Obinutuzumab for the First-Line Treatment of Follicular Lymphoma

Long Buu Huynh, Mercer University College of Pharmacy

Lymphoma is cancer of the lymphatic system and can be categorized into two main types: Hodgkin lymphoma and non-Hodgkin lymphoma (NHL). Follicular lymphoma is a type of non-Hodgkin lymphoma that is caused by B-cell abnormalities. [1]

Rituximab-based chemotherapy has been recommended as one of the first-line induction and maintenance treatment options for newly diagnosed follicular lymphoma by the European Society of Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN). [2,3] However, studies have shown that approximately 20% of patients treated with rituximab regimen experience disease progression within two years of treatment. [4]

Obinutuzumab is a glycoengineered type II, humanized, CD-20 monoclonal antibody associated with less complement-dependent cytotoxicity but greater antibody-dependent cellular toxicity compared to rituximab. [5] It has shown efficacy in chronic lymphocytic leukemia; previously treated indolent and aggressive non-Hodgkin’s lymphoma; and rituximab- refractory indolent non-Hodgkin’s lymphoma. [6]

The GALLIUM trial was conducted to compare the progression-free survival of treatment naive indolent non-Hodgkin’s lymphoma patients who are treated with obinutuzumab based chemotherapy to that of rituximab based chemotherapy. [6]

 

Obinutuzumab for the First-Line Treatment of Follicular Lymphoma
Design Randomized controlled trial; N=1,202
Objective To evaluate the efficacy and safety of obinutuzumab-based therapy (induction and maintenance) as compared to rituximab-based therapy in  patients with previously untreated indolent non-Hodgkin’s lymphoma
Study Groups
  • Obinutuzumab (n= 601)
  • Rituximab (n= 601)
Methods Patients were randomly assigned in a ratio of 1:1 to receive  

  • obinutuzumab (1,000 mg) on days 1,8, and 15 of cycle 1 and on day 1 of subsequent cycles
  • rituximab ( 375 mg dose/m2 of body surface area) on day of each cycle for six or eight cycles.

The chemotherapy regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); cyclophosphamide, vincristine, and prednisone (CVP); or bendamustine) was required at each site and the same regimen was given to patients in the same site

Inclusion criteria:

  • Patient age (18 or older)
  • Previously untreated, CD20-positive follicular lymphoma (grade 1 to 3a) with histological documents
  • At least one lesion that could be assessed by bi-dimensional measurement
  • an Eastern Cooperative Oncology Group performance status score of 0 to 2
  • adequate hematologic function (definition not provided)
Duration Enrollment period: July, 2011 -February, 2014 and median follow-up: 34.5 months
Primary Outcome Measure Progression free survival among patients with follicular lymphoma
Baseline Characteristics Demographic and Disease Characteristics of the Patients at Baseline (Intention-to-Treat Population).*
Characteristic Obinutuzumab Group (n= 601) Rituximab Group

(n= 601)

Age — yr
Median 60 58
Range 26–88 23–85
Weight — kg
Median 75.0 74.0
Range 35.3–155.0 32.4–158.0
Body-surface area — m2
Median 1.8 1.8
Range 1.2–2.6 1.1–2.8
Male sex — no. (%) 283 (47.1) 280 (46.6)
Ann Arbor stage at diagnosis — no. (%)
I 10 (1.7) 8 (1.3)
II 41 (6.8) 44 (7.3)
III 208 (34.6) 209 (34.8)
IV 339 (56.4) 336 (55.9)
Missing data 3 (0.5) 4 (0.7)
FLIPI risk status — no. (%)
Low risk 128 (21.3) 125 (20.8)
Intermediate risk 224 (37.3) 223 (37.1)
High risk 249 (41.4) 253 (42.1)
B symptoms — no./total no. (%)§ 201/601 (33.4) 206/600 (34.3)
Bone marrow involvement — no./total no. (%) 318/592 (53.7) 295/598 (49.3)
Extranodal involvement — no. (%) 392 (65.2) 396 (65.9)
Bulk disease — no./total no. (%) 255/600 (42.5) 271/600 (45.2)
Time from initial diagnosis to randomization — mo
Median 1.5 1.4
Range 0.1–121.6 0.0–168.1
Chemotherapy regimen — no. (%)
Bendamustine 345 (57.4) 341 (56.7)
CHOP 195 (32.4) 203 (33.8)
CVP 61 (10.1) 57 (9.5)
*The demographic and disease characteristics, including prognostic factors, of the patients at baseline were well bal- anced between the two treatment groups. Percentages may not total 100 because of rounding. CHOP denotes cyclophosphamide, doxorubicin, vincristine, and prednisone; and CVP cyclophosphamide, vincristine, and prednisone.

A total of 18 patients who underwent randomization after being assessed by the investigators as having follicular lymphoma of Ann Arbor stage II, III, or IV, thus meeting trial eligibility criteria, had their classification revised to stage I disease after medical review; these patients were classified as having protocol violations.

The risk groups according to the Follicular Lymphoma International Prognostic Index (FLIPI) are based on the number of risk factors: zero or one risk factor indicates low risk, two risk factors intermediate risk, and more than two risk factors high risk.

§ B symptoms are systemic symptoms such as weight loss, night sweats, and fever.

Patients with bone marrow involvement were classified as having extranodal disease.

