Efficacy and safety of biosimilar rituximab (ZytuxTM) in newly diagnosed patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia.

Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin Lymphoma (NHL) are considered parts of mature B cell neoplasms in WHO classification. They are both characterized by accumulation of B cells in blood, lymphoid tissues and bone marrow. Most of treatment protocols of NHL and CLL contain rituximab in addition to chemotherapy, which has been associated with improved survival. The aim of this study was to assess the efficacy and safety of Zytux™ (AryoGen Pharmed) in newly diagnosed patients with NHL and CLL. A prospective single center study conducted at the National Center of Hematology, Mustansiriyah University, from January 2018 till October 2018. Twenty patients were included in this study, ten of them were NHL and ten patients were CLL. All patients were treated with Zytux™ in addition to designated protocol. All patient were followed up for 6 months and evaluated at the end of each protocol. There were 20 patients in this study; the overall median age for all patients in this study was 66 years. The median age was 57.5 years for NHL and 68.5 years for CLL. There were 13 males and 7 females in total, with male predominance in both groups. Regarding safety profile, Zytux™ demonstrated similar adverse reactions in comparison to MabThera® (Roche Spa). Moreover, the overall response rate in both groups was 85% with complete response achieved in 35% and partial response in remaining 50%.This study concluded that the early results of use of Zytux™ in NHL and CLL were not inferior to reference drug MabThera® in contrast it was comparable and even better in term of safety and efficacy. ©Copyright: the Author(s).

Introduction

Hematologic B-cell malignancies comprise a large, heterogeneous group of B-cell lymphoproliferative disorders in which clonal expansion of the various stages of B lymphocytes occur in bone marrow, blood or other tissues. These disorders classified according to their nature of proliferation, which range from very aggressive lymphoma to aggressive like Diffuse Large BCell Lymphoma (DLBCL) and slowlygrowing, indolent Non-Hodgkin Lymphomas (NHL), such as Follicular Lymphoma (FL) and chronic lymphocytic leukemia. B-cell disorders represent more than 90% of all NHL and CLL cases.[1,2,3]

NHL incidence rates are higher among the elderly population than in the younger population, diagnoses of NHL is most commonly found among patients aged 65–74 years which is the same for CLL which runs slowly progressive course in which patients generally had multiple remission and relapses.[4]

As number of NHL and CLL cases are increasing because of advances in treatment and increase of aging population, therefore the treatment of these disorders will remain an important issue for health system strategy because of financial burden on the designated budget for providing chemotherapy. The management plan of NHL and CLL is depend on anti-CD20, which considered the characteristic marker for all hematological B cell neoplasms, and nowadays most international guidelines put anti-CD20 therapy like Rituximab in first line in the management of NHL and CLL. Usually the management of B-cell malignancies is determined by many factors like histologic features, staging of disease, age of patient, and the presence of comorbid disease, which can be used in international prognostic index. Staging is established using validated systems, which include Rai classification or Ann Arbor for NHL and Binet for CLL.[5,6]

Rituximab is a human/murine chimeric, glycosylated immunoglobulin (Ig) containing murine light- and heavy-chain variable region sequences, and human kappa and human IgG1 constant region sequences. Rituximab has specific affinity for the Blymphocyte transmembrane protein, CD20, which is expressed on normal B cells (excluding stem cells, pro-B cells, and plasma B cells) and on most malignant B cells.[7] Monoclonal antibodies development requires multiple complex manufacturing processes, and therefore these high-technology products are generally expensive.[8]

The requirements of health care are growing and the increases of new and expensive health care technologies are a challenge for the sustainability of health systems worldwide. Biosimilars can be one of the solutions to reduce costs of cancer treatment, retaining the same efficacy and safety of originator drugs. In order to make these expensive targets therapy more feasible for healthcare authority and to expand its outcomes and reduce costs, biosimilar agents (molecules similar in structure, function, and safety to the original biological drugs) are introduced to the market.[9]

Zytux™ (Rituximab, AryoGen Pharmed) is biosimilar product of MabThera® (Rituximab, Roche) which has demonstrated satisfactory compatibility profile during non-clinical phase. In order to prove biosimilarity of Zytux™ to MabThera®, we have conducted this pilot study on NHL and CLL patients to compare its efficacy and safety on this subset of patients.

