Adult Acute Leukemia Patients Research Articles

Secondary Histiocytic Sarcoma in a Pre-B-Acute Lymphoblastic Leukemia

AbstractHistiocytic sarcoma (HS) is a rare malignancy with grave prognosis. Adult acute lymphoblastic leukemia (ALL) patients developing HS as a secondary malignancy reported in the literature is even rarer. Through our case report, we aim to describe an adult pre-B-ALL patient who subsequently developed extensive HS while on maintenance therapy. We present the course of the disease, the management, and the resultant outcome. Active reporting of the course and management of secondary HS in adult ALL patients need to be emphasized to gain better insight into the presentation and the course of the disease, incidence as well as molecular pathology, especially given the relative silence of the literature in this regard.

Linkage of cell division cycle 42 with clinical features, treatment response and survival in adult Philadelphia chromosome negative acute lymphoblastic leukemia

Cell division cycle 42 (CDC42) regulates the progression of leukemia via mediating proliferation and immune evasion of malignant cells. The study aimed to investigate the correlation of CDC42 with clinical features, treatment response, event-free survival (EFS) and overall survival (OS) in adult Philadelphia chromosome negative acute lymphoblastic leukemia (Ph− ALL) patients. CDC42 expression in bone marrow mononuclear cells was detected in 78 adult Ph− ALL patients and 10 donors using real-time reverse transcriptase-polymerase chain reaction. CDC42 was increased in adult Ph− ALL patients compared with donors (p < .001). Besides, elevated CDC42 was linked with pro-B ALL or early-T ALL (p = .038) and white blood cell (WBC) elevation at diagnosis (p = .025). Fifty (64.1%) and 23 (29.5%) patients had complete remission (CR) at 1 month and minimal residual disease (MRD) after CR, respectively. CDC42 was inversely associated with CR at 1 month (p = .034), but not MRD after CR (p = .066). Concerning survival, patients with CDC42 ≥ 3.310 (cut by median value in patients) showed a shortened EFS (p = .006) and OS (p = .036) compared to those with CDC42 < 3.310. In detail, patients with CDC42 ≥ 3.310 and CDC42 < 3.310 had 5-year EFS rate of 29.9% and 45.4%, and 5-year OS rate of 39.4% and 63.6%, correspondingly. Further multivariate Cox’s regression analyses revealed that CDC42 ≥ 3.310 was independently related to shorter EFS (hazard ratio = 2.933, p = .005). Elevated CDC42 is related with pro-B ALL or early-T ALL, WBC elevation at diagnosis, unfavorable treatment response and worse survival in adult Ph− ALL patients.

Seroprevalence of SARS-CoV-2 and Hepatitis B Virus Coinfections among Ethiopians with Acute Leukemia.

SARS-CoV-2 and blood-borne viral coinfections are well reported. Nevertheless, little is known regarding the seroprevalence of SARS-CoV-2 and coinfection with blood-borne viruses in hematologic malignancy patients in Ethiopia. We aimed to assess the seroprevalence of SARS-CoV-2 and associated infections with hepatitis B and other viruses among adolescent and adult acute leukemia patients at Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia. A cross-sectional study was conducted from July 2020 to June 2021. Blood samples were tested for the presence of anti-SARS-CoV-2, HBV, HCV, and HIV with ELISA kits and occult hepatitis B infection with a real-time polymerase chain reaction assay. Out of a total 110 cases, the SARS-CoV-2 seroprevalence was 35.5%. The prevalence showed a significant increment from July 2020 to the end of June 2021 (p = 0.015). In 22.7% and 2.7% of leukemia cases, HBV and HIV, respectively, were detected. No HCV was identified. The rate of SARS-CoV-2 coinfection with HBV and HIV was 28% (11/39) and 2.6% (1/39), respectively; however, there was no statistically significant association between SARS-CoV-2 seropositivity with HBV and HIV (p > 0.05). There is a need for viral screening in leukemia cases to monitor infections and inform management.

Abstract 5956: FLT3 alterations and inhibition in triple negative B-cell adult acute lymphoblastic leukemia patients

