Hyper-CVAD regimen in combination with ofatumumab as frontline therapy for adults with Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia: a single-arm, phase 2 trial

Jabbour, Elias; Richard‐Carpentier, Guillaume; Sasaki, Yuya; Konopleva, Marina; Patel, Keyur P.; Roberts, Kathryn G.; Gu, Zhaohui; Wang, Feng; Huang, Xuelin; Sasaki, Koji; Jain, Nitin; Ravandi, Farhad; Kadia, Tapan M.; Alvarado, Yesid; DiNardo, Courtney D.; Issa, Ghayas C.; Pemmaraju, Naveen; Garcia‐Manero, Guillermo; Verstovšek, Srđan; Wang, Sa; Khoury, Joseph D.; Jorgensen, Jeffrey L.; Champlin, Richard E.; Khouri, Issa F.; Kebriaei, Partow; Schroeder, Heather; Khouri, Maria; Mullighan, Charles G.; Takahashi, Koichi; O’Brien, Susan; Kantarjian, Hagop M.

doi:10.1016/s2352-3026(20)30144-7

Cited by 49 publications

(46 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This improvement was markedly observed in older patients 60+ years (5‐year OS rates of 20% and 33% in Ph‐negative and in Ph‐positive ALL, respectively) ( p = .015). The addition of CD20 antibodies (rituximab, ofatumumab) to chemotherapy started in 2000, but was established as a standard of care in adult patients with ALL since 2017 11‐14,42‐44 . The use of inotuzumab and blinatumomab in frontline chemotherapy regimen is too recent to influence the SEER data results 36,37,45 .…”

Section: Discussionmentioning

confidence: 99%

“…Since 2000, the outcomes improved in adult ALL, with a shift from regimens that mimicked adult AML regimens (shorter maintenance, reliance on ASCT) to regimens that mimicked pediatric-inspired regimens (intensification of the nonmyelosuppressive drugs like steroids and vincristine in pediatricinspired ALL regimens that incorporate asparaginase, Hyper-CVAD regimen and its derivatives). 11,[39][40][41] A third important observation is the remarkable improved outcome for adults since 2010, the time when Ph-positive ALL was separated from Ph-negative ALL. The introduction of BCR-ABL1 tyrosine kinase inhibitors to chemotherapy in Ph-positive ALL regimens started in 2000.…”

Section: Discussionmentioning

confidence: 99%

“…The addition of CD20 antibodies (rituximab, ofatumumab) to chemotherapy started in 2000, but was established as a standard of care in adult patients with ALL since 2017. [11][12][13][14][42][43][44] The use of inotuzumab and blinatumomab in frontline chemotherapy regimen is too recent to influence the SEER data results. 36,37,45 The estimated survival of 73% in Ph-negative ALL could soon be significantly improved with the addition of CD20, CD19, and CD22 antibodies to the chemotherapy in adult (age 30-46 years) 45 and older ALL (age 60 + years).…”

Section: Discussionmentioning

confidence: 99%

“…[3][4][5] Since 2000, the treatment of adult and older ALL (age 60+ years) has undergone rapid positive changes. These have included: (1) the addition of imatinib, and, later, more potent BCR-ABL1 tyrosine kinase inhibitors, to chemotherapy in Philadelphia chromosome (Ph)positive and certain subtypes of Ph-like ALL 3,[6][7][8][9][10] ; (2) the incorporation of CD20-directed antibodies (rituximab, ofatumumab) into the treatment of Burkitt disease and CD20-positive B-ALL [11][12][13][14] conjugates, and chimeric-antigen receptor (CAR) T-cell therapies targeting CD19 and CD22 [15][16][17][18] ; and (4) the risk stratification by measurable residual disease. [19][20][21][22][23] Older patients with ALL have not benefited as much as younger patients from the intensive chemotherapy-based regimens due to the inherently more resistant disease features, comorbidities, and the poor tolerance of intensive chemotherapy (treatment interruptions, mortality in complete remission), as well as less transition to ASCT.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Acute lymphoblastic leukemia: A population‐based study of outcome in the United States based on the surveillance, epidemiology, and end results (SEER) database, 1980–2017

