Median Overall Survival For Patients Research Articles

Outcomes of Triple Class Refractory Multiple Myeloma Patients: A Single Center Retrospective Study

BACKGROUND Despite recent advances in the treatment of multiple myeloma (MM), the disease remains incurable. Recent studies suggest that patients who are triple class refractory (TCR) to a proteasome inhibitor (PI), immunomodulatory agent (IMiD), and anti-CD38 monoclonal antibody (mAb) have especially poor outcomes with a median overall survival (OS) of less than 1 year. However, studies with these results have been conducted in large academic institutions. In this study, we retrospectively analyzed outcomes among MM patients with TCR MM in a single clinic specializing in the care of patients with MM. METHODS A retrospective chart review was conducted among patients with TCR MM who were treated in a single clinic specializing in the care of patients with this B-cell malignancy. From July 2003 to July 25, 2022, we determined these patients' progression-free survival (PFS), OS, cytogenetics, lines of prior therapy (LOT), and first treatment they received after they became TCR. Kaplan-Meier analysis was utilized to assess differences in PFS, OS from diagnosis, and OS from TCR status based on high-risk cytogenetics, defined as the presence of t(4;14), t(14;16), t(14;20), 1q gain, or deletion 17p, compared to those with standard-risk cytogenetics. Kaplan-Meier analysis was also used to compare PFS according to number of lines of prior LOT, time to TCR, and drug class used for the first treatment after becoming TCR. RESULTS TCR developed in 121 patients. The median time from diagnosis to development of TCR disease was 33.4 months (mo; range, 1.5-187 mo). Patients with a time to TCR status of > 33.4 months had a longer PFS (median 5.2 mo) compared with patients with a time to TCR status of < 33.4 mo (median 2.5 mo; p=0.0171). The median LOT these patients received was 7 (range, 3-26). The median LOT prior to becoming TCR was 3 (range: 2-12). The median PFS of patients from their first treatment following the development of TCR was 4.5 months; patients with < or > 3 LOT prior to becoming TCR had the same median PFS (4.5 mo). However, PFS was shorter for high-risk (median = 2.5 mo) than standard risk (median = 4.2 mo) TCR MM patients, but this did not reach statistical significance (p = 0.0633). The median OS from diagnosis of MM was 94.8 mo (range, 5.8 - 320.6 mo). Cytogenetic data was available for 65 patients (54%). Of these, 35 (54%) harbored high-risk cytogenetics. The median OS of TCR patients with high-risk cytogenetics from diagnosis was 98.2 mo and was not different from those with standard risk disease (74.2 mo; p = 0.704). Notably, the median OS of patients from the time of development of TCR was 25.5 mo (range, 1.5 - 186.8 mo); OS was shorter (median 18.7 mo) among those TCR patients with high-risk cytogenetics compared with that of standard risk (38.5 mo), but this was not significant (p = 0.1109). The first line of therapy administered following the development of TCR for the majority of patients (n= 108 [89%]) was retreatment with an IMID, PI, mAb, or a combination of agents from these drug classes. Thirteen patients (11%) were treated with a venetoclax- or alkylating agent-based combination therapy. In addition, all except 2 patients received steroids as part of their first treatment after developing TCR. The regimen with the longest PFS was the combination of a mAB and steroids (median 9.0 mo) but only 6 patients were treated with this combination. The shortest PFS was among those retreated with a PI and steroids (n = 15; median 2.4 mo). The use of an IMID with steroids was the most frequently used combination treatment (n=32) with a median PFS of 3.4 mo. CONCLUSION Despite being refractory to a PI, IMID, and mAb, TCR patients in our single-center retrospective study showed a median OS of more than 2 years (25.5 mo) from the development of TCR. This OS is the longest reported to date in this population of MM patients. Cytogenetic differences failed to predict both OS and PFS from the development of TCR. In addition, the number of prior lines of therapy did not predict PFS from their first treatment after showing TCR. The time to development of TCR, however, did predict OS as patients who took longer to become TCR had a longer median OS. The results of this study show that time to becoming TCR is a prognostic factor for this group of patients. Our study shows that OS is considerably longer for patients with TCR than has been previously reported.

Survival Analysis of Adults with Acute Lymphoblastic Leukemia in Ecuador

Background Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults. Unfortunately, in Ecuador there are no survival studies in patients ≥15 years with ALL, thus, this is the first national report. The aim of the study was to describe clinical-demographic characteristics and overall survival (OS). Methods Medical records of 628 patients from 8 reference hospitals in Ecuador with acute lymphoblastic leukemia (ALL) aged ≥15 years, diagnosed between January/2015 and December/2022, were retrospectively reviewed. A high-risk group was defined as: age ≥ 35 years ; ≥ 30,000/mm3 leukocytes in B-cell acute lymphoblastic leukemia (B-ALL) or ≥ 100,000/mm3 leukocytes in T-cell acute lymphoblastic leukemia (ALL- T) ; CNS infiltration at diagnosis, and/or if EMR was not reached (<0.01%) negative at the end of induction. If none of these factors were present, it was classified as standard risk. OS and treatment-related mortality were evaluated. Before carrying out this study, the approval of a national research ethics committee was obtained, as well as the approval of the 8 participating centers. Results 628 patients with ALL were included in the study. Summary of clinical and demographic data Table 1. In this cohort of patients, 9 different regimens of intensive chemotherapy were used. 454/517 (87.8%) patients with B-ALL were considered high risk. 595/628 (94.5%) patients received intensive chemotherapy. 150/595 (25.2%) and 54/595 (9.0%) patients died during the induction and consolidation phase respectively, reaching a mortality related to the treatment of 34.2%. In 290/401 (72.3%) with B-ALL achieved a complete response (CR) after induction, also 199/401 (49.1%) patients achieved minimal residual disease (MRD) negative (<0.01%). 16/235 (6.8%) patients with B-ALL considered high risk who achieved CR received allogeneic hematopoietic stem cell transplantation (HSCT). 32/35 (91.4%) patients with T-cell acute lymphoblastic leukemia (T-ALL) received intensive chemotherapy, of which 17/24 (70.8%) achieved CR, MRD negative (<0.01%), in 8/20 (40.0%) and 3/17 (17.6%) who achieved CR received HCT. The median OS was 12 months (95% CI 9.8-14.1) with a 5-year OS of 25.6%. The median OS for intensive chemotherapy patients with B-ALL was 12 months (95% CI 9.8 - 14.1) with a 5-year OS of 25.8% and 8 months (95% CI 5.9 - 10.0) with a 5-year OS of 23.5% for T-ALL. The 5-year OS for patients with HSCT was 78.4% (median survival not reached). The median OS for patients with B-ALL who received intensive high-risk chemotherapy was 12 months (95% CI 9.7-14.2) while median survival was not reached in the standard-risk group (p=<0.01). Figure 1. In patients with ALL-B, regimens with or without L-asparaginase achieved a 5-year OS of 26.4% vs 22.9% (p=0.588), respectively. In multivariate analysis for patients with ALL-B on intensive chemotherapy, age [HR 1.02 (95% CI 1.00 - 1.04) p=0.014] was significantly associated with OS, as well as those patients who did not achieve negative an MRD [HR 1.82 (95% CI 1.23-2.69) p=<0.01]. Otherwise, the adolescent and young adults (AYA) group, BCR:ABL fusion, CNS infiltration and leukocyte number at debut, L-asparaginase chemotherapy regimens, and being classified as high-risk group did not show statistical differences associated with OS . Conclusion The reported OS rates in this cohort are considerably low when compared to with international available data, being mainly negatively affected by the high treatment-related mortality rate, and the small number of patients who reach a HSCT.

