Pub Date : 2024-08-22DOI: 10.1016/j.leukres.2024.107569
Tingting Li , Qingya Cui , Sining Liu , Zheng Li , Wei Cui , Mengyun Li , Yunju Ma , Xuanqi Cao , Xiaming Zhu , Liqing Kang , Lei Yu , Depei Wu , Xiaowen Tang
Objective
We aimed to evaluate the efficacy of decitabine consolidation after treatment with CD19/CD22 chimeric antigen receptor T-cell (CAR-T) for patients with relapsed/refractory B-cell acute lymphoblastic leukaemia (r/r B-ALL).
Methods
We retrospectively analysed 48 patients with r/r B-ALL who received CD19/CD22 CAR-T therapy between September 2017 and May 2021. Sixteen patients received decitabine consolidation (20 mg/m2/day for 5 days at 3-month intervals) after CAR-T therapy (DAC group), while 32 patients did not receive decitabine consolidation (CON group). Overall survival (OS), leukaemia-free survival (LFS), and cumulative incidence of relapse (CIR) were evaluated in both groups. Time-to-event analysis was performed using the Kaplan-Meier method.
Results
The median follow-up periods in the DAC and CON groups were 41.2 months and 28.6 months, respectively. The 4-year OS and 4-year LFS rates in both groups were 93.3 % and 64.3 % (P=0.029) and 87.5 % and 55.9 % (P=0.059), respectively. The 1-year CIR was 6.25 % and 28.6 %, respectively. Univariate and multivariate Cox regression analyses showed that decitabine consolidation after CAR-T therapy was significantly associated with superior OS (hazard ratio [HR]: 0.121, 95 % confidence interval [CI]: 0.015–0.947, P=0.044), and bridging to haematopoietic stem cell transplantation after CAR-T therapy was significantly associated with superior LFS (HR: 0.279, 95 %CI: 0.093–0.840, P=0.023).
Conclusions
Our study recommends decitabine consolidation after CD19/CD22 CAR-T therapy as a novel maintenance strategy to improve the survival outcomes of patients with r/r B-ALL.
{"title":"Decitabine consolidation after CD19/CD22 CAR-T therapy as a novel maintenance treatment significantly improves survival outcomes in relapsed/refractory B-ALL patients","authors":"Tingting Li , Qingya Cui , Sining Liu , Zheng Li , Wei Cui , Mengyun Li , Yunju Ma , Xuanqi Cao , Xiaming Zhu , Liqing Kang , Lei Yu , Depei Wu , Xiaowen Tang","doi":"10.1016/j.leukres.2024.107569","DOIUrl":"10.1016/j.leukres.2024.107569","url":null,"abstract":"<div><h3>Objective</h3><p>We aimed to evaluate the efficacy of decitabine consolidation after treatment with CD19/CD22 chimeric antigen receptor T-cell (CAR-T) for patients with relapsed/refractory B-cell acute lymphoblastic leukaemia (r/r B-ALL).</p></div><div><h3>Methods</h3><p>We retrospectively analysed 48 patients with r/r B-ALL who received CD19/CD22 CAR-T therapy between September 2017 and May 2021. Sixteen patients received decitabine consolidation (20 mg/m<sup>2</sup>/day for 5 days at 3-month intervals) after CAR-T therapy (DAC group), while 32 patients did not receive decitabine consolidation (CON group). Overall survival (OS), leukaemia-free survival (LFS), and cumulative incidence of relapse (CIR) were evaluated in both groups. Time-to-event analysis was performed using the Kaplan-Meier method.</p></div><div><h3>Results</h3><p>The median follow-up periods in the DAC and CON groups were 41.2 months and 28.6 months, respectively. The 4-year OS and 4-year LFS rates in both groups were 93.3 % and 64.3 % (P=0.029) and 87.5 % and 55.9 % (P=0.059), respectively. The 1-year CIR was 6.25 % and 28.6 %, respectively. Univariate and multivariate Cox regression analyses showed that decitabine consolidation after CAR-T therapy was significantly associated with superior OS (hazard ratio [HR]: 0.121, 95 % confidence interval [CI]: 0.015–0.947, P=0.044), and bridging to haematopoietic stem cell transplantation after CAR-T therapy was significantly associated with superior LFS (HR: 0.279, 95 %CI: 0.093–0.840, P=0.023).</p></div><div><h3>Conclusions</h3><p>Our study recommends decitabine consolidation after CD19/CD22 CAR-T therapy as a novel maintenance strategy to improve the survival outcomes of patients with r/r B-ALL.</p></div>","PeriodicalId":18051,"journal":{"name":"Leukemia research","volume":"145 ","pages":"Article 107569"},"PeriodicalIF":2.1,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142088144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-20DOI: 10.1016/j.leukres.2024.107563
