OPDIVO IN THE TREATMENT OF RECURRENT REFRACTORY HODGKIN'S LYMPHOMA ON THE EXAMPLE OF A CLINICAL CASE

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Introduction.
Hodgkin's lymphoma is one of several highly treatable oncological diseases. Over the past 20 years, the possibility of recovery of patients with advanced stages of the disease has reached 70 to 90%.
Despite the successes achieved in the treatment of Hodgkin's lymphoma, relapses occur in 20-40% of cases in patients with generalized stages of the disease (depending on the factors of unfavorable prognosis and treatment) [1].

Before the advent of combined chemotherapy, 95% of patients with advanced stages of Hodgkin's lymphoma died from disease progression within 5 years. And only 50 years ago, the first combination of chemotherapy drugs that showed the likelihood of long-term remission in patients with generalized stages was the MORP scheme (mustargen, oncovine, procarbazine, prednisone). The use of this scheme made it possible to achieve long-term relapse-free survival in almost 50% of patients [2, 3].

Ten years later, G. Bonadonna proposed another combination of chemotherapy drugs — the ABVD scheme (adriblastine, bleomycin, vinblastine, dacarbazine). This scheme demonstrated not only a greater relapse-free survival, but also the best overall survival. It took almost 20 years to recognize this advantage. And at the turn of the XX and XXI centuries, the ABVD scheme was adopted as the "gold standard" for the treatment of patients with Hodgkin's lymphoma. However, the long-term results of treatment of patients with advanced stages of the disease remained worse than the results of treatment of patients with early stages [4].

In 2003, the German GSG group, to improve the results of treatment of such patients, proposed a VEASORR-escalated chemotherapy regimen (bleomycin, etoposide, adriblastine, cyclophosphane, oncovine, prednisolone) with escalating doses of etoposide, adriblastine and cyclophosphane. Long-term results of treatment of patients with this scheme in a large randomized study demonstrated its superiority over the change of cycles of SORP and ABVD.
However, the VEASORR-escalated scheme was organotoxic (hematoxic, cardiotoxic, pulmotoxic, gonadotropically toxic), which affected both the quality of life of the treated patients and its duration [5].

The situation has changed with the introduction into clinical practice (in the USA since 2011, in Europe since 2012) of the drug Brentuximab vetodin. Significant efficacy and acceptable toxicity of the drug determined its inclusion in first-line therapy both in the group of favorable and unfavorable prognosis. The drug has also performed well in the treatment of recurrent Hodgkin's lymphoma [6].

Currently, the development and introduction into clinical practice of drugs blocking immune control points is being extensively carried out, which has changed the standards of treatment of common malignant tumors. These drugs not only demonstrated clinical activity against a wide range of solid tumors, but also had a favorable safety profile. The main advantage of immunotherapy in comparison with other approaches of antitumor therapy is a significant increase in overall survival [7]. The main thing is that drugs of this class do not show a direct effect on tumor cells, but resume the reactivity of the body's own immune system. As a result, the body begins to fight the tumor on its own with the help of the immune system, as with any other foreign cell [8].

Since December 12, 2017, the Ministry of Health of Russia has expanded information for the medical use of Opdivo (nivolumab) in the Russian Federation as monotherapy for recurrent or refractory classical Hodgkin's lymphoma (cLC) after previous autologous stem cell transplantation (autoTSC) and therapy using brentuximab vetodin.
Overexpression of PD-L1 in the tumor is considered one of the main mechanisms of the "withdrawal" of malignant cells from the control of the immune system [9].
Opdivo (Nivolumab) is a human monoclonal IgG4 antibody that blocks the connection between the programmed cell death receptor PD 1 located on the surface of the T-lymphocyte and its ligands (PD-L1 and PD-L2) present on the surface of tumor cells [10, 11]. Thus, Op divo (Nivolumab) potentiates the immune response, which makes it possible to significantly improve the frequency of overall responses, response duration and overall survival.

