Patients with complicated ascending aortic pathology, including patients with acute type A aortic dissection may be at extreme risk for open repair. Thoracic endovascular aortic repair (TEVAR), infrequently used for the ascending aorta, may be considered an alternative in this setting. We describe early results for emergency and compassionate (E&C) use of a novel endograft, specifically designed for use to treat pathology of the ascending aorta. This case series evaluated 19 patients (mean age, 68.84±13.12 years; 57.9% female) treated with ascending TEVAR for acute and chronic acute (4), subacute (1), or chronic (1) aortic dissection or pseudoaneurysm (13). Six of the 19 patients (31.5%) were treated under compassionate use and 13 patients (68.4%) were treated under the emergency use exemption. Ten patients (52.6%) received additional devices to extend treatment into the arch and descending aorta. Device delivery was achieved in all patients (100%). Thirty-day mortality and stroke occurred in 3 patients (15.8%) and in 1 patient (5.3%), respectively. In 1 patient (5.3%), with an Unanticipated Adverse Device Event, the aorta ruptured when the endograft eroded into the adventitial portion of dissection site at the posterior aspect of the ascending wall. Devices were explanted in 2 patients (10.5%), 353 and 610 days after the index procedure, respectively. Six patients had endoleaks (31.6%), including type I (n=2, 10.5%), type II endoleaks (n=3, 15.8%), and indeterminate endoleak (n=1, 5.3%). Delivery and deployment of a novel ascending thoracic stent graft with or without an additional branched arch extension is feasible in patients with complex anatomy and pathology, including acute aortic dissection and pseudoaneurysm. Additional experience with this novel device will further refine the patient population most suitable for endovascular ascending aortic repair for these pathologies. This study describes a novel stent graft specifically designed for treatment of ascending aortic pathology, including acute type A dissection. The patients described in this series constituted a group outside the formal US FDA sponsored clinical trial, and were those accepted as part of an emergency and compassionate use basis.

Treatment of systemic juvenile idiopathic arthritis.

Systemic juvenile idiopathic arthritis (sJIA) is an inflammatory disease with hallmarks of severe systemic inflammation, which can be accompanied by arthritis. Contemporary scientific insights set this paediatric disorder on a continuum with its counterpart, adult-onset Still disease (AOSD). Patients with sJIA are prone to complications, including life-threatening hyperinflammation (macrophage activation syndrome (sJIA-MAS)) and sJIA-associated lung disease (sJIA-LD). Meanwhile, the treatment arsenal in sJIA has expanded markedly. State-of-the-art therapeutic approaches include biologic agents thattarget the IL-1 and IL-6 pathways. Beyond these, a range of novel agents are on the horizon, some of them already being used on a compassionate use basis, including JAK inhibitors and biologic agents thattarget IL-18, IFNγ, or IL-1β and IL-18 simultaneously. However, sJIA, sJIA-MAS and sJIA-LD still pose challenging conundrums to rheumatologists treatingpaediatric and adult patients worldwide. Although national and international consensus treatment plans exist for the treatment of 'classic' sJIA, the treatment approaches for early sJIA without arthritis, and forrefractory or complicated sJIA, are not well defined. Therefore, in this Review we outline current approaches for the treatment of sJIA and provide an outlook on knowledge gaps.

Phage Therapy in Lung Transplantation: Current Status and Future Possibilities.

Patients with chronic lung disease and lung transplantation have high rates of colonization and infection from multidrug-resistant (MDR) organisms. This article summarizes the current state of knowledge regarding phage therapy in the setting of lung transplantation. Phage therapy has been used in several lung transplant candidates and recipients on a compassionate use basis targeting mostly MDR gram-negative infections and atypical mycobacterial infections with demonstrated clinical safety. Phage biodistribution given intravenously or via nebulization has not been extensively studied, though preliminary data are presented. Phage interacts with both the innate and adaptive immune system; current literature demonstrates the development of serum neutralization in some cases of phage therapy, although the clinical impact seems variable. A summary of current clinical trials involving patients with chronic lung disease is presented, though none are specifically targeting lung transplant candidates or recipients. In addition to treatment of active infections, a variety of clinical scenarios may benefit from phage therapy, and well-designed clinical trials involving this vulnerable patient population are needed: pre- or peritransplantation use of phage in the setting of MDR organism colonization may lead to waitlisting of candidates currently declined by many centers, along with potential reduction of waitlist mortality rates and posttransplant infections; phage may be used for biofilm-related bronchial stent infections; and, finally, there is a possibility that phage use can affect allograft function and chronic rejection.