David McCall , Tareq Abuasab , Juan Jose Rodriguez-Sevilla , Shehab Fareed Mohamed , Anish Patnaik , Kirthi Devireddy , Naszrin Arani , Irtiza Sheikh , Raehannah Jamshidi , Amber Gibson , Michael Roth , Cesar Nuñez , Miriam Garcia , Kelly S. Chien , Sanam Loghavi , Sherry A. Pierce , Koji Sasaki , Ghayas Issa , Branko Cuglievan , Hagop Kantarjian , Guillermo Garcia-Manero
Myelodysplastic syndrome, or myelodysplastic neoplasms, are a rare finding in pediatric, adolescent, and young adult (AYA) patients. More literature is needed to highlight trends of survival or treatment resistance in subpopulations to improve treatment. Here we report a single center retrospective analysis of pediatric and AYA patients from 2000 to 2022 including molecular and cytogenetic data. Using the IPSS-R and IPSS-M, which have been reported exclusively in adults, and excluding patients with bone marrow failure syndromes, we analyzed 119 pediatric and AYA patients with myelodysplastic neoplasms. Therapy-related myelodysplastic neoplasms were present in 36 % of patients, and 31 % of patients developed acute myeloid leukemia. The 5-year overall survival (OS) rate for the entire cohort was 45 %. Contrary to young adults and older adults, mutations were not common in pediatrics. Those who underwent stem cell transplant (SCT)(at any time) had significantly longer median OS. Although SCT at any time improved OS in the de novo myelodysplastic neoplasm group, the choice of the initial treatment with intensive chemotherapy, hypomethylating agents, or SCT did not significantly alter OS. Median OS was shorter in the pediatric group (<18 years old) and longer for those with isolated deletion of 5q or TET2 mutation, but these were not significant findings. Median OS was significantly shorter in those with monosomy 7 or 7q deletion and those with therapy-related myelodysplastic neoplasms. These findings build on previously reported findings and encourage the use of SCT along with molecular and cytogenetic analysis.
{"title":"Characteristics and outcomes of children, adolescent, and young adult patients with myelodysplastic neoplasms: A single-center retrospective analysis","authors":"David McCall , Tareq Abuasab , Juan Jose Rodriguez-Sevilla , Shehab Fareed Mohamed , Anish Patnaik , Kirthi Devireddy , Naszrin Arani , Irtiza Sheikh , Raehannah Jamshidi , Amber Gibson , Michael Roth , Cesar Nuñez , Miriam Garcia , Kelly S. Chien , Sanam Loghavi , Sherry A. Pierce , Koji Sasaki , Ghayas Issa , Branko Cuglievan , Hagop Kantarjian , Guillermo Garcia-Manero","doi":"10.1016/j.leukres.2024.107563","DOIUrl":"10.1016/j.leukres.2024.107563","url":null,"abstract":"<div><p>Myelodysplastic syndrome, or myelodysplastic neoplasms, are a rare finding in pediatric, adolescent, and young adult (AYA) patients. More literature is needed to highlight trends of survival or treatment resistance in subpopulations to improve treatment. Here we report a single center retrospective analysis of pediatric and AYA patients from 2000 to 2022 including molecular and cytogenetic data. Using the IPSS-R and IPSS-M, which have been reported exclusively in adults, and excluding patients with bone marrow failure syndromes, we analyzed 119 pediatric and AYA patients with myelodysplastic neoplasms. Therapy-related myelodysplastic neoplasms were present in 36 % of patients, and 31 % of patients developed acute myeloid leukemia. The 5-year overall survival (OS) rate for the entire cohort was 45 %. Contrary to young adults and older adults, mutations were not common in pediatrics. Those who underwent stem cell transplant (SCT)(at any time) had significantly longer median OS. Although SCT at any time improved OS in the de novo myelodysplastic neoplasm group, the choice of the initial treatment with intensive chemotherapy, hypomethylating agents, or SCT did not significantly alter OS. Median OS was shorter in the pediatric group (<18 years old) and longer for those with isolated deletion of 5q or TET2 mutation, but these were not significant findings. Median OS was significantly shorter in those with monosomy 7 or 7q deletion and those with therapy-related myelodysplastic neoplasms. These findings build on previously reported findings and encourage the use of SCT along with molecular and cytogenetic analysis.