Achievement Of Complete Remission Research Articles

Prevalence and Clinical Implications of Autoantibodies in Juvenile Dermatomyositis: A Single-Center Experience From India.

​​This study aimed to characterize the profile of myositis-specific and myositis-associated autoantibodies (MSAs/MAAs) in an Indian cohort of juvenile dermatomyositis (JDM) patients and correlate them with clinical features and outcomes. Forty-three children diagnosed with JDM were enrolled for this observational study. Clinical details (presentation, course, and outcome) were noted in a predesigned proforma. Serum samples were tested for 16 MSAs/MAAs by line immunoassay. MSAs/MAAs were correlated with clinical features and outcome (defined as a complete clinical response [≥6 months' disease inactivity on medication] or complete remission [≥6 months' inactivity off all drugs]). Thirty-five subjects (81.4%) had at least 1 MSA/MAA detected. The most common antibodies were anti-NXP2 (n = 13, 30.2%), anti-TIF1γ (n = 10, 23.2%), and anti-MDA-5 (n = 8, 18.6%). No patient had anti-Ku, anti-Pm Scl-100, anti-PL-12, anti-EJ, anti-OJ, or anti-Ro52. Thirty-two patients (74.4%) attained a complete clinical response over a median follow-up duration of 14 months, among which 6 (13.9%) achieved complete remission over a median follow-up duration of 30 months. Anti-TIF1γ was associated with younger age at onset (≤3 years) (odds ratio [OR], 6.25; 95% confidence interval [CI], 1.15-34.12; p = 0.034) and disease flares after attaining complete response (OR, 10.18; 95% CI, 1.64-70.93; p = 0.013). Patients with anti-NXP2 had higher odds of severe muscular weakness (OR, 3.73; 95% CI, 0.95-14.59; p = 0.058) and truncal weakness (OR, 3.89; 95% CI, 0.97-15.64; p = 0.056). One child with anti-MDA-5 positivity had interstitial lung disease. We found no association between the MSA/MAA profile and the achievement of complete clinical response or remission. MSAs/MAAs were identified in 81% of children with JDM in our study, which is higher than most other studies. The most frequently observed antibodies displayed a pattern consistent with other studies. Anti-TIF1γ was associated with a younger age at onset and disease flares even after attaining a complete clinical response. Anti-NXP2 had higher odds of severe muscular weakness. These observations suggest consistency in certain phenotypic associations observed across geographic boundaries.

Efficacy of combination of immune checkpoint inhibitors, chemotherapy, and targeted therapy in advanced/refractory cancer.

41 Background: The treatment of advanced/refractory malignancies continues to pose a major challenge, and it is associated with poor outcome. It has been shown that in some cancers, the combination of chemotherapy (CT) with immune checkpoint inhibitors (ICIs), or CT with targeted therapy (TT), are superior to chemotherapy alone. Consequently, in our treatment program (ICTriplex), TT was added to CT plus ICIs. These three modalities have convergent efficacy with divergent toxicity. Our prior data were previously reported (1-3). Methods: Treatment with ICTriplex was highly personalized and was tailored to the individual patient and their specific cancer. It was designed based on diagnosis, prior therapy, and genomic profiling. Between March 2017 and January 2024, 56 patients (pts) with advanced malignancies were treated: 31 females and 25 males, with a median age of 58. Tumor types included: lung (12), pancreas (8), colorectal (8), biliary tract (5), breast (4), stomach (4), melanoma (3), ovary (3), sarcoma (3), cervix (2), glioblastoma (2), Hodgkin’s (1), and thymoma (1). 43 pts received prior therapy: 14 received ICIs, 23 TT, and 42 CT. The agents used in ICTriplex were: 6 ICIs primarily nivolumab and pembrolizumab, 12 CT primarily taxanes, gemcitabine, and platinum, and 23 TT, primarily bevacizumab and erlotinib. Response was evaluated by both PET/CT and CT scans. A complete remission was achieved when metabolic activity completely resolved on PET/CT. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier estimator. Results: The overall response rate (ORR) was 88%. A complete remission (CR) occurred in 29 pts (52%), and a partial remission (PR) in 20 pts (36%). Of the 12 pts with lung cancer, 9 (75%) achieved CR and of these, 4 pts had brain metastases that completely resolved without radiation. Of the 8 pts with pancreatic cancer, 4 (50%) achieved CR. 4 of 5 pts with biliary tract cancer achieved CR. Toxicity was reasonable in all pts except for 3 who died from complications possibly related to ICIs. The median PFS was 11 months, and the median OS was 15 months. The achievement of CR and the PD-L1 + status, resulted in a statistically significant better PFS (p= 0.00; p= 0.02) and OS (p=0.00; p= 0.005). Patients with lung cancer showed a better PFS (p= 0.02) with the median at 19 months, and the median OS was 36 months. Potential predictors of unfavorable prognosis, such as receiving prior treatment, did not impact patients' clinical outcome. Conclusions: ICTriplex is a very effective treatment for advanced cancer that has become resistant to conventional therapy or with no available standard therapy. We strongly recommend this therapeutic approach for the treatment of such patients. 1. ASCO 2019 (e14254) 2. ASCO 2020 (e15150) 3. ASCO 2022 (e14590).

A randomised, two-arm (1:1 ratio), double blind, placebo controlled phase III trial to assess the efficacy, safety, cost and cost-effectiveness of Rituximab in treating de novo or relapsing NS in patients with MCD/FSGS (TURING)

BackgroundMinimal Change Disease (MCD) and Focal Segmental Glomerulosclerosis (FSGS) are a spectrum of disease causing the nephrotic syndrome (NS), characterised by proteinuria with debilitating oedema, as well as a high risk of venous thromboembolic disease and infection. Untreated, 50–60% patients with FSGS progress to end stage kidney disease after 5 years. These diseases respond to immunosuppression with high dose glucocorticoids, but 75% will relapse as the glucocorticoids are withdrawn, leading to significant morbidity associated with prolonged use. In children, the B cell depleting monoclonal antibody rituximab reduces relapse risk, but this drug has not been tested in randomised controlled trial in adults.Methods130–150 adults with new or relapsing MCD/FSGS, from UK Renal Units, are being randomised to receive either rituximab (two 1 g infusions two weeks apart) or placebo. Partipicipants are recruited when they present with nephrosis, and all are treated with glucocorticoids as per KDIGO guidelines. Once in remission, prednisolone is withdrawn according to a pre-specified regimen. If in remission at 6 months, participants receive a further dose of trial drug. If they relapse, they are unblinded, and if they have received placebo, they are offered open label rituximab with protocolised prednisolone as in the main phase of the trial. The primary end point is time from remission to relapse. A number of secondary endpoints will be assessed including the effect of rituximab on: (1) NHS and societal resource use and hence cost: (2) safety: (3) other measures of efficacy, such as achievement of partial and complete remission of NS and the preservation of renal function: (4) health status of participant.Trial RegistrationTURING received ethical approval on 14 Jun 2019 - REC reference: 19/LO/0738. It is registered on EudraCT, with ID number: 2018-004611-50, with a start date of 2019-06-14.

Stage-adapted treatment of HIV-associated Hodgkin lymphoma: Long-term results of a prospective, multicenter study.