Incidence and Risk Factors for Central Nervous System Relapse after Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Acute Lymphoblastic Leukemia

Background Acute lymphoblastic leukemia (ALL) is frequently accompanied with the involvement of the central nervous system (CNS). The clinical prognosis for ALL patients with CNS disease is generally unfavorable, and prophylactic measures such as intrathecal chemotherapy are highly recommended. In adult ALL patients, hematopoietic stem cell transplantation (HSCT) presents a potential curative approach. However, there are currently only a few reports available on the risk factors and epidemiology of CNS relapse after HSCT. Method We conducted a retrospective single-center cohort study involving 1043 patients diagnosed with either acute lymphoblastic leukemia (ALL) or mixed phenotype acute leukemia (MPAL). These patients were treated at our center using the same treatment protocol between 2009 and 2022. During the remission induction phase, we utilized a modified hyper-CVAD regimen, along with six rounds of prophylactic intrathecal (IT) chemotherapy. High-risk patients who had suitable donors underwent allogeneic hematopoietic stem cell transplantation (HSCT) as part of their post-remission therapy. Diagnosis of central nervous system (CNS) leukemia was established when neurologic symptoms were observed in correlation with CNS lesions on imaging studies, or when leukemic blasts were detected in the cerebrospinal fluid (CSF). In our study, we examined the incidence, risk factors, and survival outcomes of patients who experienced CNS relapse after transplantation. Results Among the entire cohort of 1043 patients, CNS involvement was observed in 3 (0.3%) patients at initial diagnosis and 12 (1.2%) during chemotherapy. We proceeded with allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 755 consecutive patients. Among these 755 patients, 3 had CNS leukemia prior to transplantation. Among the group of 755 patients, a total of 224 (29.6%) experienced relapse. Of these relapses, 142 (18.8%) were bone marrow relapses alone, 54 (7.1%) were extramedullary relapses alone (with CNS involvement in 21 [38.8%]), and 28 (3.7%) had both bone marrow and extramedullary relapses (with CNS involvement in 13 [46.4%]). Overall, extramedullary relapse was observed in 82 (10.8%) patients, with CNS involvement in 34 (4.5%) cases, following allo-HSCT. The 5-year cumulative incidence of CNS relapse was 4.6%, which was significantly higher in patients with Philadelphia chromosome-positive (Ph-positive) ALL (9.4% vs. 1.0%, p <0.001), as well as those with a high leukocyte count at diagnosis (8.3% vs. 2.6%, p = 0.001). Among the Ph-positive ALL cases, a high leukocyte count (n=151) was associated with a higher prevalence of pre-HSCT minimal residual disease (MRD) > 0.1% (n=88), which exhibited a significantly increased incidence of CNS relapse (16.6% vs. 6.8%, p = 0.009). Factors such as age, number of intrathecal chemotherapy treatments, conditioning intensity, and dose of anti-thymocyte globulin did not have a significant impact. Among the 34 patients with CNS relapse, 21 (61.7%) had isolated CNS relapse, and 7 of them showed evidence of positive MRD. With the exception of one patient who refused further treatment, the remaining 33 patients received initial CNS local therapy, including intrathecal chemotherapy combined with radiotherapy in 27 (82.0%) cases, intrathecal chemotherapy alone in 6 cases, and radiotherapy alone in 4 cases. Out of these patients, 22 were treated with dasatinib or ponatinib, while 6 received salvage chemotherapy. The median overall survival for patients with CNS relapse was 11.2 months, which was 19.8 months for those with isolated CNS relapse and 10.9 months for those with CNS relapse accompanied by bone marrow relapse (p = 0.077). The subsequent 2-year cumulative incidence of CNS relapse was 30%. Conclusion Based on our findings, the current prophylaxis strategy employed for the prevention of post-HSCT CNS relapse in adult ALL appears to be effective. However, our data indicates that MRD-positive Ph-positive ALL requires distinct management due to its significantly elevated risk of CNS relapse. New strategies including prophylactic radiotherapy for this high-risk subgroup must be considered to prevent post-HSCT CNS disease.

Invasive Fungal Infections after CAR T-Cell Therapy for B-Cell Lymphoma: A Study from the French Descart Registry

Introduction: Chimeric antigen receptor (CAR) T cell therapy has emerged as an important treatment option for patients with B-cell malignancies. Despite its major clinical impact, CAR T cell therapy holds a potential risk of increased susceptibility to infections, including invasive fungal infections (IFI). Since data about the prevalence and impact of fungal infections in this population are limited, we aimed to provide a comprehensive overview of IFI using real-world data from the national DESCAR-T registry. Methods: We performed a multi-center retrospective cohort study, quering the French DESCAR-T registry (NCT04328298), to describe type, frequency and outcomes of IFI in adults with refractory or relapsed (R/R) B cell lymphomas. In addition, healthcare providers were contacted to declare any missing cases. Demographic, biological and clinical characteristics were collected retrospectively. Each IFI case was reviewed by an infectious disease specialist and a microbiologist, and classified according to the European Organization for Research and Treatment of Cancer (EORTC) criteria (Donnelly et al. Clinical Infect Dis 2020). Results: Among the 1144 patients included in the registry from 2018 to 2022, we identified 57 suspected IFI cases. After exclusion of 25 patients not adjudicated for IFI, 32 patients (3%) were identified as having presented a proven (n = 14), probable (n = 12), or possible (n = 6) IFI. DLBCL was the primary diagnosis for 30 patients and axi-cel was the most frequent CAR T product (23/32, 72%). Seven patients (22%) had received a previous hematopoietic stem cell transplantation. All patients experienced cytokine release syndrome (including 8 grade ≥ 3) and 21 (66%) experienced immune effector cell-associated syndrome (including 13 grade ≥ 3). Overall, 27 (84%), 21 (66%), and 5 (16%) received tocilizumab (median 960mg, range 120-2880mg), corticosteroids, and anakinra, respectively. Among known risk factors for IFI, grade 4 neutropenia and late neutropenia (< 1g/L) at day 28 after infusion were identified in 25 (78%) and 14 (44%) patients respectively. Overall, 8 (25%) patients received antifungal prophylaxis, posaconazole was used for 4 of them. Over half of the IFI cases occurred between 0 and 30 days after CAR T-cell infusion (18/32, 56%), with a median onset time of 29.5 days (IQR 16.5 - 79.5). The most frequently observed infections were invasive Aspergillosis (n = 13), with pulmonary involvement in 10/13 (77%) of patients, leading to a fatal issue in 3/13 patients (23%). Other mold infections included Mucormycosis (n = 5), with pulmonary involvement in 4/5 patients and a fatal outcome in 1/5, as well as Fusariosis (n = 1). Yeast infections (n = 12) were mostly identified as Candidemia (92%) with a mortality rate of 3/12 (27%). The median overall survival of patients with IFI was 186.5 days (IQR 79-506), 7 deaths being related to IFI and 3 to lymphoma relapse. Median progression-free survival was 94 days (IQR 31 - 252). Conclusions: This study represents one of the largest investigations about IFI in B-cell lymphoma patients treated with CAR T-cells. Even though IFI represent a rare complication after CAR T-cell therapy, the related-mortality is high. Selective antifungal prophylaxis may benefit high-risk patients, while rapid preemptive diagnostic workup, particularly for lung involvement, is mandatory. Analysis to define potential risk factors for IFI are ongoing.

