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Leukemia & Lymphoma

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Blinatumomab versus chemotherapy in firstsalvage or in later salvage for B-cell precursoracute lymphoblastic leukemia

Hervé Dombret, Max S. Topp, Andre C. Schuh, Andrew H. Wei, SimonDurrant, Christopher Larry Bacon, Qui Tran, Zachary Zimmerman & HagopKantarjian

To cite this article: Hervé Dombret, Max S. Topp, Andre C. Schuh, Andrew H. Wei, SimonDurrant, Christopher Larry Bacon, Qui Tran, Zachary Zimmerman & Hagop Kantarjian(2019) Blinatumomab versus chemotherapy in first salvage or in later salvage for B-cellprecursor acute lymphoblastic leukemia, Leukemia & Lymphoma, 60:9, 2214-2222, DOI:10.1080/10428194.2019.1576872

To link to this article: https://doi.org/10.1080/10428194.2019.1576872

© 2019 The Author(s). Published by InformaUK Limited, trading as Taylor & FrancisGroup.

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ORIGINAL ARTICLE

Blinatumomab versus chemotherapy in first salvage or in later salvage forB-cell precursor acute lymphoblastic leukemia

Herv�e Dombreta, Max S. Toppb, Andre C. Schuhc, Andrew H. Weid, Simon Durrante,Christopher Larry Baconf, Qui Trang�, Zachary Zimmermang and Hagop KantarjianhaDepartment of Hematology, Hôpital Saint-Louis (Assistance Publique – Hôpitaux de Paris) and University Paris Diderot, Paris, France;bKlinik und Poliklinik II, Universit€atsklinikum W€urzburg, W€urzburg, Germany; cMedical Oncology and Hematology, Princess MargaretCancer Centre, University Health Network, Toronto, Canada; dDepartment of Haematology, Alfred Hospital and Monash University,Melbourne, Australia; eBone Marrow Transplant Unit, Royal Brisbane Hospital, Herston, Australia; fHaematology Department, St.James’s Hospital, Dublin, Ireland; gAmgen Inc, Thousand Oaks, CA, USA; hDepartment of Leukemia, University of Texas M.D.Anderson Cancer Center, Houston, TX, USA

ABSTRACTOutcomes for adults with relapsed/refractory acute lymphoblastic leukemia (ALL) are poor withchemotherapy, particularly in later salvage. The TOWER study examined survival, remission,bridge to allogeneic hematopoietic stem cell transplantation (HSCT), and safety with blinatumo-mab versus chemotherapy. This report examined outcomes separately for study treatment asfirst or later salvage. Adults with Philadelphia chromosome-negative B-cell precursor ALLrelapsed/refractory to chemotherapy were randomly assigned 2:1 to receive blinatumomab bycontinuous infusion for 4 weeks in 6-week cycles, or standard salvage chemotherapy. Overallsurvival for blinatumomab versus chemotherapy was higher both in first salvage and in later sal-vage. Safety was similar between patients in first salvage and those in later salvage.Blinatumomab as later salvage was associated with higher complete remission rates and servedas a bridge to allogeneic HSCT, supporting the use of blinatumomab in both settings. This studyis registered at www.clinicaltrials.gov as #NCT02013167.

ARTICLE HISTORYReceived 8 November 2018Revised 15 January 2019Accepted 24 January 2019

KEYWORDSAcute lymphoblasticleukemia; blinatumomab;chemotherapy; salvage;transplantation

Introduction

Patients with relapsed/refractory acute lymphoblasticleukemia (ALL) who are treated with standard of carechemotherapy have poor prognosis. After relapse,31–42% of adults with B-cell precursor (BCP) ALLachieve complete hematologic remission with chemo-therapy in first salvage [1–7], 18–25% in second sal-vage [1,2,8], and 11% in third or greater salvage [1].One-year survival rates for BCP-ALL after first, second,and third or greater salvage with chemotherapy are26%, 18%, and 15%, respectively [1].

Blinatumomab is a bispecific T-cell engagerimmunotherapy that binds simultaneously to CD3-posi-tive cytotoxic T cells and to CD19-positive B cells[9–11]. In single-arm phase 2 studies, blinatumomabinduced hematologic remission in the treatment ofheavily pretreated, relapsed or refractory, Philadelphia

chromosome-negative (Ph–) precursor BCP-ALL [12,13].The randomized, international phase 3 TOWER studycompared blinatumomab and standard of care chemo-therapy in salvage treatment of relapsed/refractory Ph–

BCP-ALL. Blinatumomab treatment resulted in signifi-cantly longer survival and significantly higher rates ofhematologic remission compared with chemotherapy[14]. Patients in the blinatumomab group with hemato-logic remission were also more likely than those in thechemotherapy group to be minimal residual disease(MRD)-negative (76% and 48%, respectively). Twenty-four percent of patients in each treatment groupreceived allogeneic hematopoietic stem cell transplant-ation (HSCT) after study treatment, including 14% and9% of patients, respectively, in the blinatumomab andchemotherapy groups who achieved hematologicremission and did not receive another anti-leukemictreatment before allogeneic HSCT.

