Wei, Wei

Abstract Introduction: Despite advent of multiple tyrosine kinase inhibitors (TKIs) and newer treatment methods for AML and ALL, the outcomes of patients (pts) with chronic myeloid leukemia in blast phase (CML-BP) remain poor. Consensus guidelines on treatment of CML-BP are scarce. A recent study from the European leukemia network blast phase registry on 240 pts reported marked heterogeneity in treatment patterns and lack of an accepted standard. Hence, we undertook this study through the H Jean Khoury Cure CML Consortium (HJKC3) to describe the treatment patterns and outcomes of pts with CML-BP in the US. Methods: This is a multi-institution, retrospective study. IRB approval was obtained at each institution and data sharing agreements were executed. All pts diagnosed with CML-BP based on modified MD Anderson Criteria (≥30% blasts in the blood or bone marrow or extramedullary (EM) disease) from 2010 to 2025 were included. Categorical variables were compared using Chi-square test. Overall survival (OS) was calculated from time of diagnosis of CML BP to death from any cause. Event free survival (EFS) was calculated from date of best response to event (death or relapse). Results: Of the 283 pts with CML-BP, 96 (33.9%) were female and 187 (66.1%) were males. At the time of diagnosis, 183 (64.6%) had CML-CP, 21 (7.4%) pts had CML-AP and 79 (27.9%) pts had de-novo CML-BP. For the 204 pts that were initially diagnosed with CML-CP or CML-AP, the median time to progression to CML-BP was 22.5 months (1-207 months). Median age at diagnosis of CML-BP was 50 years (range 16-86 years). EM disease was present in 78 (27.6%) pts (38 myeloid sarcoma, 30 central nervous system and 10 skin). Blasts were of myeloid phenotype in 168 (59.4%), lymphoid in 103 (36.4%) and mixed in 9 (3.2%) pts. The bcr-abl protein was p210 in 229 (80.9%), p190 in 8 (2.8%) and p230 in 2 (0.7%) pts. ABL kinase domain mutation was seen in 42.1% (80/190) pts, with T315I being the most common (n=32), followed by E255K (n=16). Next generation sequencing was performed in 117 pts. The most common mutations were ASXL1 (n=27), RUNX1 (n=14), BCOR (n=4), DNMT3A (n=4) and BCORL1 (n=3). Of the 283 pts, 269 underwent CML-BP directed therapy. 63 (23.4%) pts were treated with TKI monotherapy, 184 (68.4%) pts were treated with a combination of chemotherapy (chemo) and TKI and 22 (8.2%) pts were treated with chemo alone. Response rate after CML-BP directed therapy was 75.3% (n=213). Best response was return to CML-CP in 49 pts, CHR with PCyR in 18 pts, CCyR in 31 pts, MMR in 31 pts, MR4 in 18 pts, MR4.5 in 19 pts and MR5 in 47 pts. Rate of response with 2G and ponatinib was significantly better than imatinib (85.3% and 77.3% vs 63.6%; p=0.04). 149 (55.4%) pts proceeded to alloSCT. Of the 213 pts that responded, 59 (27.7%) relapsed. At a median follow-up of 47 months, the median OS for all pts was 19.7 months (95% CI: 16.3-40.2 months), with 5-year OS rate of 38% (95% CI: 32-45%). Pts with myeloid phenotype had a significantly lower OS compared to lymphoid and mixed phenotype (Median OS 14.9 vs 45.9 and 31.1 months respectively; p=0.02). OS of pts that were treated with a combination of TKI and chemo was significantly longer compared to pts treated with TKI or chemo alone (52.9 vs 16.1 or 7.5 months; p<0.0001). Dasatinib (n=99; 34.9%) and ponatinib (n=97; 34.3%) were the most used TKIs followed by imatinib (n=23; 8.1%), nilotinib (n=21; 7.4%), bosutinib (n=8; 2.8%) and asciminib (n=3; 1.1%). Pts treated with ponatinib had a numerically longer OS compared to 2G-TKI and imatinib, however this was not statistically significant (40.1 vs 30.6 and 20.3 months; p=0.52). EFS for pts treated with ponatinib was significantly longer compared to 2G-TKI or imatinib (25.9 vs 17.6 and 15.9 months; p=0.03). In a landmark analysis, pts that underwent alloSCT within 6 months of diagnosis had a significantly longer OS compared to those who did not (69.3 vs 16.0 months; p=0.006). Conclusion: CML-BP continues to have poor prognosis. Treatment is heterogenous involving various combinations of TKI and chemo. In our analysis, treatment with 2G-TKI or ponatinib led to better responses. CML-BP with myeloid phenotype had worse OS. Treatment with ponatinib was associated with a numerically longer OS and significantly longer EFS compared to 2G-TKI and imatinib. In addition, treatment with chemo in combination with TKI and alloSCT led to improved OS.

