Previous Therapies Research Articles

Treatment outcome of the tyrosine kinase inhibitor (bosutinib) in previously treated chronic myeloid leukemia patients (sample of Iraqi patients)

Abstract: BACKGROUND: Chronic myeloid leukemia (CML) is a type of myeloproliferative neoplasm characterized by the excessive accumulation of malignant myeloid cells in the bone marrow and peripheral blood. This condition is primarily triggered by a specific chromosomal translocation known as t(9;22) (q34.13;q11.23), which leads to the formation of the BCR-ABL fusion gene. The treatment landscape for CML has undergone significant changes with the approval of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 kinase activity. One such inhibitor is bosutinib, which has been available for several years to treat patients with chronic, accelerated, and blast-phase CML who have shown resistance or intolerance to previous therapies. OBJECTIVES: The aim of this study was to assess efficacy and safety of Bosutinib as a 2nd line therapy in CML patients, in addition to effect of adherence to treatment on patients response. PATIENTS AND METHODS: Eighty-five patients with CML were enrolled in a prospective cohort study from October 2021 to October 2022 at Hematology Center in Medical City Complex – Baghdad. All patients failed to at least one TKI, and all of them started escalated dose of bosutinib. The patients were followed-up by assessing molecular and cytogenetic response at 3 and 6 months and monitored carefully for adverse events (AEs) which were graded by common terminology IX criteria for AEs version 5. Adherence to bosutinib was also monitored by a specific adherence scale to optimize the response rate to treatment. RESULTS: The mean age of patients was 47.3 ± 14.9 (range: 18–77), with male:female ratio 1.4:1. Status of CML patients showed that 89.4% were in the chronic phase, 5.8% in accelerated phase, and 4.7% in blast phase. Regarding the number of previous TKIs before bosutinib, 72.9% of patients failed to prior one TKI (imatinib). At 6 months (72.3%), patients achieve optimal response according to European Leukemia Net criteria 2013. Gastrointestinal symptoms and dermatological manifestations were the most common nonhematological AEs of bosutinib. According to 9-item Morisky Medication Adherence Scale, 42% of patients were adherent to medication which showed a significant association with a higher number of optimal response (P = 0.0001). CONCLUSION: Bosutinib is effective with a high and promising response as a subsequent line treatment in CML patients, and it is generally safe and associated with mild-to-moderate tolerable and manageable AEs. Adherence to the drug plays a significant role in optimal response to bosutinib.

Peripheral Nerve Stimulation With High-Frequency Electromagnetic Coupling at the Sural and Posterior Tibial Nerves for the Treatment of Complex Regional Pain Syndrome in Lower Extremities: Case Report

BACKGROUND: Complex regional pain syndrome (CRPS) type 1 is a debilitating condition that is notoriously difficult to treat due to its various manifestations. Peripheral nerve stimulation (PNS) is generally recommended when a patient’s symptoms are refractory to conservative measures, as CRPS often is. We present one case of CRPS with intractable lower extremity pain managed effectively with PNS. CASE REPORT: A 32-year-old man developed CRPS after a work-related accident that resulted in multiple injuries, including a crushed pelvis, injured left lower extremity, and a fractured face and skull. After pelvic and hip reconstruction, the patient was left with numbness, tingling, and pain in the left foot affecting functional activities and sleep. Previous therapies, including nerve blocks, physical therapy, narcotics, opioids, anticonvulsants, antidepressants, and nonsteroidal anti-inflammatory drugs, did not alleviate symptoms. The placement of a PNS device, however, led to significant improvement. RESULTS: Pain scores at baseline compared to 12-month follow-up decreased from 6/10 to 2/10 at rest and from 8/10 to 4/10 with activity. Average hours of sleep per night increased from 4 to 8 hours (an improvement of 100%). Antidepressants have been discontinued and opioids reduced to an as-needed basis (once every few days). The patient reports decreased sensitivity to cold, reduced swelling, and improved color changes in the foot. In addition, the patient has been able to increase activity, such as walking, standing, and wearing closed-toed shoes, from 20 minutes to now 4 hours at a time with pain levels maintained at a 4/10. CONCLUSIONS: Subthreshold PNS utilizing high-frequency electromagnetic coupling at the posterior tibial and sural nerves successfully relieved the patient’s chronic, debilitating pain in the lower extremity as a result of CRPS. KEY WORDS: Peripheral nerve stimulation, chronic pain, posterior tibial, sural, CRPS, lower extremity, foot

Long-term outcomes of cyclosporin induction and ustekinumab maintenance combination therapy in patients with steroid-refractory acute severe ulcerative colitis.

Effective management of patients with acute severe ulcerative colitis (ASUC) is a major challenge and there remains a paucity of available maintenance treatment options after efficacious cyclosporin induction therapy. We investigated the long-term effectiveness and safety of cyclosporin and ustekinumab combination therapy in patients with steroid refractory ASUC. Monocentric, prospective study. We included patients with steroid refractory ASUC with multiple failed prior advanced therapies, who were treated with cyclosporin and ustekinumab combination therapy. Among the 11 included patients, 10 had prior failure to infliximab and 8 failed at least three previous biological therapies. The mean baseline Mayo and Lichtiger scores were 10.9 (9-12) and 13.3 (11-14), respectively. Ustekinumab was initiated 3.2 weeks (1-8) after initiation of cyclosporin treatment and combination therapy was continued for a mean of 11.5 (4-20) weeks. Clinical response was achieved in six patients at week 16 and clinical steroid-free clinical remission in five patients at week 48. Endoscopic remission was achieved in five patients at week 16 and together with histological remission in five patients at week 52. Intestinal ultrasound demonstrated mean bowel wall thickening in the sigmoid colon of 5.5 mm at baseline and 3.5 mm at week 52, respectively. Two patients had to undergo colectomy (mean 4.5 months, range 3-6) and three stopped ustekinumab therapy due to ineffectiveness. Overall, combination therapy was well tolerated. Combination of cyclosporin and ustekinumab therapy allowed nearly half of ASUC patients to reach clinical and endoscopic remission after 52 weeks, warranting further studies. Not applicable.

Anastomotic Leakage after Gastrectomy for Gastric Cancer.