CLAG-Based Chemotherapy in Previously Untreated AML Patients: 12 Year Follow-up

Introduction: The 7+3 combination of cytarabine plus an anthracycline is the most commonly used induction regimen for AML in the US. There is evidence FLAG-IDA may be superior to 7+3 (Solh et al Leuk Res 2020), and that cladribine is superior to fludarabine (Holowiecki et al JCO 2012). Currently we report the results of CLAG-based chemotherapy in newly-diagnosed AML patients. Methods: This single-center retrospective cohort studied all patients with newly-diagnosed AML who received CLAG-based induction therapy (with or without an anthracycline, depending on cardiac function) between February 2011 and June 2023. Chemotherapy consisted of cladribine 5 mg/m 2 daily times 5 days, cytarabine 2 gm/m 2 over 4 hrs daily times 5 days (given 2 hours after the completion of each cladribine dose), plus G-CSF 300 ug daily during chemotherapy and then based on weight after that. Patients with adequate cardiac function also received 3 days of mitoxantrone 12 mg/m 2 (CLAG-M) or idarubicin 12 mg/m 2 (CLAG-IDA) on days 1-3 or 2-4. Many of these patients were treated prior to the current era of targeted therapies and thus most received chemotherapy without targeted agents. Post-remission therapy was given at the physician's discretion based on the patient's tolerance of induction chemotherapy. Complete response (CR) was defined as less than 5% blasts in the marrow with recovery of ANC >1000/mm 3 and platelets >100,000/mm 3. Lesser responses included CRi, CRp and PR. All others were considered failures or early deaths (within 30 days). This study was approved by the IRB of New York Medical College. Results: We analyzed all 87 newly-diagnosed AML patients that were treated with CLAG-based induction therapy (CLAG alone: 10%, CLAG-IDA: 87%, CLAG-M: 3%). 4 patients with a FLT-3 mutation received a FLT-3 inhibitor concurrently. Post-remission therapy included allo transplant (13%), further CLAG+/- IDA, reduced to 4+2 days (84%), HiDAC (27%), and hypomethylators (36%), in that order of priority. The intensity of the post-remission therapy was matched with the perceived ability of the patient to tolerate it. Many patients received more than one post-remission therapy in sequence. The median age of the cohort was 65 (33-85) years. 59% were male, 47% were smokers, 6% had prior MDS and 13% had therapy-related AML. The median baseline WBC was 9.7 (0.4-392) k/mm 3. 10% of patients were stratified as favorable ELN cytogenetic risk, 45% as intermediate, and 45% as adverse. TP53 mutation was present in 22% patients and FLT3 mutation in 14% patients. CR was obtained in 67% of patients overall and did not differ significantly by age (<60: 65%, 60-70: 70%, >70: 64%). Early deaths (within 30 days) were more common in older patients (<60: 3%, 60-70: 3%, >70: 8%). The CR rate was similar across all cytogenetic risk groups (good risk: 67%, intermediate risk: 68%, poor risk: 62%) and was favorable in patients with a TP53 mutation (68%), as well as those with therapy-related AML (69%). The median overall survival (OS) was 13 months. By cytogenetic risk the median OS was good: not reached, intermediate: 25.6 months and poor: 6.8 months (Figure 1). It should be noted that two patients with good risk cytogenetics who expired included an 80-year-old woman with therapy-related AML after treatment for breast cancer who declined further therapy after cycle 1 and survived 20 months with no further therapy, as well as a second unvaccinated patient who expired due to complications of COVID. Median OS by age was <60: 18 months, 60-70: 25.6 months and >70: 8 months (Figure 2). Median overall survival for patients with TP53 mutation was 5.6 months. Conclusion: CLAG provides an alternative induction regimen to 7+3. Interestingly, in contrast to 7+3, CR rates did not differ significantly by age or cytogenetic risk group. The older patients treated on this trial were a select group that were considered eligible for intensive chemotherapy. Many of the patients on this trial would be treated differently today, with the availability of more targeted therapies. However the relatively high response rates in patient with poor risk cytogenetics and/or TP53 mutation gives fit patients the opportunity of pursuing stem cell transplantation.

Real-World Clinical Outcomes in Patients with Relapse and Refractory Multiple Myeloma Received VTD-PACE Treatment in the Era of Monoclonal Antibody

The treatment outcomes of multiple myeloma (MM) have drastically improved with the use of novel agents, including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies. However, ultimately, the disease relapses and results in a fatal outcome. Even in cases of relapse, treatment outcomes have improved with the use of novel agents. However, in situations where novel agents have been exhausted or when the disease rapidly progresses, bortezomib (Velcade), thalidomide, dexamethasone, platinum (cisplatin), adriamycin (doxorubicin), cyclophosphamide, and etoposide (VTD-PACE) is frequently utilized, with reported effectiveness. However, its outcomes in the era of monoclonal antibodies remain unclear. Therefore, this retrospective cohort study assessed the clinical outcomes of 60 patients with RRMM (median four prior treatment lines) administered VTD-PACE at the Japanese Red Cross Medical Center between June 2016 and April 2023. The characteristics of the 60 patients are shown in Table 1. The VTD-PACE regimen consisted of 1 mg/m 2 of bortezomib on days 1, 4, 8, and 11 administered subcutaneously; 200 mg of thalidomide administered orally on days 1-4; 40 mg of dexamethasone administered orally on days 1-4; and a 4-day continuous intravenous infusion of 10 mg/m 2 cisplatin, 40 mg/m 2 cyclophosphamide, 40 mg/m 2 etoposide, and 10 mg/m 2 doxorubicin. The cisplatin dose was adjusted based on renal function, as determined by the treating physician. The responses were evaluated according to the International Myeloma Working Group response criteria. High-risk cytogenetic abnormalities (HRCA) included del (17p), t(4;14), and t(14;16). Double-class refractory disease was defined as refractoriness to PIs and IMiDs, whereas triple-class refractory disease was defined as refractoriness to PIs, IMIDs, and anti-CD38 monoclonal antibodies. Penta-drug refractory disease was defined as refractoriness to bortezomib, carfilzomib, lenalidomide, pomalidomide, and anti-CD38 antibodies. The median follow-up period was 11.1 months (range, 0.5-72.0 months), during which they received a median of two cycles of VTD-PACE. The overall response (ORR), stringent complete response, complete response, and very good partial response rates were 66.7% (40 patients), 13.3% (8 patients), 5% (3 patients), and 20% (12 patients), respectively. The results of univariate analysis for factors associated with response rate are shown in Table 2. The ORRs in patients with ≥4 and ≤3 prior lines were 53.1% and 82.1%, respectively ( P = 0.027). Extramedullary disease (EMD), refractoriness to anti-CD38 antibody, HRCA, and triple-class/penta-drug refractory disease did not significantly reduce the ORR. The median overall survival (OS) was 17 months with a median progression-free survival (PFS) of 9.8 months. The median PFS in patients with and without receiving hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor T-cell therapy (CART) following VTD-PACE were 9.8 and 5.1 months, respectively ( P = 0.023). The median OS in patients with and without renal dysfunction were 10.7 months and 21.5 months, respectively ( P = 0.0091). A trend for longer OS was observed in patients with HSCT or CART following VTD-PACE (P = 0.18). Therefore, VTD-PACE is useful as a bridging therapy for HSCT or CART, as a response is expected regardless of organ damage, disease risk, or history of anti-CD38 antibody use. However, the response rate decreased in late lines; therefore, its use in early lines is recommended.

Comprehensive Molecular Stratification of Patients with AML Treated with CPX-351

Background: Liposomal cytarabine-daunorubicin (CPX-351) is approved for treatment of acute myeloid leukemia (AML) with myelodysplasia (MDS)-related changes and therapy-related AML. CPX-351 induction has been observed to result in longer periods of bone marrow suppression than with 7+3 therapy. Thus, careful consideration is warranted when selecting patients for whom CPX-351 would provide an optimal risk-to-benefit ratio. It is unknown whether any specific genetic mutations impact outcomes from CPX-351 therapy. Methods: Forty-one subsequent patients with AML at VCU Massey Comprehensive Cancer Center from 2017 to 2022 were treated with CPX-351 (liposomal cytarabine-daunorubicin). Genetic mutation profiles were obtained from our institutional multi-gene panel next generation sequencing assay. Multivariate analysis was performed using Cox proportional hazards regression. Overall survival (OS) was analyzed via the Kaplan-Meier method. Composite complete response (CCR) was defined as CR + CR with incomplete hematologic recovery + CR with partial hematologic recovery. Results: The median age of patients treated with CPX-351 was 65.2 years (range, 20.1-78.5). Median ECOG performance status was 1 (range, 0-2) and Charlson Comorbidity Index was 4 (range,2-14). The majority (65.9%) of patients had adverse risk per ELN 2022 criteria, mostly with MDS-related and complex cytogenetics (17.1% favorable risk; 14.6% intermediate risk). Multivariate analysis identified mutated PTPN11 ( PTPN11mut)and IDH2 ( IDH2mut) as independent risk factors for decreased OS in patients treated with CPX-351. The hazard ratio (HR) for death of PTPN11 mut was 2438 (p = 0.017). The HR for IDH2mut was 124.2 (p = 0.022). Mutated TP53 was also a risk factor for reduced OS, with HR 3.21, but this was not statistically significant. Mutated SRSF2 ( SRSF2mut) was an independent prognostic factor for improved OS with CPX-351, with a HR of 0.0019 (p = 0.017). ASXL1, TET2, IDH1 and FLT3-ITD mutations were associated with improved OS, but these results did not reach statistical significance. For patients with SRSF2mut treated with CPX-351, median OS was 20.5 months, compared to 8.9 months for those without SRSF2mut (HR 0.49 [95% CI 0.28-0.88], p=0.037). The CCR rate was not significantly different between patients with and without SRSF2mut (p=0.66), and measurable residual disease (MRD) status could not be assessed due to unavailable historical data. Patients with PTPN11mut had a median OS of 11.2 months, whereas those without PTPN11mut had a median OS of 21.6 months, although this comparison was not statistically significant (HR 1.51 [95% CI 0.70-3.26], p=0.207). CCR rates were not significantly different between patients with and without PTPN11 mut. The median OS for patients with IDH2mut was 16.4 months, compared to 21.6 months for patients without IDH2mut but this difference was not statistically significant. Conclusions: Among patients with AML treated with CPX-351, PTPN11 and IDH2 mutations were independently associated with inferior overall survival compared to those without these mutations. The PTPN11 gene is involved in RAS pathway regulation and has also been associated with shorter survival in AML in other studies. Here, mutated SRSF2 was associated with improved survival after CPX-351 induction. SRSF2 is an RNA splicing factor gene that is frequently found in AML with antecedent MDS but has previously been associated with adverse outcomes after conventional intensive induction chemotherapy. Interestingly, CCR and MRD negativity rates did not differ for patients with these mutations compared to those without at our institution despite the noted changes in survival. These findings remain speculative and warrant further investigation with a greater number of patients in the era of routine MRD assessment. Moreover, controlling for confounders (such as death due to toxicity rather than disease or relapse), the impact of HCT, and frailty were not accounted for in this retrospective analysis. Future work includes identifying the potential impact of cooperating mutations.