Abstract Backgroud: The prognosis of B cell ALL patients (pts) relapsing after Hematopoietic Transplant is poor and new drugs are needed. In acute myeloid leukemia, FLT3-inhibitors (FLT3i) are showing promising results in FLT3-mutated (mut) cases. Their potential use in FLT3-mut B-ALL has been poorly investigated. Aim: To assess if FLT3 could be a valid targetable marker in B-ALL. Methods: We sequenced with a capture based large RNA-seq panel (1385genes) 183 adult B-ALL [n=52 Pos for Ph or t(4;11) or t(1;19) and n=131 Triple-Negative (TN) pts that are negative for Ph (n=43), t(4;11) and t(1;19) translocations] and 15 donors. To confirm FLT3 muts, 13 available samples were further sequenced with Extended Myeloid Solution (98 genes; SOPHiA) where FLT3 gene is fully covered. In vitro studies using 5 FLT3i [Gilteritinib (Gil), Midostaurin, Crenolanib, Sorafenib and Quizartibin] and Venetoclax (Ven) were conducted on pt primary cells and on TN and other B-ALL cell lines (MUTZ5, MHH-CALL4 Ph-like; NALM6;RS4;11, 697, REH) and 2 AML cell lines (OCI-AML3 FLT3;MV-4-11 FLT3-ITD). Results: We found 15 FLT3 mut in 14/131 TN B-ALL and in 1/43 Ph+ cases: 43.8% were TKD mut, 3 ITD mut, 3 splicing site mut,1 N-terminal, 1 juxta-membrane domain and 1 Ig-like site (Fig. 1A). After pathogenicity interpretation we excluded 3 variants and one mutation was not confirmed at DNA level. Overall 7.6% of TN were mut (Ph+ 2.3%). 81.8% of FLT3mut pts potentially druggable with FLT3i, mainly TKD (63.3%). Targeted NGS revealed the co-occurrence with other mutations (range 2-15), and in particular with CSMD1 (n=4), KDM6A, KMT2D and CREBBP (n=3) alterations. Moreover, 11/13 samples carried copy number alteration (mean 12), mostly amplifications. CDKN2A &amp; IKZF1 were the most frequently altered genes (n=5;4 CN-loss). FLT3 expression was increased in 11/15 cases compared to donors and wt pts. As reported, the expression was higher in ZNF384 or MLLr B-ALL subtypes.To evaluate the effect of FLT3is in ALL, we treated ex vivo primary leukemic cells of 6 adult ALL patients (FLT3-mut n=4; FLT3-wt n=2) with increasing concentrations of 5 FLT3i for 24, 48 and 72h. We observed a trend towards greater response of FLT3-mut ALL cells compared to wt ones. The average IC50 values in response to the five FLT3i was 1.6 uM and 24.5 uM after 72h of treatment in FLT3-mut and FLT3-wt B-ALL, respectively (Fig. 1B). We than evaluated the sensitivity to the 5 Inhs in all cell lines. Interestingly MHH-CALL4 wt were more sensitive to Gil compared to OCI AML3 wt, and showed the same effect compare to MV-4-11 AML mut (F.1C). Given the effect of Gil in single agent, we combined it with Ven in wt B-ALL cells at increasing concentrations. Interestingly We noticed a strong additive effect with the higher Gil concentration and all Ven doses(F.1D). Conclusions: FLT3 alterations identify a novel subgroup of TN B-ALL with therapeutic potential also in combination regimens. Ricerca Corrente Italian MoH L3P1946. Citation Format: Anna Ferrari, Andrea Ghelli Luserna di Rorà, Federico Lo Schiavo, Eugenio Fonzi, Giorgia Capirossi, Chiara Salvesi, Maria Teresa Bochicchio, Lorenzo Ledda, Chiara Servilli, Matteo Paganelli, Giovanni Marconi, Cristina Papayannidis, Chiara Sartor, Michela Rondoni, Anna Maria Mianulli, Barbara Giannini, Crescenza Pasciolla, Fabio Giglio, Sara Galimberti, Monica Fumagalli, Prassede Salutari, Valentina Gaidano, Giovanni Martinelli, Giorgia Simonetti. FLT3 alterations and inhibition in triple negative B-cell adult acute lymphoblastic leukemia patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5956.

Comparison of valganciclovir versus foscarnet for the treatment of cytomegalovirus viremia in adult acute leukemia patients after allogeneic hematopoietic cell transplantation

Cytomegalovirus (CMV) reactivation increases treatment-related mortality (TRM) after allogeneic hematopoietic cell transplantation (allo-HCT). We analyzed 141 adult acute leukemia (AL) patients suffered allo-HCT between 2017 and 2021, who developed CMV viremia post-HCT and treated with valganciclovir or foscarnet, to evaluate effectiveness and safety of both drugs. Viremia clearance rates (14 and 21 d post treatment) and toxicities were similar in two groups. However, valganciclovir was associated with a lower cumulative incidence of CMV recurrence within 180 days (16.7% vs. 35.7%, p=0.029) post CMV clearance. Finally, 2-year TRM was lower in valganciclovir group (9.7% ± 0.2% vs. 26.2% ± 0.3%, p = 0.026), result a superior 2-year overall survival (OS; 88.1% ± 5.2% vs. 64.4% ± 5.5%, p = 0.005) and leukemia-free survival (LFS; 82.0% ± 5.9% vs. 58.9% ± 5.6%, p = 0.009). Valganciclovir might decrease CMV viremia recurrence and led to better long-term outcome than foscarnet in adult AL patients developed CMV viremia post-HCT. Considering the inherent biases of retrospective study, well-designed trials are warranted to validate our conclusion.

Significance of OCT3/4 and SOX2 antigens expression by leukemic blast cells in adult acute leukemia

ObjectiveThis study aimed to address the prognostic impact of SOX2 and OCT3/4 expression on adult acute leukemia patients’ outcomes.MethodsSOX2 and OCT3/4 expression by blast cells were evaluated by flow cytometry in 80 acute leukemia patients and 8 healthy controls.ResultsBaseline SOX2 and OCT3/4 expression were significantly higher in both ALL (P = < 0.001, P = 0.005 respectively) and AML patients (P < 0.001, P = 0.003 respectively) as compared to control, and decline at complete remission (CR) and elevated again at relapse. High SOX2 and OCT3/4 levels were significantly correlated with the presence of adverse risk stratification parameters.ConclusionOur findings indicated that both SOX2 and OCT3/4 could serve as biomarkers that could improve risk stratification of acute leukemia patients. Also, both SOX2 and OCT3/4 might be a therapeutic target, especially in resistant acute leukemia.