Materials and Methods

This is a prospective, pilot study conducted at the National Center of Hematology, Mustansiriyah University from January 2018 till October 2018. It was approved by review ethical committee of center and all patients agree and gave their written consent prior to enrollment. There were 20 patients agreed to participate in this pilot study, ten of them NHL and other ten CLL.

Inclusion criteria

The inclusion criteria were age of 18 years or more, patients with CLL or NHL who are candidates to be treated with Rituximab for total therapy duration of 6 months.

Exclusion criteria

Patients were excluded from study if they had one or more of following conditions: Patients who have received MabThera® or Rituxan® out of the the study, pregnancy or lactation, severe autoimmune hemolytic anemia, current active infections or underlying diseases such as Hepatitis B or C, HIV, severe cardiac or pulmonary disorders, recent myocardial infarction, uncontrolled hypertension and epilepsy, diabetes mellitus, elevated hepatic enzyme levels (more than 2 fold ULN), serum creatinine more than 2 mg/dL, known hypersensitivity with anaphylactic reaction to chimeric monoclonal antibodies or any of study drugs.

Demographic information, medical history, physical examination, required lab tests (including CBC with differential, liver function tests, renal function tests, whole body CT, flow cytometric evaluation of CD counts and hemoglobin), especially disease staging were assessed in first visit; all efficacy and safety measures were then reassessed at each visit prior administration of chemotherapy regimen.

All patients received combination therapy with Zytux™ and chemotherapy according to designated protocols for CLL and NHL. After 3 courses reassessment was done for all patients according to disease requirements of response. Final assessments were done after 6 courses of chemotherapy protocol.

Outcomes

The primary outcome was Overall Response Rate (ORR), which is defined by the sum of Complete Response rate (CR) and Partial Response rate (PR). These were assessed following completion of scheduled chemo-immunotherapy cycles based on IWCLL (International Workshop on CLL) response criteria[10] and for NHL according to CT scan criteria for lymphoma reported by Cheson et al.[11]

Adverse reaction

For patient’s adverse reactions evaluation was done according to NCI reference[12] using the chart below (Table 1).

Table 1.

The NCI Common Terminology Criteria for Adverse Events (CTCAE) v 3.0.

Grade	Definition
Grade 1	MILD, minor event requiring no specific medical intervention; asymptomatic laboratory findings only; marginal clinical relevance
Grade 2	MODERATE, minimal intervention; local intervention; non-invasive intervention; transfusion; elective interventional radiological procedure; therapeutic endoscopy or operation
Grade 3	SEVERE and undesirable adverse events, significant symptoms requiring hospitalization or invasive intervention; transfusion; elective interventional radiological procedure; therapeutic endoscopy or operation
Grade 4	Life Threatening or Disabling adverse events, complicated by acute, life threatening metabolic or cardiovascular complications such as circulatory failure, hemorrhage, sepsis; life–threatening physiologic consequences; need for intensive care or emergent invasive procedure; emergent interventional radiological procedure, therapeutic endoscopy or operation

NCI: National Cancer Institute Guidelines for the cancer therapy evaluation.

Statistical analysis

Data were entered into Excel sheet and then transferred to SPSS-21 (IBM company- USA). Descriptive analysis (numbers, percentages, median, means, and standard deviation [SD]) was performed for all variables.

Results

There were 20 patients in this study; the overall median age for all patients in this study was 66 years. The median age was 57.5 years for NHL and 68.5 years for CLL. There were 13 males and 7 females in total with male predominance in both group. The other demographic and laboratory parameters for all patients are shown in Table 2.

Table 2.

Baseline demographic characteristics of all patients.