Chemotherapy Refusal Patterns in Multiple Myeloma Patients: An in-Depth Analysis of the NCDB Data from 2004 to 2020

Background: Chemotherapy is a cornerstone in the treatment of multiple myeloma (MM), contributing to prolonged patient survival. However, despite its proven efficacy, some individuals opt to decline chemotherapy, leading to variations in treatment strategies and outcomes. Understanding the factors associated with the decision to decline chemotherapy in MM patients is crucial for optimizing patient-centered care and ensuring equitable access to appropriate treatments. Our investigation aims to illuminate potential areas for targeted interventions, with the goal of enhancing patient engagement and optimizing treatment strategies to improve overall outcomes in MM management. Methods: N=152,299 patients diagnosed with MM between 2004 and 2020 were identified using the NCDB, all of whom were recommended for chemotherapy. Overall survival (OS) of patients who received chemotherapy compared to those who did not receive it was evaluated and presented using Kaplan-Meier (KM) curves. Multivariate logistic regression analysis with backward elimination was used to identify factors associated with refusal of chemotherapy. SAS version 9.4 was used to analyze the data. Results: Among 152,299 patients who received a recommendation for chemotherapy from their physicians, 3,289 individuals (2.16%) opted to refuse the treatment. Descriptive statistics for patients who refused chemotherapy are presented in Table 1. The median OS for patients who received chemotherapy was 61.37 months, in contrast to 8.8 months for those who declined this treatment (Figure 1). Our multivariate logistic regression analysis revealed several significant factors associated with chemotherapy refusal in MM patients. Age exhibited a statistically significant association, with increasing odds of refusal observed in patients aged 60-69 years (OR=1.29, p=0.045), 70-79 years (OR=2.26, p<0.0001), and 80 years and older (OR=7.29, p<0.0001) compared to those younger than 50 years. Male patients exhibited lower odds for refusal (OR=0.85, p<0.0001) compared to female patients. Black patients had higher odds for refusal (OR=1.26, p<0.0001) compared to White patients. Patients with Medicare, Medicaid/other government insurance, and no insurance had higher likelihood of refusal (OR=1.71, 1.89 and 3.13 respectively, p<0.0001) than patients with private insurance. The Charlson-Deyo score demonstrated a significant association, with higher scores correlating with increased odds of refusal (p<0.0001). Patients treated at non-academic facilities had higher odds of refusal (OR=1.47, p<0.0001) compared to academic facilities. Education was significantly associated with refusal, with patients having lower education levels exhibiting increased odds of refusal. Patients living in areas where more than 21% of the area residents have no high school diploma (HSD) had higher odds of chemotherapy refusal compared to patients living in areas where less than 7% have no HSD (OR=1.28, p=0.0026). The year of diagnosis was also linked to refusal, with patients diagnosed between 2004-2007, 2008-2011, and 2012-2015 having higher odds of refusal compared to those diagnosed between 2016-2020 (OR=1.62, 1.25 and 1.27 respectively, p<0.0001). It is also important to note that geographical location played a role, with patients treated in the East North Central, Mountain, and Pacific regions exhibiting significantly higher odds for refusal compared to the South Atlantic region (OR=1.17, 1.35 and 1.16 respectively, p=0.01, 0.002 and 0.03 respectively). Conclusion: Our comprehensive analysis of MM patients shows that the chemotherapy refusal rate in the real-world setting is low at 2.16%. Despite the low rate of refusal, this study did identify several important factors significantly associated with chemotherapy refusal in this patient population. Older age, female sex, Black race, non-private insurance, higher comorbidities, lower education level, non-academic facility type, earlier year of diagnosis, and East North Central, Mountain, and Pacific facility locations were associated with higher likelihood of declining chemotherapy. Our findings emphasize the importance of considering socioeconomic (level of education, insurance status), as well as racial and regional factors, while developing targeted interventions to address disparities in order to enhance engagement in myeloma care.

Socioeconomic Determinants and the Biology and Outcomes of Acute Lymphoblastic Leukemia in Adults

Introduction Implementation of pediatric-inspired chemotherapy regimens improved survival outcomes in adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL). Prior studies demonstrated that Non-Hispanic White (NHW) patients had better survival outcomes in the real-world AYA setting, but this effect was not observed in the pivotal CALGB 10403 clinical trial. To better characterize the socioeconomic versus biologic determinants of ALL outcomes, we conducted a single-institution, retrospective analysis of adult patients with ALL at the University of Chicago. We sought to investigate the impact of socioeconomic factors on ALL outcomes when patients are treated at a multidisciplinary, tertiary-care ALL center. Methods Adult patients with ALL treated at the University of Chicago between 2010 and 2022 were studied. Subtype classification was based on the 2022 WHO criteria. ALL patients were treated according to age-appropriate regimens (AYA with CALGB 10403-based regimens, older adults (>40) with lower intensity approaches). Because of treatment differences, outcomes of AYA and older patients were analyzed separately. Self-reported race was reported with guidelines from the National Cancer Institute (https://www.nih.gov/nih-style-guide/race-national-origin). Body mass index (BMI) was recorded at diagnosis. Annual median income was estimated based on the zip code of residence and categorized as high (>$50,000), middle ($35,000-50,000), and low (<$35,000). Additionally, we extracted data from the public use US population-based cancer registries of the Surveillance, Epidemiology, and End Results (SEER, http://seer.cancer.gov) program to estimate overall survival (OS) of ALL patients diagnosed between 2005 and 2020. Results Demographic and disease characteristics of 221 adult ALL patients treated at the University of Chicago are summarized in Table 1. BCR::ABL1 was more prevalent in Black ALL patients compared to NHW and Hispanic White (HW) patients (59% vs 24% and 20%, respectively, p=0.001). This phenotypic subtype was also associated with higher BMI (OR 7.64; 95% CI=1.17-49.9, p=0.03). Compared to NHW patients, low annual household income was more frequent in HW and Black patients (2% vs 13% and 24%, respectively, p<0.001). Similar OS was seen among NHW, HW, and Black patients when stratified by age (AYA vs older adult), B vs T-lineage phenotype, or median household income. Obesity at B-ALL diagnosis was associated with adverse OS, and median OS for patients with BMI <30, 30-40, and >40 were 113 months, 34 months (HR 2.04; 95% CI=1.27-3.28, p=0.003), and 23 months (HR 2.70; 95% CI=1.34-5.42, p=0.005), respectively. In our multivariable analysis, factors that were independently associated with adverse OS were age and BMI at diagnosis (HR 6.93; 95% CI 2.27-21.1, p=0.0007; HR 10.3; 95% CI 2.56-41.5, p=0.001, respectively), while BCR::ABL1 positivity predicted favorable OS (HR 0.41; 95% CI 0.2-0.87, p=0.02, see Figure 1). Compared to the SEER cohort, OS in older University of Chicago patients was better than the national average (53 months vs 23 months, HR 0.70; 95% CI=0.56-0.88, p=0.003). Among SEER AYA patients from 2015-2020, HW (HR 1.54; 95% CI=1.26-1.91, p=<0.001) and Black (HR 1.64; 95% CI=1.14-2.36, p=0.006) patients had significantly worse OS compared to NHW patients. Finally, SEER data showed that patients with higher median household incomes had better OS than patients with lower incomes. Specifically, older adult patients who reported higher median household income had better OS at 24 months compared to older adults with medium or low income at 15 months (respectively, HR 1.25; 95% CI=1.10-1.47, p=<0.001; HR 1.52; 95% CI=1.07-2.17, p=0.01). Conclusion While SEER data demonstrated significant OS differences based on race and median household income nation-wide, these variables did not predict adverse OS at our institution. The University of Chicago has an ALL center with a dedicated AYA clinic offering resources to support patients throughout their long pediatric-inspired therapies, as well as clinical trial options for both young and older adults. Located in a historically Black and low-income neighborhood, the University of Chicago plays a critical role in addressing socioeconomic disparities in ALL care for our community. Further interventional studies are needed to modify the poor prognostic impact of obesity in patients with ALL.

