INTRODUCTION:

Cancer immunotherapy is the aiding of the immune system for treatment of cancers. Two vast strategies are commonly used for cancer immunotherapy: First, the cytotoxic agents that bind immunologically to tumor cells and second, the agents that induce effector immune cells for killing the tumor cells^1-3. Lymphoma is a cancer of the lymphocytes in the lymphoid system that can develop from B lymphocytes, T lymphocytes, or natural killer (NK) cells at various stages of maturity. It is divided into two types: Hodgkins and non-Hodgkins lymphoma (NHL). NHL accounts for over 80% of all lymphomas. B-cells are noted for their functional versatility and ability to convert into a variety of routes^4-6. Due to its functional diversity, it represents a heterogeneous group of diseases varying clinically and pathologically.

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma, accounting for about 25% to 30% of all the non-Hodgkin lymphomas⁷. Diffuse large B-cell lymphoma is the most common haemopoietic malignancy, accounting for 25% of all lymphoid neoplasms⁸. It typically presents as a rapidly growing mass or enlarging lymph nodes in a nodal or extranodal site. The clinical course of diffuse large B-cell lymphoma has greatly changed over the past 10 years. One of the most important fields in modern anti-cancer therapy involves the use of monoclonal antibodies, which selectively and efficiently bind to tumor cells after administration to patients^9-11. Various kinds of monoclonal antibodies (mAbs) have been developed and approved for immunotherapy in malignant diseases. The mAbs are considered as the most important class of anti-cancer agents, so that around 20 mAbs are in current clinical use, and many are being introduced. A pivotal trial done in 1998 showed that combining rituximab with standard cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) chemo therapy significantly improved response, event-free survival^12-13. However, despite these significant improvements, some patients are refractory to initial treatment or can relapse after a complete response. In cases where the disease is refractory to immunochemotherapy, the estimate of progression-free survival at 3 years is only 23%, even with subsequent high-dose chemotherapy and autologous stem-cell trans plantation.

B cell lymphomas are classified according to the stage of B cell development that resulted in malignancy (i.e., mantle cell vs. marginal cell lymphoma). Lymphadenopathy develops as a result of B cell proliferation in or near the germinal centre. Increased cytokine production causes systemic symptoms (B-symptoms). Elevated levels of LDH and uric acid suggest high cell turnover and release of degradation products into the bloodstream. Diffuse large B-cell lymphoma (DLBCL) is a malignancy of B cells, which are lymphocytes that produce antibodies. DLBCL can strike at any age, from puberty to old age. The CD20 antigen is a transmembrane protein that is hypothesised to be involved in B-cell proliferation, activation, differentiation, and signalling. CD20 is found on normal pre-B and B cells. Furthermore, approximately 95% of B-cell NHLs express CD20, making it a logical target in B-cell NHL treatment. CD20 is not found on normal B stem cells or the vast majority of plasmocytes. Rituximab is an anti-CD20 monoclonal antibody and administered intravenously at 375 mg/m² on day one of chemotherapy.

MATERIALS AND METHODS:

Materials:

Between December, 2020, and December, 2022, in accordance with our protocol, we did a phase 3 multicentre randomised trial in 153 haematology patients (DLBCL) in Harayana, Rajasthan, Maharastra, West Bengal, Karnatak, Gujarat, Tamilnadu, Odisha, Delhi. Male or non-pregnant, non-lactating Female ≥18 years and ≤65 years of age (both inclusive) has enrolled in the trail¹⁴. Patients with at least one measurable lesion as per International Working Group Revised Response Criteria for Malignant Lymphoma, Untreated Newly diagnosed patients with a confirmed pathologic diagnosis of CD20+ large B cell-non-Hodgkin’s lymphoma (DLBCL), Stage II-III or IV on basis of Ann Arbor classification, Age-adjusted International Prognostic Index (IPI) score 0 or 1 has screened in the trial⁵. Patients were randomized as per their eligibility for receiving Rituximab and CHOP and having adequate bone marrow, renal, cardiac and hepatic function (ANC ≥ 1500/mm3, Platelet count ≥ 100,000/mm3, Hemoglobin ≥ 9.0g/dL, Serum Creatinine ≤ 1.5 times ULN, Total bilirubin ≤1.5 × upper limit of normal (ULN), Alkaline phosphatase, alanine transaminase, and/or aspartate transaminase ≤3 × ULN or ≤5 × ULN). subjects having Left Ventricular Ejection Fraction (LVEF) ≥50% determined by either ECHO or MUGA Scan were enrolled. Subjects with a performance status of 0 to 2 according to the Eastern Cooperative Oncology Group (ECOG) were enrolled in the trail.