Abstract Introduction: HMA monotherapy (HMAm) continues to be the standard of care for HR-MDS. While the addition of VEN to azacitidine (AZA) improved overall survival (OS) and complete remission (CR) rates among older pts with acute myeloid leukemia (AML) over AZA monotherapy, the recently completed phase III VERONA trial of AZA+/-VEN in HR-MDS failed to show an OS benefit for AZA/VEN over AZA monotherapy. Using the icMDS VALIDATE database, we compared outcomes of pts with HR-MDS treated with HMA or HMA/VEN as frontline therapy. Methods: The icMDS VALIDATE database includes over 4000 adult MDS pts who received HMA-based therapy from 32 international centers in 9 countries. For this analysis, we included pts with HR-MDS defined by International Prognostic Scoring System [IPSS] ≥1.5 or IPSS-revised [IPSS-R] ≥4 (at diagnosis or HMA initiation) and treated with HMAm or HMA/VEN as frontline therapy for HR-MDS. We assessed responses based on IWG 2023 criteria (Zeidan A et al, Blood 2023). Composite complete remission (cCR) was defined as CR+CRbi+CRuni+CRh+CRequivalent. We calculated OS from time of HMA initiation to date of death from any cause. Pts lost to follow-up were censored at the date they were last known to be alive. We used Kaplan-Meier methods to calculate OS and compared OS between different groups using the log-rank test. We used Cox and logistic regression models to adjust for baseline prognostic variables as appropriate. The study was funded by an independent grant from Abbvie. Results: A total of 1907 pts met eligibility and were included (1552 AZA, 221 decitabine, 134 HMA+VEN). 479 pts subsequently underwent allogeneic stem cell transplant (allo-SCT; 430 after HMAm [32.6%]; 49 after HMA/VEN [37.1%]). Our cohort was enriched for pts with adverse disease characteristics including complex karyotype (33.6%) and TP53 mutations (28.7%). Compared to pts treated with HMA/VEN, pts treated with HMAm were more likely to be male (p=0.012), have lower baseline platelet counts (p=0.037), peripheral blood (PB) blasts (p=0.004), or bone marrow blasts (p<0.001), and were less likely to have very high risk IPSS-M (p<0.001), TP53 mutations (p<0.001), or complex karyotype (p=0.020). In unadjusted analyses, the rate of cCR was significantly lower in HMAm treated pts compared to HMA/VEN treated pts (27.7% vs. 48.8%, p<0.001). However, CR rate was not significantly different (11.7% vs. 17.1% for HMAm and HMA/VEN, respectively, p=0.22). After adjusting for age, sex, and IPSS-M, pts treated with HMA/VEN were more likely to achieve cCR compared to HMAm with an odds ratio (OR) of 2.49 (95% CI: 1.56-3.96, p<0.001). When separated by TP53 mutation status, the OR for cCR for HMA/VEN vs HMAm was 4.17 (95%CI: 2.14-8.31; p<0.001) and 1.27 (95%CI: 0.54-2.86; p=0.57) for TP53 wild-type and TP53-mutant pts, respectively. In unadjusted analyses, median OS was 17.4 months for HMAm and 19.6 months for HMA+VEN, and OS did not differ significantly by treatment type (p=0.33). For HMAm treated pts, the OS rates at year 1, 2, 3 were 0.65 (95%CI: 0.63-0.67), 0.38 (95%CI: 0.36-0.40), and 0.27 (95%CI: 0.25-0.29), respectively. For HMA/VEN treated pts, the OS rates at year 1, 2, 3 were 0.64 (95%CI: 0.56-0.73), 0.45 (95%CI: 0.36-0.56), and 0.37 (95%CI: 0.27-0.51), respectively. In a multivariate analysis adjusting for age, sex, PB blast, IPSS-M and allo-SCT