
==== Front
J Hematol Oncol
J Hematol Oncol
Journal of Hematology & Oncology
1756-8722
BioMed Central London

39218935
1597
10.1186/s13045-024-01597-8
Correspondence
Reduced-dose chemotherapy and blinatumomab as induction treatment for newly diagnosed Ph-negative B-cell precursor acute lymphoblastic leukemia: a phase 2 trial
Lu Jing 1
Qiu Huiying 1
Wang Ying 1
Zhou Xin 2
Dai Haiping 1
Lu Xuzhang 3
Yang Xiaofei 1
Gu Bin 14
Hong Ming 5
Miao Miao 1
Lu Ruinan 5
Wang Jun 4
Wu Qian 1
Xue Mengxing 1
Wang Yun 1
Deng Ailing 1
Shen Yaoyao 1
Liu Yin 1
Dou Xueqing 1
Lei Yutian 5
Wu Depei drwudepei@163.com

1
Zhu Yu zhuyu@jsph.org.cn

5
Chen Suning chensuning@sina.com

1
1 https://ror.org/051jg5p78 grid.429222.d 0000 0004 1798 0228 Department of Hematology, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, National Clinical Research Center for Hematologic Diseases, Suzhou, Jiangsu China
2 https://ror.org/05pb5hm55 grid.460176.2 0000 0004 1775 8598 Department of Hematology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, WuXi, China
3 grid.452511.6 Department of Hematology, Affiliated Changzhou Second Hospital of Nanjing Medical University, Changzhou, Jiangsu China
4 Department of Hematology, Soochow Hopes Hematonosis Hospital, Suzhou, China
5 https://ror.org/04py1g812 grid.412676.0 0000 0004 1799 0784 Department of Hematology, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province China
2 9 2024
2 9 2024
2024
17 798 7 2024
12 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Blinatumomab has emerged as a promising component of first-line therapy for acute B-cell precursor lymphoblastic leukemia (BCP-ALL), bolstering treatment efficacy. To mitigate CD19 selection pressure and reduce the incidence of blinatumomab-associated toxicities, pre-treatment chemotherapy is recommended before administering blinatumomab. From September 2022 to December 2023, we conducted a single-arm, multicenter, phase 2 trial (NCT05557110) in newly diagnosed Philadelphia chromosome-negative BCP-ALL (Ph-negative BCP-ALL) patients. Participants received induction treatment with reduced-dose chemotherapy (RDC), comprising idarubicin, vindesine, and dexamethasone over 7 days, followed by 2 weeks of blinatumomab. Those failing to achieve composite complete remission (CRc) received an additional 2 weeks of blinatumomab. The primary endpoint was the CRc rate post initial induction treatment. Of the 35 enrolled patients, 33 (94%) achieved CRc after 2 weeks of blinatumomab, with 30 (86%) achieving measurable residual disease (MRD) negativity. Two patients extended blinatumomab to 4 weeks. With either 2 or 4 weeks of blinatumomab treatment, all patients achieved CR (35/35) and 89% (31/35) were MRD negativity. The median time to CR was 22 days. Immune effector cell-associated neurotoxicity syndrome was limited (14%, all grade 1). Non-hematological adverse events of grade 3 or higher included pneumonia (17%), sepsis (6%), and cytokine release syndrome (9%). With a median follow-up of 11.5 months, estimated 1-year overall survival and 1-year progression-free survival rates were 97.1% and 82.2%, respectively. These findings affirm that RDC followed by blinatumomab is an effective and well-tolerated induction regimen for newly diagnosed Ph-negative BCP-ALL, supporting a shift towards less intensive and more targeted therapeutic approaches.

Trial registration: https://www.clinicaltrials.Gov. Identifier NCT05557110.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13045-024-01597-8.