TP53 Y220C Mutations in Patients with Myeloid Malignancies

Background: TP53 gene mutations lead to inactivation of the protein p53, causing genome instability, oncogenesis, and treatment resistance conferring an unfavorable prognosis. TP53 Y220C missense mutations in exon 6 (p.659A>G) are described as a frequent ‘hot spot’ mutation in solid tumors. A novel Y220C-targeted small molecule (PC14586) has shown preliminary efficacy and safety in patients with solid tumors (Dumbrava, E., ASCO 2022). No data has been reported about TP53 Y220C in hematologic malignancies to date. We set out to evaluate the clinicopathologic characteristics of TP53 Y220C in hematologic malignancies and particularly, myeloid neoplasms. Methods: We identified all patients with hematologic neoplasms with TP53 Y220C mutations at University of Texas MD Anderson Cancer Center and Memorial Sloan-Kettering Cancer Center, detected by standard next generation sequencing assays, and focused on patients with myeloid malignancies; summarizing the patient characteristics, disease features and outcomes for patients with this specific TP53 mutation. Overall survival (OS) was assessed by the Kaplan-Meier method from date of diagnosis to date of death from any cause or date of last follow-up. Leukemia-free survival (LFS) was calculated from time to diagnosis of TP53 Y220C mutated myelodysplastic syndrome (MDS) to date of transformation to acute myeloid leukemia (AML) or death. Survival analysis was conducted only for newly diagnosed patients with available follow-up data. Results: We identified 143 patients (pts) with hematologic malignancies harboring a TP53 Y220C mutation. MDS and AML were the most frequent diagnoses (MDS, n=66; AML, n=48). Median age was 69 years (range, 32-92) and 56% of patients were male (Table 1). We then analyzed in more detail patients with MNs, including CHIP/CCUS, MDS, AML and MDS/MPN. Among those, in 76 (64%) pts the TP53 Y220C mutation was detected at initial diagnosis and in 43 (36%) pts, TP53 Y220C was identified in the relapsed/refractory setting. Therapy-related myeloid neoplasms (MNs) accounted for 51 of 119 pts (41%). Complex karyotype was frequent (n=88/119, 74%) in the setting of TP53 Y220C. Median TP53 Y220C variant allele frequency (VAF) was 32% (range, 1%-96%). Eighty-two patients (69%) had additional co-mutations: 24 (20%) pts had additional (non-Y220C) TP53 mutations only; 34 (29%) pts had only non- TP53 co-mutations (most frequently DNMT3A and TET2) and 24 (20%) pts had additional TP53 mutations in the setting of other co-mutations. With a median follow-up of 9 months, median OS for patients with newly diagnosed TP53 Y220C MDS (n=39) and AML (n=23) was 13.1 months (95% CI, 7.6 to 18.7) and 8 months (95% CI, 5.6 to 13.4), respectively ( p=0.06) (Figure 2). For the TP53 Y220C MDS cohort, AML transformation occurred in 13 (33%) patients, after a median of 14.3 months. Median LFS for these patients was 12.2 months (95% CI, 7.9 to 16.5). Modest and non-statistically significant differences in median LFS for MDS patients who did and did not receive stem cell transplant (SCT) were identified; MDS+SCT (n=12) 14.5 months (95% CI, 4 to 25) vs MDS+no-SCT (n=27) 9.3 months (95% CI, 4.6 to 14), p=0.18. Interestingly, four patients diagnosed with TP53 Y220C mutated CHIP/CCUS with a median VAF of 2% were identified, and with a median follow-up of 34.6 months, none have developed dysplastic changes or progression to MDS or AML at the time of cut off. Additional outcomes data will be forthcoming in the analysis of this cohort of patients with TP53 Y220C mutated myeloid neoplasms. Conclusions: TP53 Y220C mutations are present in malignant blood disorders and are particularly more common in myelodysplastic syndromes and acute myeloid leukemia, with associated poor outcomes. Novel targeted therapies for this TP53 variant (Y220C) would be of interest for this patient population.

EPID-04. EVOLVING SURVIVAL IN PATIENTS WITH LEPTOMENINGEAL METASTASES FROM SOLID TUMORS

Abstract BACKGROUND The prognosis for patients with leptomeningeal metastases (LM) has been historically bleak, with an average survival < 4 months and limited treatment options. As modern therapeutics prolong the lives of cancer patients, the life expectancy of those with LM may also improve. This study aims to demonstrate survival trends in patients with LM over a 20-year time span. METHODS This is a single-institution retrospective analysis of patients diagnosed with solid tumor LM, excluding primary brain tumors, between 2002-2022. LM diagnosis was determined via unequivocal radiographic enhancement, CSF cytology, and CSF circulating tumor cell enumeration (CSF-CTC, cells/3mL). Patient characteristics, CSF-CTC enumeration at diagnosis, and therapeutic interventions post-LM were collected. Median overall survival (OS) with IQRs were calculated. RESULTS A total of 626 patients with LM were identified. The median age at LM diagnosis was 59 years (range, 13-86) with a female predominance (72.5%). Primary malignancy consisted of lung (45.2%), breast (35.7%), melanoma (4.0%), and other (15.1%). The 20-year median OS in patients with lung cancer was 4.8 months (1.9-13.0), breast cancer was 6.1 months (2.0-13.7), and melanoma was 7.1 months (2.8-14.5). Median OS was prolonged in patients with a CSF-CTC count ≤ 50 versus > 50 (8.9 vs 3.4 months, p< 0.0001). Patients who received LM-directed proton craniospinal irradiation (17.1%), photon involved-field radiation (45.5%), and no radiation (37.4%) had a median OS of 8.7 months (4.3-20.2), 4.3 months (1.5-9.1), and 3.4 months (1.2-12.5), respectively. Patients diagnosed with LM between 2017-2022 trended towards superior median OS (6.2 months, 2.2-14.0) compared to those diagnosed between 2002-2016 (5.3 months, 2.2-12.2). CONCLUSION In this largest known series of patients with LM, outcomes show signs of improvement. Superior survival trends emerge based on primary malignancy, early detection, and modern treatment modalities. Further analyses will define survival trends by patient characteristics, cancer subtypes, and systemic therapies.

CPX-351 Versus FLAG-IDA with or without Venetoclax in Previously Untreated and Relapsed or Refractory Acute Myeloid Leukemia