Treatment‐related toxicity disparities in adult Hispanic acute lymphoblastic leukemia patients receiving pegaspargase‐based regimens: A multicenter electronic health research network study

Treatment‐related toxicity disparities in adult Hispanic acute lymphoblastic leukemia patients receiving pegaspargase‐based regimens: A multicenter electronic health research network study

Epidemiological and clinical characteristics of adult acute lymphoblastic leukemia patients in Chile: A single-center analysis

BackgroundAcute lymphoblastic leukemia represents 20% of acute leukemias in adults. Currently, there is limited data in Chile regarding the clinical, cytogenetic, and prognostic characteristics of this condition. MethodsThis is a retrospective, observational, and descriptive study of 67 patients treated for acute lymphoblastic leukemia at the Arturo Lopez Perez Foundation between 2018 and 2021. The main objective is to evaluate epidemiological and clinical characteristics, as well as identifying factors associated with improved overall survival and/or progression-free survival. Results88% of the cases were B-lineage, mainly the common B phenotype. Cytogenetic analysis was performed in less than 50% of the patients, with lower yield than expected according to the literature. Molecular testing was performed in 86.5% of the patients, with the most frequent alteration being BCR-ABL. No study was performed to search for Ph-like abnormalities. The rate of complete response after induction was 83.3%, the majority of patients having negative minimal residual disease. Only 12% of the patients received consolidation with allogenic bone marrow transplant. At 2 years, the overall survival was 69% and the progression-free survival was 59%. ConclusionThe results in terms of overall survival and progression-free survival are similar to those reported in the literature. Important diagnostic gaps prevent adequate prognostic characterization. Allogeneic consolidation transplantation was performed in a lower percentage than expected, highlighting the national deficit in access to this treatment.

Management of adult acute lymphoblastic leukemia in the Gulf Cooperation Council (GCC) countries: A consensus report from the GCC Adult ALL Working Group.

Leukemia burden is growing in the Gulf Council Cooperation (GCC) countries. Nonetheless, there is no unified protocol for managing adult acute lymphoblastic leukemia (ALL) patients in the GCC-countries. Therefore, the GCC Adult-ALL Treaters working group developed this consensus to address the adult-ALL treatment protocols in the GCC-countries and related toxicities' management. Besides, the consensus aimed to highlight the current unmet needs and treatment gaps and provide recommendations to optimize adult-ALL care and patient-centered communication. A three-step modified Delphi method to develop evidence-based recommendations through two-voting rounds and in-between virtual meetings are used in the manuscript development. A 12 experts' panel from five GCC-countries and two international experts were invited to participate in this consensus. This consensus consisted of 35-statements that highlighted the experts' recommendations to optimize ALL adults' care in the first line setting and manage pediatric or pediatric-inspired regimens-related toxicities. Besides, guidance was provided for future research direction and improve patient-centered communication. In conclusion, the adult-ALL management landscape is evolving, and the current evidence highlights better response and survival outcomes with pediatric or pediatric-inspired regiments. Therefore, protocols are needed to optimize the adult-ALL management in the GCC and tailored clinical-trials findings according to the GCC patients' characteristics and local-healthcare infrastructure.

Leveraging health care technology to improve health outcomes and reduce outcome disparities in AYA leukemia.

Significant improvements have occurred for adolescent and young adult (AYA) B-cell acute lymphoblastic leukemia (B-ALL) patients following the widespread adoption of "pediatric-inspired" treatment regimens for AYA patients cared for in adult oncology settings. However, for AYA patients, aged 15 to 39, an outcomes gap remains in B-ALL, necessitating the incorporation of novel therapies into up-front treatment regimens. As a result, clinical trial enrollment remains the current standard of care for AYA B-ALL across disease subtypes when available and accessible. Currently, several up-front trials are looking to incorporate the use of inotuzumab, blinatumomab, and chimeric antigen receptor T-cell therapy into existing chemotherapy backbones for AYA patients, as well as tyrosine kinase inhibitors for both Philadelphia-positive (Ph+) and Ph-like B-ALL. In addition to ongoing attempts to improve up-front treatments by incorporating immunotherapy and targeted approaches, the increased use of next generation sequencing for measurable residual disease evaluation has led to superior risk-stratification and a decreased need to pursue consolidative hematopoietic stem cell transplantation during the first complete remission for many patients.

A NUDT15 Genetic Polymorphism Study in Adult Acute Leukemia Patients Integrating Pharmacogenomics and Clinical Practice: A Single Centre Experience from South India

Background: Severe myelosuppression secondary to thiopurines such as 6-Mercaptopurine (6-MP) in patients with acute leukemia undergoing maintenance therapy is frequently attributed to inherited genetic polymorphisms of Thiopurine Methyltransferase (TPMT); however, this is rare in the Asian population. Nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) is also responsible for encoding critical enzymes involved in 6-MP metabolism. We aimed to determine the frequency of genetic polymorphisms of NUDT15 in the South Indian population and the impact of the omission of 6-MP from the treatment protocol of these patients. Methods: We retrospectively reviewed 17 patients diagnosed with acute leukemia between May 2018 and May 2020 and analyzed the prevalence of NUDT15 genetic polymorphisms in these patients. The NUDT15 mutation study (NUDT15 415C&amp;gt;T) used allele-specific Real-Time PCR in peripheral blood. 6-Mercaptopurine (6-MP) was excluded from the treatment regimen of patients with NUDT15 genetic polymorphisms and the impact of its exclusion was also studied. Results: Among the 17 patients for whom we cared, 10 were diagnosed with B-cell Acute Lymphoblastic Leukemia (B-ALL), three with T-cell Acute Lymphoblastic Leukemia (T-ALL), one with Mixed Phenotype Acute Leukemia (MPAL), and one with Acute Promyelocytic Leukemia (APML). Treatment records could not be retrieved for 2 patients. NUDT15 mutations were present in six patients (36%) (see fig1), of whom two had homozygous (33%) polymorphisms and four had heterozygous (67%) polymorphisms. In the heterozygous group, 2 were Ph. (Philadelphia chromosome) negative B-ALL; one was treated with BFM and the other with hyper-CVAD, one Ph. positive B-ALL was treated with BFM + Ponatinib, and one High-risk APML was treated with the APML 4 protocol. In the homozygous group, treatment details could not be retrieved for one case, and the other patient had T-ALL, which was treated with hyper-CVAD. 6-MP was omitted from the treatment protocol for all NUDT15 mutation-positive patients, both homozygous and heterozygous. Of these patients, two developed grade 1 myelosuppression, one developed grade 2 myelosuppression, one developed dyselectrolytemia, and one patient did not develop any toxicity. The incidence of severe or grade 3 and 4 myelosuppression in NUDT15 polymorphisms receiving 6MP can be as high as 50% (Khaeso K et.al Front Pharmacol. 2021). In comparison, none of our patients developed grade 3 or 4 myelosuppression. Overall, treatment-related adverse events included grade 1-2 myelosuppression (n=6), grade 1-2 hepatotoxicity (n=1), deep vein thrombosis (n=2), and sepsis (n=2). Five of the 6 patients with NUDT15 mutations achieved complete remission (CR). Conclusion: The prevalence of NUDT15 polymorphisms was high in our study population. Based on a meta-analysis, the prevalence of NUDT15 in the South Indian population was 16.5%, and in patients with adverse effects, the pooled prevalence of NUDT15 polymorphisms was 49.51% (Anuraag Jena et.al. Expert Review of Clinical Pharmacology 2021). Based on our results, although limited by the small number of cases, we suggest that pre-emptive testing to detect these polymorphisms should be undertaken in all adult acute leukemia patients of South Indian origin, given their high prevalence in this population. The omission of 6-MP from treatment protocols can help prevent severe myelosuppression and treatment interruption or discontinuation, which in turn can improve treatment outcomes.