Use of Ponatinib Alone or Combined with Other Therapies in Relapsed/Refractory Ph-like Acute Lymphoblastic Leukemia. a Campus ALL Real-Life Study

Introduction. Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) employed in relapsed/refractory (R/R) and, more recently, also in newly diagnosed Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Ph-like ALL is a genetically heterogenous subgroup that shares a common transcriptional profile, similar to that of true Ph+ ALL, though lacking the BCR::ABL1 rearrangement. Ph-like ALL is characterized by a poor prognosis, a high relapse rate and a worse overall survival if treated with standard chemotherapy. Several molecular pathways are involved, including JAK/STAT, CRLF2 and ABL-class mutations, providing a heterogeneous genetic landscape with very limited data on the subsequent clinical outcome. Few isolated cases of successful treatment of R/R Ph-like ALL with ponatinib have been reported, including also patients with lesions different from ABL-class mutations. Currently, ponatinib prescription in Italy is not allowed for Ph-like ALL. Patients and Methods. Between January 2019 and July 2023, 17 patients were candidate to receive ponatinib on a nominate compassionate use basis; data were collected in the context of the Campus ALL network in Italy. The criteria for inclusion were a diagnosis of Ph-like ALL, with either hematological or molecular evidence of disease, and a treatment period of at least 28 consecutive days of ponatinib. The Ph-like signature was based on the BCR/ABL1 like-predictor (Chiaretti et al, BJH 2018) and, whenever possible, targeted RNA sequencing. Final data were collected for 15 patients (2 patients were excluded due to a treatment period &amp;lt;28 days) treated with ponatinib either as a single agent or in association with immuno and/or chemotherapy. Results. All patients had common ALL. Eight of the 15 cases were classified as high risk or very high risk ALL at diagnosis; 10 were males, the median age was 28 years (14-66) and the median white blood count at diagnosis was 25.6 x10 9/l (2.7-317 x10 9/l). Targeted RNA sequencing was carried out in 10/15 cases: 7 presented gene fusions ( ABL-class mutations in 2, JAK2 mutations in 2, and CRLF2::P2RY8, IKZF1::DDC and RB1::RCBTB2 in 1 case each); 2 additional cases had a CRLF2 rearrangement, evaluated by FISH. Copy number aberrations analysis by multiplex ligation-dependent probe amplification (MLPA) technology was performed in 12/15 cases: 5 cases had a IKZF1 plus signature, 6 had a IZKF1 loss, while 1 case was IKZF1 wild type. Ponatinib was started in first (n=2) or second (n=5) hematologic relapse in 7 patients (46%), with 3 also having an extramedullary disease; 7 additional patients (46%) were treated in first (n=5) or second (n=2) minimal residual disease (MRD) persistence/recurrence; finally, 1 patient was refractory to 3 subsequent lines of treatment. In 8/15 patients ponatinib was used as single agent or in association with steroids or intrathecal chemotherapy only, in 4 it was administered in combination with chemotherapy and in 3 with blinatumomab; 7 patients started ponatinib after having failed an allogeneic transplant (6 hematologic relapses and 1 molecular relapse). A complete hematological and molecular remission (MRD- CR) was achieved in 6 patients (40%); notably, 4 of these 6 cases carried a gene fusion (1 JAK2 rearrangement, 1 ABL-class fusion, 1 IKZF1::DDC and 1 RB1::RCBTB2); 2 further patients in hematologic relapse at the start of treatment achieved a MRD+ CR (1 patient had a ABL-class gene fusion). Thus, the overall response rate was 53%. Four patients were refractory, while 2 maintained a stable disease. After ponatinib-based treatment, 6 patients were allografted and 1 received a CAR-T cell infusion. The toxicity profile was mild: 3 patients developed a transaminitis, 1 also had a fungal pneumonia, and 1 an increase in pancreatic enzymes. At a median follow-up of 3 months (1-5), 10 patients are alive, 8 being in continuous complete remission. Conclusions. Treatment with ponatinib showed promising results in terms of CR achievement in a heavily pre-treated population of Ph-like ALL patients, with an acceptable toxicity profile. In a pre-transplant setting, ponatinib was effective as a bridge to cellular therapies in 7 out of 8 patients as intention-to-treat (ITT), thus suggesting that this strategy may represent an effective bridge to further therapies. To our knowledge, this is the largest cohort of adult Ph-like ALL cases treated with ponatinib so far reported.