</p></div>","PeriodicalId":18051,"journal":{"name":"Leukemia research","volume":"144 ","pages":"Article 107563"},"PeriodicalIF":2.1,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142040008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To investigate the safety of total body irradiation-based myeloablative conditioning (TBI-MAC) in adolescent and young adult (AYA) Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) patients treated with pediatric protocols, treatment outcomes of 106 AYA patients aged 16–39 years old undergoing allogeneic stem cell transplant (allo-SCT) with TBI-MAC in the first remission were compared according to chemotherapy types before transplant. Pediatric and adult protocols were used in 56 and 50 of the patients, respectively. The cumulative incidence (CI) of non-relapse mortality (NRM) and the overall survival (OS) rates were not significantly different between the pediatric-protocol and adult-protocol group (NRM: 4 % vs. 14 % at five years post-transplant, respectively, p = 0.26; OS: 81 % vs. 66 %, respectively, p = 0.14). Multivariate analysis for NRM revealed that a performance status >0 (hazard ratio [HR] = 4.8) and transplant due to chemotherapy toxicities (HR = 3.5) were independent risk factors, but a pediatric protocol was not (HR = 0.48). The CI of NRM and the OS rates were also similar among patients aged over 24 years old. These findings suggested that conventional allo-SCT with TBI-MAC can be performed without increasing NRM in AYA patients with Ph-negative ALL even after pediatric protocols.
{"title":"Allogeneic stem cell transplant with TBI-based myeloablative conditioning in adolescents and young adults with Philadelphia chromosome-negative ALL treated with pediatric protocols","authors":"Hiroaki Shimizu , Jun Kato , Susumu Tanoue , Shun-ichi Kimura , Takayoshi Tachibana , Kaoru Hatano , Kensuke Usuki , Jun Taguchi , Maki Hagihara , Nobuhiro Tsukada , Kaito Harada , Satoshi Takahashi , Satoru Takada , Emiko Sakaida , Shin Fujisawa , Masahiro Onoda , Nobuyuki Aotsuka , Hiroshi Handa , Yoshihiro Hatta , Reiko Nakaseko , Yoshinobu Kanda","doi":"10.1016/j.leukres.2024.107562","DOIUrl":"10.1016/j.leukres.2024.107562","url":null,"abstract":"<div><p>To investigate the safety of total body irradiation-based myeloablative conditioning (TBI-MAC) in adolescent and young adult (AYA) Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) patients treated with pediatric protocols, treatment outcomes of 106 AYA patients aged 16–39 years old undergoing allogeneic stem cell transplant (allo-SCT) with TBI-MAC in the first remission were compared according to chemotherapy types before transplant. Pediatric and adult protocols were used in 56 and 50 of the patients, respectively. The cumulative incidence (CI) of non-relapse mortality (NRM) and the overall survival (OS) rates were not significantly different between the pediatric-protocol and adult-protocol group (NRM: 4 % vs. 14 % at five years post-transplant, respectively, p = 0.26; OS: 81 % vs. 66 %, respectively, p = 0.14). Multivariate analysis for NRM revealed that a performance status >0 (hazard ratio [HR] = 4.8) and transplant due to chemotherapy toxicities (HR = 3.5) were independent risk factors, but a pediatric protocol was not (HR = 0.48). The CI of NRM and the OS rates were also similar among patients aged over 24 years old. These findings suggested that conventional allo-SCT with TBI-MAC can be performed without increasing NRM in AYA patients with Ph-negative ALL even after pediatric protocols.</p></div>","PeriodicalId":18051,"journal":{"name":"Leukemia research","volume":"144 ","pages":"Article 107562"},"PeriodicalIF":2.1,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142040010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-14DOI: 10.1016/j.leukres.2024.107561
Yael Kusne, Talha Badar, Terra Lasho, Alejandro Ferrer, Abhishek A. Mangaonkar, Christy Finke, Ludovica Marando, James M. Foran, Aref Al-Kali, Hassan B. Alkhateeb, Timothy Chlon, Mrinal M. Patnaik