The purpose of the study: to show the possibilities of oncoimmunotherapy with Op divo (Nivolumab) on a clinical example of the treatment of refractory recurrent Hodgkin's lymphoma in the advanced stage.
Methods: examination and evaluation of the effectiveness of treatment of a patient with refractory recurrent Hodgkin's lymphoma in the advanced stage were carried out by positron emission tomography combined with computed tomography (PET/CT) on a BiographmCT20 scanner with the introduction of the radiopharmaceutical "Fluorodeoxyglucose, 18F" according to the standard protocol from the level of the lower edge of the orbits to the level of the middle third of the thigh. Due to the presence of an allergic reaction to radiopaque drugs in the patient, intravenous contrast enhancement was not performed.

Results.
In the patient X . At the age of 18, in 2015, he turned to an oncologist with complaints of an increase in body temperature to subfebrile figures, an increase in the lymph nodes of the neck. Histological and immunohistochemical studies of the right supraclavicular lymph node obtained by excision biopsy made it possible to diagnose Hodgkin's lymphoma, a mixed-cell variant.

According to the results of PET/CT (July 2015), signs of lymphoproliferative disease with lesions of the lymph nodes of the neck, mediastinal lymph nodes, and the right lung were found. Trepanobiopsy data: no bone marrow lesion was detected. The diagnosis was established: Stage 4 Hodgkin's lymphoma with 81.
4 courses of chemotherapy were performed according to the BEACOPP-14 scheme with a positive complete metabolic response obtained according to the results of PET-CT (September 2015). Taking into account the positive results, 4 more courses of polychemotherapy were carried out according to the previous scheme. Upon completion of 8 courses of polychemotherapy, PET remission was registered (December 2015). To preserve the achieved antitumor effect, Vinblastine monochemotherapy and radiation therapy were performed on foci with incomplete regression in the mediastinum in a total focal dose of 23-24 Gy.

3 months after the end of treatment, according to PET/CT data, the patient had an early relapse of the disease with lesions of the supraclavicular, subsectoral, parasternal lymph node on the left and axillary lymph nodes on the left. 2 courses of high-dose chemotherapy according to the DHAP scheme with a partial positive response were performed, bone marrow autotransplantation (ATCM) was performed. When conducting a control PET/CT in October 2016, a regression pattern of metabolically active left-sided cervical, subclavian, rectopectoral, axillary lymphadenopathy was established, however, the preservation of metabolic activity of mediastinal and parasternal lymph node formation on the left was registered. To consolidate the achieved effect, monoclonal antibody therapy was performed: 6 administration of Brentuximab vetodin with an assessment of the treatment after 3 injections. After that, a complete regression of foci was noted.

In February 2017, according to PET/CT data, a second relapse of the disease was registered with a lesion of the axillary lymph node on the left with a metabolic activity of 4 points according to Deauville, and in May 2017, further progression of the process was recorded in the form of the appearance of tumor tissue with a metabolic activity of 4 points according to Deauville in the right lung and in the structure of the residual masses of the anterior mediastinum, and there are also increases in the axillary lymph nodes on the left with the metabolic activity of tumor tissue in them (5 points according to Deauville). The total metabolic volume of tumor tissue (MTV) was: 132.62 cm3 + 0.15 cm3 + 28.7 cm3=161.47 cm3.

Taking into account the recurrent, refractory nature of the disease, as well as the progression of the process after chemotherapy, radiation therapy, autologous bone marrow transplantation and therapy with Brentuximab vetodin, oncoimmunotherapy with PD-L1 inhibitors was started in June 2017. For 8 months, the patient underwent 12 injections of Op divo (Nivolumab) at a dose of 3 mg / kg of body weight every 2 weeks.

According to PET/CT data (31.10.2017), after 8 injections of Opdivo, a partial positive response was registered (a 30% decrease in the sum of the diameters of the target foci compared to their initial sum) in the form of residual vital tumor tissue in the lymph nodes of the anterior superior mediastinum (4 points according to Deauville), left-sided axillary nodes of the I-III order (4-5 points for Deauville), residual masses in the anterior upper mediastinum (2 points for Deauville). In comparison with the data of the previous study (08/03/2017), a decrease in hyperfixation of fluorodeoxyglucose (FDG) was recorded in the structures of the Waldeyer lymphoid ring, as well as in the left-sided upper jugular lymph nodes and terminal ileum, which is more typical for manifestations of the inflammatory process. The PET/CT picture according to the Deauville criteria corresponded to the stabilization of the disease picture (SMD).