Anastomotic leakage (AL) constitutes a prominent cause of significant morbidity following gastrectomy for gastric cancer. The manifestation of AL typically occurs within 7 to 10 days post-surgery, with reported incidence rates of 5.8-6.7% for open gastrectomy and 3.3-4.1% for laparoscopic gastrectomy. Various predisposing risk factors have been identified, including the individual nutritional status (excluding obesity) and preoperative corticotherapy. Interestingly, the administration of neoadjuvant therapies appears to reduce the AL occurrence. In the context of distal gastrectomies, the rates of AL are comparable between laparoscopic, robotic, and open approaches. The total gastrectomies have higher AL rate compared to distal gastrectomies, which are considered the preferred approach. Prophylactic drainage measures have not demonstrated efficacy in preventing AL. As for postoperative management, conservative treatment is indicated for patients presenting with mild clinical symptoms and increased inflammatory blood tests. This approach involves fasting, enteral or parenteral nutrition, administration of antibiotics, and percutaneous drainage. For small AL, endoscopic therapies such as stents, vacuum therapy, clips, suturing devices, and injections are appropriate treatment options. In cases of high-volume fistulas, severe sepsis or failure of previous therapies, surgical reoperation becomes the ultimate solution.

MOLECULAR BIOLOGY AND DRUG THERAPIES OF CHRONIC MYELOID LEUKEMIA: A REVIEW OF RECENT LITERATURE

Background: Chronic myeloid leukaemia (CML) is a clonal myeloproliferative disorder of blood stem cells, which is typically characterized by the presence of a Philadelphia chromosome. Even though there have been several studies on the molecular genetics, pharmacogenomics, pharmacological treatments for CML, and its mechanism is still not fully understood. Objectives: This study is designed to provide new updates and better insights into CML molecular biology and drug therapy, along with their benefits and drawbacks. Methodology: For this review, the recent literature was searched from January 2019 to 2023 through various electronic databases. Results: Review findings further suggested that imatinib mesylate was the first tyrosine kinase inhibitor (TKI) licensed as first-line therapy for affected people with CML in the chronic, blast, and rapid phases. Dasatinib is another second-generation multi-target kinase inhibitor, for imatinib-resistant CML treatment in all stages, which is 325 times more effective than imatinib and 16-fold more effective than nilotinib. Nilotinib received approval from the Food and Drug Administration (FDA) for handling imatinib-resistant patients. Bosutinib and ponatinib are other renowned TKIs taken orally. European Medicine Agency (EMA) and FDA-approved asciminib in moderate to severe, rapid, and blast-phase CML patients intolerant to previous therapies. Conclusion: In conclusion, this study indicated the need to include advanced computational tools in addition to the large sample size of cohort studies, which may result in a better understanding of pathophysiology and better clinical outcomes.

Precision cardiac targeting: empowering curcumin therapy through smart exosome-mediated drug delivery in myocardial infarction.

Nanoparticle-mediated drug delivery has emerged as a highly promising and effective therapeutic approach for addressing myocardial infarction. However, clinical translation tends to be a failure due to low cardiac retention as well as liver and spleen entrapment in previous therapies. Herein, we report a two-step exosome delivery system, which precludes internalization by the mononuclear phagocyte system before the delivery of therapeutic cardiac targeting exosomes (ExoCTP). Importantly, curcumin released by ExoCTP diminishes reactive oxygen species over-accumulation in ischemic myocardium, as well as serum levels of lactate dehydrogenase, malonyldialdehyde, superoxide dismutase and glutathione, indicating better antioxidant capacity than free curcumin. Finally, our strategy was proven to greatly potentiate the delivery and therapeutic efficacy of curcumin without systemic toxicity. Taken together, our smart exosome-mediated drug delivery strategy can serve either as therapeutics alone or in combination with other drugs for effective heart targeting and subsequent wound healing.

Real-world experience of baricitinib in atopic dermatitis: including add-on therapy for patients using dupilumab.

Little real-world experience regarding the use of baricitinib, an oral selective JAK1/JAK2 inhibitor, for treating moderate to severe atopic dermatitis (AD) has been reported. This study aimed to assess the overall outcomes in Korean patients with AD treated with baricitinib. All patients with moderate to severe AD treated with baricitinib between June 2021 and June 2022 were included, and their cases were retrospectively analyzed using medical records. Patients with moderate to severe AD, aged ≥18 years who had failed previous therapies, including those who demonstrated unsatisfactory improvement with dupilumab, were prescribed baricitinib. Patients whose follow-up period was <8 weeks were excluded. The dermatologist evaluated the AD status, including eczema area and severity index (EASI), itch Numeric Rating Scale, and improvement of remaining lesions despite dupilumab therapy. We analyzed 34 AD patients who received baricitinib. Twelve patients treated with dupilumab were additionally prescribed baricitinib due to unsatisfactory treatment effects and demonstrated improvement in the remaining lesions despite dupilumab treatment. Their itching improved after 1.4 weeks. Among them, eight patients (66.7%) had head and neck dermatitis, and seven of them demonstrated improvement after the coadministration of baricitinib. Among the other 22 patients who were prescribed baricitinib only, 10 patients (45.5%) achieved EASI 75 at 8 weeks, with five (22.7%) revealing EASI 90. Overall, baricitinib was well tolerated and resulted in clinical improvement in AD patients in a real-world clinical setting. Additionally, baricitinib may be beneficial in treating lesions refractory to dupilumab therapy.

Daratumumab for autoimmune diseases: a systematic review

ObjectiveRefractory autoimmune diseases remain a significant challenge in clinical practice and new therapeutic options are needed. This systematic review evaluates the existing reported data on the CD38-targeting antibody daratumumab as...

Abstract LB_A14: Factors associated with enrollment, participation, and survival of patients on early phase cancer clinical trials