{"title":"Absence of PNH-clones in DDX41mutant-GPS aids in their distinction from acquired BM failure syndromes","authors":"Yael Kusne, Talha Badar, Terra Lasho, Alejandro Ferrer, Abhishek A. Mangaonkar, Christy Finke, Ludovica Marando, James M. Foran, Aref Al-Kali, Hassan B. Alkhateeb, Timothy Chlon, Mrinal M. Patnaik","doi":"10.1016/j.leukres.2024.107561","DOIUrl":"10.1016/j.leukres.2024.107561","url":null,"abstract":"","PeriodicalId":18051,"journal":{"name":"Leukemia research","volume":"145 ","pages":"Article 107561"},"PeriodicalIF":2.1,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01DOI: 10.1016/j.leukres.2024.107521
Early T-cell Precursor Acute Lymphoblastic Leukemia (ETP-ALL), T-Lymphoid/Myeloid Mixed Phenotype Acute Leukemia (T/M-MPAL), and Acute Myeloid Leukemia with minimal differentiation (AML-M0) are immature acute leukemias (AL) that present overlapping T-cell lymphoid and myeloid features at different degrees, with impact to disease classification. An interesting strategy to assess lymphoid lineage commitment and maturation is the analysis of V(D)J gene segment recombination, which can be applied to investigate leukemic cells in immature AL. Herein, we revisited 19 ETP-ALL, 8 T/M-MPAL, and 12 AML-M0 pediatric patients to characterize V(D)J rearrangement (V(D)J-r) profiles associated with other somatic alterations. V(D)J-r were identified in 74 %, 25 %, and 25 % of ETP-ALL, T/M-MPAL, and AML-M0, respectively. Forty-six percent of ETP-ALL harbored ≥ 3 V(D)J-r, while there was no more than one V(D)J-r per patient in AML-M0 and T/M-MPAL. TCRD was the most rearranged locus in ETPALL, but it was not rearranged in other AL. In ETP-ALL, N/KRAS mutations were associated with absence of V(D)J-r, while NF1 deletion was most frequent in patients with ≥ 3 V(D)J-r. Relapse and death occurred mainly in patients harboring one or no rearranged locus. Molecular characterization of V(D)J-r in our cohort indicates a distinct profile of ETP-ALL, compared to T/M-MPAL and AML-M0. Our findings also suggest that the clinical outcome of ETP-ALL patients may be affected by blast cell maturity, inferred from the number of rearranged TCR loci.
{"title":"Molecular characterization of V(D)J rearrangements in immature acute leukemias","authors":"","doi":"10.1016/j.leukres.2024.107521","DOIUrl":"10.1016/j.leukres.2024.107521","url":null,"abstract":"<div><p><span>Early T-cell Precursor Acute Lymphoblastic Leukemia<span> (ETP-ALL), T-Lymphoid/Myeloid Mixed Phenotype Acute Leukemia<span> (T/M-MPAL), and Acute Myeloid Leukemia<span> with minimal differentiation (AML-M0) are immature acute leukemias (AL) that present overlapping T-cell lymphoid and myeloid features at different degrees, with impact to disease classification. An interesting strategy to assess lymphoid lineage commitment and maturation is the analysis of V(D)J gene segment recombination, which can be applied to investigate leukemic cells in immature AL. Herein, we revisited 19 ETP-ALL, 8 T/M-MPAL, and 12 AML-M0 pediatric patients to characterize V(D)J rearrangement (V(D)J-r) profiles associated with other somatic alterations. V(D)J-r were identified in 74 %, 25 %, and 25 % of ETP-ALL, T/M-MPAL, and AML-M0, respectively. Forty-six percent of ETP-ALL harbored ≥ 3 V(D)J-r, while there was no more than one V(D)J-r per patient in AML-M0 and T/M-MPAL. TCRD was the most rearranged locus in ETPALL, but it was not rearranged in other AL. In ETP-ALL, N/KRAS mutations were associated with </span></span></span></span>absence<span> of V(D)J-r, while NF1 deletion was most frequent in patients with ≥ 3 V(D)J-r. Relapse and death occurred mainly in patients harboring one or no rearranged locus. Molecular characterization of V(D)J-r in our cohort indicates a distinct profile of ETP-ALL, compared to T/M-MPAL and AML-M0. Our findings also suggest that the clinical outcome of ETP-ALL patients may be affected by blast cell maturity, inferred from the number of rearranged TCR loci.</span></p></div>","PeriodicalId":18051,"journal":{"name":"Leukemia research","volume":"143 ","pages":"Article 107521"},"PeriodicalIF":2.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141275662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-24DOI: 10.1016/j.leukres.2024.107550
Heran Cui , Yuanyang Ma , Shulin Han , Xiaodong Zhang , Weiya Fu , Shuang Yang , Tianhang Liu , Xuefang Zhang
Objective
To investigate the relationship between the treatment of acute promyelocytic leukemia (APL) with arsenic trioxide (ATO) and glycolysis, as well as its underlying molecular mechanism.