Understanding Relapsed/Refractory Acute Leukemia Patients' Treatment Preferences: Insights from Qualitative Research

Introduction Evidence on patient preferences is increasingly being used to inform regulatory and reimbursement decisions. In acute leukemia, the number of treatment options is expanding but there is limited quantitative evidence on patients' treatment preferences, especially in the event of relapse. The Acute Leukemia Advocates Network (ALAN) in collaboration with The Office of Health Economics are running a quantitative patient preference study using a discrete choice experiment (DCE) to 1/ Elicit adult acute leukemia patients' preferences for treatment outcomes and characteristics in the event of a future relapse 2/ Explore the tradeoffs that patients are willing to make between different hypothetical treatments 3/ Describe preference heterogeneity in the patient population and 4/ Provide useful insights that could demonstrate patient value for a range of upcoming health technology assessments of relapsed/refractory treatments and guide innovation and development throughout the medical product lifecycle. Here we report on two stages of qualitative research: 1/ Online bulletin boards (OBBs) to identify potential attributes for the DCE and 2/ Cognitive ‘think aloud’ pilot interviews to test participant understanding of the draft DCE survey. Methods Two structured OBBs were conducted - one each for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Each day, participants were asked up to four open questions on the following topics: “your diagnosis and expectation of treatment”, “your first experience of treatment”, “treatment following a relapse”, and “your treatment priorities”. Participants could see and respond to each other's answers. Three researchers acted as moderators and engaged in discussions where appropriate. Following the design of the DCE survey, a series of online one-on-one think-aloud interviews with AML and ALL participants was subsequently conducted to pilot the DCE survey. Interviewees were asked to verbally reflect on their responses, with occasional interviewer prompts. The pilots were conducted in two separate weeks, with a week in between to allow for changes to be made. All participants were recruited via ALAN and its members. Results A total of 12 AML and nine ALL patients took part in the OBBs, of which 15 were female. Age (range: 26-71; average: 51.1) and years of living with the disease (range: &amp;lt;3 to &amp;gt; 10 years) were varied. Both the AML and ALL groups agreed that the effectiveness of the treatment in achieving long-term stable remission would be most important. Severe long-term side effects would also be an important concern but many participants said they could put up with potentially severe short-term side effects for a good chance of long-term survival. Additional concerns were the length of hospital stays, availability of psychological/mental/emotional support, catheter-related pain and infections, and mode of administration (MoA). Several participants argued that an individualized approach to treatment is preferred. Thematic analysis of the OBB data led to the identification of five attributes for the DCE: chance of response (20-95%), duration of response (6-18 months), quality of life (QoL) during treatment (0-50%), QoL during response (25-75%), and MoA (tablets taken at home, injections requiring a hospital stay, injections as outpatient appointments). The DCE was designed using an efficient experimental design and coded as part of an online survey, and subsequently piloted (see Figure 1). In week 1 of the pilots (n=5 interviews), ‘duration of response’, was often misinterpreted as ‘duration of treatment’. Interviewees also interpreted treatment and response as potentially overlapping, and therefore struggled to separate the two QoL attributes. Therefore, we made several changes including explicitly structuring the choice tasks to distinguish treatment and response phases. The changes improved understanding in week 2 (n=5 interviews) and raised some additional minor issues for consideration. Conclusion People with acute leukemia have a range of concerns about treatments in the context of a relapse. However, the primary issues identified in the qualitative research relate to the chance and duration of treatment success, QoL during and after treatment, and the MoA. The pilot interviews were valuable in improving the wording and overall quality of the final survey, which has since been fully launched.