Results of a prospective study of stage-adapted treatment of humanimmunodeficiency virus (HIV)-associated Hodgkin lymphoma (HIV-HL) showed a 2-year overall survival (OS) of 90.7% with no significant difference between early favorable (EF), early unfavorable (EU), and advanced HL. Patients with EF HIV-HL received two to four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) + 30 Gy involved field (IF) radiation, those with EU HIV-HL received four cycles of ABVD or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) baseline + 30 Gy IF, and six to eight cycles of BEACOPP baseline were administered in advanced disease. The objective of the present analysis is to determine long-term outcomes of HIV-HL. Of 108 patients, 23 (21%) had EF HL, 14 (13%) had EU HL, and 71 (66%) had advanced-stage HL. After a median follow-up of 9.14 (range, 0-12.9) years, there were five primary refractory HL patients (5%) and 11 relapses (10%), of which seven were late relapses (>2 years). A second primary malignancy (SPM) occurred in 10 patients after a median of 7.3 years (range, 1.5-10.7) from HL diagnosis. The 10-year OS for patients with EF, EU, and advanced HL was 95.7%, 84.6%, and 76.1%, respectively. By multivariate analysis, Center for Disease Control and Prevention category C (hazard ratio [HR]3.00, 95% confidence interval [CI]:1.16-7.74, p = 0.023) and achievement of complete remission were significant for OS (HR 0.03, 95% CI: 0.01-0.08, p = 2.45 × 10-9). In conclusion, a stage-adapted treatment approach for HIV-HL is highly effective with long-term survival rates similar to those reported in HIV-uninfected HL. However, the risk for late relapse and SPM is significant.

Early versus late initiation of infliximab for refractory uveitis in a cohort of Egyptian BD patients

Introduction Behçet’s syndrome is a multisystem inflammatory disease characterized by recurrent oral aphthous ulcers, genital ulcers, skin lesions, and uveitis. Ocular involvement, occurring roughly in 50% of patients, is one of the most feared complications of Behçet’s syndrome. Recurrent severe uveitis leads to irreversible severe vision loss. Purpose The main goals in the management of patients with Behçet’s uveitis are rapid resolution of intraocular inflammation, prevention of recurrent attacks, and achievement of complete remission and preservation of vision. Corticosteroids are generally used for the treatment of acute episodes of inflammation. According to the updated EULAR recommendations for the management of BS ‘any patient with BS and inflammatory eye disease affecting the posterior segment should be on a treatment regime such as azathioprine, cyclosporine-A, interferon alpha or monoclonal tumor necrosis factor alpha antagonists. Methods Infliximab has been increasingly used in the treatment of Behçet’s syndrome patients with uveitis when they are refractory to conventional immunosuppressive therapy. However, there is no consensus on the best time to start anti- tumor necrosis factor alpha therapy. In our study we evaluated the outcome of early initiation of infliximab for refractory uveitis in cohort of Egyptian Behçet’s syndrome patients. Conclusion Early administration of Intravenous Infliximab therapy for severe sight-threatening uveitis and chorioretinitis in Egyptian Behçet’s syndrome patients has a favorable value regarding BCVA. Multidisciplinary approach in managing Behçet’s uveitis is mandatory to reach better functional visual outcome.

A hybrid protocol CLAG-M, a possible player for the first-line therapy of patients with mixed phenotype acute leukemia. A Polish Adult Leukemia Group experience.

Mixed-phenotype acute leukemia (MPAL) is a rare disease with poor prognosis. So far, no standard approach has been established as the "know-how" of MPAL is based only on retrospective analyses performed on small groups of patients. In this study, a retrospective analysis of the outcomes of adult MPAL patients included in the PALG registry between 2005 and 2024 who received the CLAG-M hybrid protocol as induction or salvage therapy was performed. Sixteen of 98 MPAL patients received CLAG-M: eight as first-line and eight as salvage therapy. In the first line, two patients achieved partial response (PR), and six achieved complete remission (CR), of whom four successfully underwent allogeneic hematopoietic stem cell transplantation (alloHSCT). Two patients who did not undergo alloHSCT promptly relapsed. Within the whole group, the overall response rate (ORR) was 75% (n = 12/16). With the median follow-up of 13 months, six out of eight patients remain in CR, however, two of them died due to acute graft versus host disease. Out of eight patients who received CLAG-M in the second line, four patients (50%) obtained CR. AlloHSCT was conducted in seven cases, six of which were in CR. Only two patients remained in CR at the time of the last follow-up. Tolerance to treatment was good. The median times for severe neutropenia and thrombocytopenia were 22 days (range, 16-24) and 17 days (range, 12-24), respectively. Overall, grade 3-4 infections were observed in 12 cases, and all infections presented successful outcomes. CLAG-M is an effective first-line salvage regimen for MPAL with an acceptable safety profile. Early achievement of CR with prompt alloHSCT allows for satisfactory disease control.

Can pharmacogenetics impact the therapeutic effect of cytarabine and anthracyclines in adult acute myeloid leukaemia patients?: A Serbian experience.

Cytarabine-anthracycline-based induction chemotherapy remains the standard of care for remission induction among patients with newly diagnosed acute myeloid leukaemia (AML). There are remarkable differences in therapy response among AML patients. This fact could be partly explained by the patients' genetic variability related to the metabolic paths of cytarabine and anthracyclines. This study aims to evaluate the effect of variants in pharmacogenes SLC29A1, DCK, ABCB1, GSTM1, and GSTT1, as well as laboratory and AML-related parameters on clinical outcomes in adult AML patients. A total of 100 AML patients were included in the study. Pharmacogenetic variants SLC29A1 rs9394992, DCK rs12648166, ABCB1 rs2032582, and GSTM1 and GSTT1 gene deletions were detected by methodology based on PCR, fragment analysis and direct sequencing. The methods of descriptive and analytic statistics were used. Survival analysis was done using the Kaplan-Meier method using the Log-Rank test. This is the first study of adult AML pharmacogenetics in the Serbian population. Clinical outcomes in our cohort of AML patients were not impacted by analysed variants in SLC29A1, DCK, ABCB1 and GSTT1, and GSTM1 genes, independently or in combinations. Achievement of complete remission was identified as an independent prognostic indicator of clinical outcome. The population-specific genomic profile has to be considered in pharmacogenetics. Since the data on AML pharmacogenetics in European populations is limited, our results contribute to knowledge in this field and strongly indicate that a high-throughput approach must be applied to find particular pharmacogenetic markers of AML in the European population.

Analysis of the treatment and prognosis of 266 cases of extranodal natural killer/T-cell lymphoma, nasal type in a single medical center.