Keywords

Blinatumomab
Reduced-dose chemotherapy
Induction treatment
B-cell precursor acute lymphoblastic leukemia
Philadelphia chromosome-negative
issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcTo the editor: Patients with Philadelphia chromosome-negative acute B-cell precursor lymphoblastic leukemia (Ph-negative BCP-ALL) typically achieve a high complete remission (CR) rate of 70–80% with conventional multi-drug introduction chemotherapy. However, 30–50% remain measurable residual disease (MRD) positive, often leading to relapse [1, 2]. Blinatumomab, approved for relapsed/refractory BCP-ALL or consolidation therapy for BCP-ALL, shows promising efficacy with ponatinib as a chemo-free strategy in Ph-positive ALL [3]. It is also being investigated for early induction in Ph-negative BCP-ALL. Given the high tumor burden in newly diagnosed BCP-ALL patients, bridging chemotherapy before blinatumomab may reduce CD19 selective pressure and associated toxicities [4, 5]. Intensive chemotherapy may impair immune cells, potentially affecting the effectiveness of blinatumomab [6]. Therefore, optimization of the dosage and duration of blinatumomab and chemotherapy in warranted.

From September 2022 to December 2023, we conducted a prospective, multicenter, single-arm, phase 2 study to assess the efficacy and safety of reduced-dose chemotherapy (RDC) combined with two weeks of blinatumomab (RDC-Blinatumomab-2 W) as first-line induction treatment for Ph-negative BCP-ALL patients (aged 15–65). The regimen included idarubicin 8 mg/m² intravenously injection (IV), day 1, vindesine 3 mg/m², up to 4 mg, IV, day 1, dexamethasone 9 mg/m²/day, IV, days 1–7 and blinatumomab 9 µg/day, days 8–14 and 28 µg/day, days 15–21. If CR/CR with incomplete recovery of blood cell counts (CRi) was not achieved at day 22, blinatumomab (28 µg/day) was extended for another 2 weeks (RDC-Blinatumomab-4 W). The primary endpoint was composite complete remission (CRc, including CR + CRi) rate after one cycle of induction treatment. Secondary endpoints included MRD detection by multi-flow cytometry (MFC) after one cycle of induction treatment, adverse events during the induction therapy and survival. This trial is registered at clinicaltrials.gov (NCT05557110), and the last follow-up was on April 15, 2024. The protocol and detailed scheme of the study are shown in supplemental material (Protocol, Additional file 1: Figure S1).

Thirty-five eligible patients were enrolled across five study sites (Additional file 1: Table S2). Both were included in the efficacy and safety analyses (Additional file 1: Figure S2). The clinical characteristics of patients are shown in Additional file 1: Table S1. The median age was 42 (15–65) years, with 9 (26%) patients having a white blood cell count over 30 × 109/L. Seventeen (49%) patients had poor-risk genetic aberrations.

Following RDC-Blinatumomab-2 W therapy, 33/35 patients (94%, 95% CI 81–98) achieved CRc. Moreover, 30/35 patients (86%, 95% CI: 71–94) achieved MRD negativity (Table 1). The results were comparable to the early findings of the GMALL-BOLD study [7]. Two patients extended blinatumomab to 4 weeks. With up to 4 weeks of blinatumomab treatment, the CR rate reached 100% (35/35) and the MRD-negative CR rate reached 89% (31/35). Notably, bone marrow (BM) evaluations of 33 patients after RDC showed no CRc or MRD negativity. Subgroup analyses revealed no significant differences in treatment responses based on traditional prognostic factors (sex, age, WBC counts and genetic risk stratification at diagnosis) or BM blasts percentage prior to blinatumomab (Additional file 1: Figure S3). Subgroup results aligns with that of a randomized controlled blinatumomab study in pediatric patients with high-risk first-relapse BCP-ALL [8].

Table 1 Overview of reduced-dose chemotherapy followed by blinatumomab as induction therapy