CONTACT Herv�e Dombret [email protected] Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75475 Paris Cedex 10, France�Former employee of Amgen Inc.Supplemental data for this article can be accessed here.

This article has been republished with minor changes. These changes do not impact the academic content of the article.� 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed,or built upon in any way.

LEUKEMIA & LYMPHOMA2019, VOL. 60, NO. 9, 2214–2222https://doi.org/10.1080/10428194.2019.1576872

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Approximately half of the patients in the TOWERstudy received blinatumomab or chemotherapy as firstsalvage (i.e. no prior salvage at study entry), and theother half received blinatumomab or chemotherapy assecond or later salvage (i.e. any prior salvage at studyentry). This analysis compared study outcomes for bli-natumomab versus chemotherapy, delivered either asfirst or later salvage.

Materials and methods

Study design and patients

The TOWER study design and primary study resultswere published previously [14]. In this prospective,randomized, phase 3, international study, investigatorsenrolled adults (18 years of age or older) with Ph–

BCP-ALL that was refractory to chemotherapy, in firstrelapse after chemotherapy with a first remission 5% blasts in bone marrow and EasternCooperative Oncology Group (ECOG) performance sta-tus of �2. Key exclusion criteria included other activecancers, a clinically relevant pathologic condition ofthe central nervous system, isolated extramedullarydisease, autoimmune disease, acute graft-versus-hostdisease (GVHD) of grade �2 or active chronic GVHD,allogeneic HSCT within 12 weeks before randomiza-tion, autologous transplantation within 6 weeks beforerandomization, chemotherapy or radiotherapy within 2weeks before randomization, use of immunotherapywithin 4 weeks before randomization, or ongoing useof investigational treatment. Each patient providedinformed consent. An investigational review board orindependent ethics committee approved the studydesign for each study center.

Treatments

Patients were randomly assigned in a 2:1 ratio toreceive open-label treatment with either blinatumo-mab or chemotherapy, stratified by age (50% bone marrow blasts orperipheral blood blast count �15,000/lL) received dexa-methasone for up to 21 days before the first infusion toprevent cytokine release syndrome. All patients in theblinatumomab group received dexamethasone withinone hour before each infusion to prevent infusion reac-tions. Intrathecal prophylaxis for central nervous systemdisease was given according to institutional or nationalguidelines. Interruption or discontinuation of blinatumo-mab infusion was required if neurologic events or otherselected adverse events occurred.

Patients in the chemotherapy group received theinvestigator’s choice of one of the following regimens:fludarabine, high-dose cytosine arabinoside, and gran-ulocyte colony-stimulating factor with or withoutanthracycline; a high-dose cytosine arabinoside-basedregimen; a high-dose methotrexate-based regimen; ora clofarabine-based regimen. Chemotherapy could bediscontinued at any time after the first treatmentcycle. The patient could subsequently undergo allo-geneic HSCT if determined to be in the patient’s bestinterest per investigator discretion. Chemotherapydose adjustment was permitted but was not requiredfor specific events.

Assessments

Complete hematologic remission was defined as �5%bone marrow blasts and no evidence of disease, as fol-lows: CR, full hematologic recovery (platelet count>100,000/mL and absolute neutrophil count >1000/mL);CRh, partial hematologic recovery (platelet count>50,000/mL and absolute neutrophil count >500/mL); orCRi, incomplete hematologic recovery (either plateletcount >100,000/mL or absolute neutrophil count>1000/mL). MRD was measured by a central laboratoryat the end of each treatment cycle using flow cytome-try for centers in the United States and Canada (64patients), and polymerase chain reaction for other cen-ters (341 patients), with a minimum sensitivity of 0.01%.MRD response was defined as

Terminology Criteria for Adverse Events (CTCAE), version4.0. Adverse events of interest, which were identified bya steering committee, included neutropenia, infection,elevated liver enzyme, neurologic event, cytokinerelease syndrome, infusion reaction, and lymphopenia.