Abstract Background: Enrollment and participation of a diverse patient (pt) population for early phase clinical trials is crucial for determining the safety and efficacy of new cancer therapies. However, strict eligibility criteria, co-occurring conditions, and socioeconomic barriers can limit pt participation. Improving methods of pt recruitment, enrollment, and support while on clinical trials has the potential to accelerate trial accrual and diversity within trial cohorts. Methods: We conducted a retrospective chart review of oncology pts seen by the Early Phase Clinic Trials Unit (EPTU) at the Mount Sinai Hospital between July 2018 and October 2022. Pts had advanced solid tumors and had already received standard of care treatment. Data including demographics, cancer diagnosis, clinical trial enrollment, and overall survival (OS) were obtained from the electronic medical record. Demographic and clinical differences were compared between patients who enrolled on an early phase trial (T) and those who did not (NT). Univariable logistic regression was used to determine predictors of successful trial enrollment. Univariable Cox proportional hazards models were conducted to analyze factors associated with survival time on trial treating death of any cause as the outcome and censoring pts lost to follow-up or alive at trial termination. Results: 261 referrals were evaluated representing 234 unique patients. Of these, 60 pts (25.64%) enrolled in a clinical trial. No significant differences were found between T and NT pts in gender, race, ethnicity, language, or insurance status. In univariable logistic regression, number of previous systemic therapies was inversely associated with likelihood of going on trial (OR 0.87 95% CI [0.75, 1.00] p= 0.045). Pts with skin cancer had a higher likelihood of going on trial compared to those with other tumor types (OR 4.57 95% CI [1.27, 18.4] p=0.021). Of T patients, 27 (45.00%) were White, 8 (13.33%) were Black, 9 (15.00%) were Asian, and 12 (20.00%) were Hispanic; 12 (20.00%) did not speak English. The median time between initial appointment and Day 1 on trial was 0.67 months. Median length of time on trial was 2.07 months, and median OS from enrollment was 4.16 months (IQR [2.21, 8.16]). In univariable Cox regression, an ECOG PS of 1 compared to 0 was associated with increased risk of death (HR 1.91 95% CI [1.01, 3.61] p=0.050). Both Spanish speaking and all non-English speaking T pts had an increased risk of death compared to English speaking T pts (HR 5.09 95% CI [2.00, 12.19]; HR 2.34 95% CI [1.04, 5.25]). Conclusion: There were no significant demographic barriers to trial enrollment. However, times on trial and overall survival were modest, with the latter associated with poorer performance status. Given their increased risk of death, more support is needed for non-English speaking patients who participate on early phase trials. Citation Format: Elena Baldwin, Grace Van Hyfte, Natalie Lucas, Kathy Wu, Gary Shelton, Suzan Aird, Grace Chung, Gabriela Fazilov, Lisa Fitzgerald, Olivia Hapanowicz, Khadijah Holley, Paula King, Ashley Lu, Nathasha Melukkaran, Miriam San Lucas, Issamar Urena, Aleksandra Wawrzyniak, Marshall Posner, Matthew D Galsky, Thomas U Marron, Deborah B Doroshow. Factors associated with enrollment, participation, and survival of patients on early phase cancer clinical trials [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A14.

Comparative Efficacy of Ciltacabtagene Autoleucel Versus Elotuzumab, Isatuximab, and Selinexor-Based Regimens in the Treatment of Patients with Relapsed or Refractory Multiple Myeloma with 1-3 Prior Lines of Therapy Using a Matching-Adjusted Indirect Comparison

Introduction: Ciltacabtagene autoleucel (cilta-cel; Carvykti) was assessed in the phase 3 randomized controlled trial CARTITUDE-4 for adult patients with relapsed and refractory multiple myeloma (RRMM) who have received 1-3 prior line(s) of therapy (LOT) that included an immunomodulatory agent (IMiD), and a proteasome inhibitor (PI) and are refractory to lenalidomide. Other therapies used to treat patients with multiple myeloma who have received at least one other therapy and are lenalidomide-refractory vary by country, but broadly include doublet and triplet regimens based on daratumumab, pomalidomide, bortezomib, and carfilzomib. This analysis aims to compare efficacy outcomes in patients randomized to the cilta-cel arm of CARTITUDE-4 versus relevant comparators based on their target trial populations. Methods: Comparators for the matching adjusted indirect comparisons (MAICs) were identified a priori based on regimens used in the target population including; SVd, EloPd, IsaKd, DKd, DVd, Kd, Vd, Pd, and Ide-cel. PVd and DPd were not of interest given their inclusion in the CARTITUDE-4 trial. Melflufen+d, PanVd, VenVd, PCd, IxaKd, D-monotherapy, V-monotherapy, CyVd, and DVCd were not of interest for the US, EU-5, the Netherlands, and Canada. A systematic literature review identified publications of relevant clinical trials for these treatments, which were assessed for feasibility of an indirect treatment comparison. Feasibility was determined based on study design and degree of overlap with the CARTITUDE-4 population (prior LOT, lenalidomide-refractoriness, and exclusion criteria around previous therapies, i.e., prior daratumumab). We report here on comparisons vs. EloPd (ELOQUENT-3), IsaPd (ICARIA-MM), and SVd (BOSTON). Due to differences in methods for the comparisons versus ide-cel (KarMMa-3) and versus DKd, Kd, DVd, Vd, and Pd, these are reported separately. Comparison to IsaKd was not feasible due to a lack of published data in the lenalidomide-refractory subgroup (baseline characteristics and efficacy data), and key differences in exclusion criteria. Given the lack of a common comparator between CARTITUDE-4 and the comparator trials, unanchored MAICs were performed utilizing individual patient-level data (IPD) from patients randomized to the cilta-cel arm of CARTITUDE-4 (N=208). The eligibility criteria from each of the comparator trials were applied to the cilta-cel IPD, and outcomes for the matched population were compared against published summary data for EloPd (N=60), IsaPd (N=154), and SVd (N=195) using reconstructed IPD for response endpoints and simulated IPD from published Kaplan-Meier (KM) curves for progression-free survival (PFS). Further imbalances in patient characteristics were adjusted by weighting the cilta-cel data to match the reported baseline characteristics of the comparator trials in terms of refractory status, cytogenetic risk, ISS stage, and presence of extramedullary disease. Comparative efficacy was estimated for overall response rate (ORR), very good partial response or better (≥VGPR) rate, complete response or better (≥CR) rate, and PFS. For binary endpoints, relative effects were quantified using relative response ratios (RRs) with 95% confidence intervals (CIs) derived from a weighted logistic regression analysis. For PFS, HRs including 95% CIs were estimated using a weighted Cox proportional hazards model. Results: After adjustment, patients in the cilta-cel arm were significantly more likely to achieve an overall response than patients in EloPd or IsaPd arms, and to achieve ≥VGPR and ≥CR versus patients in all other comparators arms ( Table 1). In addition, cilta-cel was associated with a significant reduction in the risk of disease progression or death (PFS) versus all comparators, ranging from 39% (versus SVd) to 68% (versus IsaPd) ( Table 2). Conclusions: Cilta-cel demonstrated clinical benefit over EloPd, IsaPd, and SVd for response outcomes and PFS, highlighting its potential as an effective treatment option for patients with RRMM who have received at least one other therapy and are lenalidomide-refractory. These comparisons provide valuable information to contextualize the efficacy of cilta-cel in countries where treatment for these patients may be different from DPd or PVd.