Mitoxantrone Hydrochloride Liposome Containing Regimen in Patients with Adult Acute Lymphoblastic Leukemia: A Multicenter, Retrospective, Real-World Study

Background Although the initial overall response rate is high (70%-90%) in adult acute lymphoblastic leukemia (ALL) patients (pts), a large percentage of them frequently relapse. Prognosis of relapsed/refractory (R/R) ALL remains poor and there are no clear guidelines on the best treatment approach. Currently, an anthracycline-based multidrug chemotherapy regimen remains the treatment cornerstone in ALL. Mitoxantrone is a synthetic anthracenedione anti-cancer drug that is effective in lymphoma, leukemia, and other solid tumors. Mitoxantrone hydrochloride liposome (PLM60) is the first approved mitoxantrone nano-drug, which has shown favorable pharmacokinetic characteristics and significantly prolong the survival time of animals compared with the same dose of mitoxantrone. However, there is still a lack of systematic reports about the real-world application of PLM60 in ALL. Methods A multicenter retrospective analysis was performed for 38 pts with newly diagnosed and R/R ALL, who received at least one cycle of PLM60-containing regimen between February 2022 and June 2023 (ChiCTR2200067172). Pts aged 18 years or older with ECOG PS 0-2 and diagnosed with ALL were eligible. Efficacy was assessed by complete remission (CR) rate, overall response rate (ORR), relapse-free survival (RFS), overall survival (OS), and correlative analyses. Adverse events were assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Results At the data cut-off of 15 July 2023, 38 eligible pts who received induction, consolidation or pre-transplant therapy were enrolled. The median age was 40.5 years (range 24.0-71.0), 50.0% were male, median white blood cell (WBC) count was 7.9 x 10 9 /L (range 1.4-160.9) and 68.4% had B-lineage ALL. In addition, two pts had received hematopoietic stem cell transplantation. The median dose of PLM60 in the regimen was 16.2 (range 5.4-43.2) mg/m 2. Among the 23 newly diagnosed pts, the CR rate was 91.3% (21/23, 95%CI 72.0%-98.9%) and ORR was 91.3% (21/23, 95%CI 72.0%-98.9%), the ORR after induction therapy was 75.0% (6/8). The ORR was 95% and 66.7% in the WBC＜30×10 9 /L and ≥30×10 9 /L groups, respectively. Among the 15 R/R pts, the CR rate was 33.3% (5/15, 95%CI 11.8%-61.6%) and ORR was 46.7% (7/15, 95%CI 21.3%-73.4%), the ORR after induction therapy was 42.9% (6/14). The ORR was 57.1% and 37.5% in the WBC＜30×10 9 /L and ≥30×10 9 /L groups, respectively. The ORR of pts with 1 and ≥ 2 previous induction regimens was 71.4% and 25.0%, respectively. Other efficacy indicators were RFS and OS, but data are still too early and will be reported after a long-term follow-up. Treatment-related adverse events (TRAEs) of any grade occurred in 79.0% pts. Common grade 3/4 AEs included decreased neutrophil count (50.0%), thrombocytopenia (36.8%), anemia (34.2%), febrile neutropenia (5.3%). The overall safety was acceptable and controllable. Conclusion The PLM60-containing regimen had an encouraging efficacy and showed a manageable safety profile in adult ALL with the most adverse events being hematologic toxicities.

Platelet-Based Dose-Adjusted Low Molecular Weight Heparin Treatment Is Efficacious and Safe in Newly Diagnosed Acute Leukemia Patients with Catheter-Related Thrombosis

Introduction: Catheter-related thrombosis (CRT) is a major complication in patients with acute leukemia. Severe thrombocytopenia related to either the concomitant disease or therapy underscores the challenge of CRT management, resulting in the use of suboptimal anticoagulation, potentially leading to high rates of short-term complications, including recurrent thromboembolism and hemorrhage. Due to the paucity of data regarding the impact of reduced-dose anticoagulation on this clinical setting, the current study aimed to assess the safety and efficacy of this treatment approach to CRT management in this challenging patient population. Methods: In this retrospective, case-control study, all adult (age ≥18 years) acute leukemia patients, who had arrived at the Rambam Health Care Campus (RHCC, Haifa, Israel) between 1.11.2004-30.6.2022 to receive anti-leukemia therapy via a peripherally inserted central catheter (PICC) line were screened. The inclusion criteria were: patients with acute myeloid, promyelocytic and lymphoid leukemia (AML, APL, and ALL, respectively) and CRT confirmed by Doppler ultrasound within 3 months of leukemia diagnosis. Patients were divided into full- (i.e., 1 mg/kg bid) vs. partial-dose low molecular weight heparin (LMWH) groups. The LMWH dose was based on the platelet count with a cutoff of 50K/L, distinguishing between the selected doses. Primary endpoints: A record of venous thromboembolism (VTE; including pulmonary embolism (PE), deep vein thrombosis (DVT), and catheter-related thrombosis (CRT) recurrence within 12 months as well as a major hemorrhage (including intracranial, retinal and gastrointestinal hemorrhage) within 6 months. Secondary endpoints: blood product requirement (unit/day) before and after the CRT diagnosis (from leukemia diagnosis till CRT identification and 90 days or death (if prior) from the event, respectively) assessed in a self-controlled case series manner. Data were collected from the hospital electronic medical records. Chi-square and paired samples Wilcoxon tests were utilized for statistical analysis. Results: Overall,195 patients [aged 54±15 years; 103 (53%) males], diagnosed with CRT were included. The most frequent leukemia diagnosis was AML (n=149; 76%), with ALL and APL established in 23 (12%) patients each. CRT was diagnosed in the left upper limb in 136 (70%) patients, with 99 (46%) patients suffering from DVT. Eighty-eight (45%) patients were treated with full-dose LMWH. Recurrent VTE was identified in 11(12.5%) patients treated with full-dose LMWH vs. 9 (8.4%) receiving partial-dose LMWH (p-value 0.484), while major hemorrhage was diagnosed in 12 (13.6%) patients from the former group vs. 14 (13.0%) patients from the latter group (table 1). Similar results were documented upon stratification to deep vs. superficial CRT, and the leukemia type. The packed red blood cell (RBC) administration rate was lower in the post-CRT phase (0.12 units/day, IQR 0.06-0.20) compared to the pre-CRT phase (0.20 units/day, IQR 0-0.36; p-value &amp;lt;0.0001). Platelet utilization rates were similar in both the pre-CRT and post-CRT phases (0.05 units/day, IQR 0-0.24 and 0.06 units/day, IQR 0.01-0.16, respectively; p-value 0.126). Comparable results were observed in both full and partial-dose LMWH groups. Conclusion: LMWH dose adjustment based on platelet counts, in newly diagnosed acute leukemia patients with CRT, is not associated with higher rates of VTE recurrence. Moreover, this strategy does not result in major hemorrhagic complications even in patients with severe thrombocytopenia. Notably, RBC infusion requirements were lower in the post-CRT diagnosis phase, while platelet transfusion was similar during the pre- and post-CRT phases. This analysis, including a large number of patients, demonstrates that the adjusted therapy is safe and efficient in this challenging clinical scenario.