To assess the impact of different treatment strategies and risk factors on the prognosis of patients with extranodal NK/T-cell lymphoma, nasal type (ENKTL) in a single medical center. The clinical features of 266 patients with ENKTL were retrospectively analyzed, among whom those in stages I and II received sandwich therapy, while those in stages III and IV underwent chemotherapy plus autologous hematopoietic stem cell transplantation. The Kaplan-Meier curves, univariate and multivariate Cox regression analyses were employed for survival and prognosis analysis. Statistical significance was set at P<0.05. Following treatment, the post-intervention outcomes demonstrated a complete remission (CR) rate of 71.05% and a partial remission (PR) rate of 3.76%. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 70.4% and 70.9%, respectively. In addition, the PFS for patients in stage I/II was 79.8%, with an OS of 81.1%, whereas for those in stage III/IV, the PFS was 41.7% and the OS was 40.9%. Notably, the achievement of CR immediately after treatment was an independent prognostic factor (P<0.001). Patients in stage I/II depicted a favorable 5-year OS rate, while those in stage III/IV manifested a less favorable prognosis. Stages of the disease and whether CR was achieved following treatment are important factors determining the survival and prognosis of patients with ENKTL. Further researches focusing on disease onset and mechanisms of drug resistance will contribute to better management of ENKTL.

Acute Promyelocytic Leukemia: Review of Complications Related to All-Trans Retinoic Acid and Arsenic Trioxide Therapy.

The hallmark of acute promyelocytic leukemia (APL) is the presence of the characteristic fusion transcript of the promyelocytic leukemia gene with the retinoic acid receptor α gene (PML::RARA). The PML::RARA fusion is a molecular target for all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Therapies based on ATRA plus ATO have excellent outcomes in terms of complete remission rates, overall survival, and achievement of deep and durable molecular responses with a very low incidence of relapse. However, although the combination of ATRA and ATO has lower hematologic toxicity than standard chemotherapy, its use is associated with a spectrum of distinctive toxicities, such as differentiation syndrome, liver toxicity, QT interval prolongation, and neurotoxicity. Rigorous monitoring of patients' clinical evolution is indispensable for identifying and addressing each complication. The objective is to maintain an equilibrium between treatment-induced adverse events and therapeutic efficacy. This paper focused on non-hematologic complications associated with the combination of ATRA and ATO. Additionally, we discuss late-onset complications of this therapy. In summary, the majority of treatment-related adverse events are manageable, self-limiting, and reversible. More so, there seems to be a lower incidence rate of secondary neoplasms compared to standard chemotherapy. However, further research is required to assess how the ATRA plus ATO regimen affects the emergence of additional comorbidities.

Prognostic significance of the frequencies of bone marrow lymphocyte subsets in adult acute myeloid leukemia at diagnosis.

Immune microenvironment plays an important role in the occurrence and development of acute myeloid leukemia (AML). Studies assessing the prognostic significance of bone marrow (BM) lymphocyte subsets' frequencies at diagnosis in patients with AML were limited. Fresh BM samples collected from 97 adult AML patients at diagnosis were tested for lymphocyte, T, CD4+ T, CD8+ T, γδT, NK, and B cell frequencies using multi-parameter flow cytometry. Low frequencies of lymphocytes, T, CD4+ T, and CD8+ T cells were associated with significantly lower rates of one-course complete remission (CR) (all p < 0.05). Moreover, the frequency of CD4+ T cells independently predicted one-course CR achievement (p = 0.021). Low frequencies of T and CD8+ T cells were significantly associated with lower relapse-free survival (RFS) rates (p = 0.032; 0.034), respectively, and a low frequency of CD8+ T cells was associated with a significantly lower overall survival (OS) rate (p = 0.028). Combination of frequency of CD8+ T cells and ELN risk stratification showed that patients with ELN-intermediate/adverse risk + high CD8+ T cell frequency had a similar RFS rate to those with ELN-favorable risk + high CD8+ T cell frequency and those with ELN-favorable risk + low CD8+ T cell frequency (p = 0.88; 0.76), respectively. The RFS rate of patients with ELN intermediate/adverse risk + low CD8+ T cell frequency was significantly lower than that of all aforementioned patients (p = 0.021; 0.0007; 0.028), respectively. The frequencies of BM lymphocyte subsets at diagnosis predicted clinical outcomes and could help improve risk stratification in AML.

Different Epidemiology and Characteristics of Invasive Pulmonary Aspergillosis in Acute Lymphoid Leukemia in Comparison with AML: Results of a Prospective Multicentric Observational Study of the Rete Ematologica Lombarda (REL)

Introduction. Invasive pulmonary aspergillosis (IPA) still affects the outcome of acute leukemia (AL) patients (pts). Although this aspect is better defined in acute myeloid leukemia (AML) ( Candoni et al, Mycoses 2020), some reports show a dismal impact also in acute lymphoid leukemia (ALL) ( Cattaneo et al, Leuk Lymphoma 2019). However, data concerning the epidemiology of IPA in adult ALL patients, as well as the best antifungal prophylaxis strategy, are still lacking. Therefore, to describe the incidence of IPA in AL pts and their clinical characteristics, as well as the predisposing factors, we carried out a prospective multicentric observational study within the Rete Ematologica Lombarda (REL). Methods. All consecutive AL patients diagnosed during a 3-year period and treated with curative intent were recorded. Diagnosis of IPA was defined according to EORTC/MSG criteria ( Donnelly et al, Clin Infect Dis 2020). Data concerning age, gender, AL type, chemotherapy (cht) received, complete remission (CR) achievement, antifungal prophylaxis, duration of neutropenia and 30-day mortality were collected. Patient's characteristics were analysed by standard descriptive statistics. The Student's t-test was used to compare continuous values; the Fisher's exact test was used to compare differences in percentage. P values below 0.05 were considered statistically significant. Results. Between 2018 and 2020, 207 AL pts (AML: 165, ALL: 42) were evaluated in five Hospitals participating to the REL. Median age of the whole cohort was 58y, and M/F ratio 112/95. After induction treatment, CR was achieved in 153 of the 200 evaluable pts (76.5%), more frequently in ALL (38/42, 90.5%) than in AML pts (115/158, 72.8%) (p=0.0146). During induction cht, proven/probable (p/p) and possible (poss) IPA were diagnosed in 32/207 pts (15.4%), equally divided in p/p and poss (16 each, 7.7%). P/p IPA were more frequent in ALL than in AML (ALL: 7/42, 16.6% vs AML: 9/165, 5.4%; p= 0.0235); similarly, considering also poss IPA, incidence was higher, even if not significantly (9/42, 21.4% vs 23/165, 13.9%; p=0.2374). Among ALL pts, IPA was more frequent in pts not achieving CR (2/4, 50%) than CR pts (7/38, 18%), whereas in AML CR achievement did not influence IPA frequency (CR group: 15/115, 13%; no CR group: 7/43: 16.5%). ALL pts were uniformly treated with pediatric-like protocols; in AML pts no statistically significant differences in IPA incidence were observed according to cht received (3+7/like: 13/81, 16%; 3+7+midostaurin: 2/27, 7.4%; FLAG-Ida: 3/21, 14.3%; CPX-351: 4/19, 21%). Antimould prophylaxis was protective against IPA in 202 evaluable pts (Yes: 22/171, 12.9%; No: 10/31, 32.3%, p=0.0134). Among ALL pts only 1 out of 15 (6.7%) receiving antimould prophylaxis developed IPA, as compared to 8/27 (29.6%) of those not receiving antimould prophylaxis (p=0.1235). All but two AML pts developing IPA were on posaconazole prophylaxis. Both mean age and duration of neutropenia were significantly lower in ALL than in AML pts (46.02y vs 57.75y, p&amp;lt;0.0001 and 16.66d vs27.96d, p&amp;lt;0.0001); however, an impact of mean duration of neutropenia on IPA incidence was observed only in ALL pts (IPA group: 24.38d; no IPA group: 14.79d, p=0.0359). Only 2 AML pts died at 30d: 1 (3.1%) out of 32 pts with IPA and 1 (0.6%) out of 175 pts without. No early death was observed in ALL pts. Table 1 summarizes the clinical characteristics of AL pts in relation to IPA. Conclusions. Despite younger age, shorter duration of neutropenia and higher percentage of CR achievement, IPA, particularly p/p, was more frequently observed in ALL pts than AML during induction cht. High dose induction cht seems to have no impact in IPA incidence in AML pts. On the other hand, intensive cht ALL protocols, including high doses of dexamethasone, could have a role in IPA development, as well as the lack of antimould prophylaxis, which is confirmed as a predictive factor for IPA. Therefore, studies with antimould agents as prophylaxis against aspergillosis in ALL pts during inductions would be desirable.