Statistical analysis

Endpoints included overall survival (time from ran-domization to death from any cause), complete hema-tologic remission within 12 weeks after initiation oftreatment, complete MRD response, event-free survival(EFS; time from randomization until relapse after CR/CRh/CRi or death; patients who did not achieve remis-sion were assigned an EFS of 0 months), duration ofremission (CR/CRh/CRi), rate of subsequent allogeneicHSCT, and adverse events. Efficacy analyses includedrandomized patients (intention-to-treat population).Safety analyses included patients who received at leastone dose of trial treatment (as-treated population).Remission rates were compared by stratified two-sidedCochran–Mantel–Haenszel’s tests. Survival estimateswere calculated by the Kaplan–Meier method andtreatment groups were compared by two-sided strati-fied log-rank tests. Treatment effect was expressed asa hazard ratio with a 95% confidence interval, esti-mated by a stratified Cox regression model.

Each analysis was conducted separately in patientswho received study treatment either in first salvage orin second or later salvage. Due to discrepanciesobserved between the randomization stratification vari-able for salvage in the primary analysis [14] and inves-tigator-reported data for salvage therapy, a panel ofthree medical experts with in-depth knowledge of thetrial adjudicated the number of prior salvage regimens.Two experts reviewed the treatment and disease his-tories and the third expert reconciled any discrepancybetween the other two. Overall concordance between

the investigator-reported strata for randomization andthe adjudicator-reported results was 89% in the blina-tumomab group (6% were stratified as first salvageand adjudicated as second or later salvage; 5% werestratified as second or later salvage and adjudicated asfirst salvage) and 90% in the chemotherapy group (2%were stratified as first salvage and adjudicated assecond or later salvage; 8% were stratified as secondor later salvage and adjudicated as first salvage).Results are presented according to the expert adjudica-tion for number of prior salvage regimens.

Results

Study population and treatment

Intention-to-treat analyses for efficacy included 167patients (104 blinatumomab, 63 chemotherapy) in firstsalvage and 238 patients (167 blinatumomab, 71 chemo-therapy) in second or later salvage (Figure 1). As-treatedanalyses for safety included 156 patients (103 blinatumo-mab, 53 chemotherapy) in first salvage and 220 patients(164 blinatumomab, 56 chemotherapy) in second or latersalvage (Figure 1). Patients were less likely to withdrawconsent after randomization to open-label blinatumo-mab treatment than to open-label chemotherapy, eitheras first salvage (4.8% [five of 104] versus 6.3% [four of63], respectively) or as second or later salvage (3.0% [fiveof 167] versus 12.7% [nine of 71], respectively).

Demographic and baseline characteristics were bal-anced between the blinatumomab and chemotherapygroups, both in first salvage and in second or later sal-vage (Table 1). In both treatment groups, patients insecond or later salvage were younger, and they weremore likely to be male, have ECOG performance statusscores greater than 0, have refractory disease, and tohave received previous allogeneic HSCT comparedwith patients in first salvage.

Enrolled (N=405)

Study treatment as first salvage (N=169) Study treatment as second or later salvage (N=238)

BlinatumomabAssigned to treatment (N=104)

Alive at last follow-up (N=49)Died or discontinued (N=55)

Died (N=49)Withdrew consent (N=5)Sponsor decision (N=1)Lost to follow-up (N=0)

Received treatment (N=103)

ChemotherapyAssigned to treatment (N=63)




BlinatumomabAssigned to treatment (N=167)




ChemotherapyAssigned to treatment (N=71)




Figure 1. Patient disposition.

2216 H. DOMBRET ET AL.

After first salvage, allogeneic HSCT was adminis-tered to a similar proportion of patients in the blinatu-momab and chemotherapy groups (Table 2), bothoverall (28.8% versus 30.2%; p ¼ .89), and in continu-ous hematologic remission (CR/CRh/CRi) without

subsequent anti-leukemic therapy (15.4% versus17.5%; p¼ .71). In first salvage, allogeneic HSCT wasadministered both pre-study and on-study to 3.8% ofpatients in the blinatumomab group and 4.8% ofpatients in the chemotherapy group.