Methods
The GEO database was used to analyze alterations in the expression of RPL22L1 in APL patients and its correlation with glycolysis. The levels of RPL22L1 and glycolysis were assessed in 9 paired clinical samples. NB4 cells and NB4 cells with knockdown of RPL22L1 were treated with ATO. The protein and mRNA of RPL22L1 were detected using RT-PCR and Western blot, and the content was determined by using glucose, pyruvate, and lactate detection kits. Finally, detection of cell proliferation using CCK8, migration by scratch assay, and apoptosis by flow cytometry, and the biological function of ATO in NB4 cells was examined.
Results
The expression of RPL22L1 in GSE213742 and GSE234103 datasets exhibited a significant increase in human APL cells, specifically NB4 cells. RPL22L1 in GSE213742 and GSE234103 gene expression matrix was significantly elevated in human APL cells NB4 cells, and further analysis found RPL22L1 showed a strong positive correlation with glycolysis. Cellular experiments showed that ATO inhibited RPL22L1 in NB4 cells and inhibited glycolysis in APL cells. The ATO played a pivotal role in suppressing the proliferation, migration, as well as invasion of NH4 cells.
Conclusion
ATO regulates the blycolytic pathway in APL by inhibiting RPL22L1 expression, and this may contribute to its therapeutic effects.
{"title":"Arsenic trioxide regulates the glycolytic pathway to treat acute promyelocytic leukemia by inhibiting RPL22L1","authors":"Heran Cui , Yuanyang Ma , Shulin Han , Xiaodong Zhang , Weiya Fu , Shuang Yang , Tianhang Liu , Xuefang Zhang","doi":"10.1016/j.leukres.2024.107550","DOIUrl":"10.1016/j.leukres.2024.107550","url":null,"abstract":"<div><h3>Objective</h3><p>To investigate the relationship between the treatment of acute promyelocytic leukemia (APL) with arsenic trioxide (ATO) and glycolysis, as well as its underlying molecular mechanism.</p></div><div><h3>Methods</h3><p>The GEO database was used to analyze alterations in the expression of RPL22L1 in APL patients and its correlation with glycolysis. The levels of RPL22L1 and glycolysis were assessed in 9 paired clinical samples. NB4 cells and NB4 cells with knockdown of RPL22L1 were treated with ATO. The protein and mRNA of RPL22L1 were detected using RT-PCR and Western blot, and the content was determined by using glucose, pyruvate, and lactate detection kits. Finally, detection of cell proliferation using CCK8, migration by scratch assay, and apoptosis by flow cytometry, and the biological function of ATO in NB4 cells was examined.</p></div><div><h3>Results</h3><p>The expression of RPL22L1 in GSE213742 and GSE234103 datasets exhibited a significant increase in human APL cells, specifically NB4 cells. RPL22L1 in GSE213742 and GSE234103 gene expression matrix was significantly elevated in human APL cells NB4 cells, and further analysis found RPL22L1 showed a strong positive correlation with glycolysis. Cellular experiments showed that ATO inhibited RPL22L1 in NB4 cells and inhibited glycolysis in APL cells. The ATO played a pivotal role in suppressing the proliferation, migration, as well as invasion of NH4 cells.</p></div><div><h3>Conclusion</h3><p>ATO regulates the blycolytic pathway in APL by inhibiting RPL22L1 expression, and this may contribute to its therapeutic effects.</p></div>","PeriodicalId":18051,"journal":{"name":"Leukemia research","volume":"144 ","pages":"Article 107550"},"PeriodicalIF":2.1,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141845598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-17DOI: 10.1016/j.leukres.2024.107549
Matteo Molica , Salvatore Perrone , Marco Rossi, Diana Giannarelli
FLT3 inhibitors combined with chemotherapy are the standard of care for newly diagnosed FLT3-mutated acute myeloid leukemia (AML). However, no head-to-head studies have established the superiority of one FLT3 inhibitor over another. We conducted a network meta-analysis (NMA) to evaluate overall survival (OS) among different FLT3 inhibitors. Three relevant randomized controlled trials (RCTs), involving 1.358 patients treated with midostaurin, quizartinib, and sorafenib, were included in our analysis. The hazard ratios (HRs) revealed no significant differences in OS between midostaurin and quizartinib (HR, 1.00; 95 % CI, 0.73–1.36), midostaurin and sorafenib (HR, 0.97; 95 % CI, 0.52–1.84), or quizartinib and sorafenib (HR, 0.97; 95 % CI, 0.51–1.85). This NMA, the first to explore this issue, found no OS differences among the different FLT3 inhibitors. In the absence of direct comparison trials, our findings provide practical insights for clinical decision-making.