Post-Transplant Nivolumab Plus Unselected Autologous Lymphocytes in Truly Refractory Hodgkin Lymphoma Patients Is Highly Effective and Responses Are Mediated By NK Cells

Background In the relapsed/refractory Hodgkin Lymphoma (HL) setting (RHL), the achievement of complete remission (CR) is fundamental in order to proceed with allogeneic stem cell transplantation (HSCT) consolidation. Immune checkpoint inhibitors (CI) have demonstrated clinical activity in patients relapsing after ASCT, although only 20% CR rate is observed. In order to improve the efficacy of CI in RHL, we previously reported a salvage treatment based on early CI therapy following post-autologous stem cell transplantation (ASCT) with the reinfusion of unselected autologous lymphocytes infusions (ALI). The rationale of this approach is based on the achievement of a disease debulking through ASCT conditioning. Early administration of CI (nivolumab) is performed on a minimal disease burden, while reinfusions of ALI reduce post ASCT immune depression eliciting CI efficacy. Aims The aim of this study was to evaluate the efficacy of the procedure in terms of CR rates and overall survival (OS) after an extended follow up. Biological endpoint was to investigate the lymphocyte subpopulations involved in the mechanism of response and investigate the role of NK-cells mediating anti tumor responses in HL. Methods Patient were eligible to this study after failure to respond to first line treatment (i.e. positive PET2 or PET6 scan) and underwent autologous lymphocyte apheresis upon enrollment. All patients received conventional 2nd line chemo followed by 3rd line chemo-immunotherapy with Brentuximab-Vedotin (BV) in non-responding patients. Patient failing to achieve CR after BV were enrolled in the treatment arm and proceeded to ASCT + CI and ALI, whereas patients responding to 2nd- or 3rd treatment received ASCT followed by ALI alone, as a control cohort (figure 1A). NK cell degranulation assay was evaluated by staining for CD107a (LAMP-1) expression on healthy-donors derived NK cells exposed to HL cell lines (L428 and L250), in the presence or absence of monoclonal antibodies targeting inhibitory or activating receptors. Surface and intracellular staining was performed prior to flow cytometry and analysis was performed on the CD3-/CD56+ gated population. Results Twenty-one patients with RHL (median age 32 years; range 18-65) underwent lymphocyte apheresis after failure of 1st line chemo and then proceeded to salvage therapy. Thirteen patients failed to respond to 2nd and 3rd line therapy and thus received early post-transplant CI supported with four ALI. Eight patients responded to 2nd line chemo (n=6) or 3rd line BV (n=2) and received ASCT followed by ALI alone. No adverse events were recorded, specifically, no immune-related toxicity was observed. All patients receiving ALI + CI (treated patients) achieved negative PET scan CR. Eight of them received HSCT consolidation. One patient refusing HSCT after achieving CR in this study relapsed and responded to CI re treatment followed by HSCT. All patients in the treatment arm are alive and disease-free after a median follow-up of 32 months (95% CI 26.4-51.0). Median disease-free survival (DFS) was not reached in treatment arm (Fig 1B). Four of the patients in the control arm relapsed (50%). Three of them responded to 3rd line therapy and proceeded to HSCT. One patient achieved CR with conventional CI treatment but refused HSCT and the other relapsing patient died because of progressive lymphoma after failure to achieve CR with conventional single agent CI. Median DFS in the control arm was 22 months (Fig 1B). NK cells showed higher expansion and a faster maturation in the treatment arm, compared to the control arm (p&amp;lt;0.05). As expected, HL cells lines do not express HLA class I and II, but express activating NK cells receptors (aNKG2D, aNKp30, aNKp46, aDNAM-1). In vitro, the activation of each of those receptors was able to trigger NK cells degranulation. Similarly, PD-L1 and PD-L2 blockade on HL cell lines significantly increased NK cell degranulation (p&amp;lt;0.05). Taken together, those observations support the role of NK cells in this setting. Conclusions Our data show very high anti-tumor activity of ALI + CI for RHL, allowing most patients to proceed to HSCT. RHL patients in the treatment arm had an excellent outcome if compared to the control arm, which included patient who did respond to conventional treatment. Biological data suggests that this approach may accelerate NK cell development/maturation and suggest that NK cells may mediate response to CI in HL.

Association between Molecular Profile and Outcome after Intensive Chemotherapy in Patients &amp;gt; 60 Years with Adverse Cytogenetic Risk and/or Secondary Acute Myeloid Leukemia - a Filo Study

