7009 Background: Approximately 25% of patients (pts) treated with rituximab + CHOP do not have a complete response (CR), and those with refractory/relapsed disease or high-risk features have poor outcomes. To address this unmet need, bispecific antibody combinations are being evaluated. In Part 1A (dose escalation) of the Phase 3 OLYMPIA-3 study (NCT06091865), odronextamab (Odro)-CHOP demonstrated generally manageable safety (most common treatment-emergent adverse events [TEAE] were neutropenia [81.8%] and cytokine release syndrome [CRS; 54.5%]) and encouraging preliminary efficacy in pts with previously untreated DLBCL, with CR rates of 100% on PET/CT (160 mg dose level, selected for Part 1B dose optimization). Here, we report Part 1B results. Methods: Part 1B included pts aged ≥18 years with untreated CD20+ DLBCL not otherwise specified or high-grade B-cell lymphoma with at least 1 high-risk feature. Odro-CHOP was administered in 6 × 21-day cycles, with Odro 0.7/4/20 mg step-up dosing from Cycle 1 Day 8. Pts were randomized 1:1 to receive Odro 160 mg QW/320 mg Q2W (Regimen [R] 1) or Odro 160 mg QW/160 mg Q3W (R2) with CHOP. Primary endpoint was safety. Secondary endpoints included investigator-assessed objective response rate (ORR) and CR rate per 2014 Lugano criteria. Results: At data cut-off (August 19, 2025), 40 pts were enrolled in Part 1B (20 per regimen). Median age was 67.5 years, 60.0% of pts were male, and 75.0% had an IPI score of 3–5. Median duration of treatment exposure was 18.1 weeks (R1) and 16.6 weeks (R2); 67.5% of pts completed 6 treatment cycles. Median relative dose intensity ranged from 90.1 to 100% for Odro and 92.7 to 100% for CHOP. The safety profile of Odro-CHOP was similar across regimens. TEAEs led to dose interruption/delay in 70.0% vs 50.0% of pts and to CHOP dose reduction in 10.0% vs 5.0% of pts with R1 vs R2, respectively. No TEAEs led to Odro dose reduction and 1 led to treatment discontinuation (Grade 4 neutropenic sepsis, R2). The most common TEAEs were neutropenia (57.5%), CRS (55.0%), and anemia (42.5%). CRS rates were consistent with Part 1A, predominantly Grade 1 (42.5% of pts). ICANS occurred in 3 pts (all Grade 1) and resolved completely. All enrolled pts were analyzed including 3 pts who discontinued treatment prior to tumor imaging assessment. With a median follow-up of 2.3 months in both regimens, ORRs were 95.0% (R1) and 90.0% (R2), and CR rates were 85.0% (both regimens). Conclusions: In Part 1B of OLYMPIA-3, the safety profile of Odro-CHOP was generally manageable and preliminary efficacy was encouraging with no meaningful differences between regimens, and combination with Odro did not impact the delivery of CHOP. Given these results, the less frequent Odro dosing regimen (R2) with CHOP was selected as the recommended Phase 3 dose for Part 2 (randomized controlled trial). Biomarker data will be presented. Clinical trial information: NCT06091865 .

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States.1 The NCCN Guidelines Panel for AML convenes annually to update recommendations for the diagnosis and treatment of AML in adults. These recommendations are based on a review of recently published clinical trials that have led to significant improvements in treatment or have yielded new information regarding biologic factors that may have prognostic importance. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding the monitoring and management of measurable (minimal) residual disease.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States.1 The NCCN Guidelines Panel for AML convenes annually to update recommendations for the diagnosis and treatment of AML in adults. These recommendations are based on a review of recently published clinical trials that have led to significant improvements in treatment or have yielded new information regarding biologic factors that may have prognostic importance. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding the monitoring and management of measurable (minimal) residual disease.