A Novel Dual Kinase Inhibitor for the Treatment of Chronic Graft Vs. Host Disease

Chronic Graft vs. Host Disease (cGvHD) remains a major debilitating and potentially fatal sequelae of allogeneic hematopoietic cell transplantation. Corticosteroids remain the initial therapy of clinically significant cGvHD. Since 2017 three targeted therapies have been approved for steroid refractory cGVHD, ruxolitinib, a JAK 1/2 inhibitor, is approved post one or two previous therapies. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, and belumosudil, a ROCK2 inhibitor, are both approved after two previous lines of therapy. We tested RR- RR-1752 a single digit nM dual ROCK/AURK inhibitor in a mouse model of severe cGVHD. BALB/c recipient mice were preconditioned with 7.5 Gy TBI, 8 hours later they received 10 7 T-cell depleted (TCD) C57BL/6 bone marrow cells alone (Group A, n=7) or 10 7 TCD C57Bl bone marrow cells plus 10 6 splenocytes (Groups B, n=8 and C, n=8). Beginning day 7 post cell infusion animals received either oral vehicle control (groups A and B) or vehicle with 1.0 mg/kg RR-1752 (Group C) daily. Body weight, alopecia score and eye score were monitored 3×/week through day 56 or until termination. All animals in groups B and C developed signs and symptoms of chronic graft vs. host disease. Animals in group A exhibited 20% weight loss through seven days post irradiation and cell infusion but began to recover to baseline and recovered weight to 90% of baseline. Animal weights in groups B and C dropped to less than 80% at day seven post irradiation, but only recovered to 80.38% +/- 10.18 (Group B) and 87.11% +/- 7.90 (Group C) on day 14 and then declined to 74.10% +/- 4.19 in Group B and 80.23% +/- 7.35 in Group C by day 28 (Figure 1). Animals in Group A had no significant change in eye score or alopecia. In contrast all animals in groups B and C showed signs of cGvHD. Eye showed moderate effects in Group B and mild changes in group C, while alopecia scores were moderate in both groups B and C. All animals in group A survived through day 56, median survival in group B was 16.5 days, as compared to 38 days in group C (Figure 2). In a separate study in normal mice, RR-1752 given at 1.0 mg/kg/day for 2 weeks showed no negative effects on hemoglobin, hematocrit, platelets, total WBC, or neutrophils, and only a mild decrease in lymphocytes. Using a model for cGVHD, exhibiting weight loss, alopecia, and ocular changes, we demonstrated that RR-1752 1.0 mg/kg/day slows mouse body weight loss, increases survival and shows trends to ameliorate ocular toxicity. The dose tested did not ameliorate the alopecia in the cGVHD mice. Further studies are ongoing to assess higher dose levels and dose schedule effects in the severe cGVHD mouse model. Additional studies to compare effects on cGVHD to ruxolitinib and belumosudil and in combination with those standard of care therapies need to be conducted.

CPX-351 with Venetoclax in Patients with Relapsed/Refractory Acute Myeloid Leukemia: Results of a Phase Ib Study

Introduction: Relapsed/refractory acute myeloid leukemia (rAML) remains a significant challenge, with low response to therapy and poor long-term survival. Treatments focusing on achieving a response and, in eligible patients (pts), proceeding with an allogeneic stem cell transplantation (alloSCT) offer the best prospect for improved survival. CPX-351 is a liposomal fixed-ratio formulation of cytarabine and daunorubicin, which has demonstrated higher response rates and reduced early mortality in some subsets of AML and has also been shown to be active in rAML. The BCL2 inhibitor venetoclax (Ven) has demonstrated efficacy in AML in combination with other agents, such as hypomethylating agents, low dose cytarabine, and intensive chemotherapy. We conducted a Phase Ib/II dose-finding study to evaluate the combination of CPX-351 with Ven in AML. Herein we present the results of CPX-351 plus Ven in the cohort of rAML pts treated on study (NCT03629171). Methods: The study was designed with a safety lead-in phase to establish the safe dose and schedule in R/R AML, followed by 2 expansion cohorts to explore efficacy in (1) R/R AML and (2) frontline AML. Prior Ven use was allowed for pts with R/R AML. The dose of CPX-351 was fixed : daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 IV on days 1, 3 and 5 of induction, and daunorubicin 29 mg/m2 + cytarabine 65 mg/m IV on days 1 and 3 during consolidation. The starting effective dose of Ven was 300mg (at the -1 dose level) on D2-21 for the safety lead-in cohort with appropriate dose adjustment for concomitant CYP3A inhibitors. First, interruption of Ven after D14 was implemented if a D14 bone marrow was hypocellular and without evidence of leukemia. However, a second de-escalation was required (-2 dose level) with Ven given on day 2-8 of each cycle, and daunorubicin dose reduced to 22 mg/m2 during consolidation. This was found to be the recommended phase 2 dose. Results: Between 11/2018 to 1/2022, 33 pts were enrolled. The median age was 53 yrs (range, 26-72) and 61% were female. Diploid karyotype was present in 7 pts (21%), core binding factor rearrangements in 2 (6%), MECOM rearrangement in 2 (6%) and 13 (39%) had a complex karyotype. The most frequent mutations were DNMT3A (37%), TP53 (21%) and NRAS (21%). 8 (24%) pts had secondary AML including 4 (12%) with prior HMA exposure; the median number of prior lines of myeloid-directed therapies was 1 (1-7), including 58% of them with a previous exposure to Ven. Pts received a median of 1 cycle (1-4), and the median number of cycles to first response was 1 (1-2). The ORR was 45% (15/33), with 5 patient (15%) achieving CR, 8 (24%) achieving CRi and 2 (6%) achieving MLFS. The ORR was higher in those pts with only one prior line of therapy (59%) compared to those with 2 or more previous therapies (31%). The ORR for pts with prior exposure to Ven was 37% (7/19) vs 57% (8/14) for those not previously exposed to Ven (p=0.4). The 4- and 8-week mortality was 9 and 21%. 9/15 pts (60%) underwent alloSCT including 14 with CR/CRi/MLFS and 1 pt with an aplastic bone marrow insufficient for response assessment. The most frequent grade 3 or more adverse events were infections (45%, 30% of them pulmonary), febrile neutropenia (24%), and mucositis/stomatitis (6%). Three deaths occurred on study (2 due to sepsis and 1 due to cardiac arrest), all after one cycle of therapy. Other grade 3-4 events registered included rash (6%), cerebrovascular accident (6%), and intracranial hemorrhage (3%). After a median follow-up time of 20.7 months, the OS at 12 and 24 months was 34% and 25%, respectively. The median OS was 6.4 months. The EFS at 12 and 24 months was 26% and 19%, respectively. The median EFS was 2.8 months. For those who achieved response, the 2-year cumulative incidence of relapse and death without relapse were 41% and 28%, respectively. For those who underwent alloSCT, the median OS after alloSCT was 24 months, with 4 deaths after alloSCT, all following disease relapse. Conclusion: In this phase Ib dose escalation study, standard dose CPX-351 combined with 7 days of Ven was found to safe and tolerable in pts with rAML. The combination produced encouraging response rates in a poor risk population, including those with prior Ven treatment, allowing a significant proportion to undergo allo-SCT and extended survival. The RP2D is being studied in pts with newly diagnosed and less heavily pretreated AML.