Table 1. Demographic and baseline characteristics.First salvage Second or later salvage

Characteristics Blinatumomab (N¼ 104) Chemotherapy (N¼ 63) Blinatumomab (N¼ 167) Chemotherapy (N¼ 71)Age (years)Mean ±SD 45.9±18.0 43.1±18.3 37.7±15.8 39.3±16.2Range 19, 80 18, 78 18, 77 18, 72

Male sex, n (%) 61 (58.7) 32 (50.8) 101 (60.5) 45 (63.4)Race, n (%)White 91 (87.5) 54 (85.7) 137 (82.0) 58 (81.7)Asian 7 (6.7) 5 (7.9) 12 (7.2) 4 (5.6)Black 1 (1.0) 0 (0.0) 4 (2.4) 3 (4.2)Other 5 (4.8) 4 (6.3) 14 (8.4) 6 (8.5)

Hispanic ethnicity, n (%) 10 (9.6) 5 (7.9) 16 (9.6) 6 (8.5)ECOG performance status,

n (%)0 47 (45.2) 29 (46.0) 49 (29.3) 23 (32.4)1 46 (44.2) 28 (44.4) 88 (52.7) 33 (46.5)2 11 (10.6) 6 (9.5) 30 (18.0) 14 (19.7)Missing data 0 (0.0) 0 (0.0) 0 (0.0) 1 (1.4)

Key trial inclusion criteria,n (%)Disease refractory toprimary therapy or salvage

27 (26.0) 18 (28.6) 88 (52.7) 36 (50.7)

First relapse, with durationof first remission5 to

After second or later salvage, allogeneic HSCT wasadministered to a similar proportion of patients in theblinatumomab and chemotherapy groups overall(21.0% versus 18.3%; p¼ .64) (Table 2), and to morepatients in continuous hematologic remission from bli-natumomab versus chemotherapy without subsequentanti-leukemic therapy (13.2% versus 1.4%; p ¼ .004).In second or later salvage, allogeneic HSCT wasadministered both pre-study and on-study to 6.3% ofpatients in the blinatumomab group and 8.5% ofpatients in the chemotherapy group.

Overall survival

Median overall survival for first salvage was 11.1months for blinatumomab (95% CI, 8.2 months to notestimable) and 5.5 months for chemotherapy (95% CI,3.7–9.0 months), for a hazard ratio of 0.59 (95% CI,0.38–0.91; p ¼ .016; Figure 2(A)). Median overall sur-vival for second or later salvage was 5.1 months forblinatumomab (95% CI, 3.2–7.1 months) and 3.0months for chemotherapy (95% CI, 2.1–4.0 months),for a hazard ratio of 0.72 (95% CI, 0.52–1.01; p ¼ .055;Figure 2(A)).

104 80 59 39 26 14 5 1 063 39 26 18 11 5 3 0

0 3 6 9 12 15 18 21 24Months

0.0

0.2

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0.6

0.8

1.0

(A)

(C)

Ove

rall

Surv

ival

Pro

babi

lity S1: HR (95% CI) = 0.59 (0.38, 0.91)

Stratified log-rank P = 0.016S2+: HR (95% CI) = 0.72 (0.52, 1.01)

Stratified log-rank P = 0.055

K-M Median (95% CI), months

S1: BlinatumomabS1: Chemotherapy

11.1 (8.2, NR)5.5 (3.7, 9.0)

S2+: BlinatumomabS2+: Chemotherapy

5.1 (3.2, 7.1)3.0 (2.1, 4.0)

S1: BlinatumomabPatients at risk:

S1: Chemotherapy167 96 65 40 19 13 4 3 071 32 15 9 6 2 1 1 0



S1: ChemotherapyS2+: BlinatumomabS2+: Chemotherapy

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104 43 29 13 6 4 0

167 52 26 12 5 3 2 163 14 11 7 3 2 1 0

71 3 1 0

0 3 6 9 12 15 18 21 240.0

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Months



1.9 (0.0, 6.5)0.0 (-, -)


0.0 (-, -)0.0 (-, -)

S1: HR (95% CI) = 0.70 (0.47, 1.03)Stratified log-rank P = 0.11

S2+: HR (95% CI) = 0.49 (0.29, 0.57)Stratified log-rank P < 0.001

(B)

(D)

3753 20 11 7 4 1 023 12 8 7 3 2 1 0

0 3 6 9 12 15 18 210.0

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10.7 (5.6, NR)19.0 (2.2, 19.0)


6.2 (3.8, 9.6)1.7 (0.9, 4.4)


S1: ChemotherapyS2+: BlinatumomabS2+: Chemotherapy

66 36 21 11 4 3 2 010 3 1 03

Median (95% CI), months

Patients at risk:

3 6 9 12 15 18 21 24

0.00

0.25

0.50

0.75

1.00

Surv

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lity

Months

MRD–, S1: NR (14.3, NR)

MRD–, S2+: 12.7 (11.05, NR)MRD+, S1:

MRD+, S2+:

MRD–, S1:MRD+, S1:

MRD+, S2+:

3311

12

2910

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216

5

153

3

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20

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MRD–, S2+: 41 31 19 11 7 2 1 00

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NR (8.30, NR)

10.8 (5.08, NR)++++

++++++ ++++++ ++

++ +++++ +

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Figure 2. Outcomes by line of salvage. (A) Overall survival. (B) Event-free survival (patients without remission were assigned anevent-free survival of one day). (C) Duration of remission (includes only patients who achieved remission). (D) Overall survival byMRD response and by line of salvage in the blinatumomab group, in a landmark analysis starting at day 82. CI: confidence inter-val; HR: hazard ratio; K–M: Kaplan–Meier; MRD–: MRD response; MRDþ: MRD non-response; NE: not estimable; NR: not reached;S1: first salvage; S2þ: second or later salvage; þ, censored patients.


Similar results were obtained for median overallsurvival after censoring for post-baseline allogeneicHSCT. Median overall survival for first salvage, cen-sored for allogeneic HSCT, was 9.6 months for blinatu-momab (95% CI, 7.0–15.6 months) and 4.5 months forchemotherapy (95% CI, 3.7–6.4 months), for a hazardratio of 0.49 (95% CI, 0.31–0.78; p ¼ .002). Medianoverall survival for second or later salvage, censoredfor allogeneic HSCT, was 4.7 months for blinatumo-mab (95% CI, 3.2–7.1 months) and 2.9 months forchemotherapy (95% CI, 2.1–4.0 months), for a hazardratio of 0.71 (95% CI, 0.49–1.02; p ¼ .065).

Among patients who achieved CR/CRh/CRi, medianoverall survival censored at HSCT was not reached bythe end of the study for either blinatumomab first sal-vage (95% CI, 10.0 months to not estimable) orchemotherapy first salvage (95% CI, 5.3 months to notestimable) (Figure S1). In second or later salvage,median overall survival was 12.3 months for blinatu-momab (95% CI, 7.6–15.0 months) and 5.0 months forchemotherapy (95% CI, 0.9 months to not estimable;Figure S1).

Minimal residual disease

In first salvage, complete hematologic remission (CR/CRh/CRi) rates during the first 12 weeks were 51.0% forblinatumomab and 36.5% for chemotherapy (p ¼ .069;Table 3). Among patients who achieved CR/CRh/CRiwith first salvage, complete MRD response wasachieved by 26 of 53 (49.1%) patients in the blinatumo-mab group and nine of 23 (39.1%) patients in thechemotherapy group (p ¼ .53; Table 3). In second orlater salvage, complete hematologic remission (CR/CRh/CRi) rates during the first 12 weeks were 39.5% forblinatumomab and 14.1% for chemotherapy (p< .001;Table 3). Among patients who achieved CR/CRh/CRi

with second or later salvage, complete MRD responsewas achieved by 32 of 66 (48.5%) patients in the blina-tumomab group and one of 10 (10.0%) patients in thechemotherapy group (p ¼ .008; Table 3).

In the blinatumomab group, overall survival waslonger for MRD responders than for MRD non-res-ponders, with a greater difference in first salvage thanin second or later salvage (Figure 2(D)). In first salvage,median overall survival was not reached in the blina-tumomab group, either for MRD responders (95% CI,14.3 months to not estimable) or for MRD nonres-ponders (95% CI, 8.3 months to not estimable). Insecond or later salvage, median overall survival in theblinatumomab group was 12.7 months for MRD res-ponders (95% CI, 11.1 months to not estimable) and10.8 months for MRD nonresponders (95% CI, 5.1months to not estimable). This landmark analysisstarted at day 82 (i.e. after scheduled MRD assess-ment); no patient in the blinatumomab group diedbefore day 82 and was excluded from analysis. In thechemotherapy group, the number of MRD responders(13 in first salvage and 3 in second or later salvage)was too small for a meaningful analysis of overall sur-vival by MRD response.