Background CD4 is expressed across several hematopoietic malignancies, including T-cell malignancies (TCM), chronic myelomonocytic leukemia (CMML), and subsets of acute myeloid leukemias (AML), but not on normal hematopoietic stem cells or other tissues. In addition, CD4 is expressed on immune-suppressive cell populations, including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and monocytic leukemia stem cells (LSCs), including those associated with venetoclax resistance. These features collectively identify CD4 as a promising but underexplored therapeutic target. Methods We initiated multi-center, first-in-human (FIH) phase I clinical trials to evaluate the safety, feasibility and potential immune modulating effects of CD4-targeted chimeric antigen receptor (CD4CAR) T cell therapy in patients with relapsed or refractory CD4-positive hematologic malignancies. The CD4CAR construct is a third-generation lentiviral vector–encoded receptor that incorporates both CD28 and 4-1BB costimulatory domains to enhance T cell activation, persistence, and antitumor function. Autologous T cells were transduced and expanded ex vivo and infused following lymphodepletion with either fludarabine/cyclophosphamide or bendamustine. A standard 3+3 dose-escalation design was employed to determine the recommended phase 2 dose, and treatment-related toxicities, pharmacodynamics, and immunologic biomarkers were systematically assessed. Adverse events were graded per CTCAE v5.0. Results Fourteen patients were treated: CD4+ AML (n=2), CMML (n=3), and TCM (n=9). Median age was 65.5 years (range 18-78), and patients received a median of 2 prior therapies (range 1–5). CD4CAR was infused at doses ranging from 8.0×10⁴ to 1.6×10⁵ CAR+ cells/kg (Cohorts 1 and 2). Cell products were successfully manufactured for all patients without the need for CD4+ cell, negative selection. CD4CAR was well tolerated, with no dose-limiting toxicities. Grade ≥3 lymphopenia resolved by day 30 without DLT qualifying infections. Grade 1 cytokine release syndrome (CRS) occurred in two patients and resolved without steroids or tocilizumab. No immune effector cell - associated neurotoxicity was observed. The low rate of CRS may reflect may be attributable to the final product composition, which consisted predominantly of CD8+ CAR+ T cells with minimal or absent CD4+ CAR+ T cells. CD4CAR expansion was observed in blood and marrow, with a median time to peak CAR T cell count of 14.5 days (range 7-120) and a median peak of CAR+/CD3+ percentage at 9.5 days (range 7-150). CD4CAR Persistence extended beyond day 90 in most patients and up to day 365 in one case with evidence of in vivo Tcm phenotype. Updated timepoint analyses continue to demonstrate reductions in Tregs and MDSCs, particularly monocytic subsets (CD45+/CD11b+/CD193−/CD84−/CD16+14+ or 16−), across AML, CMML, and TCM. LSCs were detected at baseline in several AML and CMML patients and showed early and durable clearance post-infusion. Among evaluable patients (n=7), the overall response rate was 71.4%, including 57.1% complete responses. All complete responders remain in remission at last follow-up (median 5.7 months). During manufacturing, fratricide-related T cell exhaustion remained minimal despite sustained target (CD4+ T cels) CAR engagement. Conclusions CD4CAR therapy is feasible and safe, with evidence of biologic activity, immune modulation, as well as early clinical responses across CD4-expressing hematologic malignancies. The predominance of CD8+ CAR T cells in the infused product did not impair in vivo expansion or persistence. These findings support the continued development of CD4-targeted CAR T cell therapies.