Efficacy and Safety of Axicabtagene Ciloleucel (Axi-cel) for the Treatment of Relapse/Refractory Non-Hodgkin Lymphoma: Real-World Data in Chinese Population

Background: Autologous CD-19 directed chimeric antigen receptor (CAR) T-cell therapy has become the standard of care of patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) who have received two or more prior lines of therapy. In June 2021, Axi-cel was approved by the China National Medical Products Administration (NMPA) for the treatment of these patients as the first commercial CAR-T product in China. To better understand the efficacy and safety of commercial Axi-cel in Chinese R/R NHL patients in a real-world setting, we conducted this multi-center, non-interventional study (ChiCTR2100047990). The accrual goal is 200 patients, and the primary endpoint is mOS. Here we made the pre-specific interim analysis and the reported the clinical outcomes. Methods: We included R/R NHL patients treated with commercial Axi-cel at 17 authorized treatment centers from November 2021 to February 2023. All the patients signed written informed consent. We reported best objective response rate (bORR), best complete response (bCR) rate and adverse events of special interest (AESI), including cytokine release syndrome (CRS) and neurological events (NE). Results: To the cut-off date of June 8, 2023, a total of 101 R/R NHL patients had undergone efficacy evaluation at month 3. The median age of patients was 56.5 (22, 80) years, with 23 patients (22.8%) aged 65 years or older. Fifty-nine patients were male. The baseline characteristics of these patients included 81 (80.2%) with diffuse large B-cell lymphoma, 4 (4.0%) with primary mediastinal B-cell lymphoma, and 7 (6.9%) with high-grade B-cell lymphoma. More than 50% of patients had an International Prognostic Index (IPI) score ≥3. The median number of prior treatment was 2. Thirty-eight patients (37.6%) had received 3 or more previous therapies and 10 patients (9.9%) had undergone autologous stem cell transplantation (ASCT). The primary refractory subgroup reached 46 (45.5%), and 41(40.6%) patients were refractory to second-line or subsequent therapy. Notably, compared to the baseline characteristics of Axi-cel real-world studies for R/R LBCL in other countries, a greater proportion of Chinese patients had an ECOG PS score ≥2 (32.7%), HBsAg (+) with normal HBV-DNA (23.1%), HBsAg (-) accompany with HBcAb (+) (37.1%). Bridging therapy was given in 73 patients (72.3%), while combination anti-lymphoma therapy was used after Axi-cel infusion and before disease progression in 52 patients (51.5%). The median follow-up was 12.7 months. The bORR and bCR rate was 83.2% (95%CI, 74.4 - 89.9) and 63.4% (95%CI, 53.2 - 72.7), respectively (Fig 1). The bORR was consistent across covariates including disease type, cell of origin and refractory subgroup, ECOG PS score ≥2, HBsAg (+) and normal HBV-DNA, and HBsAg (-) accompany with HBcAb (+), etc.. The median duration of response (DOR) was 13.7 months (95% CI, 11.1 - NA). mDOR was not reached in bCR patients (95% CI, 11.2 - NA), while patients with best response as PR have a median DOR as 4.7 months (95% CI, 1.8- 6.7). Median progression-free survival (PFS) was 14.6 months (95% CI, 7.6 - NA). Patients with ECOG PS score ≥2 had a shorter median PFS [7.6 months (95%CI 3.0 - NA)] compared to patients with PS 0-1 [14.6 months (95%CI 12.1 - NA)]. Median PFS also differed among patients based on their response at month 3. Patients with CR/PR/non-response at month3 had a median PFS of NR (95% CI, 12.1 - NA), NR (95%CI, 6.1 - NA) and 3.0 months (95%CI, 2.4 - 3.3), respectively (Fig 2). The median OS was not reached, and the estimated OS at 12 months was 80.4% (95%CI, 70.5 - 87.2). No new safety signals were observed in the Chinese population. The most common adverse events of grade ≥3 were decreased white blood cell count (82.2% of patients), neutropenia (81.3%) and lymphocytopenia (68.2%). CRS of any grade occurred in 90 patients (84.1%), with 15 patients (14.0%) experiencing grade ≥3. NE of any grade occurred in 27 patients (25.2%), with only 1 patient (0.9%) experiencing grade 4. No grade 5 CRS or NE appeared. Conclusions: This pre-specific interim analysis demonstrated the consistent efficacy of Axi-cel in Chinese R/R NHL patients, while NE of any grade and ≥grade 3 were lower. Similar to the result of the ZUMA-1 study, response at month 3 may predict PFS in Chinese R/R NHL patients treated with Axi-cel in real-world practice.

Trial in Progress: An Open Label Phase I/II, Multicenter Study Evaluating Safety, Pharmacokinetics and Efficacy of S65487, a BCL-2 Inhibitor Combined with Azacitidine in Adults with Previously Untreated Acute Myeloid Leukemia Ineligible for Intensive Treatment

Preclinical and clinical data support combining Bcl-2 inhibitors (Bcl-2i) with hypomethylating agents (HMAs) in the treatment of acute myeloid leukemia (AML). S65487, a potent intravenous Bcl-2i, has shown promising synergistic activity when combined with azacitidine against in vitro AML models. Based on those data, we initiated a Phase I/II multicenter study of S65487 combined with azacitidine for newly diagnosed patients aged 18 years or older with de novo or secondary AML ineligible for intensive chemotherapy in 6 countries in Europe and Asia (NCT04742101). Secondary AML was defined as those related to previous leukemogenic therapies or transformed from a myelodysplastic syndrome. Patients with AML originating from myeloproliferative disorders were excluded. Ineligibility to intensive chemotherapy was defined as age of at least 75 years or the presence of significant co-morbidities. Previous use of HMA was allowed in the first six dose levels tested in the Phase I portion of the study, but was excluded afterwards, including during the Phase II part. Other eligibility criteria were standard for this patient population. Each cycle of therapy lasts for 28 days. Subcutaneous or intravenous azacitidine is administered at a dose of 75mg/m 2 in 7 consecutive administrations per cycle starting on day (D) 1 with a 2-day interval during weekends. Three schedules of S65487 are planned to be tested during the Phase I part to increase its concurrent administration with azacitidine and their synergism. Schedule 1 consists of weekly administrations (doses on D1, 8, 15, and 22). Two more intensified schedules consist of S65487 administration on D1, D3, D5, D8 (schedule 2) or D1 through D5, D8, and D9 (schedule 3) on the same days of azacitidine dosing. S65487 is administered over 30 minutes. When administered on the same day, S65487 is given first followed by azacitidine within 30 to 60 minutes. Treatment should be discontinued due to disease progression, or if other standard withdrawal criteria are met. The Phase I portion of the study follows a standard design guided by an adaptive Bayesian Logistic Regression Model with overdose control to estimate the maximum tolerated dose (MTD) based on the occurrence of dose-limiting toxicities during cycle 1. Patient accrual for the Phase I portion of this study is ongoing. The planned testing of schedule 1 is limited due to the expected low synergism with azacitidine. Once the recommended Phase II dose (RP2D) or MTD are established for schedules 2 and 3, the Phase II part will start and will be comprised of a maximum of two cohorts, each containing up to 27 patients. A Bayesian optimal design based on complete remission rate will guide the Phase II. Interim futility analyses are planned after enrollment of 10 and 20 evaluable patients. Randomization will not be used to allocate patients to one of the two cohorts planned during the Phase II portion of the study. The primary objective during the Phase I is to determine the safety, tolerability, and the RP2D or MTD of S65487 in combination with azacitidine. The primary objective of the Phase II is to assess the efficacy of this therapy. Pharmacokinetic analyses are included as secondary objectives in both parts of the study. Measurable residual disease will be assessed as a secondary objective in the Phase II part using a well validated, standard flow-cytometry panel. Pharmacodynamic analyses are conducted as exploratory objectives in both parts of the study. In particular, the disruption of the BCL2/BIM complex is followed in peripheral-blood mononuclear cells to guide the estimation of the RP2D.

