A phase 1/2 study of mini-hyper-CVD plus venetoclax in patients with relapsed/refractory acute lymphoblastic leukemia

被引：17

作者：

Short, Nicholas J. ^{[1
,6
]}

Jabbour, Elias ^{[1
,6
]}

Jain, Nitin ^{[1
]}

Senapati, Jayastu ^{[1
]}

Nasr, Lewis ^{[1
]}

Haddad, Fadi G. ^{[1
]}

Li, Zhenhua ^{[2
]}

Hsiao, Yu-Chih ^{[2
]}

Yang, Jun J. ^{[2
]}

Pemmaraju, Naveen ^{[1
]}

Ohanian, Maro ^{[1
]}

Wierda, William G. ^{[1
]}

Montalban-Bravo, Guillermo ^{[1
]}

Borthakur, Gautam ^{[1
]}

Han, Lina ^{[1
]}

Xiao, Lianchun ^{[3
]}

Huang, Xuelin ^{[3
]}

Abramova, Regina ^{[1
]}

Zhao, Min ^{[1
]}

Garris, Rebecca ^{[1
]}

Konopleva, Marina ^{[1
,4
,5
]}

Ravandi, Farhad ^{[1
]}

Kantarjian, Hagop ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX USA

[2] St Jude Childrens Res Hosp, Dept Pharm & Pharmaceut Sci, Memphis, TN USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX USA

[4] Montefiore Einstein Canc Ctr, Dept Oncol, New York, NY USA

[5] Albert Einstein Coll Med, New York, NY USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, 1515 Holcombe Blvd,Unit 428, Houston, TX 77030 USA

来源：

BLOOD ADVANCES | 2024年 / 8卷 / 04期

基金：

美国国家卫生研究院;

关键词：

ACUTE MYELOID-LEUKEMIA; SINGLE-ARM; INOTUZUMAB OZOGAMICIN; CLINICAL-TRIALS; CHEMOTHERAPY; ADULTS; BCL-2; SENSITIVITY; CYTARABINE; INHIBITOR;

D O I：

10.1182/bloodadvances.2023012231

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Preclinical studies suggest that Bcl-2 inhibition with venetoclax has antileukemic activity in acute lymphoblastic leukemia (ALL) and may synergize with conventional chemotherapy. We designed a phase 1/2 clinical trial to evaluate the safety and efficacy of low-intensity chemotherapy in combination with venetoclax in adults with relapsed or refractory ALL. Patients received the mini-hyper-CVD regimen (dose-attenuated hyperfractionated cyclophosphamide, vincristine, and dexamethasone alternating with methotrexate and cytarabine) in combination with venetoclax (200 mg or 400 mg daily) on days 1 to 14 in cycle 1 and on days 1 to 7 in consolidation cycles. Twenty-two patients were treated. The median number of prior therapies was 2 (range, 1-6). Thirteen patients (59%) had undergone prior allogeneic stem cell transplant (allo-SCT), and 7 of 18 patients (39%) with B-cell ALL had previously received both inotuzumab ozogamicin and blinatumomab. The recommended phase 2 dose of venetoclax in the combination regimen was 400 mg daily. The composite complete remission (CR) and CR with incomplete hematologic recovery (CRi) rate was 57% (CR, 43%; CRi, 14%), and 45% of responders achieved measurable residual disease negativity by multiparameter flow cytometry. Four patients proceeded to allo-SCT. The median duration of response was 6.3 months. The median overall survival was 7.1 months, and the 1-year overall survival rate was 29%. The most common grade >= 3 nonhematologic adverse events were infection in 17 patients (77%) and febrile neutropenia in 4 patients (18%). Overall, the combination of mini-hyper-CVD plus venetoclax was active in heavily pretreated relapsed/refractory ALL. Further development of venetoclax-based combinations in ALL is warranted. This trial is registered at www.clinicaltrials.gov as #NCT03808610.

引用

页码：909 / 915

页数：7

共 27 条

[1] BH3 Inhibitor Sensitivity and Bcl-2 Dependence in Primary Acute Lymphoblastic Leukemia Cells [J].