Background TCM are aggressive diseases with poor outcomes. Translating the CAR T-cell therapy success from B-cell diseases to TCM has proven challenging. CD4 is an attractive therapeutic target, owing to its restricted expression on normal tissues. In this first-in-human phase I study, we investigate the autologous third generation CD4-redirected CAR T-cell safety, tolerability, manufacturing feasibility, trafficking and preliminary efficacy in patients with R/R CD4+ TCM who failed standard therapies. Methods The investigational construct is engineered with a single-chain variable fragment (ScFV) and dual co-stimulators (CD28; 4-1BB), fused to CD3zeta and CD8 leader sequence, packaged in lentivirus and transducer into T-cells. Patients received conditioning therapy with fludarabine and cyclophosphamide. CD4CAR product is administered in a 3+3 dose-escalation scheme. Dose-limiting toxicities (DLT) were monitored during the initial 42-days post-treatment. Treatment-emergent adverse events (AE) were graded by CTCAE v5.0 Results Three patients with median age of 63 years (range, 18-68) were enrolled and treated at DL1 (2.0x10^5/kg), including 2 (66%) women and 2 (66%) African-American. Median number of prior therapies was 3 (range, 2-4) (Figure). AEs included grade 3-4 hematologic toxicity in 3 (100%) patients, all present before enrollment. There was no protocol defined DLTs. All grade ≥3 lymphopenia reverted to grade 2 by day 30 and no related infections occurred between CAR infusion and hematopoietic stem cell transplantation (HSCT). Since infusion, the CAR T-cells percentage in peripheral blood had continued to expand. CD4CAR T-cells were detectable in all patients for at least 28 days post-infusion, meeting the primary endpoint, and on D111 in one patient. CD4CAR expansion was reflected on by a decrease in CD4/CD8 ratio and flow cytometry using ScFV Fab2 specific antibodies (Figure). Cytokine response analysis CD4CAR was associated with variable but significant production that seems to correlate with clinical responses (Figure; More data at meeting). No cytokine-mediated organ toxicities were observed. Bone marrow and peripheral blood flow cytometry confirmed complete remission (CR) in 2 patients at day 30 (PTCL and T-ALL). Patient 3 (mycosis fungoides) achieved hematological CR with stable skin lesions. Post-treatment day 30 skin biopsy demonstrated persistent disease with marked loss of CD4. Conclusions CD4CAR T-cell therapy is feasible in patients with R/R CD4+ TCM. 2/3 patients achieved CR and the third achieved hematological CR with stable skin disease. Toxicities were manageable without DLT upon completion of cohort 1. The cytokine response suggests immune activation and tumor recognition by CD4CAR T-cells. Dose escalation will proceed. NCT03829540

ObjectiveThe diagnostic accuracy and yield of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is not well established in lymphoma and other mediastinal-related diseases. The objective of this study was to examine the yield of a combined technique of EBUS-TBNA and endobronchial ultrasound-guided transbronchial forceps biopsies (EBUS-TBFB) compared with each modality alone in lymphoma and other mediastinal-related diseases.MethodsThis was a retrospective review of cases of mediastinal lymphadenopathy of unknown etiology accessed using TBNA and TBFB. The McNemar test was used to compare the diagnostic yield of TBNA, TBFB, and the combined technique.ResultsThe combined approach yielded a definitive diagnosis in 31/35 cases (88.6%). In 9/10 cases (90%), Hodgkin's and non-Hodgkin's lymphomas were diagnosed and subtyped without further need for invasive testing. All of the granulomatous inflammation cases were confirmed using the combined technique. Two cases led to adequate whole-genome sequencing of lung cancer, and one patient was diagnosed as having dedifferentiated liposarcoma despite a nondiagnostic preprocedural mediastinoscopy. There was only one procedure-related complication, a pneumomediastinum that required no further intervention. There were no significant adverse events.ConclusionsThe combination of EBUS-TBFB and EBUS-TBNA is safe and provides a high yield in the diagnosis of mediastinal adenopathy of unknown etiology, especially lymphoma. Furthermore, the larger samples obtained from TBFB increased its sensitivity to detect granulomatous disease and provided specimens for clinical trials of malignancy when needle aspirates were insufficient.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malig-nancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. Like AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a myeloid malignancy. It is a rare malignancy characterized by the ag-gressive proliferation of precursors of plasmacytoid dendritic cells that frequently involves the bone marrow, skin, central nervous system, and other organs and tissues. This discussion section focuses on the diag-nosis and management of BPDCN as outlined in the NCCN Guidelines for AML.