Bulk disease was defined as a tumor that was 7 cm or larger in the greatest dimension

Results Efficacy Results in the Intention-to-Treat Population.*
Variable Obinutuzumab Group (n= 601) Rituximab Group (n= 601)
Median observation time (range) — mo 34.8 (0 to 53.8) 34.4 (0 to 54.5)
Primary endpoint: investigator-assessed progression-free survival
Patients with progression, relapse, or death — no. (%) 101 (16.8) 144 (24.0)
Rate of estimated 3-yr progression-free survival (95% CI) — % 80.0 (75.9 to 83.6) 73.3 (68.8 to 77.2)
Hazard ratio for progression, relapse, or death (95% CI) 0.66 (0.51 to 0.85)
p value by log-rank test 0.001
Independent review committee–assessed progression-free survival
Patients with progression, relapse, or death — no. (%) 93 (15.5) 125 (20.8)
Rate of estimated 3-yr progression-free survival (95% CI) — % 81.9

(77.9 to 85.2)

77.9

(73.8 to 81.4)

Hazard ratio for progression, relapse, or death (95% CI) 0.71 (0.54 to 0.93)
p value by log-rank test 0.01
Treatment response at end of induction phase
Complete response or partial response 532 (88.5) 522 (86.9)
Difference (95% CI) — percentage points 1.6 (−2.1 to 5.5)
p value by Cochran–Mantel–Haenszel test 0.33
Complete response 117 (19.5) 143 (23.8)
Difference (95% CI) — percentage points −4.3 (−9.1 to 0.4)
p value by Cochran–Mantel–Haenszel test 0.07
Duration of response in patients with complete or partial response
Patients with progression, relapse, or death — no./total no. (%) 88/571 (15.4) 124/567 (21.9)
Hazard ratio for progression, relapse, or death (95% CI) 0.66 (0.50 to 0.87)
Disease-free survival among patients with complete response
Patients with progression, relapse, or death — no./total no. (%) 27/298 (9.1) 33/281 (11.7)
Hazard ratio for progression, relapse, or death (95% CI) 0.81 (0.48 to 1.35)
Event-free survival as assessed by investigator
Patients with progression, relapse, death, or start of new anti-lymphoma treatment — no. (%) 112 (18.6) 159 (26.5)
Hazard ratio for progression, relapse, death, or start of new anti- lymphoma treatment (95% CI) 0.65 (0.51 to 0.83)
p value by log-rank test <0.001
Start of new anti-lymphoma treatment
Patients who started new anti-lymphoma treatment — no. (%) 80 (13.3) 111 (18.5)
Estimated 3-yr rate of new anti-lymphoma treatment — % (95% CI) 87.1 (84.0 to 89.6) 81.2 (77.6 to 84.2)
Hazard ratio for new anti-lymphoma treatment (95% CI) 0.68 (0.51 to 0.91)
p value by log-rank test 0.009
Overall survival
Patients who died — no. (%) 35 (5.8) 46 (7.7)
Estimated percentage of patients alive at 3 yr — % (95% CI) 94.0

(91.6 to 95.7)

92.1

(89.5 to 94.1)

Hazard ratio for death (95% CI) 0.75 (0.49 to 1.17)
p value by log-rank test 0.21
* All analyses were stratified according to FLIPI risk status and chemotherapy regimen. Percentage differences may not sum as expected because of rounding. Disease-free survival was defined as the time from the date of first occurrence of a documented complete response to the date of disease progression, relapse, or death from any cause among patients who had had a complete response at any time before the start of new anti-lymphoma treatment. Event-free survival was defined as the time from randomization to progression, relapse, death from any cause, or start of new anti-lymphoma treatment.

The treatment response and duration of response were assessed by the investigator.

No p value was being calculated for this analysis, as specified in the protocol.

Adverse Events Common Adverse Events: any grade in the whole trial
Obinutuzumab group Rituximab group
Infusion-related events 59% 48.9%
Nausea 46.9% 46.6%
Neutropenia 48.6% 43.6%
Serious Adverse Events:
Obinutuzumab group Rituximab group
Infusion-related reactions 4.4% 1.8%
Neutropenia 2.9% 3.2%
Febrile neutropenia 3.0% 2.2%
Pyrexia 2.5% 2.7%
Pneumonia 2.4% 3.0%
Percentage that Discontinued due to Adverse Events:

  • 16.3% in the obinutuzumab group (n= 97)
  • 14.2% in the rituximab group (n= 85)
Study Author Conclusions Progression-free survival was longer in obinutuzumab-treated patients compared to rituximab treated patients.

The results of the study suggest that it may be reasonable to use obinutuzumab instead of rituximab in newly diagnosed/untreated follicular lymphoma patients. This outcome has been reflected in the 2017 NCCN guidelines for follicular lymphoma that obinutuzumab based chemotherapy is listed as one of the first-line treatment options. [3]   

 

References

[1] Follicular lymphoma. Lymphoma Research Foundation. http://www.lymphoma.org/site/pp.asp?c=bkLTKaOQLmK8E&b=6300155. Updated December 2016. Accessed November 4th, 2017

[2] Dreyling M, Ghielmini M, Rule S, et al. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017

[3] National Comprehensive Cancer Network. B- cell Lymphomas (Version 5.2017). https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Accessed November 9th, 2017.

[4] Casulo C, Byrtek M, Dawson KL, et al. Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the National LymphoCare Study. J Clin Oncol. 2015;33:2516-22.

[5] Herter S, Herting F, Mundigl O, et al. Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models. Mol Cancer Ther. 2013;12(10):2031-42.

[6] Marcus R, Davies A, Ando, K, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med 2017;377:1331-44.

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