Methods:

Randomisation and masking:

Our trial was an accessor blind trial. After full filling the Screening criteria, the subjects were randomized in the trail as per combining opinion of investigator and medical monitor of the sponsor. Subjects were allotted with randomization number and IMP as per kits provided by the sponsor. As per allotted kit No. subjects were administered with study drug (Test Product/Reference Product).

Procedures:

After successful completion of Screening Period (Visit 1), subjects were administered with study drug in Randomization visit (Visit 2) i.e. cycle 1 of chemotherapy. Then next study drug administration was after 21 days of cycle 1 and next 4 cycles of chemotherapy was proceeded in a duration of 21 days from the previous cycle. In each cycle of day 1, subject was administered with Rituximab (Test or Reference) 375mg/m² in IV over 3 hrs, after that CHOP regimen was administered. Cyclophosphamide 750mg/m2, Doxorubicin 50mg/m2, Vincristine 1.4mg/m2 were administered in IV over 1.5 hrs, 30mins and 15 mins respectively. And subject was advised to take 100mg of Prednisolone PO from day 1 to day 5 of each cycle.

3ml of blood for Pharmacokinetic and Pharmacodynamic and 5ml of blood for immunogenicity assessment were drawn from the subjects as per scheduled protocol (Table 1) provided by the sponsor.

Tumor assessment was done in Visit 1 (Screening Visit), Visit 5 (After completion of Cycle 3 and before starting of Cycle 4) i.e. interim visit and Visit 8 (After completion of Cycle 6) i.e. end of treatment visit. And measurement of lesions were compared from visit to visit whether the disease was progressed, reduced or stable and depending on the condition of the disease and according to investigator’s suggestion, subjects were administered with next cycles.

Table 1: Schedule for Pharmacokinetic, Pharmacodynamic and Immunogenicity Assessments

	Study Visits
Cycle (n)	C1	C2	C3	C4	C5	C6	End of Treatment	FU1	FU2	FU3
Pharmacokinetic of patients enrolled for PK and PD assessment
Pre dose	X	X	X	X	X	X
Mid infusion	X					X
EOI	X					X
2h	X					X
4h	X					X
6h	X					X
24h	X					X
48h	X					X
72h	X					X
168h	X					X
336h	X					X
480h						X
Pharmacodynamic of patients enrolled for PK and PD assessment
Pre-dose	X	X		X			X
Immunogenicity of all patients
Pre-dose	X			X			X	X	X	X

Figure 1: Schematic Diagram of Study Design

For each drug we calculated dose intensity as observed dose intensity divided by planned dose intensity. We calculated observed dose intensity by dividing the observed total dose received during the first four cycles by the observed period between the first and fourth cycles. The total planned cumulative dosage received during the first four cycles was divided by the theoretical time elapsed between the first and fourth cycles to calculate planned dose intensity.