{"title":"The impact of different FLT3-inhibitors on overall survival of de novo acute myeloid leukemia: A network meta-analysis","authors":"Matteo Molica , Salvatore Perrone , Marco Rossi, Diana Giannarelli","doi":"10.1016/j.leukres.2024.107549","DOIUrl":"10.1016/j.leukres.2024.107549","url":null,"abstract":"<div><p>FLT3 inhibitors combined with chemotherapy are the standard of care for newly diagnosed FLT3-mutated acute myeloid leukemia (AML). However, no head-to-head studies have established the superiority of one FLT3 inhibitor over another. We conducted a network meta-analysis (NMA) to evaluate overall survival (OS) among different FLT3 inhibitors. Three relevant randomized controlled trials (RCTs), involving 1.358 patients treated with midostaurin, quizartinib, and sorafenib, were included in our analysis. The hazard ratios (HRs) revealed no significant differences in OS between midostaurin and quizartinib (HR, 1.00; 95 % CI, 0.73–1.36), midostaurin and sorafenib (HR, 0.97; 95 % CI, 0.52–1.84), or quizartinib and sorafenib (HR, 0.97; 95 % CI, 0.51–1.85). This NMA, the first to explore this issue, found no OS differences among the different FLT3 inhibitors. In the absence of direct comparison trials, our findings provide practical insights for clinical decision-making.</p></div>","PeriodicalId":18051,"journal":{"name":"Leukemia research","volume":"144 ","pages":"Article 107549"},"PeriodicalIF":2.1,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-07DOI: 10.1016/j.leukres.2024.107548
Chunfang Kong , Mei Wu , Qilin Lu , Bo Ke , Jianhui Xie , Anna Li
Purpose
Pirtobrutinib, a non-covalent Bruton’s tyrosine kinase (BTK) inhibitor, has been approved as the first agent to overcome resistance to covalent BTK inhibitors (such as ibrutinib, acalabrutinib, and zanubrutinib). However, the mechanisms of pirtobrutinib resistance in chronic lymphocytic leukemia (CLL) remain poorly understood.
Methods
To investigate pirtobrutinib resistance, we established resistant cell models using BTK knock-out via CRISPR-Cas9 or chronic exposure to pirtobrutinib in MEC-1 cells. These models mimicked intrinsic or acquired resistance, respectively. We then analyzed differential protein expression between wild-type (WT) and resistant MEC-1 cells using Revers Phase Protein microArray (RPPA) and confirmed the findings through Western Blot. Additionally, we evaluated potential drugs to overcome pirtobrutinib resistance by conducting cell proliferation assays, apoptosis studies, and animal experiments using both sensitive and resistant cells.
Results
MEC-1 cells developed resistance to pirtobrutinib either through BTK knock-out or prolonged drug exposure over three months. RPPA analysis revealed significant activation of proteins related to the PI3K/AKT pathway, including AKT and S6, in the resistant cells. Western Blot confirmed increased phosphorylation of AKT and S6 in pirtobrutinib-resistant MEC-1 cells. Notably, both the PI3K inhibitor (CAL101) and the AKT inhibitor (MK2206) effectively reduced cell proliferation and induced apoptosis in the resistant cells. The anti-tumor efficacy of these drugs was mediated by inhibiting the PI3K/AKT pathway. In vivo animal studies further supported the potential of targeting PI3K/AKT to overcome both intrinsic and acquired resistance to pirtobrutinib.
