Open-label, phase 2 study of blinatumomab after frontline R-chemotherapy in adults with newly diagnosed, high-risk DLBCL

Figures & data

Figure 1. Study design and patient disposition. The figure shows (A) Study design. (B) Patient disposition. *All patients (whether enrolled prior to cycle 1 or prior to cycle 2 of R-chemotherapy) who completed 6 cycles of SOC R-chemotherapy. ^†In patients who were receiving radiation therapy to bulky disease, this occurred after cycle 6 SOC R-chemotherapy and PET/CT was completed. ^‡PET/CT was performed 3 weeks (±3 days) after cycle 6 SOC R-chemotherapy. ^§PET/CT must be performed 3 weeks (+3 days) after the last blinatumomab dose of cycle 1 (day 78 of cycle 1). ^ǁAt the discretion of the investigator, a second cycle of blinatumomab was administered to patients who did not have progressive disease. ^¶PET/CT was performed 3 weeks (±3 days) after the last blinatumomab dose of cycle 2 (day 50 of cycle 2). ^#Safety follow-up visit was completed 30 days (±3 days) after the last dose of blinatumomab. ^∗∗Patients should be followed for 1 year since the first dose of blinatumomab. ^††If only cycle 1 of blinatumomab was given, long-term follow-up began 3 months (±3 weeks) after the last scan (day 78 of cycle 1). ^‡‡If cycle 2 was given, long-term follow-up began 3 months (±3 weeks) after cycle 2 day 50. DLBCL: diffuse large B-cell lymphoma; IV: intravenous; PET/CT: positron emission tomography/computed tomography; R-chemotherapy: rituximab with chemotherapy; SOC: standard of care.

Table 1. Patient demographics and baseline disease characteristics.

Characteristics	R-Chemotherapy Run-In Only (n = 19)	Blinatumomab (n = 28)	Total (N = 47)
Age, median (range), years	65.0 (50–81)	64 (35–81)	64 (35–81)
Age group, n (%)
18–64 years	8 (42.1)	18 (64.3)	26 (55.3)
65–74 years	7 (36.8)	7 (25.0)	14 (29.8)
75–84 years	4 (21.1)	3 (10.7)	7 (14.9)
Gender, n (%)
Men	8 (42.1)	10 (35.7)	18 (38.3)
Women	11 (57.9)	18 (64.3)	29 (61.7)
Disease stage at diagnosis, n (%)
I and IE	1 (5.3)	1 (3.6)	2 (4.3)
II	1 (5.3)	0 (0.0)	1 (2.1)
III	4 (21.1)	5 (17.9)	9 (19.1)
IV	11 (57.9)	22 (78.6)	33 (70.2)
Not available	2 (10.5)	0 (0.0)	2 (4.3)
IPI risk score at diagnosis,^a n (%)
1	1 (5.3)	0 (0.0)	1 (2.1)
2	2 (10.5)	2 (7.1)	4 (8.5)
3	6 (31.6)	17 (60.7)	23 (48.9)
4	8 (42.1)	7 (25.0)	15 (31.9)
5	2 (10.5)	2 (7.1)	4 (8.5)
Double-hit,^b n (%)	2 (10.5)	7 (25.0)	9 (19.1)
Triple-hit,^c n (%)	2 (10.5)	1 (3.6)	3 (6.4)
Double protein expression, n (%)	8 (42.1)	10 (35.7)	18 (38.3)
Cell of origin determination, n (%)
GCB	10 (52.6)	16 (57.1)	26 (55.3)
Non-GCB^d	4 (21.1)	8 (28.6)	12 (25.5)
ABC^d	0 (0.0)	1 (3.6)	1 (2.1)
Not done	5 (26.3)	3 (10.7)	8 (17.0)

ABC: activated B-cell; GCB: germinal center B-cell; IPI: International Prognostic Index; R-chemotherapy, rituximab with chemotherapy.

^aLow, 0 or 1; low-intermediate, 2; high-intermediate, 3; high, 4 or 5.