Table 2: Baseline Characteristics: (Data are n (%) unless otherwise stated. R-CHOP=Rituximab, Cyclophosphamide Hydrochloride, Vincristine (Oncovin) Prednisolone. ECOG=Eastern Co-operative Oncology Group.) “Some included patients had an Age Adjusted International Prognostic Index other than 1 at data review”

Parameters	R-CHOP (Test) (n=81)	R-CHOP (Reference) (n=71)
Sex
Male	46 (56%)	57 (80%)
Female	36 (44%)	14 (20%)
ECOG Performance status
0-1	82 (100%)	71 (100%)
2-4	0 (0%)	0 (0%)
B Symptoms
Yes	39 (48%)	43 (61%)
No	43 (52%)	28 (39%)
Ann Arbor Stage
I-II	25 (30%)	38 (54%)
III-IV	57 (70%)	33 (46%)
Largest mass diameter >10 cm
No	37 (45%)	49 (69%)
Yes	45 (55%)	22 (31%)
Number of extra nodal sites
0-1	28 (34%)	32 (45%)
>1	54 (66%)	39 (55%)
Bone Marrow Involvement
No	26 (32%)	45 (63%)
Yes	56 (68%)	26 (37%)
Not assessed	0 (0%)	0 (0%)
Age-adjusted international prognostic index
0	34 (41%)	28 (39%)
1	48 (59%)	43 (61%)
2	0 (0%)	0 (0%)

Table 3: Analysis of endpoints in the intension-to-treat population: (Data are n (%) unless otherwise stated. R-CHOP=Rituximab, Cyclophosphamide Hydrochloride, Vincristine (Oncovin) Prednisolone. Deaths from lymphoma progression or related to treatment of relapse or progression)

	R-CHOP (Test Group)	R-CHOP (Reference Group)
Events for Event free survival	3 (4%)	4 (6%)
Unplanned treatment for lymphoma	1 (1%)	2 (3%)
Unplanned Chemotherapy	2 (2%)	2 (3%)
Unplanned Radiotherapy	2 (2%)	3 (4%)
Progression or relapse	1 (1%)	2 (3%)
Death	0 (0%)	0 (0%)
Events for Progression free survival	51 (62%)	48 (68%)
Progression or relapse	0 (0%)	0 (0%)
Death	0 (0%)	0 (0%)

Our analyses of efficacy and safety were of the intention to-treat population. One patient who withdrew consent before any procedure was excluded from this population. All p values are two-sided. Statistical analyses were done with SAS 9.1.3 software by the investigators of the Cadila Healthcare Ltd. statistical office.

Role of the funding source:

Cadila Healthcare Ltd, was involved in the random assignment procedure, distribution and collection of case report forms, data entry and validation, coordination of monitoring procedures, elaboration and mailing of queries, reporting of serious adverse events, coordination of histological review, relation with investigators, transmission of enrolment status to the sponsor, statistical analysis, and production of the report.

RESULT:

Figure 2 shows the trial profile. We enrolled 153 patients into our trial, who received at least one dose of protocol-planned treatment. The main characteristics of our patients were similar in the two groups. The main criteria providing an age-adjusted International Prognostic Index score of 1 and Ann Arbor stage III–IV in 44% and 55% of patients, respectively. 62 patients had an age-adjusted International Prognostic Index score other than 1 (table 2). A central pathological review was performed on 133 patients (87%), all of whom had diffuse large B-cell lymphoma.19 patients did not complete either treatment regimen (figure 2). 81 patients (53%) in the R-CHOP (Test group) received the first four cycles of the planned treatment and 71(47%) in the R-CHOP (Reference group). The interval between these cycles was 21 days for both treatment groups.