Efficacy outcomes for RDC-Blinatumomab-2 W regimen	
After RDC	N = 33	
 BM blasts < 5%	11 (33%) [20–50]	
 BM blasts ≥ 5%	22 (67%) [50–80]	
0·01% < MFC MRD < 1%	11 (33%) [20–50]	
 MFC MRD ≥ 1%	22 (67%) [50–80]	
After RDC-Blinatumomab-2 W	N = 35	
 Composite complete remission	33 (94%) [81–98]	
 CR	28 (80%) [64–90]	
 CRi	5 (14%) [6–29]	
 MFC MRD < 0.01%	30 (86%) [71–94]	
Treatment related adverse events for RDC-Blinatumomab-2 W regimen	
	Grade 1–2	Grade 3–4	
Hematologic AEs			
Leukopenia	0	26 (74%)	
Neutropenia	0	24 (69%)	
Febrile neutropenia	0	9 (26%)	
Anemia	3 (9%)	8 (23%)	
Thrombocytopenia	9 (26%)	8 (23%)	
Blinatumomab related AEs			
Cytokine release syndrome	16 (45%)	3 (9%)	
ICANS	5 (14%)	0	
Other non-hematologic AEs			
Pneumonia	0	6 (17%)	
Sepsis	0	2 (6%)	
Other infections	6 (17%)	0	
Fatigue	13 (37%)	0	
Alanine aminotransferase elevation	12 (34%)	1 (3%)	
Fever	10 (29%)	1 (3%)	
Nausea or vomiting	9 (26%)	0	
Rash	6 (17%)	0	
Edema	6 (17%)	0	
Purpura	4 (11%)	0	
Mucositis	3 (9%)	0	
Diarrhea	2 (6%)	0	
Data are n (%) or n (%) [95% CI].

N, number; BM, bone marrow; CR, complete remission; CRi, complete response with incomplete count recovery; ICANS: immune effector cell-associated neurotoxicity syndrome; MFC, multiparameter flow cytometry; MRD, measurable residual disease; RDC, reduced-dose chemotherapy; RDC-Blinatumomab-2 W, reduced-dose chemotherapy followed by blinatumomab for 2 weeks

The median follow-up time was 11.5 (IQR: 7.4–13.1) months. The estimated one-year overall survival rate was 97.1% (95% CI: 91.8–100) and one-year progression-free survival rate was 82.2% (95% CI: 69.0–98.0) (Fig. 1). One patient died of thrombocytopenia-related intracranial hemorrhage after the first consolidation chemotherapy. All patients received hyper-CVAD-based consolidation therapy and underwent standard central nervous system prophylaxis with 8–12 intrathecal injections. 13 patients underwent allogenic transplantation based on their MRD levels or patients’ preference. Four patients relapsed: one isolated CNS relapse, one hematologic relapse, and two MRD-positive relapses. Among these, three were CD19-positive and one was CD19-negative.

Fig. 1 Swimmer plot and survival analysis

(a) Swimmer plot of patients after induction therapy. (b) Overall survival analysis. (c) Progression-free survival analysis

MRD: measurable residual disease; allo-HSCT, allogeneic hematopoietic stem cell transplantation

During induction therapy, no deaths occurred within 4 weeks, significantly lower than the 2–10% mortality rate observed with intensified chemotherapy [9]. Grade 3–4 neutropenia occurred in 24 (69%) patients and grade 3–4 thrombocytopenia in 8 (23%) patients (Table 1). The median time to neutrophil recovery was only 7 days (IQR: 4–13), much shorter than the 16–20 days for conventional chemotherapy [10]. Grade 3–4 infections were observed in 23% (8/35) of patients, significantly lower than 37% reported in the MDACC study [11]. Cytokine release syndrome (CRS) occurred in 19 (54%) patients, with 3 (9%) patients experiencing grade 3 CRS. Patients with BM blasts ≥ 5% had a higher incidence of CRS compared to those with BM blasts < 5% before blinatumomab treatment (73% vs. 18%, P = 0.0094). Immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 14% (5/35) patients, all grade 1. The incidences of CRS and ICANS were similar to previously reported results at comparably low levels [12].

In conclusion, our study provides compelling evidence for efficacy and safety of the RDC-Blinatumomab regimen as first-line induction therapy. These findings support a shift towards less intensive, more targeted therapeutic approaches for young patients with Ph-negative BCP-ALL. Due to the single-arm design and small sample size, further investigation in larger, randomized controlled trials with longer follow-ups is warranted.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Supplementary Material 2

Acknowledgements

We would like to express our gratitude to all the patients and their families for participating in this study. We appreciate the efforts of the clinical staff at all participating centers for their dedication and hard work. Special thanks to our research team for their invaluable contributions to the study design, data collection, and analysis.