Event-free survival and duration of remission

In first salvage, median EFS was 1.9 months for blina-tumomab (95% CI, 0.0–6.5 months) and 0.0 monthsfor chemotherapy (a majority of chemotherapypatients did not achieve remission and were assignedan EFS of 0 months) (Figure 2(B)). Estimated EFS at 6months was 40.8% for blinatumomab (95% CI,31.0–50.3%) and 25.9% for chemotherapy (95% CI,15.3–37.8%), and the hazard ratio for EFS was 0.70(95% CI, 0.47–1.03; p ¼ .11). Within the subset ofpatients with CR/CRh/CRi (n¼ 53 for blinatumomab

Table 3. Best hematologic response and minimal residual disease response within 12 weeks of treatment initiation.First salvage Second or later salvage

Blinatumomab(N¼ 104) Chemotherapy (N¼ 63)

Blinatumomab(N¼ 167)

Chemotherapy(N¼ 71)

Response category No. % 95% CI No. % 95% CI pa No. % 95% CI No. % 95% CI pa

Best hematologic responseCR 46 44.2 34.5, 54.3 18 28.6 17.9, 41.3 .050 45 26.9 20.4, 34.3 3 4.2 0.9, 11.9

and n¼ 23 for chemotherapy), median duration ofremission was 10.7 months for blinatumomab (95% CI,5.6 months to not estimable) and 19.0 months forchemotherapy (95% CI, 2.2–19.0 months) (Figure 2(C)).Median duration of remission, censored at HSCT, was10.8 months for blinatumomab (95% CI, 5.6 months tonot estimable) and not reached for chemotherapy(95% CI, 1.8 months to not estimable; Figure S2).

In second or later salvage, median EFS was 0.0months in each treatment group. Estimated EFS at 6months was 24.0% for blinatumomab (95% CI,17.4–31.3%) and 1.6% for chemotherapy (95% CI,0.1–7.5%), and the hazard ratio for EFS was 0.49 (95%CI, 0.29–0.57; p< .001; Figure 2(B)). Within the subsetof patients with CR/CRh/CRi (n¼ 66 for blinatumomaband n¼ 10 for chemotherapy), median duration ofremission was 6.2 months for blinatumomab (95% CI,3.8–9.6 months) and 1.7 months for chemotherapy(95% CI, 0.9–4.4 months) (Figure 2(C)). Median dur-ation of remission, censored at HSCT, was 6.2 monthsfor blinatumomab (95% CI, 3.8–7.6 months) and 1.7months for chemotherapy (95% CI, 0.9–4.4 months;Figure S2).

Safety

In first salvage, any adverse event was reported in98.1% of patients in the blinatumomab group and in100.0% of patients in the chemotherapy group, includ-ing any Grade 3 adverse event in 61.2% and 83.0%,respectively, any Grade 4 adverse event in 34.0% and50.9%, respectively, and any serious adverse event in57.3% and 41.5%, respectively. In second or later sal-vage, any adverse event was reported in 98.8% of

patients in the blinatumomab group and in 98.2% ofpatients in the chemotherapy group, including anyGrade 3 adverse event in 67.7% and 75.0%, respect-ively, any Grade 4 adverse event in 36.0% and 53.6%,respectively, and any serious adverse event in 64.6%and 48.2%, respectively.

Within each salvage subgroup, the most commonlyreported adverse events of any grade occurred withsimilar incidences in the blinatumomab and chemo-therapy groups (Table 4). Adverse events of interestwere reported infrequently in first salvage andincluded Grade 3 neurologic events (7.8% blinatumo-mab versus 7.5% chemotherapy), Grade 4 neurologicevents (1.0% versus 1.9%), or Grade 3 cytokine releasesyndrome (3.9% versus 0.0%). No patient developedGrade 4 cytokine release syndrome with first salvage.Adverse events of interest were also reported infre-quently in second or later salvage and included Grade3 neurologic events (9.1% blinatumomab versus 7.1%chemotherapy), Grade 4 neurologic events (0.6% ver-sus 1.8%), Grade 3 cytokine release syndrome (4.9%versus 0.0%), and Grade 4 cytokine release syndrome(0.6% versus 0.0%).

Grade 3 or 4 neurologic adverse events that werereported for more than one patient in either treatmentgroup in first salvage were encephalopathy (2.9% bli-natumomab versus 0.0% chemotherapy) and syncope(0.0% versus 3.8%). Grade 3 or 4 neurologic adverseevents that were reported for more than one patientin either treatment group in second or later salvagewere confusional state (1.8% blinatumomab versus0.0% chemotherapy), somnolence (1.8% versus 0.0%),seizure (0.6% versus 3.6%), and headache (0.0% ver-sus 3.6%).