1. Introduction A recent randomized comparison of liposomal daunorubicin and cytarabine (CPX-351) did not improve response rates or overall survival compared with FLAG-IDA in newly diagnosed acute myeloid leukemia (AML) - although subgroup analyses appeared to show some benefit with CPX-351. The real-world outcomes of these cohorts are unknown. Additionally, there is little data on the relative outcomes of these cohorts in the relapsed or refractory (RR) setting. We aimed to explore the efficacy of CPX-351 and FLAG-IDA with or without venetoclax in newly diagnosed and RR AML outside of clinical trials. 2. Methods We analyzed 142 patients from the Project ERIS database with newly diagnosed or relapsed or refractory (RR) AML treated with CPX-351 or FLAG-IDA from January 1, 2013 to April 18, 2023 at VCU Massey Comprehensive Cancer Center. We recorded baseline patient-related and disease characteristics, including age, ECOG, Charlson comorbidity index (CCI) scores, molecular profiling and ELN 2022 cytogenetic risk, dates of regimen initiation, and survival. We used the D'Agostino & Pearson method for normality testing and the t-test or Mann-Whitney (as applicable) tests for between-group comparisons. Categorical comparisons used Fischer's exact test. We applied the Bonferroni correction if multiple comparisons were made. The Wilson-Brown method was used for 95% confidence intervals. We analyzed survival by the Kaplan-Meier method with significance determined by the log-rank test. The event for calculating the overall survival (OS) was the date of death. Patients were otherwise censored at the date of last contact. 3. Results First, we analyzed 43 (30.3%) patients with newly diagnosed AML fit for intensive chemotherapy: 33 (76.7%) received CPX-351 and 10 (23.3%) received FLAG-IDA. In the FLAG-IDA cohort, three (30.0%) patients received concurrent venetoclax. There were no significant differences in baseline characteristics, including age, sex, race, or CCI scores, shown in Table A. However, patients in the CPX-351 cohort had significantly worse ECOG performance status compared with the FLAG-IDA cohort (median, 1 vs 0, p = 0.007). There were no significant differences in the proportion of patients that had ELN 2022 adverse risk cytogenetics between the CPX-351 and FLAG-IDA cohorts (65.6% vs 55.6%, p = 0.701). The composite complete response rate (CRc; CR + CRi + CRh) was 53.6% (95% CI: 35.8-70.5) in the CPX-351 cohort and 62.5% (95% CI: 30.6-86.3) for FLAG-IDA (p = 0.709). The rate of MRD negativity was 33.3% for CPX-351 (95% CI: 5.9-70.0) and 50.0% (95% CI: 2.6-97.4) for FLAG-IDA. A similar proportion of patients proceeded to allogeneic stem cell transplant (alloSCT; 39.4% vs 40.0%, p > 0.999). There was no significant difference in the median overall survival in patients treated with CPX-351 or FLAG-IDA (16.1 m. vs 11.4 m., p = 0.129, Figure B). Next, we analyzed 96 (90.7%) patients that received FLAG-IDA and ten (9.3%) that received CPX-351 for RR AML in any subsequent line; three (2.1%) patients in the overall cohort received either CPX-351 or FLAG-IDA in the first-line setting, then crossed over to the other arm at disease progression. Sixteen (16.7%) patients received venetoclax with FLAG-IDA. There were no significant baseline differences between cohorts, as shown in Table A. The CRc for CPX-351 was 33.3% (95% CI, 5.9-70.0) compared with 47.7% (95% CI, 37.6-58.0, p = 0.681) for FLAG-IDA. The rate of MRD negativity was 50.0% (95% CI, 2.6-97.4) for CPX-351 and 66.7% for FLAG-IDA (95% CI, 39.1-86.2, p > 0.999). There was no significant difference in the median overall survival in patients treated with CPX-351 or FLAG-IDA (12.7 m. vs 14.5 m., p = 0.561). 4. Discussion There was no significant difference in the rates of CRc, MRD negativity, or overall survival in patients that received CPX-351 or FLAG-IDA with or without venetoclax in the first-line setting or at the time of disease progression. Both approaches appear to be viable in carefully selected cohorts of patients. A comprehensive toxicity analysis and exploratory molecular subgroup analysis are ongoing.

Real World Outcomes of CPX-351 Compared to Traditional Chemotherapy with Cytarabine Consolidation for Treatment of Secondary Acute Myeloid Leukemia

Introduction: Outcomes in patients with secondary AML (sAML) are inferior to those with de novo AML which has led investigators to seek alternatives to traditional treatment. Liposomal daunorubicin and cytarabine, or CPX-351, for the treatment of sAML has shown superior complete remission/complete remission with incomplete count recovery (CR/CRi), event-free survival (EFS), and overall survival (OS) compared to the traditional non-liposomal formulations of daunorubicin and cytarabine (“7+3”). However, this agent was originally studied in combination with a suboptimal consolidation regimen which did not include standard of care high dose cytarabine (HiDAC). This is often cited as a limitation of the study and may have contributed to the significantly lower response rates reported when compared to historical data. Here we present a real-world comparison of the efficacy and safety of patients with sAML receiving CPX-351 versus traditional 7+3 with HiDAC consolidation. Methods: Patients were at least 18 years of age with sAML, defined as: t-AML, AML-with Myelodysplasia-Related Changes (MRC), or AML with a history of chronic myelomonocytic leukemia (CMML). Patients were included if they had received induction (and consolidation, if applicable) with CPX-351 or induction with 7+3 (daunorubicin 60 mg/m 2 for 3 days and cytarabine 100 mg/m 2 for 7 days), followed by consolidation with cytarabine (≥1000 mg/m 2 x 6 doses). Nominal data were analyzed using chi squared tests or Fisher's exact tests. Continuous data were analyzed using the Mann-Whitney U test. A Kaplan Meier estimator was used for survival outcomes. Results: Overall, 58 patients with sAML were included, with 36 (62%) receiving CPX-351 and 22 (38%) receiving 7+3 followed by cytarabine-based consolidation between April 2013 and June 2022. Patients in the CPX-351 were older (67.5 vs 62 years, p=0.04) and had a higher prevalence of poor-risk cytogenetics (p=0.22). Other baseline characteristics were similar (Table 1). The rate of CR/CRi following induction was significantly higher in patients who received 7+3-based induction vs patients who received CPX-351 (81.8% vs 44.4%, p=0.01). Twenty-five percent of patients achieved CR/CRi in the CPX-351 arm with one induction cycle, compared to 95.5% in the 7+3 group. Median progression-free survival (PFS) was 3 vs 6.1 months (p=0.67) and median OS was 18.3 vs 9.3 months (p=0.73) in the CPX-351 and 7+3 cohorts, respectively (Figure 1). Thirty-nine percent of patients in the 7+3 cohort proceeded to allogeneic stem cell transplant compared to 81% in the CPX-351 cohort, however median OS in patients who underwent transplant was similar between the two cohorts (16.8 vs 15.8 months). Median OS was longer in the CPX-351 cohort however this was not statistically significant (Figure 1). Rates of both febrile neutropenia (94.3% vs 95.5%; P>0.99) and confirmed infections (54.3% vs 50%) were similar amongst those treated with CPX-351 and 7+3. Bacteremia and pneumonia were the most common infections in both cohorts. Median duration of neutropenia was significantly longer in the CPX-351 cohort (43 days vs. 27 days, p=0.002) with no major difference in duration of thrombocytopenia. In the 7+3 cohort, 11 deaths were directly attributed to progression, while 5 were associated with infection. In the CPX-351 cohort, 6 deaths were directly attributed to progression, while 8 were attributed to infection. At day 60, two deaths were observed in the CPX-351 cohort and there were no deaths in the 7+3 cohort. Conclusion: These findings suggest use of traditional 7+3 induction followed by HiDAC consolidation may be an alternative to CPX-351 for patients with sAML. Although median PFS was longer in the 7+3 cohort, this did not translate into longer median OS, likely due to the low rate of patients proceeding to transplant. Similar rates of overall survival in patients undergoing allogeneic stem cell transplantation support the hypothesis that transplant should be the goal for most patients with sAML. The retrospective nature of the study may limit broader application of this data.

A Phase 2 Study of Canakinumab in Patients with Lower-Risk Myelodysplastic Syndromes or Chronic Myelomonocytic Leukemia