Background: Recognizing the prognostic importance of genetic characteristics rather than clinical history, secondary acute myeloid leukemia (AML), i.e., arising from prior cytotoxic therapy and/or an antecedent hematologic disorder (AHD), is now considered a diagnostic qualifier rather than a separate disease entity (Döhner, Blood 2022). To assess the relationship between clinical history and/or adverse cytogenetics and outcome, we report herein the molecular profile of AML patients &amp;gt;60 years with secondary AML and/or adverse cytogenetics included in a multicentric prospective trial. Methods: Fit patients &amp;gt;60 years with secondary AML and/or adverse cytogenetics according to the European LeukemiaNet, included in the Rev-5-Aza trial (NCT01301820), received induction therapy with lomustine 200 mg/m 2 day 1, idarubicin 8 mg/m 2 days 1-5, and cytarabine 100 mg/m 2 days 1-7. Patients in complete remission (CR) after one induction cycle received consolidation therapy with 12 cycles of alternating azacitidine 75 mg/m 2 days 1-7 and lenalidomide 10 mg days 1-21 every 28 days (Hunault-Berger M, Blood Cancer J 2017). Mutational profile was determined by targeted sequencing of complete coding regions, including splice sites, of 77 genes recurrently mutated in myeloid malignancies using custom SureSelect QXT capture system (Agilent, Santa Clara, CA, USA) on NextSeq500 platform (Illumina, San Diego, CA, USA). As a validation cohort, we determined the molecular profile of 73 patients with adverse cytogenetic risk and/or secondary AML in first CR after the same induction therapy but who received standard chemotherapy consolidation with 6 cycles of idarubicin 8 mg/m 2 day 1 and cytarabine 50 mg/m 2/12 hours days 1-5. Results: Between March 2011 and February 2013, 117 fit patients &amp;gt;60 years included in the Rev-5-Aza trial received induction therapy with 56% reaching first CR and four patients undergoing allogeneic hematopoietic cell transplantation. The molecular profile could be established in 97 of these patients (83%; median age 70 years, interquartile range (IQR): 65-73; therapy-related AML, 32%; AHD, 46%; adverse cytogenetic risk, 70%). Secondary-type mutations were the most frequently observed (49%; ASXL1, 12%; BCOR, 16%; EZH2, 2%; RUNX1, 18%; SF3B1, 8%; SRSF2, 14%; STAG2, 10%; U2AF1, 8%; and ZRSR2, 0%) followed by TP53 mutations (44% of patients). Patients with TP53 mutations were more likely to have adverse risk cytogenetics (95%) in comparison to patients with secondary-type mutations (64%). No clinical or biological characteristic was associated with the achievement of CR (secondary-type mutations, 51%, TP53 mutation, 49%). Clinical history was not associated with overall survival (OS) as patients with therapy-related AML had the same outcome as other patients (hazard ratio [HR]=1.04, P=0.9) and patients with AHD had a more favorable outcome (HR=0.57, P=0.02). On the other hand, adverse cytogenetics was associated with decreased OS (HR=3.32, P&amp;lt;0.001). Whereas TP53 mutations were associated with decreased OS (HR=3.71, P&amp;lt;0.001), secondary-type mutations were not (HR=0.64, P=0.049; Figure A). After multivariable analysis, both complex karyotype (CK; HR=0.006, P=0.006) and TP53 mutations (HR=2.12, P=0.03) were independently associated with OS. Considering both CK and TP53 mutations identified three groups of patients with differential OS (median 1.57 vs. 0.91 vs. 0.45 years, P&amp;lt;0.001; Figure B). Similar results were observed in the validation cohort. Patients in first CR from both cohorts were then compared to identify molecular subgroups for which a lenalidomide/azacitidine consolidation was associated with improved OS in comparison to standard chemotherapy. No molecular subgroup had increased OS with lenalimomide/azaciditine consolidation while standard chemotherapy was associated with improved outcomes in patients with adverse risk cytogenetics. Conclusion: Together, these data suggest that the clinical history contains limited prognostic value compared to genetics, supporting the most recent approach to use cytogenetic and molecular data to assess disease risk. In this patient population, complex karyotype and TP53 mutations, rather than secondary-type mutations, were associated with outcome. Figure. (A) Overall survival according to secondary-type and TP53 mutations status. (B) Overall survival according to complex karyotype (CK) and T P53 mutation status.

The Kinetics of FLT3L during Induction Chemotherapy for Pediatric Acute Lymphoblastic Leukemia Suggests a Novel Clinical Diagnostic and Treatment Strategy

Acute lymphoblastic leukemia (ALL), one of the most common malignancies, has been reported to account for nearly one-third of all pediatric cancers. Failure of induction chemotherapy is the leading cause of relapse and mortality in pediatric patients treated for ALL. Monitoring the therapeutic efficacy of induction chemotherapy and improving its success rate are critical to the clinical management of ALL. FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that is expressed on progenitor cells and ALL blasts. FLT3 ligand (FLT3L) is detectable during homeostasis and increases in hypoplasia due to genetic defects or treatment with cytoreductive agents. Here, we continuously monitored changes in FLT3L levels during induction chemotherapy in children with ALL to provide a more sensitive assessment of MRD, similar to NGS. The study included 54 children with ALL whose peripheral blood FLT3L levels were measured by ELISA weekly during induction chemotherapy. Weekly sampling revealed a significant difference in the kinetics of FLT3L response between children in complete remission (CR) and partial remission (PR), at day 14 of treatment (CR:519±10pg/ml vs PR:54±10pg/ml, P＜0.001). Furthermore, the achievement of CR in these patients was associated with higher FLT3L (150±10pg/ml vs 32±10pg/ml, P＜0.05) at day 28. Clinical prediction models show that combining minimal residual disease (MRD) status with FLT3L measurements better predicts whether patients will achieve CR after induction chemotherapy. Moreover, FLT3L levels were positively correlated with DC and T cells and negatively correlated with WBC, PLT and LDH during induction chemotherapy in children with ALL. Therefore, we hypothesized that higher levels of FLT3L might improve antitumor immunity by activating DC and T cells. However, further research is needed. In conclusion, measurement of FLT3L in children with ALL during induction may provide added value in assessing early treatment response to chemotherapy, the impact on long term outcome needs further study.

Sequential Chemotherapy and Blinatumomab to Improve Minimal Residual Disease in Adult Ph- B-Lineage Acute Lymphoblastic Leukemia. Final Results of the Phase II Gimema LAL2317 Trial

Introduction. The outcome of adult patients with acute lymphoblastic leukemia (ALL) has markedly improved following the introduction of a pediatric inspired chemotherapy backbone coupled with minimal residual disease (MRD) monitoring at well-defined timepoints (TP), translating into a rational patients' stratification for allogeneic transplantation (Tx). Immunotherapy, in particular blinatumomab, represents a further advancement in the management of ALL. We designed a phase II trial (GIMEMA LAL2317) for adult Ph- CD19+ B-lineage ALL (Ph- B-ALL) consisting of a pediatric chemotherapy backbone - with dose adjustment in patients &amp;gt;55 years - to which 2 cycles of blinatumomab were added, the first after early consolidation cycle 3 (high-dose methotrexate and Ara-C) and the second after late consolidation cycle 6. Tx allocation was based on MRD assessment, carried out in most cases by RQ-PCR and by flow cytometry when a sensitive molecular marker was not identified. The primary objective of the trial was to assess the impact of blinatumomab in increasing the rate of early MRD negativity at end of week 14 (TP3). Patients and methods. The protocol was designed for adults up to the age of 65 years with newly diagnosed Ph- B-ALL; 149 patients were enrolled. Median age was 41 years (18-65), with 28 patients (19%) being older than 55. Eighty-one patients were males, and the median white blood count (WBC) was 4.5x10 9/l (1-474); 12 cases harbored the KMT2A rearrangement, 5 the TCF3:: PBX1 transcript and 31 were classified as Ph-like according to the BCR/ABL1-like predictor . The median follow-up is 37.5 months (0.55-62.8) Results. At the end of induction (TP1, after cycles 1 and 2), 131 patients (88%) were in complete remission (CR), with a significant difference according to age: 94%, 92% and 64% in the 18-40, 40.55 and &amp;gt;55 years cohorts, respectively (p&amp;lt;0.001). All patients with KMT2A and TCF3::PBX1 rearrangements achieved a CR, while 5 Ph-like patients did not. At TP2, i.e. after early consolidation, 85 patients (70%) became MRD-negative (MRD neg). TP3, after the 1 st blinatumomab cycle, 102 patients were MRD neg; the rate of MRD negativity increased to 93% (p&amp;lt;0.001). Imposable results were obtained considering only paired MRD samples. Eight patients remained MRD pos, including 4 with a KMT2A rearrangement and 1 with a E2A::PBX1 rearrangement. OS and DFS at 36 months are 71% and 66% on the whole cohort. OS was significantly different (p=0.00013) according to age cohorts: 76%, 74% and 49% for patients aged 18-40, 40-55 and &amp;gt;55 years, respectively. Likewise, DFS was 71%, 62% and 42% for the same age cohorts, without reaching statistical significance. When patients were stratified for TP2 MRD, OS and DFS were significantly better for MRD neg vs MRD pos cases (p=0.0006 and p&amp;lt;0.0001, respectively). At variance, at TP3, with the caveat of the small sample size of MRD pos patients, the differences between MRD neg and MRD pos patients at TP3 were abolished: indeed, OS and DFS were 82% and 68% for MRD neg, 80% and 70% for MRD pos and 88% and 72% for those lacking MRD evaluation (Figure). Finally, 30 relapses have so far occurred, including 10 Ph-like, 1 KMT2A and 3 TCF3::PBX1 rearranged cases. The overall cumulative incidence of relapse (CIR) was 27.5%; of note, within TP3 MRD neg patients CIR was 42.5% in Ph-like cases vs 17.5% in the remaining patients. By univariate analysis, significant factors for OS were age (p&amp;lt;0.001), CR achievement (p&amp;lt;0.001) and TP2 MRD (p=0.002); TP2 MRD retained significance in multivariate analysis (p=0.001). Univariate analysis for DFS showed as significant the Ph-like signature (p=0.026) and TP2 MRD (p&amp;lt;0.001); both retained statistical significance in multivariate analysis (p=0.021 and &amp;lt;0.001, respectively). Toxicity details will be provided. Conclusions. This phase II trial shows the benefit of adding blinatumomab for the management of Ph- B-ALL, with the primary objective being achieved with 93% of patients being MRD neg after the 1 st cycle of blinatumomab. With a median follow-up of 37.5 months, OS and DFS are 71% and 66%, respectively, better than in historical results, particularly in patients up to the age of 55. Importantly, at TP3 the MRD status no longer impacted, highlighting the therapeutic role of blinatumomab, as observed in Ph+ ALL. Finally, the Ph-like signature retains its negative prognostic impact, suggesting that a combination strategy, similar to that in place for Ph+ ALL, is required.

