TP53 deletion (ΔTP53) in myeloma is known to be a high-risk finding associated with poorer prognosis. The prognostic impact of underlying cytogenetic heterogeneity in patients with myeloma associated with ΔTP53 is unknown. We studied 90 patients with myeloma associated with ΔTP53 identified by interphase fluorescence in situ hybridization and assessed the impact of karyotype and coexisting alterations of IGH, RB1, and CKS1B. There were 54 men and 36 women with a median age of 59 years (range 38–84); 14 patients had a normal karyotype (NK/ΔTP53), 73 had a complex karyotype (CK/ΔTP53), and 3 had a non-complex abnormal karyotype. Patients with CK/ΔTP53 showed a significantly poorer overall survival compared with patients with NK/ΔTP53 (P=0.0243). Furthermore, in the CK/ΔTP53 group, patients with IGH rearrangement other than t(11;14)(q13;q32)/CCND1-IGH, designated as adverse-IGH, had an even worse outcome (P=0.0045). In contrast, RB1 deletion, CKS1B gain, ploidy, additional chromosome 17 abnormalities, or ΔTP53 clone size did not impact prognosis. Stem cell transplant did not improve overall survival in either the NK/ΔTP53 or CK/ΔTP53 (P=0.8810 and P=0.1006) groups, but tandem stem cell transplant did improve the overall survival of patients with CK/ΔTP53 (P=0.0067). Multivariate analysis confirmed in this cohort that complex karyotype (hazard ratio 1.976, 95% CI 1.022–3.821, P=0.043), adverse-IGH (hazard ratio 3.126, 95% CI 1.192–8.196, P=0.020), and tandem stem cell transplant independently correlate with overall survival (hazard ratio 0.281, 95% CI 0.091–0.866, P=0.027). We conclude that comprehensive genetic assessment adds to TP53 status in the risk stratification of myeloma patients.

Background: Intrachromosomal amplification of chromosome 21 (iAMP21) results from breakage-fusion-bridge cycles and chromothripsis is a distinct marker of a subgroup of B cell acute lymphoblastic leukemia (B-ALL) cases associated with a poor prognosis. iAMP21 accounts for 2% of pediatric B-ALL and occurs predominantly in older children or adolescents. ETV6-RUNX1 fusion, resulting from t(12;21)(p13;q22), is associated with an excellent outcome in younger children with B-ALL. Coexistence of iAMP21 with ETV6-RUNX1 fusion is extremely rare with limited clinical information available. Results: We report the case of an 18-year old Caucasian man diagnosed with ETV6-RUNX1 fusion positive B-ALL. He was treated with intensive chemotherapy and achieved remission for 6 months before relapse, 15 months after the initial diagnosis. G-band karyotyping and Fluorescence in situ hybridization (FISH) analyses performed on bone marrow revealed complex abnormalities: 41,X,-Y,der(3)t(3;20)(p11.2;q11.2),-4,t(5;22)(q32;q11.2),del(9)(p13),dic(9;17) (p13;p11.2),t(12;21)(p13;q22),der(14)t(14;17)(p11.2;q11.2),der(17;22)(q11.2;q11.2),-20,add(21)(q22),-22[4]/46,XY [15] with an iAMP21 and an ETV6-RUNX1. Additional molecular studies confirmed ETV6-RUNX1 fusion and with a TP53 mutation. High-resolution single nucleotide polymorphism microarray (SNP array) revealed the iAMP21 to be chromothripsis of 21q and subsequent metaphase FISH further delineated complex genomic aberrations. Although the patient received intensive chemotherapy with allogenic stem cell transplant, he died 26 months after initial diagnosis. We searched the literature and identified six cases showing coexisting iAMP21 and ETV6-RUNX1. The median age for these six patients was 10 years (range, 2-18) and males predominated. The median overall survival (OS) was 28 months. Conclusions: Patients with B-ALL associated with both iAMP21 and ETV6-RUNX1 tend to be older children or adolescents and have a poor prognosis.

8525 Background: Although the combination of PD-L1 inhibitor and platinum-etoposide chemotherapy has been the preferred 1L treatment for patients (pts) with ES-SCLC, the clinical benefit of the addition of PD-L1 inhibitor was still modest. QL1706 is a novel bifunctional antibody, containing a mixture of anti-PD-1 IgG4 and anti-CTLA-4 IgG1 antibodies produced by MabPair. In phase I trials, QL1706 monotherapy has shown promising antitumor efficacy in nasopharynx cancer and cervical cancer, as well as other advanced solid tumors including SCLC (to be published). This study aims to assess the safety and efficacy of QL1706 plus EC in treatment-naïve ES-SCLC. Methods: In this phase II, open-label, single-arm, multi-center study, eligible pts (18-75 years, ECOG 0-1) received 4-6 cycles of QL1706 (5mg/kg, IV, Q3W) plus EC (etoposide, 100 mg/m2, D1-3, Q3W; carboplatin, AUC = 5, D1, Q3W), followed by the maintenance therapy of QL1706 until disease progression, intolerable toxicity or other discontinuation events defined in the study protocol. Tumor imaging was performed every 6 weeks for the first year and every 9 weeks thereafter. The primary endpoint is safety. Results: From Apr 18, 2022 to Jul 27, 2022, a total of 40 pts were enrolled with a median age of 58.5 years (range, 38−73). 87.5% pts were men, 80% were smokers and 90% had ECOG PS of 1. As of data cutoff (Jan 16, 2023), the median QL1706-treatment duration was 5.9 (range, 0.7−8.9) mo. Twenty pts remained on treatment and 20 pts discontinued due to progressive disease (16, 40.0%) or patient decision (4, 10.0%). Thirty two (80.0%) pts had at least one TRAE (QL1706-related). Fifteen (37.5%) pts experienced grade 3-4 TRAEs, including neutropenia (8, 20%), thrombocytopenia (4, 10%), anemia (3, 7.5%), WBC count decreased (2, 5.0%), AST increased (2, 5.0%), ALT increased (1, 2.5%), gamma-GT increased (1, 2.5%), rash (1, 2.5%), and diarrhea (1, 2.5%). No grade 5 TRAE occurred. No AE led to discontinuation of any treatment. Of the 39 pts who had at least 1 post-baseline tumor assessment, 37 achieved PR (35 confirmed and 2 unconfirmed) and 1 achieved SD. Thus, the confirmed ORR was 89.7% (95% CI, 75.8%−97.1%), and the DCR was 97.4% (95% CI, 86.5−99.9%) (per RECIST v1.1). The mDoR was 4.5 (95% CI, 4.2−not evaluable) mo, with the longest response duration more than 7.2 mo and ongoing. The mPFS was 5.7 (95% CI, 5.4−7.1) mo, together with 3 mo- and 6 mo-PFS rates of 94.8 (95% CI, 80.8−98.7%) and 44.7% (95% CI, 27.3−60.6%), respectively. With a median follow-up time for OS of 6.2 mo, the mOS has not been reached. Conclusions: QL1706 plus EC chemotherapy showed tolerable safety profile and promising efficacy as first-line treatment for pts with ES-SCLC. These data support further clinical development of QL1706 in ES-SCLC. Clinical trial information: NCT05309629 .