et al. 2021

Self Cite

View full text Add to dashboard Cite

The treatment in acute lymphoblastic Leukemia (ALL) has evolved and improved dramatically over the past four decades. We assessed the outcome of ALL overall, and the two major subsets of Philadelphia chromosome (Ph)‐positive and Ph‐negative ALL by age, time periods, ethnicity, median household income, and geographic county area. A total of 12 788 patients diagnosed with ALL from 1980 to 2017 were included. We performed an analysis to better evaluate the outcome evolution in ALL according to time period and patient's demographic factors. The overall 5‐year survival rates have improved significantly over time, from 51% before 1990 to 72% since 2010. The survival rates for children (age 0 to 14 years) and adolescents (age 15 to 19 years) have improved from 73% and 55% before 1990 to 93% and 74% since 2010, respectively. Similarly, the rates had improved from 33% to 59% for adults 20 to 29 years old, 24% to 59% for 30 to 39 years old, and 14% to 43% for 40 to 59 years old between the two time periods. The rates remained under 30% in older patients (60+ years). Since 2010, patients with Ph‐negative ALL had 5‐year survival rate of 73% and those with Ph‐positive ALL 50%. African Americans, Hispanic ethnicity, and lower household income were associated with inferior survival. The outcome of patients with ALL showed continued improvement across all age groups in the US. The recent introduction of targeted therapies, together with optimized supportive care, will continue to improve outcomes, particularly in older patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Acute lymphoblastic leukemia: A population‐based study of outcome in the United States based on the surveillance, epidemiology, and end results (SEER) database, 1980–2017

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…In particular, CD20 is neither internalized nor secreted following ligand/antibody engagement. There are several monoclonal antibodies against CD20 including Rituximab (FDA-approved in 1997), Ofatumumab (FDA-approved in 2014), and Obinutuzumab (FDAapproved in 2013), which have been investigated or used for the treatment of B-ALL and other hematologic malignancies (101)(102)(103).…”

Section: Other Proposed Targetsmentioning

confidence: 99%

In Like a Lamb; Out Like a Lion: Marching CAR T Cells Toward Enhanced Efficacy in B-ALL

Kozani

O’Connor

2021

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Combining synthetic biology with adoptive T-cell transfer has led to promising advances in the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), diffuse large B-cell lymphoma (DLBCL), and mantle cell lymphoma (MCL). Chimeric antigen receptors (CARs) are synthetic receptors that redirect T-cell specificity against cancer. CARs include “built-in” signaling domains that reprogram T-cell metabolism, enhance effector function, and support long-term persistence. Despite their success in blood-based malignancies, relapse can occur in CD19-redirected CAR T-cell therapies for several reasons, including poor engraftment, impaired in vivo proliferation, and T-cell senescence. Herein, we explain how subtle alterations in CAR design may overcome barriers to effective adoptive immunotherapy. We also discuss how the physiochemical properties of the single-chain variable fragment (scFv) affect differentiation and persistence. Moreover, we describe innovative advances in CAR engineering and provide insight into the development of humanized scFvs whose proposed benefits include increased persistence and improved clinical outcomes. Tumor cells can evade CAR T-cell–mediated detection and elimination due to the emergence or presence of CD19-negative leukemic cell subpopulations. We also discuss the opportunities and challenges in targeting other B-ALL–associated antigens. Identifying alternate targets is fundamentally necessary to restore the success of CAR T-cell therapies in CD19-negative patients with B-ALL.

show abstract

Acute Lymphoblastic Leukemia

Jabbour¹,

Jain²,

Kantarjian³

et al. 2022

Holland‐Frei Cancer Medicine

View full text Add to dashboard Cite

Overview Acute lymphoblastic leukemia (ALL) is characterized by clonal proliferation of lymphoid progenitors. In the last decade, significant advances in understanding the disease pathogenesis, refining prognostic groups, and developing novel therapies that target specific subsets, have improved our treatment strategies and patient outcomes. Therapies targeting either specific transcripts (e.g., BCR‐ABL1 tyrosine kinase inhibitors) or specific leukemic cell surface antigens (e.g., CD20, CD22, and CD19 monoclonal antibodies, chimeric antigen receptor T‐cell therapies) produced major therapeutic breakthroughs. These novel therapies and combinations are transforming our strategies for adults with ALL and are resulting in significant improvements in survival. Many of these approaches focus on decreasing or eliminating the role of chemotherapy, with the goal of making these regimens more tolerable in older adults and decreasing the morbidity and mortality associated with myelosuppression‐related infections and other complications of intensive chemotherapy.

show abstract

Hyper-CVAD regimen in combination with ofatumumab as frontline therapy for adults with Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia: a single-arm, phase 2 trial

Cited by 49 publications

References 29 publications

Acute lymphoblastic leukemia: A population‐based study of outcome in the United States based on the surveillance, epidemiology, and end results (SEER) database, 1980–2017

Acute lymphoblastic leukemia: A population‐based study of outcome in the United States based on the surveillance, epidemiology, and end results (SEER) database, 1980–2017

In Like a Lamb; Out Like a Lion: Marching CAR T Cells Toward Enhanced Efficacy in B-ALL

Acute Lymphoblastic Leukemia

Contact Info

Product

Resources

About