Conclusion
The PI3K/AKT pathway plays a crucial role in both intrinsic and acquired resistance to pirtobrutinib in CLL. Therapeutically targeting this pathway may offer a promising strategy to overcome pirtobrutinib resistance.
{"title":"PI3K/AKT confers intrinsic and acquired resistance to pirtobrutinib in chronic lymphocytic leukemia","authors":"Chunfang Kong , Mei Wu , Qilin Lu , Bo Ke , Jianhui Xie , Anna Li","doi":"10.1016/j.leukres.2024.107548","DOIUrl":"10.1016/j.leukres.2024.107548","url":null,"abstract":"<div><h3>Purpose</h3><p>Pirtobrutinib, a non-covalent Bruton’s tyrosine kinase (BTK) inhibitor, has been approved as the first agent to overcome resistance to covalent BTK inhibitors (such as ibrutinib, acalabrutinib, and zanubrutinib). However, the mechanisms of pirtobrutinib resistance in chronic lymphocytic leukemia (CLL) remain poorly understood.</p></div><div><h3>Methods</h3><p>To investigate pirtobrutinib resistance, we established resistant cell models using BTK knock-out via CRISPR-Cas9 or chronic exposure to pirtobrutinib in MEC-1 cells. These models mimicked intrinsic or acquired resistance, respectively. We then analyzed differential protein expression between wild-type (WT) and resistant MEC-1 cells using Revers Phase Protein microArray (RPPA) and confirmed the findings through Western Blot. Additionally, we evaluated potential drugs to overcome pirtobrutinib resistance by conducting cell proliferation assays, apoptosis studies, and animal experiments using both sensitive and resistant cells.</p></div><div><h3>Results</h3><p>MEC-1 cells developed resistance to pirtobrutinib either through BTK knock-out or prolonged drug exposure over three months. RPPA analysis revealed significant activation of proteins related to the PI3K/AKT pathway, including AKT and S6, in the resistant cells. Western Blot confirmed increased phosphorylation of AKT and S6 in pirtobrutinib-resistant MEC-1 cells. Notably, both the PI3K inhibitor (CAL101) and the AKT inhibitor (MK2206) effectively reduced cell proliferation and induced apoptosis in the resistant cells. The anti-tumor efficacy of these drugs was mediated by inhibiting the PI3K/AKT pathway. In vivo animal studies further supported the potential of targeting PI3K/AKT to overcome both intrinsic and acquired resistance to pirtobrutinib.</p></div><div><h3>Conclusion</h3><p>The PI3K/AKT pathway plays a crucial role in both intrinsic and acquired resistance to pirtobrutinib in CLL. Therapeutically targeting this pathway may offer a promising strategy to overcome pirtobrutinib resistance.</p></div>","PeriodicalId":18051,"journal":{"name":"Leukemia research","volume":"144 ","pages":"Article 107548"},"PeriodicalIF":2.1,"publicationDate":"2024-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0145212624001140/pdfft?md5=0b6090d405f87272f93ede9712591792&pid=1-s2.0-S0145212624001140-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141623408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Acute myeloid leukemia with antecedent hematologic disorder (AHD-AML) and therapy related AML (t-AML) constitute a heterogenous disease with inferior outcomes. It is often characterized by high-risk cytogenetic and molecular alterations associated with AHD or prior cancer therapy. Historically, the standard of care treatment has been intensive induction with “7 + 3”, with an improved overall response rate and survival with CPX-351. Results from large registry-based studies suggested that allogeneic hematopoietic stem cell transplant is preferable to consolidation chemotherapy alone for achieving long-term survival in patients with AHD-AML. Prevalence of high-risk genetic features and advanced age and comorbidities in patients make AHD-AML and t-AML clinically challenging subgroups to treat with intensive approaches. Recent reports on less intensive treatment options, particularly the hypomethylating agent-venetoclax combination, have shown encouraging response rates in these patients. However, emerging resistance mechanisms compromise duration of response and overall survival. Several novel agents targeting apoptotic machinery, signaling pathways, and immune checkpoints are under clinical investigation, with an aim to truly improve overall outcomes in this subgroup. We reviewed updates in biology, classification, and clinical data comparing safety and efficacy of intensive and less intensive treatment options, and summarized ongoing studies with promising novel therapies in AHD-AML and t-AML.