Impact of Concurrent and Previous Multidrug Resistant Bacteria Colonization in Adult Allogenic Hematopoietic Stem Cell Transplant Patients with Acute Leukemia: A Single Center Retrospective Study

Background Multidrug resistant bacteria (MDRB) pose a major challenge in allogenic hematopoietic stem cell transplant (allo-HSCT) since patient colonization with Gram - or Gram + MDRB has been identified as a risk factor for infections, acute graft versus host disease (aGVHD) and reduced overall survival (OS). Nevertheless, data on the prognostic value of MDRB colonization are still scarce, and whether it should represent a limit to allo-HSCT eligibility is controversial. Few data are also available on the impact of previously detected colonization that are absent at transplant time. Methods This is a retrospective single center study on 60 patients with acute myeloid or lymphoblastic leukemia who underwent allo-HSCT from January 2014 to March 2023 according to JACIE standards.All patients were treated at our department starting from induction. In each hospital stay MDRB colonization was assessed by rectal swabs performed at admission, and thereafter weekly. In case of fever 3 sets of blood culture from peripheral vein and central venous catheters, urine culture and chest X-ray were performed, and empiric antibiotic therapy initiated. In MDRB colonized patients, targeted antibiotic therapy was administered if clinically indicated. All patients received fluroquinolones as antimicrobial prophylaxis. Data were retrieved from hospital records. Aim of the study To assess the epidemiology of MDRB colonization and the related impact on allo-HSCT outcome in terms of MDRB-related infections, aGVHD within day 100, OS and non-relapse mortality (NRM). Results MDRB colonization was detected in 26/60 (43.4%) patients, in 13 (21.7%) at hospital admission and in additional 13 (21.7%) after allo-HSCT. Overall, 33 MDRB strains were isolated (Table 1). Among patients colonized at hospital admission, Gram - MDRB accounted for 10/16 (62.5%) strains, mostly Escherichia Coli producing extended-spectrum beta-lactamases (ESBL) and Klebsiella Pneumoniae ESBL, while Gram + MDRB were 6 (37.5%), mostly represented by vancomycin-resistant Enterococcus faecium (VRE). In 14/16 (87.5%) cases the colonization has been previously detected, in 78.5% since the first two hospital stays. Among patients with positive rectal swabs after allo-HSCT, Gram - MDRB accounted for 16/17 (94.1%) strains, mostly Escherichia Coli ESBL and Klebsiella Pneumoniae ESBL (1 producing carbapenemases). In these patients the rectal swab turned out positive after a median time of 10 (2-24) days after allo-HSCT, mostly during neutropenia. Albeit absent at hospital admission, 13/17 (76.5%) MDRB strains had been previously isolated in the same patients, being firstly identified during the first two hospital stays in 76.9% cases. No significant differences in patient baseline characteristics, leukemia classification, type of donor and conditioning or hospitalization length were observed between MDRB carriers (26, 43.4%) and non-carriers (34, 56.8%) (Table 2). During the whole hospital stay, 18/26 (69%) carriers and 32/34 (94%) non-carriers reported at least one febrile event (p=0.01). Only carriers experienced MDRB (Gram -) infections based on blood (4, 22%) and urine (7, 38%) culture, while the rate of positive chest X-ray (4, 22,2% vs 5, 15.6%, p=0.5) did not differ. Targeted antibiotics were administered to 14/18 (77.8%) febrile carriers, in 10 (71%) at fever onset and in 4 (29%) at fever persistence. Four (22.2%) did not receive treatment because not clinically indicated. Intensive care unit was never required in both cohorts. The incidence of aGVHD was similar between carriers and non-carriers (10, 38.5% vs 17, 50%, p=ns), but the proportion of grade 2-4 tended to be higher in the first group (70% vs 35.5%, p=0.08). Overall, 73% patients are alive with a median follow-up of 18 (0.8-49) months. Median OS was not reached in both groups (p=0.09). There was no difference in NRM between carriers and non-carriers (5, 19% vs 2, 6%, p=0.11). Conclusion In our series 43.3% of allo-HSCT patients were colonized by MDRB that, in line with recent literature, were mostly Gram -. The absence of life-threatening infections and the non-significantly inferior OS and NRM in colonized patients suggest that a careful investigation of concurrent and previous colonization and a prompt use of targeted antibiotics may temper the negative impact of MDRB-related infections in adult acute leukemia patients undergoing allo-HSCT. Larger prospective studies are awaited.