Historical standard of care treatments of T-cell malignancies generally entailed the use of cytotoxic and depleting approaches. These strategies are, however, poorly validated and record dismal long-term outcomes. More recently, the introduction and approval of chimeric antigen receptor (CAR)-T cell therapy has revolutionized the therapy of B-cell malignancies. Translating this success to the T-cell compartment has so far proven hazardous, entangled by risks of fratricide, T-cell aplasia, and product contamination by malignant cells. Several strategies have been utilized to overcome these challenges. These include the targeting of a selective cognate antigen exclusive to T-cells or a subset of T-cells, disruption of target antigen expression on CAR-T constructs, use of safety switches, non-viral transduction, and the introduction of allogeneic compounds and gene editing technologies. We herein overview these historical challenges and revisit the opportunities provided as potential solutions. An in-depth understanding of the tumor microenvironment is required to optimally harness the potential of the immune system to treat T-cell malignancies.

An amendment to this paper has been published and can be accessed via the original article.

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease. Despite good responses to standard of care frontline chemoimmunotherapy, the prognosis of relapsed/refractory (R/R) patients remains obscured by the possible inadequate responses to salvage therapy, eligibility for autologous transplantation, age and comorbidities. Polatuzumab vedotin is an antibody-drug conjugate formed by a CD79b antibody conjugated to the highly cytotoxic agent monomethyl auristatin E by means of a cleavable linker. Following significant clinical efficacy in R/R DLBCL, polatuzumab vedotin was granted accelerated Food and Drug Administration (FDA) approval in combination with bendamustine plus rituximab for patients who have failed at least two prior therapies. Other clinical studies involving polatuzumab vedotin in combination with other therapy regimens are also under evaluation for previously untreated DLBCL patients. In this article, we review the different phases from the preclinical development of polatuzumab vedotin to studies leading to its first approval, and highlight the potential future roles of this molecule in the treatment landscape of DLBCL.

Relapse rates following allogeneic stem cell transplantation for acute myeloid leukemia remain unacceptably high and a major cause of death. Maintenance therapies post-transplant administered either to patients with impending relapse or at high risk of relapse could present a strategy to improve survival and overall outcomes. With the increasing use of molecular and genomic characterization of the disease, more novel therapies became available as maintenance strategies. These options were, however, hindered by excessive toxicities, mostly hematologic, especially with the use of myeloablative conditioning regimens. Several key questions have also emerged including the efficacy of these therapies, the duration of maintenance, as well as the potential modulation of the graft and the immune microenvironment. These issues are further complicated by the paucity of well-designed prospective randomized clinical trials evaluating these agents. Future directions in this field should include better risk stratification and patient selection based on assays of minimal residual disease, as well as the incorporation of novel targets and pathways of leukemogenesis. In this article, we highlight the current evidence behind the use of post-transplant maintenance therapy, the optimal patient and disease selection, as well as the challenges faced by these strategies in an area that remains quite controversial. We will focus on therapies targeting leukemia stem cells that directly or indirectly modulate the allografted immune microenvironment and augment the graft-versus-leukemia impact.