Compassionate Use of Emapalumab in Children with Life-Threatening Disorders: Real-World Data

Introduction: Life threatening hyperinflammation occurs in hemophagocytic lymphohistiocytosis (HLH) and during acute rejection of hematopoietic stem cell (HSC) grafts. Both conditions reflect acute activation of the immune system, in part due to overproduction of proinflammatory cytokines, particularly interferon gamma (IFNγ). Emapalumab, a fully human monoclonal antibody that binds to IFNγ, is approved by the FDA for refractory or recurrent primary HLH (pHLH) or in patients intolerant to conventional therapy. Off-label use of emapalumab has been reported for treatment of secondary HLH (sHLH) and for HSC graft rejection. The European Medicines Agency did not approve emapalumab for the treatment of HLH and many other regulatory authorities, including the Israeli Ministry of Health, have yet to approve emapalumab for clinical use. Pending such regulatory approval, emapalumab is available in Israel exclusively though the Managed Access Request Program (MAP) on a compassionate basis sponsored by Sobi (Swedish Orphan Biovitrum AB,Reg. no. 556038-9321). Experience that accumulates through on- and off-label use of emapalumab obtained via MAP enriches the knowledge base regarding the uses of this drug in the real-world clinical setting. Methods: We summarized the data of patients receiving emapalumab at our tertiary pediatric center. The medication was received after application to the MAP sponsored by Sobi International with import approval of the Israel Ministry of Health on a named-patient basis. Results: Seven patients (Pt) aged 2.5 months-17.5 years were treated with emapalumab between 3/2020-6/2023. Patients 1-5 fulfilled HLH-2004 diagnostic criteria. Indications for the use of emapalumab included treatment of HLH in a newborn with severe hepatotoxicity after treatment with the standard HLH-94 protocol (Pt. 3), treatment of acute graft rejection with recurrence of HLH in a patient with pHLH (Pt.1), secondary HSC graft failure and disease relapse in a child with pHLH (Pt. 4), sHLH with multi-organ failure (MOF) requiring extracorporeal membrane oxygenation (ECMO) (Pts 2&amp;5) and HSC primary graft rejection with suspected 2 nd rejection (Pts.6&amp;7). Table 1 summarizes the clinical characteristics of all cases. The patient outcomes were closely related to their clinical status at treatment initiation. Pt.3 was able to reach remission and successfully bridge to SCT without complications after only 4 doses of VP-16 with continuation therapy using only dexamethasone and emapalumab. Pt.4, who experienced relapsed pHLH with concomitant HSC graft loss, attained complete remission with emapalumab, dexamethasone and IVIG, facilitating a successful second HSC graft. Pt. 1 expired after initial graft failure, severe sepsis and relapse of pHLH. Pts. 2&amp;5, despite showing improvement of their HLH criteria after treatment with emapalumab, succumbed to MOF that was already present when they were referred to our center for ECMO support. Following unsuccessful emapalumab treatment for primary graft rejection, Pts. 6&amp;7 underwent successful 2 nd HSC transplants with early emapalumab treatment for suspected re-rejection. Conclusions: Emapalumab is a safe, effective, and well tolerated treatment for various HLH scenarios, and for similar hyper-inflammatory medical conditions. Administration of emapalumab early in the disease course is likely to be more effective as compared to administration of the drug when MOF has occurred or when the HSC graft has already been rejected. Since these diseases are life-threatening, eliminating delays in procurement of emapalumab is essential to expedite treatment before irreversible organ failure ensues.