Alford, Sarah E. ;

Kotharil, Anisha ;

Loeff, Floris C. ;

Eichhorn, Joshua M. ;

Sakurikar, Nandini ;

Goselink, Henriette M. ;

Saylors, Robert L. ;

Jedema, Inge ;

Falkenburg, J. H. Frederik ;

Chambers, Timothy C. .

CANCER RESEARCH, 2015, 75 (07) :1366-1375

[2] Venetoclax-based salvage therapy for adult patients with relapsed/refractory acute lymphoblastic leukemia [J].

Canaani, Jonathan ;

Frisch, Avraham ;

Pollyea, Daniel A. ;

Schwartz, Marc ;

Aumann, Shlomzion ;

Ganzel, Chezi ;

Haran, Arnon ;

Even-Zohar, Noa Gross ;

Shaulov, Adir ;

Vainstein, Vladimir ;

Moshe, Yakir ;

Ofran, Yishai ;

Wolach, Ofir ;

Nachmias, Boaz .

EUROPEAN JOURNAL OF HAEMATOLOGY, 2023, 111 (03) :365-372

[3] Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: Cancer and Leukemia Group B study 19801 [J].

DeAngelo, Daniel J. ;

Yu, Daohai ;

Johnson, Jeffrey L. ;

Coutre, Steven E. ;

Stone, Richard M. ;

Stopeck, Alison T. ;

Gockerman, Jon P. ;

Mitchell, Beverly S. ;

Appelbaum, Frederick R. ;

Larson, Richard A. .

BLOOD, 2007, 109 (12) :5136-5142

[4] Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia [J].

DiNardo, C. D. ;

Jonas, B. A. ;

Pullarkat, V. ;

Thirman, M. J. ;

Garcia, J. S. ;

Wei, A. H. ;

Konopleva, M. ;

Doehner, H. ;

Letai, A. ;

Fenaux, P. ;

Koller, E. ;

Havelange, V. ;

Leber, B. ;

Esteve, J. ;

Wang, J. ;

Pejsa, V. ;

Hajek, R. ;

Porkka, K. ;

Illes, A. ;

Lavie, D. ;

Lemoli, R. M. ;

Yamamoto, K. ;

Yoon, S. -S. ;

Jang, J. -H. ;

Yeh, S. -P. ;

Turgut, M. ;

Hong, W. -J. ;

Zhou, Y. ;

Potluri, J. ;

Pratz, K. W. .

NEW ENGLAND JOURNAL OF MEDICINE, 2020, 383 (07) :617-629

[5] Venetoclax Combined With FLAG-IDA Induction and Consolidation in Newly Diagnosed and Relapsed or Refractory Acute Myeloid Leukemia [J].

DiNardo, Courtney D. ;

Lachowiez, Curtis A. ;

Takahashi, Koichi ;

Loghavi, Sanam ;

Xiao, Lianchun ;

Kadia, Tapan ;

Daver, Naval ;

Adeoti, Maria ;

Short, Nicholas J. ;

Sasaki, Koji ;

Wang, Sa ;

Borthakur, Gautam ;

Issa, Ghayas ;

Maiti, Abhishek ;

Alvarado, Yesid ;

Pemmaraju, Naveen ;

Bravo, Guillermo Montalban ;

Masarova, Lucia ;

Yilmaz, Musa ;

Jain, Nitin ;

Andreeff, Michael ;

Jabbour, Elias ;

Garcia-Manero, Guillermo ;

Kornblau, Steven ;

Ravandi, Farhad ;

Konopleva, Marina Y. ;

Kantarjian, Hagop M. .

JOURNAL OF CLINICAL ONCOLOGY, 2021, 39 (25) :2768-+

[6] Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia [J].