^bRearrangement of myc and either bcl-2 or bcl-6.

^cRearrangement of myc, bcl-2, and bcl-6.

^dThe non-GCB subtype is the same as the ABC subtype. Patients were classified per site-specific nomenclature followed by local institutions where genetic screening was performed.

Table 2. Incidence of TEAEs of interest.

	Blinatumomab (N = 28)
	Any grade	Grade ≥ 3	Grade 4 only
TEAEs of interest, n (%)	23 (82.1)	9 (32.1)	5 (17.9)
Cytokine release syndrome, n (%)	5 (17.9)	0 (0.0)	0 (0.0)
Elevated liver enzyme, n (%)	1 (3.6)	0 (0.0)	0 (0.0)
Embolic and thrombotic events, n (%)	1 (3.6)	0 (0.0)	0 (0.0)
Infusion reaction,^a n (%)	2 (7.1)	0 (0.0)	0 (0.0)
Infections, n (%)	12 (42.9)	3 (10.7)	1 (3.6)
Lung infection	2 (7.1)	1 (3.6)	0 (0.0)
Upper respiratory tract infection	2 (7.1)	0 (0.0)	0 (0.0)
Bacteremia	1 (3.6)	1 (3.6)	0 (0.0)
Cellulitis	1 (3.6)	0 (0.0)	0 (0.0)
Conjunctivitis	1 (3.6)	0 (0.0)	0 (0.0)
Device related infection	1 (3.6)	0 (0.0)	0 (0.0)
Nasopharyngitis	1 (3.6)	0 (0.0)	0 (0.0)
Oral candidiasis	1 (3.6)	0 (0.0)	0 (0.0)
Sepsis	1 (3.6)	1 (3.6)	1 (3.6)
Skin infection	1 (3.6)	0 (0.0)	0 (0.0)
Staphylococcal bacteremia	1 (3.6)	0 (0.0)	0 (0.0)
Urinary tract infection	1 (3.6)	0 (0.0)	0 (0.0)
Neurologic events, n (%)	17 (60.7)	3 (10.7)	0 (0.0)
Tremor	10 (35.7)	1 (3.6)	0 (0.0)
Headache	7 (25.0)	0 (0.0)	0 (0.0)
Insomnia	4 (14.3)	0 (0.0)	0 (0.0)
Ataxia	2 (7.1)	0 (0.0)	0 (0.0)
Dizziness	2 (7.1)	0 (0.0)	0 (0.0)
Dysphonia	2 (7.1)	0 (0.0)	0 (0.0)
Paresthesia	2 (7.1)	0 (0.0)	0 (0.0)
Amnesia	1 (3.6)	0 (0.0)	0 (0.0)
Anxiety	1 (3.6)	0 (0.0)	0 (0.0)
Aphasia	1 (3.6)	1 (3.6)	0 (0.0)
Confusional state	1 (3.6)	0 (0.0)	0 (0.0)
Encephalopathy	1 (3.6)	0 (0.0)	0 (0.0)
Euphoric mood	1 (3.6)	0 (0.0)	0 (0.0)
Lethargy	1 (3.6)	0 (0.0)	0 (0.0)
Neurotoxicity	1 (3.6)	1 (3.6)	0 (0.0)
Oral paresthesia	1 (3.6)	0 (0.0)	0 (0.0)
Neutropenia and febrile neutropenia, n (%)	5 (17.9)	4 (14.3)	4 (14.3)
Neutropenia	3 (10.7)	2 (7.1)	2 (7.1)
Neutrophil count decreased	2 (7.1)	2 (7.1)	2 (7.1)

^aInfusion reaction without considering duration included cytokine release syndrome, pyrexia, and rash.

TEAEs were coded per MedDRA version 22.0 and severity was graded per CTCAE version 4.0 wherein 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, and 5 = fatal.

Some patients who had treatment-emergent infections and neurologic events of any grade and TEAEs of interest at grade ≥ 3 had more than one AE. No patient experienced grade 5 TEAEs.