Table 4. Treatment emergent adverse events.First salvage, n (%) Second or later salvage, n (%)

Preferred termBlinatumomab

(N¼ 103)Chemotherapy

(N¼ 53)Blinatumomab

(N¼ 164)Chemotherapy

(N¼ 56)Any treatment emergent adverse event 101 (98.1) 53 (100.0) 162 (98.8) 55 (98.2)Event leading to early discontinuation of study treatment 9 (8.7) 1 (1.9) 24 (14.6) 8 (14.3)Serious adverse event 59 (57.3) 22 (41.5) 106 (64.6) 27 (48.2)Fatal serious adverse event 10 (9.7) 8 (15.1) 41 (25.0) 11 (19.6)Grade 3 or 4 adverse events of interesta Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4No. of patients with any event of interest 63 (61.2) 35 (34.0) 44 (83.0) 27 (50.9) 111 (67.7) 59 (36.0) 42 (75.0) 30 (53.6)Cytopenia 40 (38.8) 30 (29.1) 34 (64.2) 24 (45.3) 67 (40.9) 44 (26.8) 25 (44.6) 26 (46.4)Neutropenia 28 (27.2) 18 (17.5) 25 (47.2) 18 (34.0) 54 (32.9) 22 (13.4) 24 (42.9) 16 (28.6)Infections 23 (22.3) 3 (2.9) 24 (45.3) 9 (17.0) 42 (25.6) 12 (7.3) 25 (44.6) 5 (8.9)Elevated liver enzyme 12 (11.7) 1 (1.0) 4 (7.5) 2 (3.8) 19 (11.6) 5 (3.0) 10 (17.9) 1 (1.8)Neurologic event 8 (7.8) 1 (1.0) 4 (7.5) 1 (1.9) 15 (9.1) 1 (0.6) 4 (7.1) 1 (1.8)Infusion reaction 5 (4.9) 0 (0.0) 0 (0.0) 0 (0.0) 4 (2.4) 0 (0.0) 1 (1.8) 0 (0.0)Cytokine release syndrome 4 (3.9) 0 (0.0) 0 (0.0) 0 (0.0) 8 (4.9) 1 (0.6) 0 (0.0) 0 (0.0)Tumor lysis syndrome 4 (3.9) 0 (0.0) 0 (0.0) 0 (0.0) 3 (1.8) 1 (0.6) 1 (1.8) 0 (0.0)Decreased immunoglobulins 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 6 (3.7) 1 (0.6) 0 (0.0) 0 (0.0)

Reported by decreasing incidence in the blinatumomab group for first salvage.aEvent of interest category reported in at least 3% of patients in any group.


https://doi.org/10.1080/10428194.2019.1576872https://doi.org/10.1080/10428194.2019.1576872

In the chemotherapy group, a Grade 3 or 4 adverseevent of decreased immunoglobulins was not reportedfor any patient either in first salvage or in second orlater salvage. In the blinatumomab group, a Grade 3or 4 adverse event of decreased immunoglobulins wasreported for no patient in first salvage and 4.3% ofpatients in second or later salvage. Mean (SD) valuesfor immunoglobulin G at baseline and at cycle 1 day29 were as follows: in first salvage, 6.81 (2.55) g/Lbefore and 5.47 (2.18) g/L after cycle 1 of blinatumo-mab, and 7.73 (2.34) g/L before and 7.77 (2.68) g/Lafter cycle 1 of chemotherapy; in second or later sal-vage, 6.40 (2.31) g/L before and 4.97 (1.80) g/L aftercycle 1 of blinatumomab, and 6.89 (2.34) g/L beforeand 6.94 (2.87) g/L after cycle 1 of chemotherapy.

Discussion

In the international, randomized, phase 3 TOWERstudy, higher rates of complete hematologic remissionand longer overall survival were achieved with blinatu-momab treatment compared with chemotherapy inadults with Ph– BCP-ALL that was relapsed or refrac-tory to at least one previous therapy [14]. In this sub-group analysis of the TOWER study by salvageregimen, complete hematologic remission, MRDresponse, EFS, and overall survival consistently favoredblinatumomab over chemotherapy both in first sal-vage and in second or later salvage.

In first salvage, which comprised 41.2% of the studypopulation overall (38.4% of the blinatumomab groupand 47.0% of the chemotherapy group), median over-all survival was 11.1 months for blinatumomab and5.5 months for chemotherapy, suggesting that blinatu-momab may be particularly beneficial for overall sur-vival in first salvage. Previous studies reported thatmedian overall survival in adults with ALL in firstrelapse is 4.5 months overall [6] and 8.4 monthsamong those in relapse who are treated with first sal-vage chemotherapy [2]. Thus, overall survival forchemotherapy in first salvage in this study was con-sistent with previously reported results, despite thehigh prevalence of risk factors for worse outcomes inthis study population, such as refractory disease orearly relapse. In first salvage, blinatumomab was alsoassociated with a higher rate of complete hematologicremission than chemotherapy (51.0% versus 36.5%)and a higher rate of MRD response (49.1% versus39.1%). Allogeneic HSCT rates were similar betweenthe treatment groups in first salvage. Duration ofremission did not favor blinatumomab over chemo-therapy in first salvage, but these analyses were