Feasibility of a Novel Academic Anti-BCMA Chimeric Antigen Receptor T-Cell (CART) (HBI0101) for the Treatment of Relapsed and Refractory AL Amyloidosis

BACKGROUND: While anti-BCMA chimeric antigen receptor T-cell therapy (CART) have proven safe and efficient in multiple myeloma (MM), its application to AL amyloidosis (AL), has been restricted due to the frailty of this population and rarity of disease. HBI0101 therapy is a novel anti-BCMA CART-based therapy developed at Hadassah Medical Center and Bar-Ilan University for MM treatment. In a phase Ia-b/2 study (NCT04720313), HBI0101 has demonstrated manageable safety with therapeutic efficacy in over 70 MM patients. Although BCMA targeting in AL has been questioned because of relatively low expression of this antigen on AL plasma cells (PC), we have previously reported that this level of expression is sufficient to enable PC eradication by HBI0101 CART ex vivo. Based on this observation, we have treated 9 AL patients in our study, which represent the largest cohort of AL treated with anti-BCMA CART reported so far. METHODS: The patients were treated within the following cohorts: 1 received 150x10^6 CART cells, 2 received 450x10^6 CART cells and 6 received 800x10^6 CART cells. Two of the patients were treated on a compassionate basis due to concomitant myelodysplastic syndrome (MDS) / ECOG 4 performance status. Patients with creatinine clearance ≥30ml/min (n=7) received lymphodepletion with fludarabine 25mg/m 2 and cyclophosphamide 250mg/m 2 on days -5 to -3 before infusion, and patients with creatinine clearance &amp;lt;30ml/min (n=2) received lymphodepletion with bendamustine 90mg/m 2 and on days -4 and -3 before infusion. Two patients with NYHA stage 3 and MAYO stage 3b AL-related heart failure were admitted electively to the intensive care unit before infusion for close monitoring. RESULTS: Nine AL patients with relapsed/refractory disease were included, with a median of 6 prior lines of therapy (range: 3-10), all refractory to their last line of therapy. All patients were triple refractory to PI, IMiD and anti-CD38 antibody, 6 were penta-refractory and 5 were refractory to the anti-BCMA antibody drug conjugate belantamab mafodotin. Seven had cardiac involvement, including 4 with MAYO-stage 3a/3b at study entry. Hematologic adverse events included: grade 3-4 neutropenia in 5 patients, Grade 2-3 anemia in 3 patients, and worsening of pre-existing thrombocytopenia to grade 4 in 1 patient. Three patients developed AL-related organ deterioration (kidney- 2, heart- 1), subsequently resolved to baseline function. Cytokine-released syndrome (CRS) was observed in 7/9 (grade 1-2- 5 patients; grade 3- 2 patients). None of the patients developed immune effector cell-associated neurotoxicity syndrome (ICANs). There were no treatment-related deaths. Eight out of nine patients were evaluable for efficacy (one patient has not yet completed the first post-treatment evaluation). The overall hematological response rate was 100%, including complete responses in 5 patients, very good partial responses in 2, and partial response in 1 patient. Minimal residual disease (MRD) negativity based on flow cytometry 10^-5 was achieved in 5/8. Best hematological response was achieved after 17 to 57 days (median- 28.5 days). The hematologic responses translated into clinical improvement in all patients, whereas 6/8 met the official criteria for organ responses. With a median follow-up of 7.3 months (range: 2.5-16.5), the median duration of response thus far is 5m (range: 2.5-16.5). Updated results will be communicated at the presentation time. CONCLUSION: In the largest cohort of AL patients treated with CART reported to date, we demonstrated acceptable toxicity in this frail population, with a remarkable hematologic efficacy, leading to organ responses in most participants. Our data suggests that anti-BCMA CART modality may become a powerful clinical tool to improve organ function and survival, even in advanced AL patients.

Программы раннего доступа лекарственных препаратов: опыт БРИКС, Европейского Союза, Соединенных Штатов Америки

Timely accessibility of effective and safe medicinal products is one of the main tasks of healthcare. The goal of the present review is to assess various approaches that provide an early access to medicinal products within the BRICS group (list of participants as of 01.10.2023), European Union and United States of America. The stage of the life cycle of medicinal products is closely associated with their further movement in the market, patient access rate, and partially with the issues of their financing and reimbursement, which directly influence their affordability for population. The article contains data about the specifics of expanded access to unregistered medicinal products used on a compassionate basis and presenting therapy under early access programs financed by pharmaceutical companies; it also describes approaches to accelerated registration and registration of medicinal products in case of limited clinical data. Experience of the reviewed countries in early access programs is described.