A Phase Ib, Open-Label Study of Add on Therapy with CK0804 in Participants with Myelofibrosis and Suboptimal Response to Ruxolitinib

Background: JAK2 inhibitor ruxolitinib leads to improvements in symptom burden and spleen volume in patients with myelofibrosis (MF), but suboptimal response represents a major unmet clinical need. Deregulated inflammatory pathways including CXCR4/CXCR12 axis might limit the therapeutic efficacy of ruxolitinib and contribute to disease progression ( Miwa et al. Pathology. 2013), where agents targeting bone marrow (BM) inflammation could be promising. Adoptive therapy with allogeneic, cord blood-derived regulatory T cells (Tregs) (CK0801- HLA 3/ 6 match, fresh infusion) showed safety and early clinical signal in MF ( Kadia et al., Blood. 2020). In preclinical studies, the next generation product, CK0804, consisting of CXCR4 enriched Tregs [CK0804] shows preferential homing to BM and decrease inflammatory cytokines including TGFα, TNFβ, IL-13 and TGFβ when compared to unmanipulated control Treg cells ( Huang et al., Cytotherapy, 2023). Methods:This phase Ib study evaluates the safety and activity of CK0804 (non-HLA matched, Cryopreserved, Multi-Dose) Treg therapy in patients with suboptimal response to ruxolitinib. The study design consists of a safety run-in phase of 9 patients followed by an expansion of additional 15 patients. Participants will continue ruxolitinib and receive infusion of CK0804 at a fixed dose of 100 million Treg cells every 28 days up to 6 cycles. All patients are monitored for 6 months following the last infusion. Patients with MF on ruxolitinib for ≥12 weeks and stable dose for ≥8 weeks, who have palpable splenomegaly, symptoms or grade 2 cytopenia are eligible. Primary objective is safety, secondary objective includes overall response per IWG-MRT criteria at 24 weeks. Exploratory objectives evaluate pharmacodynamics, pharmacokinetics, markers of immunogenicity and inflammation. Results: As of 1 st of July 2023, 5 patients were enrolled and treated with a median age of 68 years [range 60-78], 60% males (table). Median number of previous MF therapies was 1.5 (range 1-4), median duration of previous ruxolitinib therapy was 38 months (range, 10-132). At enrollment, all patients were symptomatic with median MPN-SAF TSS of 35 (range, 24-40), 3 patients had worsening splenomegaly and 3 patients were transfusion dependent. All patients had grade 2+ reticulin marrow fibrosis with most also having significant collagen or osteosclerosis, 40% were JAK2 V617F mutated and 80% had additional co-mutations (table). Two (2) patients received all six (6) doses of CK0804, two patients have ongoing treatments: one patient received 5 doses and one patient received 3 doses. One patient has withdrawn consent after receiving 2 doses. This patient experienced an infusion reaction to her second dose of CK0804 likely due to the excipient dimethylsulfoxide (DMSO) used for cryopreservation of cells. All other patients tolerated their infusions well with no adverse reactions. No hematologic adverse events were observed. Ruxolitinib dose remained unchanged in all patients throughout the study. Among the three (3) patients who were transfusion dependent, two (2) were evaluable for response. Their monthly transfusion requirements by the end of the sixth (6 th) cycle improved from the baseline value of four (4) units and 1.2 units to 2.8 and 0.8 units, respectively. Spleen volume at four (4) months assessment (3 patients) remained stable. MPN-SAF TSS showed improvement in all patients on therapy, although it requires longer follow-up (figure). Correlative studies including longitudinal analysis of inflammatory cytokines and immune reconstitution will be presented at the conference. Conclusion: The preliminary analysis of this study evaluating CK0804 (CXCR4 enriched T regs cell therapy) as addition to ruxolitinib shows initial safety with no myelosuppressive adverse events and promising clinical activity. The study is actively enrolling participants (NCT05423691). MD Anderson Cancer Center has an institutional conflict of interest with Cellenkos related to the research presented herein. Institutional Conflict of Interest Management and Monitoring Plan is being implemented with respect to MD Anderson Cancer Center's conduct of this research.

Use of a Tissue-Targeting Recombinant Human Interleukin-22 Fusion Molecule (F-652) for the Treatment of Advanced Refractory Lower GI Acute Gvhd