Introduction Second-generation FLT3i demonstrated composite CR rates (CRc) of 45-55% in pts with relapse/refractory (R/R) FLT3-mutated AML in phase II/III (ADMIRAL, QUANTUM-R) trials. However, >85% of pts treated in these trials were prior FLT3i naïve as these trials enrolled most of their pts prior to midostaurin approval. The response rates to sequential FLT3i exposure remain poorly defined. The goal of this analysis was to provide benchmark response rates to second and even potentially third sequential FLT3i exposures. Methods We retrospectively reviewed adult pts with FLT3-mutated AML treated between Jan 2006 and Dec 2019 at our institution. Single agent FLT3i, FLT3i-based combinations with cytotoxic chemotherapy (CCT) and with low intensity therapy (LIT) (hypomethylating agent or low-dose cytarabine based combinations) were included. Cohort 1 (Figure 1A) included pts who received first FLT3i-based therapy in the "frontline induction" followed by post-induction FLT3i-based salvage therapies. Cohort 2 (Figure 1B) included pts who received their first FLT3i-based therapy in "salvage" followed by sequential FLT3i based therapies in subsequent salvages. Results A total of 239 pts with FLT3-ITD and/or FLT3-D835 mutated AML who received FLT3i based treatments were identified (Table 1). Cohort 1 - First FLT3i exposure in frontline setting In frontline pts who received a FLT3i (cohort 1), the CRc rates with the first "induction" (n=56), and post-induction salvage: second (n= 32) and third FLT3i-based (n= 8) therapies, were 77%, 31%, and 25% respectively (Table 2A). The median overall survival (OS) with the first, second and third FLT3i-based therapies were 16.7 months, 6.0 months, and 1.4 months, respectively. Cohort 2 - First FLT3i exposure in salvage setting In pts receiving a FLT3i-based therapy for the first time in a R/R AML setting (i.e. no FLT3i with induction) (cohort 2), the CRc rates and median OS were 45%, 21%, and 10%, and 7.9 months, 4.0 months, and 4.1 months with the first (n=183), second (n=89), and third/fourth (n=29) sequential FLT3i-based therapies, respectively (Table 2B). Single-agent versus Combination FLT3i-based therapies In cohort 1, in the post-induction salvage setting, the CRc rates with single-agent FLT3i (n=21) versus combinations (n=19) were 19% versus 42%, respectively. (Table 2A). In cohort 2, the CRc rates with single-agent FLT3i (n=82) versus FLT3i-based combinations (n=101) in first FLT3i exposure were 34% versus 53%, respectively, and with single agent FLT3i (n=63) versus FLT3i-based combinations (n=55) in the second/third/fourth sequential FLT3i exposures were 13% versus 25%, respectively (Table 2B). The median OS with the first FLT3i-based therapy in salvage AML was 5.4, 10.4, and 9.9 months with single-agent, LIT, and CCT FLT3i-based therapies, respectively (P<0.001) (Figure 2A). Median OS with the second FLT3i-based therapy exposure in salvage AML was 2.8, 5.3, and 4.7 months, with single-agent, LIT, and CCT FLT3i-based therapies, respectively (P=0.174) (Figure 2B). Impact of Minimal Residual Disease at CRc in Cohort 2 In the salvage AML (cohort 2), 104 of 301 achieved CRc, and 84 of 104 (80%) of these pts had serial FLT3-ITD/TKD PCR checked on the bone marrow at baseline and at CRc. Pts who achieved MRD negativity by FLT3-PCR had improved OS (16.3 versus 8.5 months, P=0.04) and event free survival (EFS) (12.2 versus 3.3 months, P<0.001) (Figure 3A-B). Achievement of MRD-negativity by MFC at CRc was however not associated with a significant impact on OS (9.8 vs 10.7 months, P=0.55) nor EFS (4 vs 3.4 months, P=0.19). Conclusion The CRc rates and median OS dropped with sequential FLT3i exposure, from induction to post-induction salvage (cohort 1) and sequentially in subsequent salvages (cohort 2). FLT3i combinations demonstrated improved CRc rates and improved OS compared with single agent FLT3i's in all similar FLT3i exposure settings. Achievement of MRD negativity by FLT3-PCR improved OS in R/R setting. These data provide benchmark expectations in the "post-midostaurin" and now "post-gilteritinib" era for clinical trials evaluating combinations of FLT3i's with chemotherapy, hypomethylating agents, venetoclax, and triplets of hypomethylating agents with venetoclax and FLT3i's in R/R FLT3-AML, a majority of whom will have received one or more prior FLT3 TKI therapies. Disclosures Yilmaz: Pint Pharma: Honoraria; Pfizer: Research Funding; Daicho Sankyo: Research Funding. Kadia:Pfizer: Honoraria, Research Funding; Novartis: Honoraria; BMS: Honoraria, Research Funding; Celgene: Research Funding; Incyte: Research Funding; Genentech: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Cyclacel: Research Funding; Astellas: Research Funding; JAZZ: Honoraria, Research Funding; Astra Zeneca: Research Funding; Ascentage: Research Funding; Pulmotec: Research Funding; Cellenkos: Research Funding; Amgen: Research Funding. DiNardo:Agios: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; Jazz: Honoraria; Novartis: Consultancy; Notable Labs: Membership on an entity's Board of Directors or advisory committees; MedImmune: Honoraria; Syros: Honoraria; Takeda: Honoraria. Borthakur:Incyte: Research Funding; PTC Therapeutics: Research Funding; Nkarta Therapeutics: Consultancy; BioTherix: Consultancy; Treadwell Therapeutics: Consultancy; Argenx: Consultancy; FTC