Kinetics of Complete Remission (CR) and CR Duration and Its Impact on Overall Survival (OS) and Event-Free Survival (EFS) in Quantum-First

Background Results from the phase 3 QuANTUM-First study (NCT02668653) showed that in patients (pts) with newly diagnosed (nd) acute myeloid leukemia (AML) and positive for FMS-like tyrosine kinase 3-internal tandem duplication ( FLT3-ITD+), the addition of the oral, highly potent, and selective, type 2 FLT3 inhibitor quizartinib (Quiz) to standard chemotherapy ± allogeneic hematopoietic cell transplantation (allo-HCT), followed by continuation monotherapy for up to 3 years, decreased the relative risk of death by 22.4% vs placebo (PBO) (PMID: 37116523). We assessed 1) the impact of CR duration on OS and EFS and 2) the kinetics of CR achievement over time after induction. Methods QuANTUM-First enrolled pts aged 18-75 years with FLT3-ITD+ nd AML, randomized to receive standard induction chemotherapy with either Quiz (40 mg/d) or PBO, and stratified by region (Europe, North America, or Asia/Australia/South America), age (&amp;lt;60 years, ≥60 years), and white blood cell count (WBC; &amp;lt;40×10 9/L, ≥40×10 9/L) at diagnosis. Pts who achieved CR or CR with incomplete hematologic recovery (CRi) received up to 4 cycles of high-dose cytarabine combined with Quiz (40 mg/d) or PBO and/or allo-HCT followed by up to 3 years (36 cycles) of continuation therapy with Quiz (30-60 mg/d) or PBO. OS was the primary endpoint, EFS and rates of CR and composite complete remission (CRc) were secondary endpoints; CR duration was an exploratory endpoint. The impact of CR duration on OS was analyzed by extended Cox regression model stratified by region, age, and WBC count at diagnosis and included treatment group and CR duration status (time-dependent covariate). CR duration status was 0 for pts who did not achieve CR, 1 for CR pts throughout the duration of sustained CR, and 0 for CR pts after they relapsed. Results Of the 539 randomized pts enrolled in QuANTUM-First (Quiz, n=268; PBO, n=271), there were 297 CR pts (Quiz, n=147; PBO, n=150) based on independent review committee assessment after 1 to 2 courses of induction. Among 533 treated pts, 20% had 2 induction cycles. Baseline characteristics in CR pts were well balanced between arms: median age in years (range), 56.0 (23-75) vs 55.5 (20-74); females, 55.8% vs 60.0%; ECOG ≥1, 64.6% vs 63.3%; mutated NPM1 / CEBPA,66.7% vs 64.7% / 25.9% vs 23.3%; variant allele frequency (VAF) &amp;gt;25%, 68.7% vs 66.7%; and WBC count at diagnosis ≥40×10 9/L, 55.8% vs 49.3%. Median OS in CR pts was not reached (95% CI 48.6 months-NE) in the Quiz arm vs 35.4 (95% CI 15.1-NE) months in the PBO arm (HR 0.572, 95% CI 0.400-0.816; Figure 1). Although CR rates were similar between arms (55% in both), median CR duration was longer with Quiz vs PBO (38.6 months, 95% CI 21.9-NE vs 12.4 months, 95% CI 8.8-22.7; HR 0.621, 95% CI 0.451-0.857). Based on the extended Cox model, CR duration status covariate was strongly predictive for OS (HR 0.156, 95% CI 0.113-0.216; nominal P&amp;lt;0.0001; Figure 2). Importantly, the HR for Quiz vs PBO effect on OS in the model with the time-dependent covariate CR duration status was higher (HR 0.851, 95% CI 0.672-1.076) vs the HR of the primary OS analysis (HR 0.776, 95% CI 0.615-0.979), implying that a substantial fraction of OS benefit was mediated through its effects on achieving a durable CR (Figure 2). EFS favored Quiz over PBO when induction treatment failure (ITF) was defined as not achieving CRc or CR, by the end of induction up to day 56 from the last induction cycle, with HR 0.729 (95% CI 0.592-0.897; nominal P=0.0031) and 0.818 (95% CI 0.669-0.999; nominal P=0.032), respectively. EFS was similar between arms when ITF was defined, according to FDA guidance, as not achieving CR by day 42 from the start of the last induction cycle (HR 0.916, 95% CI 0.754-1.114; P=0.24; primary EFS analysis). Between day 42 and the end of the induction phase, there were 51 pts who achieved CR (Quiz, n=33; PBO, n=18), and they were considered as ITF with EFS event on day 1 in the primary analysis of EFS. Among these 51 pts, 9 (Quiz, n=5; PBO, n=4) had CRi by day 42 and became CR after day 42 in the induction phase. Conclusions These analyses demonstrated that in QuANTUM-First: 1) a substantial fraction of the estimated effect of Quiz on OS was mediated through its effect on achieving a durable CR and 2) more pts in the Quiz arm vs the PBO arm achieved CR after day 42 of the last induction cycle, suggesting that there was a delay in CR achievement with Quiz. Longer EFS was observed in Quiz over PBO based on the EFS definition including CRs between day 42 and end of induction.