Background: Steroid-refractory (SR) gastrointestinal acute GVHD (GI aGVHD) is a serious complication after allogeneic hematopoietic transplantation (allo-HCT), and subsequent lines of treatment following steroid failure are often ineffective. The JAK 1/2 inhibitor ruxolitinib is the only FDA-approved treatment for SR aGVHD, and patients for whom ruxolitinib is not effective or not tolerated have limited therapeutic options and high mortality. Interleukin-22 (IL-22) is a tissue-protective IL-10-family cytokine that has been shown to support intestinal mucosa after damage, directly signaling to the intestinal epithelium and promoting its survival, regeneration, and production of innate antimicrobial molecules. F-652, a recombinant human (rh)IL-22 fusion protein composed of an IL-22 dimer and IgG2 Fc fragment, has recently been studied in a phase 2 trial for patients with newly diagnosed lower GI aGVHD, demonstrating a promising day 28 treatment response rate and improved gut microbial health. Given this, we examined F-652 administration in 3 patients with severe SR GI aGVHD. Methods: Three patients with hematologic malignancies underwent MUD allo-HCT with tacrolimus and methotrexate GVHD prophylaxis ( Table). The patients were initially treated for GI aGVHD with methylprednisolone at a dose of 2 mg/kg/day without response. All patients presented with or progressed to stage 4 gut aGVHD and failed several lines of therapy, including ruxolitinib. All patients also had multiple episodes of bacteremia and at least some degree of GVHD-associated GI bleeding. F-652 treatment was initiated under single-patient-use authorization as the 5 th-7 th line of therapy and was administered at a dose of 45 mcg/kg IV weekly. In vitro cultures suggested that rho kinase inhibition did not interfere with trophic effects of IL-22 on intestinal epithelium, so patients were permitted to continue belumosidil upon F-652 initiation. While there was concern that JAK inhibition could compromise the activity of IL-22, continuation of ruxolitinib was considered on a case-by-case basis. C-reactive protein (CRP) is an acute phase reactant induced by IL-22, and circulating CRP levels served as a pharmacodynamic marker of in vivo biologic activity of F-652. Results: Consistent CRP elevations were observed 3 days after F-652 dosing in patients A and C, both of whom demonstrated a reduction in GVHD symptoms following F-652 treatment. These CRP elevations occurred despite concurrent use of belumosidil in Patient A and ruxolitinib in Patient C. CRP levels increased in Patient B after the first two doses, but not the third ( Figure). By day 28 following F-652 initiation, 2-of-3 patients (A and C) achieved a partial response, with decreased stool output and resolution of GI bleeding. Patient A had experienced 21 episodes of bacteremia prior to initiating rhIL-22 therapy but continued to demonstrate a partial response at day 56 and resolutiuon of bacteremias. Further improvement during the continued treatment (12 total doses) allowed for hospital discharge after 14 months of hospitalization. Patient B received 4 failed lines of therapy beyond ruxolitinib and was experiencing GI bleeding necessitating frequent transfusions prior to F-652 initiation. The symptoms persisted following F-652 treatment, and the patient passed at day 149 post-HCT. Patient C continues on active F-652 treatment and remains in a partial response as of this submission (&amp;gt; 50 days after treatment initiation). Overall, F-652 treatment has been well tolerated, and no significant adverse events attributable to the drug were observed. Conclusions: This is the first report of IL-22 therapy in SR aGVHD. Treatment was well tolerated, and 2-of-3 patients achieved a response following rhIL-22 administration after failing multiple previous therapies. Whereas most treatments for GVHD target immune cells and deepen immunosuppression, IL-22 is understood to act directly upon epithelial cells where it can support tissue recovery, improve barrier function, and promote innate antimicrobial immunity. CRP elevations post-treatment suggest that IL-22 administration may be able to exert these effects even with concurrent use of a JAK inhibitor. Our findings support further development of this approach and provide proof-of-concept for the use of tissue-supportive strategies to enhance the recovery of damaged gastrointestinal mucosa in advanced lower GI aGVHD.

Treatment of Patient with Cutaneous Lupus Erythematosus with Roflumilast Cream 0.3%

Introduction: Cutaneous lupus erythematosus (CLE) is the cutaneous form of a common autoimmune disease, lupus erythematosus, driven by a dysfunction within the adaptive and innate immune system. CLE is subcategorized further into acute, subacute and chronic disease. Here we report a case of a patient with systemic and refractory cutaneous disease with improvement in manifestations demonstrating efficacy following treatment with roflumilast cream 0.3% in a complex chronic CLE patient with uncontrolled disease, intense pruritus and scarring. Case Report: A 48-year-old Asian female with history of smoking, chronic refractory SLE since 2008 with a new onset of pruritic rash. Previous therapies including thalidomide, hydroxychloroquine, methotrexate, mycophenolate mofetil, numerous research trials, oral and intramuscular steroids that failed to control her systemic LE. A Rheumatology colleague referred the patient for new onset cutaneous manifestations. Initial presentation revealed lesions involving 2% of the occipital scalp. Pathology confirmed the diagnosis of discoid lupus. Intralesional triamcinolone , plus topical betamethasone dipropionate 0.05% twice daily (BID) and timolol 0.5% OP solution for wound healing were initiated. Fifteen months later the patient had disease progression of her CLE on to her scalp, face, legs and arms, with the chief complaint of persistent pruritus despite oral prednisone, hydroxychloroquine and thalidomide. The patient’s rheumatologist requested alternative treatment for cutaneous disease without use of long term topical high potency steroids. A second series of intralesional triamcinolone injections plus betamethasone dipropionate 0.05% BID for 3-4 weeks and titrate down to 2-3 applications per week, and addition of roflumilast cream 0.3% was initiated once daily to her face, scalp, and lower legs. On the third office visit, four weeks later, the patient reported pruritus and cutaneous manifestations in lower legs controlled and scalp and face have marked improvement. After 8 weeks on this regimen, the patient return reported that scalp and face continued to improve and disease on the legs continue to be controlled despite not using topical treatment for four weeks. Roflumilast cream 0.3% once daily was continued as monotherapy. Two months later, the patient reported that her skin was fully controlled was starting to repigment with monotherapy. Conclusions: This case report of a 48-year-old female with refractory treatment resistant chronic SLE and CLE treated with roflumilast cream 0.3%, a phosphodiesterase-4 (PDE-4) inhibitor, resulted in disease control, the symptom improvement of improved pruritus as well as repigmentation of the skin. The results observed in this patient suggest this topical intervention, if implemented at the beginning of treatment for cutaneous onset of disease, may have the potential to halt the progression of cutaneous involvement. This case report serves to highlight a promising intervention that may lead to better cutaneous control without long term side effects of topical steroid use.

Effective venetoclax-based treatment in relapsed/refractory multiple myeloma patients with translocation t(6;14).

Introduction: The selective Bcl-2 inhibitor venetoclax has shown promising therapeutic potential in multiple myeloma, particularly in cases associated with t(11;14) IGH::CCND1 translocation. However, the efficacy of venetoclax in myeloma patients with the t(6;14) IGH::CCND3 translocation remains less investigated. Methods: In this study, we conducted a retrospective analysis to investigate the efficacy of venetoclax-based therapy in relapsed/refractory myeloma patients with t(6;14) translocation. The treatment courses of three patients, that included previous therapies and responses to venetoclax, were assessed. Clinical data, laboratory results, and adverse events were analyzed to evaluate treatment outcomes. Results: Our findings demonstrated remarkable therapeutic responses in three consecutive patients with t(6;14) translocation-associated myeloma who received venetoclax-based therapy. Patient 1, a lenalidomide-bortezomib-daratumumab and alkylator treatment refractory patient, achieved sustained stringent complete remission (sCR) after combining carfilzomib-dexamethasone with venetoclax, which was his best response ever. Similarly, Patient 2, refractory to frontline bortezomib-thalidomide-dexamethasone therapy, attained CR following a transition to bortezomib-dexamethason-venetoclax treatment. Patient 3, who was immunomodulatory (IMID)-intolerant, showed a highly favorable response to venetoclax-dexamethasone therapy after his first relapse following autologous stem cell transplantation. No significant adverse effects were observed in any of the patients. Discussion: Our study provides compelling preliminary evidence for the efficacy of venetoclax in t(6;14) translocation-associated myeloma. The outcomes observed in our patients suggest that venetoclax-based therapy holds substantial promise as an effective treatment option for this specific genetic subgroup. Furthermore, the similarities in treatment response between t(11;14) and t(6;14) translocation subgroups highlight the importance of personalized approaches targeting specific genetic abnormalities to optimize therapeutic outcomes.