Therapeutics: Consultancy; Curio Science LLC: Consultancy; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; BioLine Rx: Research Funding; GSK: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; BioLine Rx: Consultancy; PTC Therapeutics: Consultancy; Cyclacel: Research Funding. Konopleva:Eli Lilly: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Sanofi: Research Funding; Forty-Seven: Consultancy, Research Funding; Agios: Research Funding; AstraZeneca: Research Funding; Kisoji: Consultancy; Genentech: Consultancy, Research Funding; Amgen: Consultancy; F. Hoffmann La-Roche: Consultancy, Research Funding; Ascentage: Research Funding; AbbVie: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; Cellectis: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Ablynx: Research Funding. Jabbour:Amgen: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding. Garcia-Manero:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Onconova: Research Funding; Merck: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Amphivena Therapeutics: Research Funding; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Pemmaraju:Plexxikon: Research Funding; Cellectis: Research Funding; AbbVie: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; SagerStrong Foundation: Other: Grant Support; Celgene: Honoraria; Novartis: Honoraria, Research Funding; Samus Therapeutics: Research Funding; Stemline Therapeutics: Honoraria, Research Funding; Incyte Corporation: Honoraria; DAVA Oncology: Honoraria; Roche Diagnostics: Honoraria; Daiichi Sankyo: Research Funding; Affymetrix: Other: Grant Support, Research Funding; MustangBio: Honoraria; LFB Biotechnologies: Honoraria; Blueprint Medicines: Honoraria. Issa:Novartis: Membership on an entity's Board of Directors or advisory committees; Syndax: Research Funding; Celegene: Research Funding. Short:Astellas: Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding. Andreeff:Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy. Cortes:Sun Pharma: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Telios: Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Immunogen: Research Funding; Merus: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Kantarjian:Ascentage: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Janssen: Honoraria; Oxford Biomedical: Honoraria; Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Ravandi:AstraZeneca: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding. Daver:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Tyrosine kinase inhibitors (TKIs) are teratogenic. Chronic myeloid leukemia (CML) is increasingly identified in younger patients who wish to conceive, the management of CML during pregnancy is challenging. We reviewed 51 pregnancies involving 37 patients (30 women, 10 with >1 pregnancy and 7 men) who were either diagnosed with CML during pregnancy or receiving TKI at the time of conception. Ten women were involved in >1 pregnancies. Fifteen women were diagnosed with CML during pregnancy: 10 were treated with hydroxyurea (n = 5), interferon-alfa (n = 3), leukapheresis (n = 1), or nilotinib (n = 1). There were 14 (82%) healthy babies born on term including 2 sets of twins, 2 spontaneous miscarriages (12%), and 1 elective abortion (6%). Within 1 month of delivery or abortion, all women started TKI and achieved MR4.5 (n = 6) and MMR (n = 8) within 3-48 months. One patient, treated with interferon during pregnancy, died of blast phase within 2 months. Four of the 14 remaining women later conceived 5 other pregnancies while on TKI (3 unplanned, 2 planned). Twenty-six patients (7 men; 19 women) conceived while on TKI, with a total of 36 pregnancies. Fifteen women had 20 unplanned pregnancies while receiving TKI and discontinued immediately upon recognition of pregnancy. The median time of TKI exposure was 3 weeks (range, 2-11). Five pregnancies ended in miscarriages and 3 in elective abortion. All 7 men fathered 7 full-term healthy babies. Of 20 babies born to men and women (including one set of twins), 1 had minor abnormality. Seven women lost their responses during pregnancy but at the end of pregnancy all but 2 resumed TKI and regained responses. Seven women involved in 9 planned pregnancies discontinued TKI prior to conception for a median of 4 months (range, 1-20); 3 lost responses during pregnancy. Only 5 patients resumed therapy after delivery. Outcomes were 6 full-term healthy babies, one premature, and two miscarriages. Conception among CML patients while on TKI could be uncomplicated. While patients may lose response following treatment interruption, nearly all regain response upon resuming therapy. Therapy during pregnancy is rarely needed.