After 12 injections of Opdivo, according to PET / CT data (02/28/2018), stabilization of the tumor process was achieved: vital tumor tissue was preserved in the left-sided axillary nodes of the I-III order (4-5 points according to Deauville), residual masses in the anterior upper mediastinum (2-3 points according to Deauville). The immunotherapy of Op divo was continued up to 15 injections.

The next 3rd relapse of the disease was registered in February 2019: an increase in the left axillary lymph nodes of the I-III order (4-5 points according to Deauville). Continued administration of the drug Op divo. On the control PET/CT from 05.09.2019, data on the presence of vital tumor tissue in the groups of left-sided axillary, subsectoral and subclavian lymph nodes were recorded (5 points according to Deauville); residual conglomerative masses in the anterior superior mediastinum were preserved. After 17 injections of the drug on PET / CT from 03/25/2020g, stabilization of the metabolic picture of the disease (SMD) was already noted (according to the criteria of Lugano): the number of affected left-sided axillary, subsectoral, subclavian lymph nodes with intensive accumulation of FDG has not changed (5 points according to Deauville), but the size of the majority of affected nodes has increased significantly. There were no signs of complications of the treatment available for visualization.

A new 4th relapse of the disease was diagnosed in February 2021. By PET/CT from 01.02.2021, an increase in the size and peak metabolic activity of multiple left-sided axillary lymph nodes was registered; the appearance of increased accumulation of FDG in the residual mediastinal nodes of the prevascular group (5 points according to Deauville). Continued oncoimmunotherapy Fuel. In November 2021, after the 23rd introduction of Op divo on PET /CT (11/16/2021), positive dynamics was recorded in the form of a decrease in the size of left-sided subsectoral, axillary lymph nodes; residual mediastinal nodes of the prevascular group (5 points according to Deauville).

conclusions:
Oncoimmunotherapy with Op divo (Nivolumab), carried out for 4.5 years, allowed the patient with recurrent refractory generalized Hodgkin's lymphoma to achieve stabilization of the process.

 

About the authors

Tatiana Sergeyevna Chernyanskaya

Воронежский Государственный Медицинский Университет им. Н.Н. Бурденко

Email: al.mit4ell@yandex.ru

ординатор кафедры онкологии ФГБОУ ВО «Воронежский Государственный Медицинский Университет им. Н.Н. Бурденко» Минздрава России

Russian Federation, 394036, г. Воронеж, ул. Студенческая, 10

Ivan Petrovich Moshurov

Воронежский Государственный Медицинский Университет им. Н.Н. Бурденко

Email: ipmoshurov@vrngmu.ru

доктор медицинских наук, профессор, профессор кафедры онкологии ФГБОУ ВО «Воронежский Государственный Медицинский Университет им. Н.Н. Бурденко»

Russian Federation, 394036, г. Воронеж, ул. Студенческая, 10

Elena Ustinova

"Voronezh State Medical University named after N.N. Burdenko"

Author for correspondence.
Email: ustinova48@list.ru
ORCID iD: 0000-0002-6893-4657
SPIN-code: 4129-1488

Doctor of Medical Sciences, Professor, Department of Oncology

Russian Federation, Voronezh region, Voronezh, st. Student, house 10

Svetlana Aleksandrovna Stikina

Воронежский Государственный Медицинский Университет им. Н.Н. Бурденко

Email: stikina.pedfak@yandex.ru

кандидат медицинских наук, доцент  кафедры онкологии ФГБОУ ВО «Воронежский Государственный Медицинский Университет им. Н.Н. Бурденко»

Russian Federation, 394036, г. Воронеж, ул. Студенческая, 10

References

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