Comparison of Myeloablative Conditioning with Cyclophosphamide and Total-Body Irradiation (Cy/TBI) Vs. Fludarabine, Melphalan, and Total-Body Irradiation (Flu/Mel/TBI) in Patients Undergoing Allogeneic Stem Cell Transplant for AML/ALL

Background: Cyclophosphamide combined with total-body irradiation (Cy/TBI) has been widely used worldwide as the standard myeloablative conditioning (MAC) for allogeneic stem cell transplantation (allo-HCT), but there are concerns about the antitumor effects of CY, as well as side effects, including cardiotoxicity and mucosal toxicity. A few studies suggest that the addition of an anticancer agent to a Cy/TBI regimen may reduce recurrence rates, but comparative studies of Cy/TBI regimens versus other TBI regimens are scarce. Furthermore, the recent expansion of post-transplant cyclophosphamide as graft-versus-host disease (GVHD) prophylaxis has increased its utility for cyclophosphamide-free conditioning regimens. Our institution has extensive experience with cord blood transplantation for relatively elderly patients with high-risk leukemia and has worked to develop safer and more effective MAC regimens other than Cy/TBI. The purpose of this study is to examine the safety and efficacy of fludarabine and melphalan combined with total-body irradiation (Flu/Mel/TBI) regimen, which is widely used at our institution, compared to Cy/TBI. Methods: We retrospectively analyzed adult acute leukemia patients who underwent allo-HCT between August 1994 to February 2023 at Toranomon Hospital. The inclusion criteria were as follows: a diagnosis of acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), the first allo-HCT, and Cy (120mg/kg) /TBI (8-12Gy) or Flu (180mg/m 2) /Mel (80-120mg/m 2) /TBI (8-12Gy) as MAC regimen. We excluded patients who underwent haploidentical transplantation with post-transplant cyclophosphamide. The primary endpoint was the 5-year cumulative incidence of relapse, and the secondary endpoints were the 5-year cumulative incidence of non-relapse mortality (NRM), 5-year overall survival (OS), and relapse-free survival (RFS). OS and RFS were estimated by the Kaplan-Meier method and multivariate Cox proportional hazard models. The cumulative incidence of relapse and NRM were investigated with a competing risk analysis using Gray's test and multivariable Fine and Gray competing risk regression. Results: A total of 198 patients were included in this study, comprising 101 patients treated with Cy/TBI and 97 treated with Flu/Mel/TBI. Patients who received Flu/Mel/TBI were of higher age (Median age: Cy/TBI 36 years vs. Flu/Mel/TBI 53 years, p&amp;lt;0.01), higher ECOG PS score (PS≥1: 51.5% vs. 66.0%, p=0.044), fewer AML (49.5% vs. 22.7%, p&amp;lt;0.01), and more frequent CBT (45.5% vs. 76.3%, p&amp;lt;0.01). Disease status at HCT (CR1: 53.5% vs. 43.3%, p=0.154) and HCT-CI scores (HCT-CI≥1: 35.6% vs. 44.3%, p=0.214) were not different between the two regimen groups. Regarding the primary endpoint, the 5-year cumulative incidence of relapse was significantly lower in Flu/Mel/TBI group (36.8% vs. 24.9%, p= 0.035). The cumulative incidence of NRM was not significantly different between the two groups (19.1% vs. 25.2%, p=0.345). In the multivariate analysis, conditioning with Flu/Mel/TBI was significantly associated only with a lower risk of relapse (HR: 2.817; 95%CI: 1.183-6.712; p=0.019). Regarding NRM, only disease status not in CR1 was associated with a higher risk (CR1 vs. non-CR1 HR: 2.21; 95%CI: 1.095-4.468; p=0.027). There was no significant difference in 5-year OS (Cy/TBI 48.1% vs. Flu/Mel/TBI 51.4%, p=0.604) and RFS (44.2% vs. 49.9%, p=0.24). Conclusion: Despite older age and worse PS in the Flu/Mel/TBI group, Flu/Mel/TBI had a significantly lower 5-year cumulative relapse rate than Cy/TBI, with no significant difference in NRM. Our results suggest that Flu/Mel/TBI is a reasonable alternative to CY/TBI and may be a superior TBI-containing MAC regimen.

Real World Utilization of Cranial or Craniospinal Radiation in Adult Acute Lymphoid Leukemia Patients: Data from the Center for International Blood and Marrow Transplant Research

Though CNS involvement at diagnosis in adult acute lymphoid leukemia (ALL) is relatively rare (3-7%), >50 % of patients will develop CNS relapse without CNS-directed therapy. Radiation therapy is commonly used as part of stem cell transplant (SCT) conditioning. Historically, a cranial boost was given to reduce risk of CNS relapse. While a CNS boost is not a universal part of prophylaxis, CNS directed RT is used in patients at highest risk for CNS relapse following transplantation, typically those with CNS disease at diagnosis or after induction. There is little data on real world utilization of CNS directed radiation as part of SCT for adult ALL patients. The Center for International Blood and Marrow Transplant Research (CIBMTR) database was queried for adult ALL patients undergoing SCT between 2013 - 2019 who received TBI as part of their regimen where data was available on CNS directed RT. Patient demographics, pre-transplant response to induction, CNS status pre/post-transplant, and overall survival information were collected. Results were stratified by cranial irradiation (CNS-RT), craniospinal irradiation (CSI), or no cranial RT (nCRT). Radiation dose is not collected by the CIBMTR. The data presented here are preliminary and were obtained from the Statistical Center of the Center for International Blood and Marrow Transplant Research. The analysis has not been reviewed or approved by the Advisory or Scientific Committees of the CIBMTR. A total of 1240 patients were identified, of which 59 (5%) received CNS-RT, 2 (0.2%) received CSI, 989 (80%) received nCRT, and 190 (15%) had unknown CNS RT status. Median age was younger in patients receiving CNS-RT (26y, range 19-66y) or CSI (34y, 22-46y) compared to patients receiving nCRT (42y, 18-79y). Patients receiving CNS radiation had more advanced disease at time of transplant (17% requiring 3+ lines of induction before CR vs 50% vs 5%, respectively). 24% of CNS-RT patients and 50% of CSI patients had CNS disease at diagnosis compared to 7% of nCRT patients. 37% of CNS-RT patients and 100% of CSI patients had CNS disease prior to transplant compared to 11% of nCRT patients. Overall survival at 1-5 years was numerically higher with CNS-RT compared to no RT, though 95% confidence intervals overlapped at each follow up point. Data from the CIBMTR on real world utilization of CNS-RT or CSI in adult ALL patients suggest inconsistent practice patterns with 11% of patients without any cranial RT having CNS disease prior to transplant and 57% of CNS-RT patients having no CNS disease prior to transplant. These data offer an interesting analysis of current CNS radiation practice patterns in the past 10 years for adult ALL patients, though interpretation is limited by the retrospective nature of the study and by significant limitations of available data.