Transforming Perspectives in Cardiac Cell Therapy: Hypothesis and Commentary Following Updated Results of a Pilot Study Investigating Very Long-Term Clinical Outcomes in Severe AMI Patients Following Trans-Epicardial Injection of Peripheral Blood CD34+ Cells

Ischemic heart attack is the leading cause of death worldwide. Ten percent of cases will die within an hour. Of the survivors, around 30% will have suffered a severe infarction which will lead to the irreparable destruction of 1 to 2 billion myocardial cells, causing an irreversible secondary heart failure with a poor prognosis in the short. The heart is a totally differentiated organ with a very low capacity for self-regeneration. No current treatment can prevent this fatal outcome, but only slow it down. For these reasons, cell therapy has generated enormous hope, but achieved somewhat disappointing results, depending on the type/source of cells which were used. From the end of 2002, our group conducted a Pilot study using immuno-selected autologous peripheral-blood (PB) CD34+ cells in a small cohort of patients who had experienced a heart attack with poor prognosis. Three of these patients were immediately considered for heart transplant but lacked a readily available donor. CD34+ cells were trans-epicardially delivered at the end of a coronary artery by-pass graft (CABG) operation without reperfusing the ischemic area, which was performed on a compassionate basis. All but one patient showed a marked and sustained improvement in their cardiac function parameters from the baseline values, associated with both cardiac tissue repair and revascularization, as demonstrated by PetScan examination. The patients’ outcomes have been recently updated. Six out of seven patients have survived in good enough conditions for at least 12 years after cell therapy, including those three initially recommended for heart transplant and who have avoided it. Presently, five out of seven patients are still alive with an average follow-up of 17 years (range 16–20 years), which is very unusual after CABG for patients with such a poor initially prognosis.Graphical

An analysis of sintilimab combined with ruxolitinib as compassionate therapy for 12 adults with EBV-associated hemophagocytic lymphohistiocytosis.

Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a severe hyperinflammatory illness that affects adults and is caused by an EBV infection. Without allogeneic hematopoietic stem cell transplantation (allo-HSCT), the overall survival of adult patients with EBV-HLH is unsatisfactory, necessitating the development of innovative therapeutic approaches. The clinical records of twelve EBV-HLH patients who received sintilimab therapy combined with ruxolitinib on a compassionate basis at the First Affiliated Hospital of Soochow University were retrospectively examined in this investigation. All the patients responded without fever, but three patients relapsed within a week. Among the nine patients achieving complete response (CR), 55.6% (5/9) maintained CR for >4.5 months, and 33.3% (3/9) relapsed following CR. Neither patients with no response (NR) nor relapsed patients were fit for allo-HSCT, and all died soon after discharge. Six patients had clinical CR with a median follow-up of 5 (4.4-14.7) months. There were no documented severe negative effects. Additional information on this innovative treatment for adult EBV-HLH is provided in our report.

A H3K27M-targeted vaccine in adults with diffuse midline glioma.

Substitution of lysine 27 to methionine in histone H3 (H3K27M) defines an aggressive subtype of diffuse glioma. Previous studies have shown that a H3K27M-specific long peptide vaccine (H3K27M-vac) induces mutation-specific immune responses that control H3K27M+ tumors in major histocompatibility complex-humanized mice. Here we describe a first-in-human treatment with H3K27M-vac of eight adult patients with progressive H3K27M+ diffuse midline glioma on a compassionate use basis. Five patients received H3K27M-vac combined with anti-PD-1 treatment based on physician's discretion. Repeat vaccinations with H3K27M-vac were safe and induced CD4+ T cell-dominated, mutation-specific immune responses in five of eight patients across multiple human leukocyte antigen types. Median progression-free survival after vaccination was 6.2 months and median overall survival was 12.8 months. One patient with a strong mutation-specific T cell response after H3K27M-vac showed pseudoprogression followed by sustained complete remission for >31 months. Our data demonstrate safety and immunogenicity of H3K27M-vac in patients with progressive H3K27M+ diffuse midline glioma.