Background Myelodysplastic syndromes (MDS) lie on a continuum of myeloid neoplastic progression between clonal hematopoiesis (CH) and acute myeloid leukemia (AML). Interleukin 1 beta (IL-1β)-induced inflammasome activation is a mechanism of cancer initiation and progression. Given that IL-1β upregulation induces aberrant myeloid differentiation of hematopoietic stem and progenitor cells (HSPCs), we hypothesize that IL-1β plays a critical role in MDS pathogenesis, and targeting IL-1β signaling will overcome aberrant MDS HSPCs' myeloid skewing. Here, we report final results of a phase 2 study evaluating the safety and efficacy of canakinumab, an IL-1β inhibitor, in patients with lower-risk MDS or chronic myelomonocytic leukemia (CMML). Methods We conducted a single center, open-label phase 2 trial at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients aged ≥ 18 with IPSS-R ≤ 3.5 MDS/CMML who have previously been treated were included in the study. Patients received 300 mg of canakinumab on day 1 of a 4-week cycle. The primary objective was to determine the clinical activity of canakinumab in MDS/CMML patients. Response was assessed using the modified International Working Group 2006 criteria for MDS (Cheson et al. 2006). Secondary objectives were to evaluate the safety profile including rate of transfusion independence (TI), duration of response (DoR), progression-free survival (PFS), and overall survival (OS). All patients who received 1 dose of study drug were included in the analyses. This study is registered with ClinicalTrials.gov (NCT04239157). Findings Between August 2020 and May 2023, 27 patients were enrolled in the phase 2 portion of this study, and 2 patients failed screening. The median age was 74 years with 15 (60%) male patients; 20 patients (80%) were post-hypomethylating agent failure with a median number of prior lines of therapy of 2 (1-5). Transfusion dependency was observed in 24 patients (96%) prior to canakinumab initiation. Fourteen (56%) patients showed normal karyotype. IPSS-R stratification revealed an intermediate-2 risk in 12 (48%) patients and a high risk in one (4%). The most common mutations were SF3B1 (40%), TET2 (32%), DNMT3A (28%), and RUNX1 (24%). IPSS -M risk score was calculated for 24 cases showing one (4%) very low (VL), four (16%) low (L), 14 (16%) moderate low (ML), eight (32%) moderate high (MH), five (20%) high (H), and two (8%) very high (VH) risk categories. Canakinumab was well tolerated and no drug-related toxicities were observed. One death due to sepsis, which was deemed not treatment-related, occurred on the study drug. Out of 23 evaluable patients, the overall response rate was 17·4%, with erythroid and platelet hematological improvement (HI-E and HI-P, respectively) confirmed in 3 (13.0%) patients and 1 (4.3%) patient, respectively. Thirteen patients had stable disease (56·5%) and 6 (26·1%) progressed during therapy, 1 of which transformed to AML (Fig. 1). TI was achieved in 3 patients (median DoR 8·53 months (95% CI 0·41-16·1) and 2 of them maintained TI for over 12 months. With a median follow-up time of 22·6 months (95% CI 15·0-29·4), median OS was 17·3 months (95% CI 14·3-not estimable). We performed separate univariate analyses to evaluate any associations between the IPSS-M and OS/PFS. The median OS in patients with higher-risk MDS by IPSS-M (MH, H, VH) was 15·0 months vs 29·4 months in the lower-risk disease by IPSS-M (VL, L, ML) group (p=0·12). Interestingly, statistically significant findings were observed with 1-year PFS when stratifying patients into higher vs lower risk MDS by IPSS-M (64·3% vs 100·0%, respectively; p=0·022, Fig. 2). Conclusion In this cohort of MDS patients who had experienced multiple lines of prior therapy and exhibited high-molecular-complexity, canakinumab showed limited efficacy (HI 17.3%). Nevertheless, canakinumab showed a good safety profile and yielded sustained long-term responses in patients with single somatic driver mutation in TET2 or DNMT3A. This suggests that clonal complexity, and therefore disease burden, may be a determining factor in response to canakinumab. Therefore, we have amended the protocol of a phase 1/2 clinical trial evaluating the safety and activity of canakinumab in clonal cytopenia of unknown significance (CCUS) and low-molecular complexity MDS patients. Our results will clarify the role of IL-1β signaling in MDS initiation and progression.

The Diversity of FLT3-ITD and the Prognostic Impact in Adult Acute Myeloid Leukemia

Introduction FLT3 internal tandem duplication (ITD) is commonly detected in patients with acute myeloid leukemia (AML) and is known to confer poor prognosis. It has different insertion numbers, mutation burden, insertion sizes, insertion sites and insertion nucleotide sequences, showing complex diversity. However, the guideline of AML did not sufficiently consider the impact of the diversity of FLT3-ITD on treatment responses, and previous studies have not been consistent with the impact of FLT3-ITD diversity on clinical prognosis. In this study we examined the diversity of FLT3-ITD and correlated these parameters with clinical outcome in adult AML. In addition, we revealed the correlation between FLT3-ITD and drug resistance through evolutionary trajectories in primary resistant patients. Methods We included adult patients from 2016-2021 at Henan Cancer Hospital with newly diagnosed adult AML. next generation sequencing (NGS) was performed for all patients at diagnosis. The FLT3-ITD was also detected using conventional methods based on PCR, with a cut-off of 3% for positivity. The comparative analysis of NGS and PCR was done to validate the diversity of FLT3-ITD. Whole genome sequencing (WGS) data for multiple time points were used to analyze clonal evolution. Data were collected by chart review. The chi-squared or Fisher's exact test, Mann-Whitney U test, log-rank and Cox regression analyses were performed. Results Among 406 newly diagnosed adult AML patients, 24.4% (99/406) patients were detected with FLT3-ITD. The FLT3-ITD diversity was validated by NGS and PCR data from 90 FLT3-ITD positive patients. 61.1% (55/90) patients had single FLT3-ITD (sFLT3-ITD) (31M/24F, median age 46 at diagnosis, range 18-64), and 38.9% (35/90) patients carried multiple FLT3-ITDs (mFLT3-ITD) at the same time (23M/12F, median age 47 at diagnosis, range 19-64). A total of 161 FLT3-ITDs were detected, with a median mutation burden of 21.51% (0.71-93.21%) and a median insertion length of 36bp (9-189 bp). 80.20% of FLT3-ITD insertions were in the near-membrane region, and 45.54% of FLT3-ITD insertions contained exogenous nucleic acid sequences. Patients with mFLT3-ITD had a significantly lower CR rate than those with sFLT3-ITD (25.7% vs 60.0%, p=0.001), while the CR rate of patients with sFLT3-ITD was similar to patients without FLT3-ITD (60.0% vs 58.6%, p=0.521). In the setting of NPM1, the CR rate of patients with sFLT3-ITD+NPM1 mut improved significantly when compared to patients with sFLT3-ITD+NPM1 wild (76.9% vs 44.8%, p=0.015). Unfortunately, the state of NPM1 had no impact on the CR rate of patients with mFLT3-ITD. After a median follow-up of 38.9 months, the median overall survival (OS) has not been reached for patients with a single FLT3-ITD, and the median OS for patients with multiple FLT3-ITDs was only 12.4 months (95 CI, 3.8 to 20.9) ( p=0.028). Multivariate analysis confirmed its prognostic significance on CR rate (HR 2.13, 95% CI, 1.38-4.20, p=0.020) but not on OS. The mutation burden, insertion sizes, insertion sites and insertion nucleotide sequences of FLT3-ITD had no significant impact on the CR rate or OS. To explore the clonal architecture of mFLT3-ITD, single cell DNA sequencing on one patient showed that respective FLT3-ITD variants were detected in completely separated cell populations. This suggested that mFLT3-ITD independently occurred in different subclone. WGS data of persistent primary resistant patients at multiple time points were used to analyze the evolutionary trajectory under chemotherapy. We observed complete separation of evolving trajectory of different FLT3-ITD variants over the course of chemo-treatment. Importantly, FLT3-ITD subclone of diagnosis evolved into the dominant clone at resistance. Conclusion In summary, by exploring the impact of the FLT3-ITD diversity on clinical prognosis and the evolutionary trajectory of mFLT3-ITD, the FLT3-ITD number may be a biomarker to refine the risk stratification and further identify adverse populations among FLT3-ITD positive AML patients.

Resection rates and intention-to-treat outcomes in borderline and locally advanced pancreatic cancer: real-world data from a population-based, prospective cohort study (NORPACT-2).

Systemic chemotherapy is the initial treatment strategy for borderline resectable and locally advanced pancreatic cancer to facilitate curative resection. The aim of this study was to investigate the resection rates and overall survival in patients with borderline resectable pancreatic cancer and locally advanced pancreatic cancer. Consecutive patients with borderline resectable pancreatic cancer/locally advanced pancreatic cancer discussed by Oslo University Hospital multidisciplinary team between 2018 and 2020, serving a population of 3.1 million within a geographically defined area in south-eastern Norway, were included in this prospective Norwegian Pancreatic Cancer Trial-2 study, according to intention-to-treat principles. The total number of patients with pancreatic cancer was sought from the Cancer Registry of Norway. A total of 1178 patients were diagnosed with pancreatic cancer, of whom 618 were referred to Oslo University Hospital. After multidisciplinary team evaluation, 230 patients were considered to have borderline resectable pancreatic cancer/locally advanced pancreatic cancer. The final study group consisted of 188 patients (borderline resectable pancreatic cancer n = 96, locally advanced pancreatic cancer n = 92) who were fit to receive primary chemotherapy. Resection rates were 46.9% (45 of 96) for borderline resectable pancreatic cancer and 13% (12 of 92) for locally advanced pancreatic cancer (P <0.001). Median overall survival was 14.6 months (borderline resectable pancreatic cancer 16.4 months; locally advanced pancreatic cancer 13.7 months, (P = 0.2)). Adjusted for immortal time bias, median overall survival for patients undergoing resection versus only chemotherapy was 24.4 months versus 10.1 months (P <0.001) for borderline resectable pancreatic cancer and 28.4 months versus 12.6 months for locally advanced pancreatic cancer (P = 0.001). Resection rates and survival in patients with borderline resectable pancreatic cancer and locally advanced pancreatic cancer treated at a high-volume centre in a universal healthcare system compare well with those treated at international expert centres.Registration number: NCT04423731 (http://www.clinicaltrials.gov).