Advanced Hybrid Closed-Loop System Achieves and Maintains Recommended Time in Range Levels for Up To 2 Years: Predictors of Best Efficacy.

Aim: To evaluate the long-term efficacy, up to 2 years, of an advanced hybrid closed-loop (AHCL) system and to assess predictors of best results of the therapy. Methods: We retrospectively evaluated 296 adults with type 1 diabetes mellitus [mean age 42.8 ± 16.5 years, men 42.9%, duration of diabetes 22.5 ± 12.8 years, body mass index 24.9 ± 4.7 kg/m2, baseline glycated hemoglobin (HbA1c) 63.4 ± 12.2 mmol/mol (8.0 ± 1.1%) ] who used the MiniMed™ 780G system. Demographic and clinical data were recorded. Continuous glucose monitoring (CGM)-derived metrics and insulin requirement were analyzed from the 4 weeks before and from every quarter after the switch to the AHCL system. Results: In the first quarter of AHCL treatment, all CGM metrics improved. Time in range (TIR) increased from 58.1 ± 17.5% to 70.3 ± 9.5% (P < 0.0001). The improvement lasted for up to 2 years of observation regardless of previous insulin therapies. Throughout the period of observation, 53.4% of participants achieved mean TIR >70%, 92.6% mean time below range <4%, and 46% mean glucose management indicator <53 mmol/mol (7.0%). At univariable logistic regression older age, lower baseline HbA1c and insulin requirement were associated with mean TIR >70%. At multivariable analysis, lower HbA1c remained independently associated with a better glycemic control. However, mean TIR increased more in participants with a higher baseline HbA1c. Conclusions: Switching to an AHCL leads to a rapid improvement in glycemic control lasting for up to 24 months along with a low risk for hypoglycemia, confirming the safety of the system. Lower baseline HbA1c was the main predictor of better efficacy of therapy, although higher baseline HbA1c was associated with the greatest improvement in mean TIR.

Evaluating the Performance of Large Language Models in Hematopoietic Stem Cell Transplantation Decision Making

Introduction: Large Language Models (LLMs) are a form of Artificial Intelligence (AI), by identifying patterns and connections within data, they can predict the most likely words or phrases in specific contexts. Previous studies have indicated that GPT (Generative Pre-trained Transformer; OpenAI) performs well in answering single-choice clinical questions. However, its performance seems to be less satisfactory when dealing with multiple-choice questions and more intricate clinical cases (Cosima et al. 2023 EAO; Cascella et al. 2023 J Med Syst). Notably, no study has evaluated LLMs responses in the context of Transplantation Decision Making, a complex process heavily reliant on physician expertise. Additionally, most studies focused solely on GPT's performance, without considering other competitive LLMs like Llama-2 or VertexAI. Our study aims to assess the performance of LLMs in the domain of hematopoietic stem cell transplantation. Methods: We modified and anonymized the clinical histories of six hematological patients. An experienced hematologist reviewed and validated these modified clinical histories, which included demographic data, past medical history, hematology disease features (genetic data and MRD when available), treatment responses, adverse events from previous therapies, and potential donor information (related/unrelated, HLA, CMV status). We presented these clinical cases to six experienced bone marrow transplant physicians from two major JACIE accredited hospitals and 11 hematology residents from the University Milano-Bicocca. LLMs employed for the analysis were: GPT-4, VertexAI Palm 2, Llama-2 13b and 70b. LLMs were configured with different temperature settings to control token selection randomness, always maintaining low levels for more deterministic responses. A triple-blinded survey was conducted using Typeform, where both senior hematologists and residents provided anonymized responses with personal tokens. The senior hematologists, residents, and LLMs testers were unaware of the responses provided by the other groups. We calculated Fleiss K (K) and overall percentage of agreement (OA) between residents and LLMs, considering the consensus answer (CoA) among experts as the most frequent response. Subsequently, OA and K values for both residents and LLMs were compared using T- or Mann-Whitney tests with Graphpad v 10.0.1. Results: The results showed perfect agreement among experts in patient transplant eligibility assessment (K=1.0) and substantial agreement in the choice of donors and conditioning regimens (K=0.62 for both questions). Fair agreement was observed in Transplant Related Mortality (TRM) estimation (K=0.22). The median OA and K value between residents and the CoA of experts were 76.5% (range 52.9-88.2%) and 0.61 (range 0.4-0.8), respectively. The median OA and K value between LLMs answers and experts were 58.8% (range 47-71%) and 0.45 (range 0.3-0.61), respectively. The mean OA and K value of residents were significantly higher compared to LLMs (p=0.02). Specifically, residents showed higher median OA and K values in patient eligibility assessment (median OA 100 vs. 83% and K 1 vs. 0.78; p=0.01). However, there was no significant difference in median K for donor choice (0.56 vs. 0.56), conditioning regimen (0.67 vs. 0.33), and TRM evaluation (0.33 vs. 0) (Table 1). The median K values of GPT-4, Palm-2, Llama2-13b, and Llama2-70b were 0.49, 0.53, 0.33, and 0.53 respectively (Figure 1). Conclusion: Our study sheds light on the potential and limitations of LLMs in complex hematopoietic stem cell transplantation decision-making. While LLMs showed promising results with a median OA of 59%, residents demonstrated superior performance. LLMS displayed good performances in patients' eligibility and donor choice but showed shortcomings in conditioning regimens and TRM evaluation. Not using a rating scale from experts when evaluating LLMs responses aimed to avoid potential bias. However, it is important to note that the consensus answer, even though it was the most frequent, does not necessarily imply that other responses provided by the experts were incorrect. Therefore, the lower consensus among the experts in TRM evaluation, possibly due to the challenge of precisely calculating TRM in a survey-based evaluation, should also lead to a cautious approach when evaluating residents and LLMs answers in this setting.