as a time-varying covariate, treatment with HMA/VEN vs HMAm did not significantly influence OS (hazard ratio (HR) of OS for HMA/VEN vs HMAm: 0.89, 95%CI: 0.69-1.13, p=0.33). When stratified by TP53 mutation status, HR of HMA/VEN vs. HMAm was favorable for TP53 wild-type (HR: 0.47; 95%CI: 0.29-0.74) but not TP53-mutant pts (HR=0.96; 95%CI: 0.66-1.41). Adjusting for other variables in the model, HR for pts who underwent vs. those who did not undergo allo-SCT were 0.65 (95% CI: 0.49-0.85) and 0.36 (95%CI: 0.24-0.53) in TP53 wild-type and mutant patients, respectively. Conclusion: In this large, international retrospective analysis from the icMDS VALIDATE database, HMA/VEN was associated with higher cCR rates—but not CR rates—compared to HMAm among pts with HR-MDS, though we observed no significant differences in OS. In our analysis, clinical benefit from the addition of VEN was most clear in TP53 wild-type pts, and allo-SCT was associated with improved OS regardless of baseline TP53 status. Our analysis was limited by the relatively small number of HMA/VEN-treated pts and heterogeneous real-world treatment patterns.

Introduction The International Prognostic Scoring System (IPSS) and its revised version (IPSS-R) were developed using datasets from patients (pts) with untreated MDS. The cytogenetic risk groups used in IPSS-R were expanded to 5 groups from the 3 used in IPSS. Among the new groups introduced in IPSS-R is the “very complex” karyotype (VCK) where ≥4 karyotypic abnormalities are seen compared to “complex karyotype (CK)” with only 3 abnormalities. However, the prognostic impact of VCK vs CK, as well as individual cytogenetic abnormalities and TP53 mutation (TP53mut) status within the CK and VCK subgroups in pts with MDS treated with hypomethylating agents (HMAs) has not been well studied. Hence, we analyzed these questions in a large cohort of HMA-treated MDS pts in the icMDS VALIDATE database. Methods The icMDS VALIDATE database contains MDS pts treated with frontline HMA monotherapy or HMA-based combinations from 22 specialized international centers. Pts with unknown HMA type, date of HMA initiation, missing age, missing sex, missing cytogenetic data, bone marrow or peripheral blood blasts ≥20%, or missing survival status were excluded. We performed time-to-event analyses using the Kaplan-Meier method and compared groups by the log-rank test. We measured overall survival (OS) from time of HMA initiation. VALIDATE protocol was exempted, acknowledged, or approved by all centers' IRBs. VALIDATE is supported by an independent grant from Abbvie. Results A total of 1940 pts were included. Median age was 70 (range: 18-99) years and 66% were men. According to IPSS-R cytogenetic risk groups, 1.9% (37) were very good, 43.4% (841) good, 15.5% (301) intermediate, 11.6% (226) poor, and 27.6% (535) very poor. By HMA type, 71% of pts were treated with azacitidine, 14% with decitabine, 6% with HMA and venetoclax, and 9% with another HMA combination. Approximately 28% of pts underwent allogeneic hematopoietic stem cell transplant (alloHSCT). The IPSS-R cytogenetic risk groups had different OS (p<0.001)with median OS (mOS; months [mo], 95% CI) as follows: very good (43.4, 34.7-72.5), good (41.7, 36.4-46.8), intermediate (24.5, 23.1-32.4), poor (24.2, 19.2-28.5), and very poor (13.6, 12.5-14.5). The difference remained significant (p=0.001) after censoring at time of alloHSCT with mOS as follows: very good (40.4, 23.2-64.3), good (24.3, 22.2-26.3), intermediate (19.3, 15.1-22.2), poor (12.2, 10.3-14.8), and very poor (9.1, 8.2-19.7). Interestingly, the difference between mOS for intermediate and poor risk cytogenetics became more apparent after censoring at time of alloHSCT. Next, we compared the outcomes of pts with CK and VCK to non-complex karyotype (NCK) MDS. The mOS for pts with VCK MDS (13.6 mo, 12.5-14.5) was worse compared to pts with CK (19.9 mo, 19.9-16.8; p=0.004) and NCK (36.1 mo, 32.7-37.8; p<0.001) MDS. Among the 1458 pts with available molecular data, more pts with VCK (75%, 330) MDS had a concurrent TP53mut compared to pts with CK (40%, 21; p<0.001) and NCK (7%, 64 p<0.001) MDS. Considering only patients with TP53mut MDS, mOS for pts with VCK (12.2, 11.1-13.9) was worse compared with NCK (24.2, 16-1-53.1; p<0.001) but not with CK (19.9, 9.5-NR; p=0.9); the difference between CK and NCK was not significant (p=0.16). Among pts with TP53 wildtype (TP53WT) MDS, VCK (15.0, 13.2-18.2) had a similar mOS to TP53WT CK (18.8, 12.6-41.1; p=0.19) while both groups had worse mOS compared to TP53WT NCK (33.4, 30.1-37.0) (p=0.01). In a survival analysis of 616 pts with MDS with ≥3 cytogenetic abnormalities, -17/del(17p) (12.8 mo; p=0.009), inv(3)/t(3q)/del(3q) (10.9 mo; p=0.006), and del(7q) (12.1mo; p=0.024), though not -7 (12.6mo; p=0.23), were associated with lower mOS compared to the pts with MDS without these abnormalities (14.3mo). Conclusions Using one of the largest databases of HMA-treated MDS pts, we show that IPSS-R cytogenetic risk categories associate with significantly different survivals among HMA-treated MDS pts, even after censoring at time of alloHSCT. Importantly, VCK MDS was associated with worse mOS compared to CK and NCK MDS but not in pts with a concurrent TP53mut. Among pts with MDS with ≥3 chromosomal abnormalities, having -17/del(17p), inv(3)/t(3q)/del(3q), or del(7q) was associated with worse survival.

Cholangiocarcinoma (CCA) is the second most common malignancy arising in the liver. It carries a poor prognosis, in part because its pathogenesis is not well understood. The type 3 inositol 1,4,5‐trisphosphate receptor (ITPR3) is the principal intracellular calcium ion (Ca2+) release channel in cholangiocytes, and its increased expression has been related to the pathogenesis of malignancies in other types of tissues, so we investigated its role in CCA. ITPR3 expression was increased in both hilar and intrahepatic CCA samples as well as in CCA cell lines. Deletion of ITPR3 from CCA cells impaired proliferation and cell migration. A bioinformatic analysis suggested that overexpression of ITPR3 in CCA would have a mitochondrial phenotype, so this was also examined. ITPR3 normally is concentrated in a subapical region of endoplasmic reticulum (ER) in cholangiocytes, but both immunogold electron microscopy and super‐resolution microscopy showed that ITPR3 in CCA cells was also in regions of ER in close association with mitochondria. Deletion of ITPR3 from these cells impaired mitochondrial Ca2+ signaling and led to cell death. Conclusion: ITPR3 expression in cholangiocytes becomes enhanced in CCA. This contributes to malignant features, including cell proliferation and migration and enhanced mitochondrial Ca2+ signaling.