Analysis of CD58 As a Predictive Marker of Morphologic Response to Inotuzumab Ozogamicin in Patients with B-Cell Acute Lymphoblastic Leukemia

BACKGROUND Clinical outcomes for B-cell Acute Lymphoblastic Leukemia (B-ALL) have significantly improved in the last decade, owing to the introduction of newer agents such as inotuzumab ozogamicin (INO) and blinatumomab. Both of these antibody-based therapies are effective in adults with relapsed or refractory (R/R) B-ALL and have shown promising results in the frontline setting as well. Given the utility of these therapies, there have been efforts to identify predictive markers for these treatments in B-ALL patients. Recently, CD58 was identified as a modulator of response to blinatumomab due to its role as a CD2 ligand in T-cell activation (Li et al. Sci Adv 2022). This costimulatory relationship between CD58 and CD2 has also been linked to Natural Killer cell mediated lysis, which has been described as a mechanism of action of INO (Fu et al. Signal Transduct Target Ther 2022; Huntington et al. Nat Rev Cancer 2020). In this study, we evaluated the correlation of CD58 expression with achievement of morphologic Complete Remission (CR) or Complete Remission with incomplete blood count recovery (CRi) after treatment with INO. METHODS Retrospective chart review was performed to identify patients in our institution's B-ALL database who received INO between 09/15/2011 and 03/10/2023 with blood or bone marrow samples available for flow cytometry analysis prior to INO infusion. Because all patients had measurable CD58 expression by flow cytometry, mean fluorescence intensity (MFI) was used instead of percent positivity to perform a simple logistic regression analysis to evaluate the relationship between CD58 MFI and achievement of CR/CRi after treatment with INO. We then calculated the odds of achieving CR/CRi by age, molecular risk at diagnosis, and R/R disease status. Two patients lacked diagnostic cytogenetic data. Molecular risk stratification and assessment of morphologic response were performed according to National Comprehensive Cancer Network (NCCN) guidelines. To account CD58 MFI outliers, we then confirmed our results by comparing response rates between patients with a CD58 MFI above our median (CD58 MFI-high) to patients with a CD58 MFI below our median (CD58 MFI-low) using Fisher's exact test. RESULTS We found 34 patients who met our criteria for analysis, 2 of which had previously received INO (Table1). Median Overall Survival (OS) was 21.5 months (range, 1-58) with a median leukemia-free survival (LFS) of 13.5 months (range, 1-52). Response rates after INO were high, including 28 patients (82.4%) achieving CR, 30 patients (88.2%) achieving CR/CRi, and 27 patients (79.4%) achieving Measurable Residual Disease (MRD) negativity. Both patients with a history of prior treatment with INO attained CR with MRD negativity. The chi-square test statistic for our simple logistic regression model was not statistically significant (Figure1, p=0.915). The logistic regression coefficient showed no statistically significant association between CD58 MFI and CR/CRi rates after treatment with INO ( p=0.913). Our model predicted an 88.6% probability of achieving CR/CRi for a CD58 MFI of 8,727.97 (Q1), 88.4% for 11,719.88 (Q2), 88.0% for 19,622.85 (Q3), and 85.7% for 55,217.74 (Q4). There was no statistically significant difference in the odds of achieving CR/CRi in patients with poor molecular risk at diagnosis (OR=0.06, 95% CI [0.01, 1.22]), age &amp;gt;35 years (OR=2.75, 95% CI [0.33, 22.9]), or R/R disease (OR=0.98, 95% CI [0.01, 1.97]). When comparing response rates between CD58 MFI-high and CD58 MFI-low patients, each group contained 15 patients that achieved CR/CRi and 2 patients with refractory disease. This confirmed an equal response rate to INO between CD58 MFI-high and CD58 MFI-low patients ( p=1.000). CONCLUSION Overall, we did not find a statistically significant correlation between CD58 MFI and achievement of CR/CRi. Our study is limited by our small sample size, single-center location, and retrospective design. However, it is important to note the high rates of CR/CRi that were seen, regardless of the intensity of CD58 expression. Further work is needed to evaluate the role of CD58 as a predictive marker for other therapies in B-ALL. These data suggest that INO is likely to remain an effective option for these patients, regardless of the intensity of CD58 expression.

How Induction Cycles before Remission Influence Long-Term Survival in Acute Myeloid Leukemia

Background ： Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by accumulation and expansion of immature myeloid cells in the bone marrow, peripheral blood and other tissues. Despite the progress made in mechanisms and approval of new therapeutics, the clinical outcome of AML remains suboptimal. The achievement of complete remission (CR) after induction chemotherapy is critical because the prognosis of refractory AML was especially unfavorable. However, little is known about the association between remission after first induction therapy and the overall survival (OS) in different subgroups of AML. Study Design and Methods: We retrospectively analyzed patients with newly diagnosed AML from January 2019 to August 2022. The diagnosis and treatment strategies were based on European Leukemia Net (ELN) criteria and National Comprehensive Cancer Network (NCCN) guideline. Composite complete remission (CRc) rate (CR+CR with incomplete recovery [CRi]) were assessed at the completion of induction or re-induction therapy. Minimal residual disease (MRD) was assessed using multiparameter flow cytometry with a minimum sensitivity of 0.1%. OS was measured from the day of diagnosis until death or the last follow-up date. Results : In total, 679 patients were included and the median age was 59.0 (range, 14.0-93.0) years old. There were 56.8% (386/679) of patients who achieved CRc after the induction therapy (group A), 18.1% (123/679) achieved CRc after the re-induction therapy (group B). The median follow-up period was 24.2 months. Even though there was no significant difference between group A and group B on OS, group A exhibited improved OS when censored at allogenic hematopoietic stem cell transplantation (HSCT) compared to that in group B (group A vs group B:3-year OS rates 65.7% vs 51.1%，p=0.004，Figure A). We further explored the effects of remission depth on survival. The results showed that, after induction therapy, patients achieved CR exhibited superior OS compared with that in CRi (CR vs. CRi, 3-year OS rates 69.4% vs 51.6%, p=0.006). Also, compared with these patients who failed to achieved MRD negativity within re-induction therapy, patients achieved MRD negativity within re-induction therapy showed superior OS when censored at HSCT (MRD- vs. MRD+, 3-year OS rates 64.7% vs 34.9%, p=0.040). After the first reduction therapy, patients achieved CRc but MRD positive benefit from HSCT (HSCT vs Non-HSCT, 3-year rates 83.0% vs 57.9%, p=0.017), but in patients with MRD negativity, HSCT did not improve the survival outcomes (HSCT vs Non-HSCT, 3-year rates 76.8% vs 65.7%, p=0.078). The next-generation sequencing (NGS) results were available in 520 patients. Based on the 2022 ELN risk stratification, the 3-year OS rates were 60.3%, 44.2% and 35.0% in favorable, intermediate and adverse group, respectively. Moreover, there were 43, 47, 60 patients in favorable, intermediate, and adverse subgroups underwent HSCT subsequently. In intermediate risk subgroup, patients who failed to achieve CRc after the first induction therapy, HSCT may serve as an effective intervention to prolong survival (3-year rates 100% vs 12.1%, P&amp;lt;0.001,). On the contrary, patients who achieved CRc in induction therapy, the overall survival were not influenced by HSCT status (3-year rates 81.5% vs 31.7%, p=0.153, Figure B). Conclusion: Our finding indicated that remission after the first cycle of induction therapy may be a prognostic factor for OS. Moreover, earlier and deeper remission may lead to improved survival. For those patients in intermediate risk group, who achieved CRc in induction therapy or achieved CRc with MRD negativity within re-induction therapy, HSCT may not influence the survival outcome.