Background Second-generation FLT3-inhibitors (FLT3i) demonstrated single-agent composite CR rates (CRc) of 45–55% in patients with relapsed/refractory (R/R) FLT3-mutated AML in phase II/III trials. However, > 85% of patients treated were prior FLT3i naïve. The response rates to sequential FLT3i exposure remain poorly defined. Methods We retrospectively reviewed patients with FLT3 -mutated AML between November 2006 and December 2019. Results In frontline patients treated with a FLT3i (cohort 1), the CRc rates and median overall survival (OS) with the first ( n = 56), second ( n = 32), and third FLT3i-based ( n = 8) therapy were 77%, 31%, and 25%, and 16.7 months, 6.0 months, and 1.4 months, respectively. In patients receiving a FLT3i-based therapy for the first time in a R/R AML setting (cohort 2), the CRc rates and median OS were 45%, 21%, and 10%, and 7.9 months, 4.0 months, and 4.1 months with the first ( n = 183), second ( n = 89), and third/fourth ( n = 29) FLT3i-based therapy, respectively. In cohort 1, CRc rates with single-agent FLT3i ( n = 21) versus FLT3i-based combinations ( n = 19) in second/third sequential FLT3i exposures were 19% versus 42%, respectively. In cohort 2, the CRc rates with single-agent FLT3i ( n = 82) versus FLT3i-based combinations ( n = 101) in first FLT3i exposure were 34% versus 53%, respectively, and those with single-agent FLT3i ( n = 63) versus FLT3i-based combinations ( n = 55) in second/third/fourth sequential FLT3i exposures were 13% versus 25%, respectively. Conclusion CRc rates drop progressively with sequential exposure to FLT3i’s in FLT3 -mutated AML. In all settings, CRc rates were higher with FLT3i-based combinations compared with single-agent FLT3i therapy in similar FLT3i exposure settings.

While germline and somatic mutations in the gene PTPN11 , encoding a phosphatase which regulates the RAS signaling pathway, are well characterized in children with Noonan syndrome and juvenile myelomonocytic leukemia, less is known about their clinical impact in adults with acute myeloid leukemia (AML). To elucidate the effect of PTPN11 mutations ( PTPN11 mut ) on clinical outcomes, we screened adult patients with AML treated at our institution using targeted next-generation sequencing. Among 1406 consecutive patients, 112 (8%) had PTPN11 mut . These mutations were more commonly associated with the acute myelomonocytic/monocytic leukemia subtype than was wild-type PTPN11 , while none were detected in patients with core-binding factor AML. They co-occurred more commonly with NPM1 mutations and FLT3 internal tandem duplications and less commonly with mutations in IDH2 and a complex karyotype. Compared with the wild-type allele, PTPN11 mut was associated with lower complete response rates (54% vs 40%; P = 0.04), and shorter overall survival (median 13.6 vs 8.4 months; P = 0.008). In a multivariate analysis, PTPN11 mut independently increased the risk of death, with a hazard ratio of 1.69 (95% CI, 1.25–2.29; P = 0.0007). In summary, mutations in PTPN11 have a characteristic phenotype in adults with AML and are associated with an adverse prognosis.

Purpose of review We herein review some of the major patterns of resistance and lessons learned from the use of earlier targeted therapies in two genotype-driven solid tumors. Recent findings Targeted agents have rapidly expanded in the field of oncology over the past 2 decades. The breakthroughs achieved by these agents have been, however, hindered by the inevitable development of drug resistance. Intrinsic or acquired mechanisms of resistance eventually lead to treatment tolerance and tumoral plasticity with phenotypic switch and evasion of the original targeted pathway. Failures in such therapies also result from poor selectivity of the target, drug delivery, and unaffordable costs. Summary Based on above findings, collaborative efforts are advancing at the molecular level to design better drugs or combinatorial strategies and to develop more sensitive assays to monitor responses and the emergence of resistance.