{"title":"Updates in biology, classification, and management of acute myeloid leukemia with antecedent hematologic disorder and therapy related acute myeloid leukemia","authors":"Kanak Parmar , Rupayan Kundu , Abhishek Maiti , Somedeb Ball","doi":"10.1016/j.leukres.2024.107546","DOIUrl":"10.1016/j.leukres.2024.107546","url":null,"abstract":"<div><p>Acute myeloid leukemia with antecedent hematologic disorder (AHD-AML) and therapy related AML (t-AML) constitute a heterogenous disease with inferior outcomes. It is often characterized by high-risk cytogenetic and molecular alterations associated with AHD or prior cancer therapy. Historically, the standard of care treatment has been intensive induction with “7 + 3”, with an improved overall response rate and survival with CPX-351. Results from large registry-based studies suggested that allogeneic hematopoietic stem cell transplant is preferable to consolidation chemotherapy alone for achieving long-term survival in patients with AHD-AML. Prevalence of high-risk genetic features and advanced age and comorbidities in patients make AHD-AML and t-AML clinically challenging subgroups to treat with intensive approaches. Recent reports on less intensive treatment options, particularly the hypomethylating agent-venetoclax combination, have shown encouraging response rates in these patients. However, emerging resistance mechanisms compromise duration of response and overall survival. Several novel agents targeting apoptotic machinery, signaling pathways, and immune checkpoints are under clinical investigation, with an aim to truly improve overall outcomes in this subgroup. We reviewed updates in biology, classification, and clinical data comparing safety and efficacy of intensive and less intensive treatment options, and summarized ongoing studies with promising novel therapies in AHD-AML and t-AML.</p></div>","PeriodicalId":18051,"journal":{"name":"Leukemia research","volume":"144 ","pages":"Article 107546"},"PeriodicalIF":2.1,"publicationDate":"2024-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141568541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-25DOI: 10.1016/j.leukres.2024.107544
Mobil Akhmedov , Pervin Zeynalova , Alexander Fedenko
Infections are major cause of morbidity and mortality in patients with multiple myeloma. Current treatment landscape of newly-diagnosed multiple myeloma includes different classes of drugs, such as proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies, all of which are characterized by specific risk and pattern of infectious complications. Additionally, autologous and allogeneic hematopoietic cell transplantation, widely used in the treatment of multiple myeloma, are complex procedures, carrying a significant risk of complications, and mainly infections. Finally, novel treatment modalities such as bispecific T-cell engagers and chimeric antigen receptor T-lymphocytes have been changing the paradigm of myeloma treatment in relapsed-refractory setting. These agents due to unique mechanism of action carry distinct pattern of infectious complications. In this review, an attempt has been made to summarize the incidence, risk factors, and patterns of infections during different stages of myeloma treatment including novel treatment modalities, and to provide evidence underlying the current concept of infectious disease prophylaxis in this category of patients.
{"title":"Multiple myeloma and infections in the era of novel treatment modalities","authors":"Mobil Akhmedov , Pervin Zeynalova , Alexander Fedenko","doi":"10.1016/j.leukres.2024.107544","DOIUrl":"10.1016/j.leukres.2024.107544","url":null,"abstract":"<div><p>Infections are major cause of morbidity and mortality in patients with multiple myeloma. Current treatment landscape of newly-diagnosed multiple myeloma includes different classes of drugs, such as proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies, all of which are characterized by specific risk and pattern of infectious complications. Additionally, autologous and allogeneic hematopoietic cell transplantation, widely used in the treatment of multiple myeloma, are complex procedures, carrying a significant risk of complications, and mainly infections. Finally, novel treatment modalities such as bispecific T-cell engagers and chimeric antigen receptor T-lymphocytes have been changing the paradigm of myeloma treatment in relapsed-refractory setting. These agents due to unique mechanism of action carry distinct pattern of infectious complications. In this review, an attempt has been made to summarize the incidence, risk factors, and patterns of infections during different stages of myeloma treatment including novel treatment modalities, and to provide evidence underlying the current concept of infectious disease prophylaxis in this category of patients.</p></div>","PeriodicalId":18051,"journal":{"name":"Leukemia research","volume":"143 ","pages":"Article 107544"},"PeriodicalIF":2.1,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}