Fewer events were recorded in both the groups (Table 3). Event-free survival was significantly longer for patients treated with R-CHOP (Test group) than for those treated with R-CHOP (Treatment group) (p=0·4488), with 2-year estimates of 81% (95% CI 75–86) for R-CHOP (Test group) and 67% (59–73) for R-CHOP (Reference group). In this cohort, the HR of the CHOP (Test group) for incident-free survival demonstrates that this regimen lowered the chance of experiencing an event by 15% compared to R-CHOP (Reference group). The R-CHOP (Test group) had considerably longer progression-free survival, with a 2-year progression-free survival of 87% (81-91) with R-CHOP (Test group) and 73% (66-79) with R-CHOP (Reference group). The overall response rate was 70% in the R-CHOP (Test group) and 62% in the R-CHOP (Treatment group). A complete response or unconfirmed complete response was achieved in 58 patients (72%) in the R-CHOP (Test group) and 42 (59%) in the R-CHOP (Reference group). In complete responders, the disease-free survival was significantly longer in the R-CHOP (Test group), with a 2-year estimate as compared with the R-CHOP (Reference Group). 1 patient in the R-CHOP (Test group) and 2 in the R-CHOP (Reference group) experienced a relapse. There was no CNS relapse in the both the groups. There were no deaths in both the groups. Overall survival differed significantly, with a 2-year estimate of both the groups.

As per-protocol studies of patients who met all eligibility criteria, had histologically confirmed diffuse large B-cell lymphoma, and underwent at least four cycles of the assigned treatment (81 patients in the R-CHOP (Test group) and 71 patients in the R-CHOP (Reference Group)).

Table 4: Response to treatment by study drug: (Data are n (%) unless otherwise stated. R-CHOP=Rituximab, Cyclophosphamide Hydrochloride, Vincristine (Oncovin) Prednisolone. Response to treatment was assessed in accordance with the international workshop 1999 criteria.)

	R-CHOP (Test) (n=81)	R-CHOP (Reference) (n=71)
Complete Response	58 (72%)	42 (59%)
Unconfirmed Complete Response	11 (14%)	13 (18%)
Partial Response	07 (9%)	09 (13%)
Stable Disease	02 (2%)	03 (4%)
Progressive Disease	03 (4%)	04 (6%)
Death	00 (0%)	00 (0%)
Not Assessed	00 (0%)	00 (0%)

Table 5: Toxic Effect by Treatment Group: (Date are number and proportion of patients with an event in at least one cycle).

	R-CHOP (Test) (n=81)	R-CHOP (Reference) (n=71)
Weakness	54 (66%)	64 (90%)
Hair Fall	66 (80%)	61 (86%)
Swelling in lower limbs	43 (52%)	46 (65%)
Fever	76 (92%)	68 (96%)
Nausea and Vomiting	75 (91%)	66 (93%)
Tingling Effect	42 (51%)	48 (68%)
Neutropenia	47 (58%)	49 (69%)
Anaemia	36 (44%)	34 (47%)
Thrombocytopenia	51 (62%)	48 (67%)

The presence of a bulky mass was the only factor identified as unfavourable for overall survival but not for progression-free survival. 2-year progression-free survival of patients with bulky disease was 77% in the R-CHOP (Test group) and 73% in the R-CHOP group (Reference Group).

The most common adverse events were haematological toxic effects in both groups (Table 5). Patients taking R-CHOP (Reference group) showed greater rates of anaemia, thrombocytopenia, and neutropenia, all of which were grade 0 or 1 (Test Group). Recorded infections during neutropenic periods were also more common in the both the groups.

DISCUSSION:

After more than 2 years of follow-up, all our study endpoints were met, with significant improvements of event-free, progression-free, disease-free, and overall survival in patients treated with R-CHOP (Test group).

The introduction of rituximab in association with CHOP chemotherapy has substantially improved the outcome of patients with diffuse large B-cell lymphoma. In recent years, several phase 2 trials have shown promising results regarding the association of intensive chemotherapy and rituximab^16–19. Most of these regimens were proposed for patients with high-risk disease and contained an intensive chemotherapy schedule with stem-cell support^16–18.

R-CHOP has been used in India to treat patients with aggressive lymphoma for the past 30 four cycles with higher doxorubicin and cyclophosphamide doses, given at a shortened interval. Patients are given a sequential consolidation treatment using medicines that were not used during induction during the second phase. In trials comparing patients with localised diffuse large B-cell lymphoma and individuals with more advanced illness, rituximab in conjunction with CHOP beats CHOP regimen^18-19. The association of rituximab with CHOP in patients younger than 65 years with an age adjusted International Prognostic Index score of 1, as in our trial, seems to improve progression-free survival from 65% at 2 years to 70%²⁰.