Author contributions

Contribution: concept and design: CSN, WDP, LJ. Provision or treatment of research patients: LJ, QHY, WY, ZX, LXZ, YXF, GB, HM, MM, LRN, WJ, WQ, XMX, WY, DAL, SYY, LY, DXQ, WDP, ZY, CSN. Data collection and assembly: LJ, LYT. Data analysis and interpretation: LJ, DHP, CSN. Draft of the manuscript: LJ and DHP wrote the first draft of the manuscript. CSN and ZY read and revised the manuscript. All authors gave final approval for submission of the manuscript.

Funding

Funders are not involved in any aspect of the research process. This includes research design, data collection, data analysis and interpretation, or report writing.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

Studies were conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of the First Affiliated Hospital of Soochow University (Approval number: 2022235).

Consent for publication

Written informed consent was obtained from all patients or their guardians.

Competing interests

The authors declare no competing interests.

Abbreviations

BCP-ALL acute B-cell precursor lymphoblastic leukemia

BM bone marrow

CR complete remission

CRc composite complete remission rate

CRi complete remission with incomplete blood cell count recovery

CRS cytokine release syndrome

ICANS immune effector cell-associated neurotoxicity syndrome

IV intravenous

MFC multiparameter flow cytometry

MRD measurable residual disease

Ph-negative Philadelphia chromosome-negative

RDC reduced-dose chemotherapy

RDC-Blinatumomab reduced-dose chemotherapy combined with blinatumomab

RDC-Blinatumomab-2W RDC combined with 2 weeks of blinatumomab

RDC-Blinatumomab-4W RDC combined with 4 weeks of blinatumomab

TKI Tyrosine kinase inhibitor

WBC white blood cell

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Jing Lu, Huiying Qiu, Ying Wang, Xin Zhou and Haiping Dai contributed equally to this work.
==== Refs
References