The use of pegaspargase in adult Ph-negative acute lymphoblastic leukemia patients in the treatment according to the all-2016 protocol

The use of pegaspargase in adult Ph-negative acute lymphoblastic leukemia patients in the treatment according to the all-2016 protocol

Prognostic Immune Effector Signature in Adult Acute Lymphoblastic Leukemia Patients Is Dominated by γδ T Cells.

The success of immunotherapy has highlighted the critical role of the immune microenvironment in acute lymphoblastic leukemia (ALL); however, the immune landscape in ALL remains incompletely understood and most studies have focused on conventional T cells or NK cells. This study investigated the prognostic impact of circulating γδ T-cell alterations using high-dimensional analysis in a cohort of newly diagnosed adult ALL patients (10 B-ALL; 9 Philadelphia+ ALL; 9 T-ALL). Our analysis revealed common alterations in CD8+ T cells and γδ T cells of relapsed patients, including accumulation of early stage differentiation and increased expression of BTLA and CD73. We demonstrated that the circulating γδ T-cell signature was the most discriminating between relapsed and disease-free groups. In addition, Vδ2 T-cell alterations strongly discriminated patients by relapse status. Taken together, these data highlight the role of ɣδ T cells in adult ALL patients, among whom Vδ2 T cells may be a pivotal contributor to T-cell immunity in ALL. Our findings provide a strong rationale for further monitoring and potentiating Vδ2 T cells in ALL, including in the autologous setting.

Intracranial hemorrhage (ICH) in acute leukemia (AL): A single-center study from a general hospital with two cases managed with middle meningeal artery (MMA) embolization.

e19033 Background: ICH is a devastating and potentially fatal complication in patients with AL. Contributing factors for ICH include thrombocytopenia, hyperleukocytosis, and coagulopathy. Acute promyelocytic leukemia (APL) has a higher risk of disseminated intravascular coagulation (DIC) and fatal ICH, contributing to early deaths from the disease. At our institution, we have incorporated MMA embolization into traditional methods of observation and surgery for the management of ICH in AL patients. Methods: We performed a single-center retrospective study of adult AL patients with ICH at Memorial Hermann Hospital Texas Medical Center from January 1, 2013, to December 31, 2022. Data collected included: age at diagnosis, type of AL, white blood cell count (WBC), platelet count, coagulation profile, Glasgow Coma Scale score at presentation, response to platelet transfusion, need for surgical, minimally invasive intervention, and mortality rates at 72 hours and 30 days. Descriptive statistics were used to analyze the data. Results: Among 160 consecutive AL patients, we identified 22 (13.75%) with ICH at presentation (APL = 11, AML = 6, B-ALL = 3, Burkitt leukemia = 1, myeloid sarcoma = 1). All were newly diagnosed except for one (an intracranial relapse of AML). Median age was 54 (range, 20–82) years; 60% were women. Subject races included white (n = 10), Asian (n = 5), Hispanic (n = 2), African American (n = 2), and others (n = 3). Median WBC count at admission was 23 (range, 0.2–400) × 109/L. Thrombocytopenia (platelet levels &lt; 50,000/μL) was present in 16 patients (72%), and 3 had platelet counts &lt; 10,000/μL. Twelve patients (54%) had evidence of DIC. Sites of ICH included intraparenchymal (n = 8), subarachnoid (n = 3), subdural (n = 10), cerebellum (n = 1). In 3 patients, ICH extended into the ventricles. Three patients had ≥2 types of ICH. Three patients had middle cerebral artery ischemic stroke in addition to ICH. One patient with myelofibrosis and myeloid sarcoma had bilateral subdural hematomas (SDHs) on admission and developed a fatal basal ganglia ICH during induction chemotherapy. All APL patients were promptly started on all-trans retinoic acid. Two patients had refractory thrombocytopenia. Five patients required craniotomy, with 2 deaths from recurrent ICH. Two patients with SDH underwent MMA embolization with favorable outcomes. Four patients (18%) died within 72 hours of admission (APL = 3, AML = 1). The 30-day mortality rate among patients presenting with ICH was 31% (n = 7). Conclusions: ICH in AL continues to be a major cause of mortality and morbidity. Early diagnosis, transfusion support, correction of coagulopathy, and neurosurgical expertise are critical in improving outcomes in AL-associated ICH. MMA embolization is a new, minimally invasive strategy for the management of SDH in these critically ill patients.