The lower rate of disease progression during the treatment phase and fewer relapses in patients who reached a complete response accounted for the prolonged progression-free survival and overall survival in our R-CHOP (Test group). A trial is ongoing that aims to assess the quality of remission after R-CHOP by comparing CT/PET CT after two and four induction cycles²¹. The role of consolidation is probably important. High-dose methotrexate plus calcium folinate rescue is associated with a low risk of CNS relapse in diffuse large B-cell lymphoma Pegfilgrastime, Acyclovir, Multi Vitamins were prescribed as the concomitant medications, after receiving the study drug^{17, 22}.

Outcome data in our patients treated with standard R-CHOP (Test Group) are consistent with our initial hypothesis (panel), but the 2-year event-free survival 72% seems to be in the higher range of the equivalent population of the MabThera International Trial:5 74% (66–84) for bulk disease or 76% (67–86) for no bulk disease¹². In the Mab Thera International Trial, various chemotherapy regimens plus rituximab did not produce major differences in outcome. However, none of the patients treated with the rituximab received radiotherapy.

The profile of toxic effects for the both the groups is well characterised. Because the induction phase is associated with notable haematological toxic effects, the regimen is exclusively utilised in patients under the age of 65¹⁹. Most patients experience substantial neutropenia between day 9 and day 13 of each cycle, with a substantial proportion having a febrile episode despite the use of growth factor. However, our trial and previous ones involving the R-CHOP regimen have shown that life threatening complications related to treatment are uncommon in a population of patients younger than 65 years with good performance status²³. The care of many patients included in our trial has been managed in the Haemato-oncology departments of community hospitals, Govt. and private multispeciality hospitals of the 34 participating centres all over India. Although R-CHOP is an intensified regimen, the total dose of doxorubicin and cyclophosphamide given is less than the dose received during six cycles of CHOP.

In the context of chemotherapy, interactions between the microenvironment and cancer cells, especially lymphoma cells, are complex²⁴. There is some evidence that antibody-dependent cellular cytotoxicity mediated by activation of natural-killer cells contributes to the clinical response to rituximab²⁵. According to researchers, intensive chemotherapy may reduce the efficiency of rituximab by affecting immune cells mechanisms. However, the results of our study do not favour such a hypothesis.

Modifications to immunochemotherapy regimens are still worthwhile and are now being evaluated. We found no evidence in our sample population to suggest that one patient group would benefit more from treatment than another. The favourable results obtained with R-CHOP (Test group) front-line regimen should be further assessed in view of the biological heterogeneity of diffuse large B-cell lymphoma, to assess whether some patients with specific subtypes are more to likely to benefit from this intensive therapy, as it has been suggested R-CHOP might be sufficient for others rather than other therapies²⁶. The option of reducing the strength of immunochemotherapy could also be investigated in selected patients who exhibit a quick response to treatment as measured by interim PET/CT.

CONTRIBUTORS:

Cadila Healthcare designed the study. The below mentioned sites collected data. Investigators were responsible for the histological review. Cadila Healthcare analysed and interpreted the data and wrote the report. All authors had full access to the final version of the report and agreed to the submission.