1. Kantarjian H Thomas D O’Brien S Cortes J Giles F Jeha S Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia Cancer 2004 101 12 2788 801 10.1002/cncr.20668 15481055
Kantarjian H, Thomas D, O’Brien S, Cortes J, Giles F, Jeha S, et al. Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer. 2004;101(12):2788–801.15481055 10.1002/cncr.20668
2. Bassan R Chiaretti S Della Starza I Spinelli O Santoro A Paoloni F Pegaspargase-modified risk-oriented program for adult acute lymphoblastic leukemia: results of the GIMEMA LAL1913 trial Blood Adv 2023 7 16 4448 61 10.1182/bloodadvances.2022009596 37276451
Bassan R, Chiaretti S, Della Starza I, Spinelli O, Santoro A, Paoloni F, et al. Pegaspargase-modified risk-oriented program for adult acute lymphoblastic leukemia: results of the GIMEMA LAL1913 trial. Blood Adv. 2023;7(16):4448–61.37276451 10.1182/bloodadvances.2022009596
3. Jabbour E Short NJ Jain N Huang X Montalban-Bravo G Banerjee P Ponatinib and Blinatumomab for Philadelphia chromosome-positive acute lymphoblastic leukaemia: a US, single-centre, single-arm, phase 2 trial Lancet Haematol 2023 10 1 e24 34 10.1016/S2352-3026(22)00319-2 36402146
Jabbour E, Short NJ, Jain N, Huang X, Montalban-Bravo G, Banerjee P, et al. Ponatinib and Blinatumomab for Philadelphia chromosome-positive acute lymphoblastic leukaemia: a US, single-centre, single-arm, phase 2 trial. Lancet Haematol. 2023;10(1):e24–34.36402146 10.1016/S2352-3026(22)00319-2
4. Cabannes-Hamy A Brissot E Leguay T Huguet F Chevallier P Hunault M High tumor burden before blinatumomab has a negative impact on the outcome of adult patients with B-cell precursor acute lymphoblastic leukemia. A real-world study by the GRAALL Haematologica 2022 107 9 2072 80 10.3324/haematol.2021.280078 35263986
Cabannes-Hamy A, Brissot E, Leguay T, Huguet F, Chevallier P, Hunault M, et al. High tumor burden before blinatumomab has a negative impact on the outcome of adult patients with B-cell precursor acute lymphoblastic leukemia. A real-world study by the GRAALL. Haematologica. 2022;107(9):2072–80.35263986 10.3324/haematol.2021.280078
5. Zhao Y Aldoss I Qu C Crawford JC Gu Z Allen EK Tumor-intrinsic and -extrinsic determinants of response to blinatumomab in adults with B-ALL Blood 2021 137 4 471 84 10.1182/blood.2020006287 32881995
Zhao Y, Aldoss I, Qu C, Crawford JC, Gu Z, Allen EK, et al. Tumor-intrinsic and -extrinsic determinants of response to blinatumomab in adults with B-ALL. Blood. 2021;137(4):471–84.32881995 10.1182/blood.2020006287
6. Laqua A Raifer H Kelm M Horns J Sharma A Möricke A In-Depth Immune Profiling in Children with BCP-ALL within the AIEOP-BFM ALL 2017 study Blood 2023 142 Supplement 1 595 10.1182/blood-2023-186998
Laqua A, Raifer H, Kelm M, Horns J, Sharma A, Möricke A, et al. In-Depth Immune Profiling in Children with BCP-ALL within the AIEOP-BFM ALL 2017 study. Blood. 2023;142(Supplement 1):595.10.1182/blood-2023-186998
7. Goekbuget N Schwartz S Faul C Topp MS Subklewe M Renzelmann A Dose reduced chemotherapy in sequence with Blinatumomab for newly diagnosed older patients with Ph/BCR::ABL negative B-Precursor adult lymphoblastic leukemia (ALL): preliminary results of the GMALL bold trial Blood 2023 142 Supplement 1 964 10.1182/blood-2023-180472
Goekbuget N, Schwartz S, Faul C, Topp MS, Subklewe M, Renzelmann A, et al. Dose reduced chemotherapy in sequence with Blinatumomab for newly diagnosed older patients with Ph/BCR::ABL negative B-Precursor adult lymphoblastic leukemia (ALL): preliminary results of the GMALL bold trial. Blood. 2023;142(Supplement 1):964.10.1182/blood-2023-180472
8. Locatelli F Zugmaier G Rizzari C Morris JD Gruhn B Klingebiel T Effect of Blinatumomab vs Chemotherapy on event-free survival among children with high-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia: a Randomized Clinical Trial JAMA 2021 325 9 843 54 10.1001/jama.2021.0987 33651091
Locatelli F, Zugmaier G, Rizzari C, Morris JD, Gruhn B, Klingebiel T, et al. Effect of Blinatumomab vs Chemotherapy on event-free survival among children with high-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia: a Randomized Clinical Trial. JAMA. 2021;325(9):843–54.33651091 10.1001/jama.2021.0987
9. O’Brien S Thomas DA Ravandi F Faderl S Pierce S Kantarjian H Results of the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone regimen in elderly patients with acute lymphocytic leukemia Cancer 2008 113 8 2097 101 10.1002/cncr.23819 18720356
O’Brien S, Thomas DA, Ravandi F, Faderl S, Pierce S, Kantarjian H. Results of the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone regimen in elderly patients with acute lymphocytic leukemia. Cancer. 2008;113(8):2097–101.18720356 10.1002/cncr.23819
10. Larson RA Dodge RK Linker CA Stone RM Powell BL Lee EJ A randomized controlled trial of filgrastim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111 Blood 1998 92 5 1556 64 9716583
Larson RA, Dodge RK, Linker CA, Stone RM, Powell BL, Lee EJ, et al. A randomized controlled trial of filgrastim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111. Blood. 1998;92(5):1556–64.9716583
11. Jabbour E Short NJ Jain N Thompson PA Kadia TM Ferrajoli A Hyper-CVAD and sequential blinatumomab for newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic leukaemia: a single-arm, single-centre, phase 2 trial Lancet Haematol 2022 9 12 e878 85 10.1016/S2352-3026(22)00285-X 36279879
Jabbour E, Short NJ, Jain N, Thompson PA, Kadia TM, Ferrajoli A, et al. Hyper-CVAD and sequential blinatumomab for newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic leukaemia: a single-arm, single-centre, phase 2 trial. Lancet Haematol. 2022;9(12):e878–85.36279879 10.1016/S2352-3026(22)00285-X
12. Kantarjian H Stein A Gökbuget N Fielding AK Schuh AC Ribera JM Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia N Engl J Med 2017 376 9 836 47 10.1056/NEJMoa1609783 28249141
Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, et al. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N Engl J Med. 2017;376(9):836–47.28249141 10.1056/NEJMoa1609783