AE: adverse event; CTCAE: Common Terminology Criteria for Adverse Events; MedDRA: Medical Dictionary for Regulatory Activities; N: number of patients who received at least one dose of blinatumomab; SAE: serious adverse event; TEAE: treatment-emergent adverse event.

Table 3. Summary of best response before and at the end of cycle 1 of blinatumomab.

Response^a after R-chemotherapy run-in	Best response^b at cycle 1 of blinatumomab treatment, n (%^c) (95% CI^d)
	CR	PR	Stable disease	PD	ORR (CR + PR)
CR (n = 20)	17 (85.0) (62.1, 96.8)	1^e (5.0) (0.1, 24.9)	0 (0.0) (0.0, 16.8)	2 (10.0) (1.2, 31.7)	18 (90.0) (68.3, 98.8)
PR (n = 4)	3 (75.0) (19.4, 99.4)	0 (0.0) (0.0, 60.2)	0 (0.0) (0.0, 60.2)	1 (25.0) (0.6, 80.6)	3 (75.0) (19.4, 99.4)
Stable disease (n = 4)	4 (100.0) (39.8, 100.0)	0 (0.0) (0.0, 60.2)	0 (0.0) (0.0, 60.2)	0 (0.0) (0.0, 60.2)	4 (100.0) (39.8, 100.0)
Total (n = 28)	24 (85.7) (67.3, 96.0)	1 (3.6) (0.1, 18.3)	0 (0.0) (0.0, 12.3)	3 (10.7) (2.3, 28.2)	25 (89.3) (71.8, 97.7)

Best response per Lugano criteria [15] and size of the target lesion.

CI: confidence interval; CR: complete response; ORR: objective response rate; PD: progressive disease; PR: partial response; R-chemotherapy: rituximab with chemotherapy.

^aPer assessment by the local laboratory.

^bPer assessment by the central laboratory.

^c% is based on row total.

^d95% CI is calculated using Clopper and Pearson methodology.

^eThe response status for this patient after R-chemotherapy was assessed as CR by the local lab; however, the response status upon treatment with blinatumomab was assessed as PR by the central lab. This patient was reported to be in continuous remission during the long-term follow-up following treatment with blinatumomab.

Figure 2. Effect of cIV infused blinatumomab on peripheral T-cells during the first treatment cycle. (A) T-cell counts in four patients with stable disease (blue lines) and in other patients for whom data were available (gold lines) are presented as a fold-change from baseline during the first treatment cycle with blinatumomab. The expression of the immediate early activation marker CD69 on the surface of gated (B) CD4⁺ and (C) CD8⁺ T-cell subpopulations was determined by flow cytometry at baseline and throughout treatment for four patients with stable disease (blue lines) and other patients for whom data were available (gold lines). The percentages of activated, CD69⁺ T-cell subpopulations were calculated and presented as an absolute fold-change from baseline during the first treatment cycle with blinatumomab. Fold-change was calculated as c × 2 raised to the power of the c × log₂ ratio of the post-treatment result over the pretreatment result, where c = +1 for log₂ ratios ≥0 or c = −1 for log₂ ratios <0. Absolute change for percentage endpoints was calculated as a difference between the post-treatment and pretreatment result. C: cycle; CD: cluster of differentiation; cIV: continuous intravenous; CR: complete response; D: day; HR: hour; PR: partial response; R-chemotherapy: rituximab with chemotherapy.

Figure 3. Assessment of pharmacokinetics of blinatumomab during cycle 1 and cycle 2. Mean (SD) blinatumomab serum concentration-time profiles after cIV blinatumomab at 9 µg/day (week 1), 28 µg/day (week 2), and 112 µg/day (week 3 onward) for cycles 1 and 2 in adult patients with newly diagnosed, high-risk DLBCL. cIV: continuous intravenous; DLBCL: diffuse large B-cell lymphoma; SD: standard deviation.

Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059–3068.

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