TRIAL INVESTIGATORS:

Dr Lovenish Goyal (Aadhar health institute, Harayana), Dr Tara Chand Gupta (Apex Hospital Private Limited, Rajasthan), Dr Nirmal Raut (Bhakti Vedanta Hospital & Research Institute, Maharastra), Dr Kalyan Kusum Mukherjee (Chittaranjan National cancer Institute, West Bengal), Dr Biju George (Christian Medical College, Tamilnadu), Dr Mukesh Choudhary (Global Abhishek Cancer Hospital & Research Centre, Rajasthan), Dr Sateesh CT (Global Enterprise, Karnatak), Dr Tushar Patil (Global Hospital & Research Institute, Maharastra), Dr Sushil Meshram (Government Medical College and Hospital, Maharastra), Dr Minish Jain (Grant Medical Foundation Ruby Hall Clinic, Maharastra), Dr Arun Seshachalan (GVN Cancer Institute (A Unit of GVN Hospital), Tamilnadu), Dr Ashish Kaushal (HCG Cancer Centre, Ahmedabad), Dr Mahato Pinaki Sasadha (HCG Cancer Centre, Gujarat), Dr Rajnish Nagarkar (HCG Manavata Cancer Centre, Maharastra), Dr Priyanka Samal (Institute of Medical sciences(IMS) ) and SUM Hospital Department of Medical Oncology, Odisha), Dr Niraj Bhatt (Kailash Cancer Hospital and Research Center, Gujarat), Dr Prakash SS (KR Hospital Mysore Medical College & Research Center, Karnatak), Dr Sachin Hingmire (Lata Mangeshkar medical foundation’s, Deenanath Mangeshkar Hospital and Research Center, Maharastra), Dr Kishore Singh (Maulana Azad Medical College, Delhi), Dr Kasi Viswanathan Thiagarajan (Meenakshi Mission Hospital and Research Centre, Tamilnadu), Dr Bhushan Nemade (Navsanjeevani Hospital, Maharastra), Dr Bodhisatta Roy (Netaji Subhash Chandra Bose cancer Hospital, West Bengal), Dr Tuphan Kanti Dolai (Nil Ratan Sircar Medical College and Hospital, West Bengal), Dr Ravikumar Watengaonkar (Orange Hospital, Maharastra), Dr Narendra Agrawal (Rajiv Gandhi cancer institute and research centre, Delhi), Dr Vikas Goyal (Sanjeevani CBCC Cancer Hospital, Chhattisgarh), Dr Sampath Kumar MN (Sapthagiri Institute of Medical Sciences & Research Centre, Karnatak), Dr Kartikeya Jain (Shree Himalaya Cancer Hospital & Research Institute, Gujarat), Dr Ghanshyam Biswas (Sparsh Hospital and Critical care Private Limited, Odisha), Dr KC Lakshmaiah (Srinivasam Cancer Care Multispecialty Hospitals India Pvt Ltd., Karnatak), Dr. Deepan Rajamnickam (Thangam Hospital and Thangam Cancer Center, Tamilnadu), Dr Ankit Patel (Unique Hospital & Multispeciality & Research Institute, Gujarat), Dr P Vijay Veeran (Universal Cancer Hospital, Tamilnadu), Dr Amit Jain (Valentis Cancer Hospital, Meerut).

CONCLUSION:

Functionalization of MWCNT was performed successfully to assess toxicity taking into consideration various parameters known to quantify functionalization and toxicity. It was observed that the functionalization of MWCNT reduced material toxicity. Additionally, it can be concluded that MWCNT after functionalization is safe, potential drug carrier in inhalation drug delivery and enhance regional lung deposition with better flow properties. The formulation of cefdinir loaded FMWCNTs DPI for drug delivery is useful to reduce the dose of the drug and synergistically enhance the activity against gram-positive and gram-negative bacteria due to site-specific delivery with increased bioavailability.

CONFLICT OF INTEREST:

The authors declare that, they have no conflict of interest.

ACKNOWLEDGMENTS:

We would like to convey my deepest gratitude to CRO Pharmatrendz Pvt. Ltd. for providing required facilities with enthusiastic environment to complete the novel research work and also thank to School of Pharmacy, ARKA JAIN University, Jharkhand.

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Received on 07.01.2023 Modified on 12.06.2023

Asian J. Res. Pharm. Sci. 2024; 14(3):203-210.

DOI: 10.52711/2231-5659.2024.00033