Parameter	NHL no.10	CLL no. 10	Total no. 20
Age year
Range	17-81	46-76	17-81
Mean±SD	56.5±19.42	65.7±10.35	61.1±16.22
Median	57.5	68.5	66
Gender
Male	6	7	13
Female	4	3	7
Staging system	Rai	Binet
	Stage 1= 0	Stage A=0
	Stage 2=2	Stage B= 6
	Stage 3= 1	Stage C= 4
	Stage 4= 7
Performance status		1
ECOG 0	4	2
ECOG1	3	7
ECOG2	3
Type of NHL
DLBCL	7
FL	2
Type of treatment protocol	R-CHOP=9	RFC=3
	R-COP =1	RB= 4
		REP= 3
Splenomegaly	6	6	12
Hepatomegaly	3	5	8
Lymphadenopathy	9	8	17
Hematological profile
Mean Hemoglobin (range)gm/dL	11.89 (8.8-18)	12.7 (10-14)	12.34 (8.8-18)
Mean Leucocytes (range) x109/L	8.69 (2.2-24)	69 (19-180)	38.845 (2.2-180)
Mean Platelets (range) /mm3	208000 (81000-461000)	192400 (86000-414000)	200150 (81000-461000)
Liver disease	0	0
Cardiac disease	Heart failure=1	IHD =3 CMP=1	7
		HT=1Stroke =1
Renal disease	0	0	0
Others	Hepatitis B+ve	DM=1	2

Regarding overall response rate for all patients was 85%, for NHL group was 80% while for CLL group was 90%. In regard to complete remission, it was achieved in 50% of CLL patients with 2 patients who got negative minimal residual disease as confirmed by flowcytometry. In NHL group just 20% of patients achieved complete remission as shown in Table 3.

Table 3.

Clinical response rates.

Response	NHL (10 patients) (%)	CLL (10 patients) (%)	NHL+CLL (20 patients) (%)
Overall response rate	8(80)	9(90)	17(85)
Complete response	2(20)	5(50)	7(35)
Partial response	6(60)	4(40)	10(50)
No response	2(20)	1(10)	3(15)

There were just 4 patients who experience infusion related reactions during first cycle Table 4.

Table 4.

Incidence of infusion-related reactions for Zytux™.

Infusion Cycle	NHL group	CLL group	Overall
First cycle	2	2	4
Subsequent cycles	1	0	1

Table 5 shows hematological adverse effects. Most of them were trivial and easy manageable, Table 6 shows that there was no registration of non-hematological adverse reaction during the study.

Table 5.

Hematologic adverse reactions of Zytux™.

Hematologic adverse reactions	NHL, 10 patients	CLL, 10 patients	Overall, 20 patients (%)
Thrombocytopenia
Grade I (<150000 to 75,000/mm3)	3	5	8
Grade II (50,000 to 75,000/mm3)	0	1	1
Grade III (25,000 to 50,000/mm3)	0	0	0
Grade IV (<25,000/mm3)	0	0	0
Total	3	6	9(45)
Anemia (hemoglobin level)
Grade I (<12 to 10 g/dL)	3	2	5
Grade II (8.0 to 10.0 g/dL)	2	1	3
Grade III (<8.0 g/dL)	0	0	0
Total	5	3	8(40)
Neutropenia
Grade I (<4000 to 1500/mm3)	7	10	17(85)
Grade II (1000 to 1500/mm3)	1	1	2
Grade III (500 to 1000/mm3)	1	0	1
Grade IV (<500/mm3)	0	0	0
Total	9	11	20(100)

Table 6.

Type of non-hematologic adverse reactions for Zytux™.

Adverse reaction	NHL Grade		CLL grade		Both, any grade
	1+2	3=4	1+2	3+4
Cardiovascular					0
Peripheral edema
Hypertension
Hypotension
Gastrointestinal					0
Nausea
Diarrhea
Abdominal pain
Dermatologic					0
Skin Rash
Pruritus
Night sweats
Neuromuscular and skeletal					0
Weakness
Muscle spasm
Arthralgia
Central nervous system					0
Fatigue
Chills
Headache
Neuropathy
Insomnia
Pain
Respiratory					0
Cough
Shortness of breath
Pharyngitis
Infection					0
Hepatic					0
Increased ALT/SGPT
Endocrine and metabolic					0
Weight gain
Others