HGG-05. PERTURBING GABAERGIC NEURONAL LINEAGE IN DIFFUSE HEMISPHERIC GLIOMA, H3G34-MUTANT, HIGHLIGHTS CDK6 AS A CLINICALLY ACTIONABLE TARGET

Abstract Diffuse hemispheric gliomas, H3G34R/V-mutant (DHG-H3G34), are uniformly lethal malignancies with currently no targeted therapies available. They exclusively occur in the cerebral hemispheres of adolescents and young adults, and have been linked to a distinct interneuronal lineage of origin. The developmental spectrum and functional role of this interneuronal lineage in DHG-H3G34 remain incompletely understood. Here, through integrating bulk and single-cell multi-omics with genome-wide CRISPR-Cas9 screens, we resolve a putative cellular hierarchy that follows a continuum of interneuronal lineage development, ranging from a self-renewing progenitor-like cell to a more differentiated cell resembling early immature GABAergic interneurons, along with quiescent astrocyte-like and mesenchymal-like cells. We validate these single-cell states in patient DHG-H3G34 tissue sections by multiplexed immunofluorescence, and describe spatial structures that resemble nests of early migratory interneurons surrounded by progenitor cells, characteristic of human embryonal interneuron development. Intriguingly, we reveal the majority of CRISPR-Cas9 screen-derived gene dependencies are upregulated in interneuronal lineage tumor cells, specifically in less differentiated progenitor-like cells, highlighting these as a driver of DHG-H3G34. We validate the essentiality of these interneuronal lineage associated targets in patient-derived in vitro and in vivo models, and highlight CDK6 as a druggable target selectively upregulated in DHG-H3G34. Inhibition of CDK6 leads to a decrease of undifferentiated progenitor-like signatures, reduced tumor growth, and prolonged survival of patient-derived xenograft models. Encouraged by these findings, we treated a patient upon a second relapse of a DHG-H3G34 with ribociclib on a compassionate use basis, who, as of the time of submission, has shown stable disease within four cycles of ribociclib treatment after progression on PCV chemotherapy. In sum, we reveal CDK6 inhibition as a rationally informed and clinically actionable therapeutic avenue that selectively perturbs the unique interneuronal lineage in DHG-H3G34, paving the way for rapid clinical translation.

Hydroxychloroquine sulfate: A novel treatment for lipin-1 deficiency?

BackgroundLipin-1 deficiency is a life-threatening disease that causes severe rhabdomyolysis (RM) and chronic symptoms associated with oxidative stress. In the absence of treatment, Hydroxychloroquine sulfate (HCQ) was administered to patients off label use on a compassionate basis in order to improve their physical conditions. MethodsEleven patients with LPIN1 mutations were treated with HCQ. Clinical and biological efficacy and tolerance were assessed, including pain and quality of life, physical capacities, cardiopulmonary parameters, creatine kinase levels and plasma proinflammatory cytokines. To explore a dose-dependent effect of HCQ, primary myoblasts from 4 patients were incubated with various HCQ concentrations in growth medium (GM) or during starvation (EBSS medium) to investigate autophagy and oxidative stress. FindingsUnder HCQ treatment, patient physical capacities improved. Abnormal cardiac function and peripheral muscle adaptation to exercise were normalized. However, two patients who had the highest mean blood HCQ concentrations experienced RM. We hypothesized that HCQ exerts deleterious effects at high concentrations by blocking autophagy, and beneficial effects on oxidative stress at low concentrations. We confirmed in primary myoblasts from 4 patients that high in vitro HCQ concentration (10 µM) but not low concentration (1 µM and 0.1 µM) induced autophagy blockage by modifying endolysosomal pH. Low HCQ concentration (1 µM) prevented reactive oxygen species (ROS) and oxidized DNA accumulation in myoblasts during starvation. InterpretationHCQ improves the condition of patients with lipin-1 deficiency, but at low concentrations. In vitro, 1 µM HCQ decreases oxidative stress in myoblasts whereas higher concentrations have a deleterious effect by blocking autophagy.

Managing Patient and Clinician Expectations of Phage Therapy in the United Kingdom.

Bacteriophage (phage) therapy is a promising alternative antimicrobial approach which has the potential to transform the way we treat bacterial infections. Phage therapy is currently being used on a compassionate basis in multiple countries. Therefore, if a patient has an antibiotic refractory infection, they may expect their clinician to consider and access phage therapy with the hope of improvement. The expectations of clinicians may be similar and may also include expectations around data collection. However, there are multiple biological and practical barriers to fulfilling patient and clinician expectations. While it is possible to access phage therapy, the path to acquisition is not straightforward and expectations therefore need to be managed appropriately to avoid raising false hope and undermining confidence in phage therapy. Phage scientists have an important contribution to make in educating clinicians and the broader public about phage therapy. However, it is clinicians that are responsible for managing the expectations of their patients and this relies on clear communication about the barriers and limitations.

Proteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia

Rearrangments in Histone-lysine-N-methyltransferase 2A (KMT2Ar) are associated with pediatric, adult and therapy-induced acute leukemias. Infants with KMT2Ar acute lymphoblastic leukemia (ALL) have a poor prognosis with an event-free-survival of 38%. Herein we evaluate 1116 FDA approved compounds in primary KMT2Ar infant ALL specimens and identify a sensitivity to proteasome inhibition. Upon exposure to this class of agents, cells demonstrate a depletion of histone H2B monoubiquitination (H2Bub1) and histone H3 lysine 79 dimethylation (H3K79me2) at KMT2A target genes in addition to a downregulation of the KMT2A gene expression signature, providing evidence that it targets the KMT2A transcriptional complex and alters the epigenome. A cohort of relapsed/refractory KMT2Ar patients treated with this approach on a compassionate basis had an overall response rate of 90%. In conclusion, we report on a high throughput drug screen in primary pediatric leukemia specimens whose results translate into clinically meaningful responses. This innovative treatment approach is now being evaluated in a multi-institutional upfront trial for infants with newly diagnosed ALL.

Phage Therapy for Nontuberculous Mycobacteria: Challenges and Opportunities.

Non-tuberculous mycobacterium (NTM) infections are often clinically challenging, with lengthy antibiotic regimens that fail to resolve the infections with few good outcomes remaining. Mycobacteriophages-viruses that infect Mycobacterium hosts-show promise as therapeutic agents for NTM infections and have been used in 20 compassionate use cases. Favorable outcomes were observed in many but not all cases, although the phages show exceptional safety profiles and no evidence of phage resistance was observed, even when only a single phage was administered. Phage-specific antibodies are commonly present following intravenous administration and are often neutralizing for the phage in vitro. However, phage neutralization does not consistently correlate with poor treatment outcomes and may not be a therapeutic limitation in all patients, even when immunocompetent. Currently, the therapeutic potential of phages is substantially limited by the great variation in phage susceptibility and a relatively small repertoire of therapeutically useful phages. As many as 45% of clinical isolates can have a smooth colony morphotype, and phages that both efficiently infect and kill these strains have yet to be described. In contrast, ~ 75% of rough strains are susceptible to and killed by one or more phages and therapeutic options can be considered on a compassionate use basis. Although therapies must currently be personalized, elucidating the determinants of phage host specificity, expanding the useful phage repertoire, and identifying the key determinants of clinical outcomes will reveal their full therapeutic potential.

Human monkeypox outbreak: Epidemiological data and therapeutic potential of topical cidofovir in a prospective cohort study

Human monkeypox has become increasingly frequent worldwide since the outbreak was first reported in May 2022. As cidofovir is effective against vaccinia and other Orthopoxvirus diseases, we hypothesize that its topical use could be an effective treatment for monkeypox skin lesions, avoiding the adverse effects of systemic administration. We conducted a prospective study to collect data on the clinical and virologic course of patients with monkeypox. All patients were offered symptomatic treatment. They were also offered treatment with topical cidofovir on a compassionate use basis. Twelve patients received treatment with topical cidofovir 1%, while the others received only symptomatic treatment. Prospective visits were scheduled for the collection of clinical and virological data. Lesions cleared quicker in the cidofovir-treated group (hazard ratio, 4.572; P=.0039). The median time to resolution was 12 (11.5-15) and 18 (16-21) days, respectively. On day 14, polymerase chain reaction-positive skin lesions were detected in 10% of the cidofovir sample, compared with 62.5% of the non-treated group (P= .019). Local adverse effects were frequent (50%), especially in the anogenital region. No systemic adverse effects were reported. The study is not a clinical trial and lacks a placebo-controlled arm. Topical cidofovir is a potentially relevant therapy in patients with skin lesions but mild systemic involvement. Reducing time to resolution could shorten isolation time and improve the cosmetic impact in areas such as the face.