A CD19/CD20-Directed Bispecific CAR-T Cell Therapy in Relapsed or Refractory Aggressive B-Cell Non-Hodgkin Lymphoma (NHL)

Three CD19-directed chimeric antigen receptor (CAR) T cell products are approved in the US for patients with relapsed or refractory (R/R) aggressive B cell lymphoma. Most patients treated in the third or later line will experience disease progression. Resistance to CD19-directed CAR T cell therapy may be due to tumor, T cell, or microenvironmental factors. Tumor-intrinsic causes of relapse include CD19 antigen loss, which is observed in approximately one third of relapsed cases(Spiegel, Dahiya, et al., 2021). Lower pretreatment CD19 antigen density has also been associated with treatment failure(Spiegel, Patel, et al., 2021). Conversely, enrichment of memory CD8+ T cells within the infusion product has been associated with achievement of complete remission (CR)(Deng et al., 2020). IMPT-314 is an autologous, naïve/memory enriched T cell product transduced by a lentivirus to express a tandem, OR-gate CD19/CD20-directed CAR with a 4-1BB co-stimulatory domain(Zah et al., 2016). IMPT-314 incorporates the same CAR and a highly similar manufacturing process as CART19/20, which was evaluated in a single-institution, Phase 1 study (NCT04007029)(Larson et al., 2023; Puliafito et al., 2023). Eleven patients with R/R B cell NHL have been treated at two dose levels (50 x 10 6 ± 30%, n=8; 200 x 10 6 ± 30%, n=3). Ten patients were evaluable for safety, and eleven patients were evaluable for response. Cytokine release syndrome (CRS) occurred in 60% of patients, however there were no CRS events above Grade 1. No patients experienced immune effector cell associated neurotoxicity syndrome (ICANS) of any grade. The overall response rate (ORR) and CR rate were 91% and 73%, respectively. As of March 6, 2023, with a median follow-up of 20.7 months, median progression-free survival (PFS) was 18.2 months (2.6-not estimable), and the median overall survival (OS) has not been reached (5.7-not estimable). This study of CART19/20 demonstrates the potential of simultaneous targeting of CD19 and CD20 with a bispecific CAR. Study Design The MPCT-012L study (NCT05826535) is a Phase 1/2 multicenter, open label study to evaluate the safety and efficacy of IMPT-314 in participants with relapsed/refractory aggressive B-cell NHL, defined as diffuse large B cell lymphoma (DLBCL), transformed follicular lymphoma (tFL), primary mediastinal large B cell lymphoma (PMBCL), and high-grade B-cell lymphoma (HGBL), after 2 or more lines of systemic therapy. Participants who have progressed after prior CD19 CAR-T cell therapy are eligible and are included in a separate cohort. All participants must have received prior anti-CD20 monoclonal antibody and an anthracycline. Patients with tFL must have received at least one line of therapy after transformation to DLBCL. Subjects with active (symptomatic or untreated) CNS involvement are excluded. There is no requirement for demonstration of CD19 or CD20 tumor expression at baseline. Phase 1 will be conducted using a modified 3+3 design with a starting dose of 100 x 10 6 CAR-T cells. Dose limiting toxicities (DLTs) will be evaluated for 28 days post-dosing. If a dose level is determined to be safe based on the DLT incidence, a total of up to 15 total subjects may be backfilled at that dose, per cohort. The primary objectives for Phase 1 are to evaluate the safety of IMPT-314 and to determine the recommended Phase 2 dose. The primary objective of Phase 2 is to estimate the efficacy of IMPT-314 as measured by CR rate. Secondary endpoints include evaluation of pharmacokinetics and time to event outcomes.

Novel Gene Mutations Associated with Disease-Free Survival in Elderly Patients with Acute Myeloid Leukemia Receiving First-Line Induction-Consolidation with or without Azacitidine Post-Remission Treatment

Background: The achievement of complete remission (CR) is an important milestone for patients with acute myeloid leukemia (AML) undergoing curative-intent therapy. However, patients who achieve CR with induction therapy for AML will relapse within months. Therefore, research is focused on prolonging leukemia-free survival (DFS). We have recently reported on the randomized phase III study to compare the efficacy and safety of azacitidine (AZA) versus best supportive care (BSC) for treatment of AML in elderly patients who achieved first CR after a homogeneous intensive induction and consolidation phase (QoLESS AZA-AMLE, Oliva et al. Cancers 2023). At 2 and 5 years, DFS was 6.0 (95% CI:0.2-11.7) months in the BSC arm vs. 10.8 (95% CI:1.9-19.6 p=0.23) months in the AZA arm. We report on the ancillary translational study (QOL-ONE Trans-2) to evaluate biological changes in bone marrow samples through Next Generation Sequencing (NGS). Objective: In patients enrolled in the trial who reached CR and were randomized to receive AZA or BSC, the endpoint of the present study was to evaluate the effect modification by gene mutations at AML diagnosis on the relationship between treatment allocation and relapse (disease-free survival, DFS). Methods: The study was performed on available biological samples collected at baseline, randomization, and 6-month post remission. DNA was subjected to high throughput NGS using genes commonly mutated in myeloid malignancies and prepared with a home-set of 350 genes for Illumina (University of Kyoto, Japan) for all subjects with available vials. Only variants with high-quality reads, were considered. A Variant Allele Frequency (VAF) ≥ 4% was considered an appropriate threshold for minimal burden of clonality to be reported. Results: Samples were available for 24 patients, 12 males, of median age 71 (65-74) years, 11 allocated in AZA arm and 13 in BSC arm. At diagnosis, mutations were detected in all patients with a range of 5 to 17 (median 10) simultaneous mutations, the most frequent being DNMT3A (42%), NPM1 (33%) and TET2 (33%). The most frequently mutated genes at diagnosis are represented in the figure. Only FANCA gene, mutated in 4 patients was associated with a hazard risk (HR) 4.96 (95% CI 1.34 - 18.35; p=0.02) of relapse and, interestingly, HLA-A, which was mutated in 7 patients, was associated with a HR 0.277 (95% CI 0.08 - 0.95; p=0.049). Patients with HLA-A mutation had a significantly longer survival (Figure 2). Three HLA-A mutated patients were allocated in 5-Aza arm and 4 in BSC arm. In a multivariate COX model, the effect of baseline HLA-A mutation on DFS is independent of the allocation arm (P=0.041). HLA Class I and Class II alleles were assessed based on the Luminex xMAP technology: for all cases, the HLA-SNPs are located on chromosome 6 in exon 2, 3 and 4 within protein-codifying sequences. Conclusions: HLA gene mutations are not usually investigated for diagnostic or prognostic purposes in AML. The extensive 350-gene panel used in this study included HLA genes and has revealed a possible favorable role of HLA-A polimorphisms for the prognosis of elderly patients with AML undergoing intensive chemotherapy. Further specific HLA NGS analyses are undergoing to determine whether this concerns genuine somatic mutations. The present finding is worthy of further investigation to confirm its value in prognosis and its therapeutic implications.