Discussion

Clinical experience with intravenously administered rituximab in B-cell hematologic malignancies is extensive, which extending to more than 20 years and to about four million patients exposed to this treatment worldwide. The requirements of health care are growing and the increases of new and expensive health care technologies are a challenge for the sustainability of health systems. Biosimilars can be one of the solutions to reduce costs of cancer treatment, keeping the same efficacy and safety of reference drugs. In order to make these expensive targets therapy more feasible for healthcare authority and to expand its outcomes and reduce costs, biosimilar agents are developed and marketed to be successful substitute. Several biosimilar rituximab has been introduced into the market, one of these is Zytux™.

Clinical experience with intravenously administered rituximab in B-cell hematologic malignancies is extensive, which extending to more than 20 years and to about four million patients exposed to this treatment worldwide. The requirements of health care are growing and the increases of new and expensive health care technologies are a challenge for the sustainability of health systems. Biosimilars can be one of the solutions to reduce costs of cancer treatment, keeping the same efficacy and safety of reference drugs. In order to make these expensive targets therapy more feasible for healthcare authority and to expand its outcomes and reduce costs, biosimilar agents are developed and marketed to be successful substitute. Several biosimilar rituximab has been introduced into the market, one of these is Zytux™.

In regards to NHL group this study showed that the ORR 80% (CR 20% + PR 60%) despite short follow-up period and small sample size, this result is within the reported previous studies.[17-19]

In regards to CLL group this study showed that the ORR was 90% (CR 50%+ PR 40%): 2 patients got negative minimal residual disease and one patient got complete remission within 3 month and stop treatment by himself. All 3 patients above were using Benadmustine Rituximab protocol. Despite that, ORR of this study was comparable to that reported by Fischer et al., but result of CR was much better than reported in Fischer study who stated that 88% had ORR and 23% had CR.[20] For those patient who were using Rituximab, Fludarabine, Cyclophosphamide protocol, the result was comparable to that reported by other studies.[21,22] The result of Zytux efficacy in CLL patients was also comparable to that reported by Iranian study in which they use Zytux™ for patient with newly diagnosed CLL with ORR 88% this is may be due to small sample size.

The other objective was to assess the safety Zytux™ in CLL and NHL, following administration of designated protocol. Infusion reactions are the most anticipated adverse reactions associated with rituximab administration, especially during the first cycle of treatment, this study showed that just 4 patient (20%) experienced mild infusion reaction grade 1 and 2 in which all of them completed the dose of Zytux™ after giving steroid and paracetamol. It has been reported that MabThera®infusion reactions may reach up to 77% of patients at early stages of the first cycle of infusion,[23] but in other study it reach up to 35% and because less in subsequent cycles.[24] The difference in reported infusion relate reaction between this study and that in the literature could be due to exact implementation of infusion protocol and close monitoring applied for patient setting. The most occurred reactions in the current study were chills, nausea and hot flashes.

Hematologic adverse reactions induced by chemotherapy regimens are of particular importance as they are directly associated with patient’s quality of life and treatment outcomes. Regarding these facts, the safety profile of biosimilar products concerning hematologic toxicities needs to be closely considered. The results of the current study demonstrated that there were no statistically or clinically meaningful diversity between Zytux™ and MabThera® according to the hematologic toxicities. The hematologic events were in line with literature in terms of frequency and intensity, and none of the events led to therapy discontinuation.

For non-hematologic adverse reactions, this study did not recorded any of these as shown in Table 5 in contrast to many other studies which showed that some patients may got renal or cardiac adverse event.[23] We think that the short follow-up and design of study lead to this result.

The limitations of this study included small sample size and lack of survival information of patients because the complete follow- up still going on.

Conclusions

This study concluded that the early results of use of Zytux™ in NHL and CLL was not inferior to reference drug MabThera® in contrast it was comparable and even better in term of safety and efficacy, and our recommendation is to conduct head to head, multicenter study with larger sample size to confirm these results.