Clinical Profile and Treatment Outcomes of Malignant Mixed Mullerian Tumors of the Uterus: A Single-Center Experience.

Background A malignant mixed Mullerian tumor (MMMT), otherwise known as carcinosarcoma, is a rare and aggressive malignancy involving the uterus. Despite aggressive treatment, they have poor outcomes. We performed this study to analyze the clinical profile, prognostic features, and treatment outcomes of patients treated for MMMT of the uterine corpus in our center. Methodology A study sample from a database of patients treated at a tertiary care center in South India between January 2015 and December 2019 was analyzed retrospectively. A total of 29 non-metastatic patients were included in the study. The diagnosis of MMMT was confirmed by a pre-operative biopsy specimen or endometrial curettage. Information regarding the patient, tumor characteristics, details of the surgery, adjuvant therapy, and follow-up details were collected retrospectively. Disease-free survival (DFS) and overall survival (OS) were plotted using the Kaplan-Meier method, and the log-rank test was used to identify any significant prognostic factor. Statistical analyses were performed using IBM SPSS software, version 21 (IBM Corp., Armonk, NY). Results The population's median age was 60 years (interquartile range (IQR): 52-65). The homologous type was the most common pathology seen in 21 patients. The median size of the tumor was 7 centimeters (cm) (IQR: 6-10). Around two-thirds of the patients received adjuvant radiation therapy. Paclitaxel and carboplatin-based adjuvant chemotherapy were used in 60% of the patients. Nearly 90% of the recurrences were distant recurrences. During the follow-up, 17 patients developed a recurrence. The median DFS was 12 months (95% CI: 7.7-16.2). The median OS was 26 months (95% CI: 10.6-41.3). The three-year OS rate was 42%. Patients with an age >60 years had a median overall survival of 11 months, compared to 37 months for patients <60 years (p = 0.026). The median overall survival of patients with tumor sizes >10 cm was 12.5 months, and it was 35 months when the tumor size was less than 10 cm (p = 0.03). Patients receiving radiotherapy (RT) had an improved survival (39 months) compared to those who did not receive RT (12.5 months) (p = 0.046). The median overall survival for patients after the recurrence was 12 months. As most patients were elderly with an Eastern Cooperative Oncology Group (ECOG) performance status of two at baseline, only a few patients were fit for second-line chemotherapy. Conclusion A malignant mixed Mullerian tumor is an aggressive tumor of the uterine corpus with poor survival rates. Surgical resection remains the mainstay of treatment. Adjuvant radiation therapy improves survival. The age of the patient, myometrium invasion, tumor size, and positive peritoneal cytology were found to be prognostic factors.

The role of spleen volume change in predicting immunotherapy response in metastatic renal cell carcinoma

IntroductionResistance to immune checkpoint inhibitors (ICI) is a significant issue in metastatic renal cell carcinoma (mRCC), as it is in the majority of cancer types. An important deficiency in immunooncology today is the lack of a predictive factor to identify this patient group. Myeloid-derived suppressor cells (MDSC) are a type of cell that contributes to immunotherapy resistance by inhibiting T cell activity. While it accumulates in the tumor microenvironment and blood, it can also accumulate in lymphoid organs such as the spleen and cause splenomegaly. Therefore we aimed to evaluate the effect of increase in splenic volume, which can be considered as an indirect indicator of increased MDSC cells, on survival outcomes in mRCC patients.MethodsWe analyzed 45 patients with mRCC who received nivolumab as a second-line or subsequent therapy. Splenic volume was analyzed from baseline imaging before starting nivolumab and from control imaging performed within the first 6 months of treatment initiation. Additionally, we analyzed how patients’ body mass index (BMI), IMDC risk score, ECOG performance status, nephrectomy status, neutrophil-lymphocyte ratio (NLR), Platelet-to-lymphocyte ratio (PLR) and sites of metastasis.ResultsMedian splenic volume change was 10% (ranging from − 22% to + 117%) during follow-up. Change in splenic volume was found to be associated with overall survival (OS) and progression-free survival (PFS) (p = 0.025, 0.04). The median PFS in patients with increased splenic volume was 5 months, while it was 17 months in patients without increased splenic volume. (HR 2.1, 95% CI (1–4), p = 0.04). The median OS in patients with increased splenic volume was 9 months, while it was 35 months in patients without increased splenic volume (HR 2.7, 95% CI (1.1–6.2), p = 0.025). In four patients with decreased splenic volume, neither PFS nor OS could reach the median value. Log-rank p value in respectively (0.015, 0.035), The group in which an increase in volume was accompanied by a high NLR had the shortest survival rate. Basal splenic volume was analyzed separately. However, neither PFS nor OS differed significantly.ConclusionOur findings suggest that the change in splenic volume throughout immunotherapy regimens may be utilized to predict PFS and OS in mRCC patients undergoing treatment.

Switch to generic formulation of temozolomide results in statistically significant increase in grade 3 and 4 bone marrow toxicity in glioma patients in the province of Alberta.

Temozolomide (TMZ) is an oral, systemic chemotherapy used chiefly for treating high-grade glioma. Due to the rising costs of systemic chemotherapy, many jurisdictions have replaced brand name with generic formulations. The aim of this study was to determine whether or not there was difference in the incidence of grade 3 or 4 bone marrow toxicity and median overall survival in patients treated with brand name versus generic TMZ in the province of Alberta, Canada. The province suspended the use of generic TMZ based on preliminary data pointing to excess toxicity. This multicenter, retrospective study included data from patients with newly diagnosed high-grade glioma that received treatment with TMZ in Alberta. Multivariate logistic regression analysis was performed to determine the association between grade 3 or 4 toxicity to generic versus brand name TMZ exposure, ECOG score, and age. Kaplan-Meier survival estimates and log-rank testing were used to determine differences in overall survival between the brand name and generic TMZ cohorts, as well as the cytopenic versus non-cytopenic patients. Furthermore, a screening analysis for grade 3 or 4 bone marrow toxicity was conducted on all de novo glioma patients treated with brand name TMZ after Alberta preemptively stopped generic TMZ. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 15% and 19% of patients treated with generic TMZ (n = 156) as compared to 3% and 5% of patients (n = 100) treated with brand name TMZ-treated patients; P= .003 and .001. A trend toward increased median overall survival in glioblastoma patients treated with generic TMZ (13.7 months) versus brand name (15.8 months, P = .178.) was also observed through meeting statistical significance. Based on these results, the province stopped the use of generic TMZ and reverted to the Merck TMZ. An initial review of all new glioma patients (n = 89) treated with Merck TMZ since the province stopped the generic drug demonstrated 3.4% and 10.1% grade 3 or 4 neutropenia, respectively. The statistically significant difference in toxicity profile has prompted the province of Alberta to replace generic TMZ with brand name TMZ in high-grade glioma patients pending more detailed analysis. Our study provides evidence supporting the importance of conducting prospective studies on long-term safety for generic chemotherapies.

Disparities in Pancreatic Cancer Outcomes in the Disaggregated Asian American Population.

The Asian American, Native Hawaiian, and Pacific Islander (AANHPI) population is among the fastest-growing population in the USA. However, this is not reflected in scientific research, in which ethnic groups are often combined. We identified trends in treatment and outcomes for pancreatic cancer in a disaggregated AANHPI population. We hypothesize that patients from different AANHPI groups have differences in survival. A retrospective analysis of the National Cancer Database between 2010 and 2019 identified patients treated for pancreatic cancer. We identified demographic factors for patients of Caucasian, African American, and disaggregated Asian subpopulations. Survival curves were generated and multivariate analysis was performed to help determine which factors impacted overall survival. A total of 296,448 patients met the inclusion criteria. Of those, 8568 (3%) patients were Asian. Median survival of AANHPI patients was 11.3 months, as compared with Caucasians (8.9 months) and African Americans (8.1 months) (p<0.0001). Asian Indians had the highest median survival (14.3 months), whereas the Japanese subpopulation had the lowest (7.6 months) (p<0.0001). There were significant differences in median survival between the different AANHPI subpopulations irrespective of stage. Multivariate analysis demonstrated that belonging to an AANHPI racial/ethnic group, excluding Japanese and Filipino, was associated with decreased risk of overall mortality. Significant differences were identified in the overall median survival for patients with pancreatic cancer between AANHPI subpopulations. Disparities in socioeconomic factors may have played a role in overall survival. This study highlights the need to include disaggregated data in future studies to subdue disparities in cancer care for patients.