Frismantas, Viktoras ;

Dobay, Maria Pamela ;

Rinaldi, Anna ;

Tchinda, Joelle ;

Dunn, Samuel H. ;

Kunz, Joachim ;

Richter-Pechanska, Paulina ;

Marovca, Blerim ;

Pail, Orrin ;

Jenni, Silvia ;

Diaz-Flores, Ernesto ;

Chang, Bill H. ;

Brown, Timothy J. ;

Collins, Robert H. ;

Uhrig, Sebastian ;

Balasubramanian, Gnana P. ;

Bandapalli, Obul R. ;

Higi, Salome ;

Eugster, Sabrina ;

Voegeli, Pamela ;

Delorenzi, Mauro ;

Cario, Gunnar ;

Loh, Mignon L. ;

Schrappe, Martin ;

Stanulla, Martin ;

Kulozik, Andreas E. ;

Muckenthaler, Martina U. ;

Saha, Vaskar ;

Irving, Julie A. ;

Meisel, Roland ;

Radimerski, Thomas ;

Von Stackelberg, Arend ;

Eckert, Cornelia ;

Tyner, Jeffrey W. ;

Horvath, Peter ;

Bornhauser, Beat C. ;

Bourquin, Jean-Pierre .

BLOOD, 2017, 129 (11) :E26-E37

[7] Venetoclax for Children and Adolescents with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma [J].

Gibson, Amber ;

Trabal, Adriana ;

McCall, David ;

Khazal, Sajad ;

Toepfer, Laurie ;

Bell, Donna H. ;

Roth, Michael ;

Mahadeo, Kris M. ;

Nunez, Cesar ;

Short, Nicholas J. ;

DiNardo, Courtney ;

Konopleva, Marina ;

Issa, Ghayas C. ;

Ravandi, Farhad ;

Jain, Nitin ;

Borthakur, Gautam ;

Kantarjian, Hagop M. ;

Jabbour, Elias ;

Cuglievan, Branko .

CANCERS, 2022, 14 (01)

[8] Mini-hyper-CVD plus inotuzumab ozogamicin, with or without blinatumomab, in the subgroup of older patients with newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic leukaemia: long-term results of an open-label phase 2 trial [J].

Jabbour, Elias ;

Short, Nicholas J. ;

Senapati, Jayastu ;

Jain, Nitin ;

Huang, Xuelin ;

Daver, Naval ;

DiNardo, Courtney ;

Pemmaraju, Naveen ;

Wierda, William ;

Garcia-Manero, Guillermo ;

Bravo, Guillermo Montalban ;

Sasaki, Koji ;

Kadia, Tapan M. ;

Khoury, Joseph ;

Wang, Sa A. ;

Haddad, Fadi G. ;

Jacob, Jovitta ;

Garris, Rebecca ;

Ravandi, Farhad ;

Kantarjian, Hagop M. .

LANCET HAEMATOLOGY, 2023, 10 (06) :E433-E444

[9] Salvage Chemoimmunotherapy With Inotuzumab Ozogamicin Combined With Mini-Hyper-CVD for Patients With Relapsed or Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia A Phase 2 Clinical Trial [J].

Jabbour, Elias ;

Ravandi, Farhad ;

Kebriaei, Partow ;

Huang, Xuelin ;

Short, Nicholas J. ;

Thomas, Deborah ;

Sasaki, Koji ;

Rytting, Michael ;

Jain, Nitin ;

Konopleva, Marina ;

Garcia-Manero, Guillermo ;

Champlin, Richard ;

Marin, David ;

Kadia, Tapan ;

Cortes, Jorge ;

Estrov, Zeev ;

Takahashi, Koichi ;

Patel, Yogin ;

Khouri, Maria R. ;

Jacob, Jovitta ;

Garris, Rebecca ;

O'Brien, Susan ;

Kantarjian, Hagop .

JAMA ONCOLOGY, 2018, 4 (02) :230-234

[10] A Multicenter Phase I Study Combining Venetoclax with Mini-Hyper-CVD in Older Adults with Untreated and Relapsed/Refractory Acute Lymphoblastic Leukemia [J].

Jain, Nitin ;

Stevenson, Kristen E. ;

Winer, Eric S. ;

Garcia, Jacqueline S. ;

Stone, Richard M. ;

Jabbour, Elias ;

Ravandi, Farhad ;

Stewart, Jeremy M. ;

Legg, Dean R. ;

Kantarjian, Hagop M. ;

Neuberg, Donna S. ;

Letai, Anthony G. ;

Konopleva, Marina Y. ;

DeAngelo, Daniel J. .

BLOOD, 2019, 134

← 1 2 3 →