complicated by the small subset of patients thatachieved remission with chemotherapy in first salvage.Analyses of MRD response and duration of remissionwere more descriptive than comparative because theanalysis set for this outcome depended on having apost-randomization event (CR/CRh/CRi), which wasachieved by a greater proportion of patients in the bli-natumomab group than in the chemotherapy group.Thus, a nonrandom subgroup of the full analysis setwas analyzed for duration of remission. Analyses ofEFS, which included all patients and represented thedifferences in remission rates, addressed this issue.

In second or later salvage, the overall survival bene-fit for blinatumomab compared with chemotherapywas less pronounced. Blinatumomab was neverthelesssubstantially more effective than chemotherapy insecond or later salvage for complete hematologicremission (39.5% versus 14.1%) and EFS. While rates ofallogeneic HSCT were similar overall in the blinatumo-mab and chemotherapy groups, patients in second orlater salvage were more likely to receive allogeneicHSCT in continuous remission after blinatumomabthan after chemotherapy, with a large differencebetween treatment groups, suggesting that blinatu-momab may be a better bridge to transplant in thesepatients with advanced disease.

In both treatment groups, remission rates and otheroutcomes appeared to be worse in second or later sal-vage than in first salvage, which was consistent withprevious reports [1,7,8]. These results were also con-sistent with responses to prior therapy at baseline:patients in second or later salvage were nearly twiceas likely as those in first salvage to have ALL that wasrefractory to prior treatment. Regardless of prior sal-vage, neurologic adverse events or cytokine releasesyndrome occurred infrequently with blinatumomaband safety results in each salvage subgroup were con-sistent with those previously reported for the overallstudy population [14]. Immunoglobulin G appeared todecrease from baseline to the end of cycle 1 in theblinatumomab group, but not in the chemotherapygroup, with Grade 3 or 4 adverse events of decreasedimmunoglobulins in 4% of patients who received bli-natumomab in first salvage. Decreased immunoglobu-lins have been reported previously withblinatumomab treatment; patients should be moni-tored and treated appropriately for signs and symp-toms of infection.

MRD response as a prognostic factor was strongerin first salvage than in second or later salvage.However, MRD response was a post-randomizationvariable, complicating interpretation. The study was

BLINATUMOMAB IN FIRST VS. LATER SALVAGE 2221

designed and powered to compare the primaryefficacy endpoint, overall survival, between theblinatumomab and chemotherapy groups for allpatients who underwent randomization [14].The randomization was stratified by line of salvagetherapy (first versus second or later), as well as ageand previous allogeneic HSCT. The study was notpowered for statistical comparisons between treat-ment groups within each salvage subgroup, limitingthe interpretation of p values, particularly for second-ary endpoints such as hematologic response andMRD response.

In either first salvage or in second or later salvage,blinatumomab was associated with greater remissionor survival than chemotherapy and similar or highertransplantation rates. Blinatumomab was associatedwith similar or better safety than chemotherapy inboth populations. Salvage therapy with blinatumomabmay be particularly beneficial compared with chemo-therapy for overall survival as first salvage in adultswith Ph– precursor BCP-ALL, and it may serve as abridge to transplant in patients in later salvage.

Acknowledgements

Jonathan Latham of PharmaScribe, LLC (on behalf of AmgenInc.) assisted the authors with the preparation and submis-sion of the manuscript. Robert Dawson of CACTUS (onbehalf of Amgen Inc.) assisted the authors with preparationof the images.

Data deposition

Qualified researchers may request data from Amgen clinicalstudies. Complete details are available at http://www.amgen.com/datasharing.

Potential conflict of interest: Disclosure forms providedby the authors are available with the full text of this articleonline at http:\\doi:10.1080/10428194.2019.1576872

Funding

This study was funded by Amgen Inc.

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AbstractIntroductionMaterials and methodsStudy design and patientsTreatmentsAssessmentsStatistical analysis

ResultsStudy population and treatmentOverall survivalMinimal residual diseaseEvent-free survival and duration of remissionSafety

DiscussionAcknowledgementsData depositionPotential conflict of interestReferences

blinatumomab versus chemotherapy in first salvage or in later ...approximately half of the patients...

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