wjpls, 2022, Vol. 8, Issue 4, 32 – 37.

Research Article ISSN 2454-2229

Nakhli et al. World Journal

World Journal of Pharmaceutical of Pharmaceutical
and Life Sciences and Life Science
WJPLS
www.wjpls.org SJIF Impact Factor: 6.129

CHRONIC LYMPHOPROLIFERATIVE SYNDROMES: A STUDY OF 99 CASES

*Dr. Raja Nakhli, Ghita Elghouat, Hicham Yahyaoui and Mohamed Chakour

Laboratory of Haematology of Avicenna Military Hospital, Marrakech Faculty of Medicine, University Cadi Ayyad,
Marrakech.

Corresponding Author: Dr. Raja Nakhli

Laboratory of Haematology of Avicenna Military Hospital, Marrakech Faculty of Medicine, University Cadi Ayyad, Marrakech.

Article Received on 12/02/2022 Article Revised on 02/03/2022 Article Accepted on 22/03/2022

ABSTRACT
Introduction: Chronic lymphoproliferative disorders (CLPD) are an heterogeneous group of diseases
characterized by uncontroled production of lymphocytes that cause clonal lymphocytosis, lymphadenopathy, and
bone marrow infiltration. Methods: A retrospective analysis (2014 to 2020) was carried out on the basis of 99
patients with lymphoproliferative disorders in the Laboratory of hematology of the Avicenne military hospital in
Marrakech to describe the epidemiological, clinical, cytological characteristics of lymphoproliferative disorders.
Results: Among 99 registered cases, there were 62 cases of multiple myeloma (MM) (62,62 %), 32 cases of
chronic lymphoid leukemia (CLL) (32,3%), 3 cases of Sézary syndrome (SS) (3 %), a single case of Hairy Cells
Leukemia (HCL) (1%) and a single case of prolymphocytic leukemia(LPB) (1%) were described. The median age
of the patients was 61 (range: 41 to 80) years. There were 76 males (76%) and 23 females (24%), Male-to-female
sex ratio was 3. Myelomas are the most frequently encountered in our series,bone pain is present in 78% of
multiple myeloma patients, 6% have vertebral compression and 7% present chronic renal failure. Monoclonal
gammopathy with kappa-type IgG is found in 60% of cases, IgG lambda in 26% of cases, IgA kappa in 5% of
cases, IgM kappa in 4% of cases, and kappa light chains in 5% of cases.We found 32 cases of CLL, the average
age is 65 years with extremes ranging from 45 to 78 years with a sex ratio of 5. Peripheral lymphadenopathy is the
most frequent revealing symptom of the disease in 31 cases (50%) associated with splenomegaly in 2 cases, 45 %
of cases were clinically asymptomatic. Conclusions: This retrospective study provides a clinical, epidemiological
and cytological description of lymphoproliferative disorders in 101 cases

KEYWORDS: Lymphoproliferative syndromes - chronic lymphoid leukemia-multiple myeloma.

INTRODUCTION The objective of our work is determining the

epidemiological aspects, the clinical signs of discovery
Chronic lymphoproliferative disorders represent a
and the various cytological characteristics of the chronic
relatively heterogeneous group of malignant blood
lymphoproliferative syndromes.
diseases affecting mature cells of B and T lymphoid
lineages.[1]
MATERIALS AND METHODS
They should be classified according to the revised It is a descriptive and analytic study of 99 patients with
2016 WHO classification. The diagnostic is based on a lymphocytosis confirmed by morphological examination,
multidisciplinary approach taking into account clinical greater than or equal to 5 G / L, chronic (value stable for
presentation, cytological, histopathological, more than three months), between January 2014 and
immunophenotypical and cytogenetic. December 2020 in The laboratory of hematology of the
Avicenne military hospital in Marrakech.
There is a significant heterogeneity of clinical
presentation and prognosis between the different chronic Inclusion criteria
lymphoprliferative disorders, clinical evolution is The inclusion criteria consisted of a diagnosis of multiple
characterized by relapses, cytological progression and myeloma, chronic lymphoid leukemia, Sezary syndrome,
transformation into diffuse large B cell lymphoma, Hairy Cells Leukemia and prolymphocytic leukemia.
aggressive lymphoma or high-grade lymphomas. These Diagnosis is made by clinical orientation, hemogram
blood diseases each have specific clinical and biological result and the morphological study of cells on blood
features. smears and myelogram, Electrophoresis of serum

www.wjpls.org │ Vol 8, Issue 4, 2022. │ ISO 9001:2015 Certified Journal │ 32

Nakhli et al. World Journal of Pharmaceutical and Life Science

proteins, Serum protein immune-fixation and In this series, the prevalence of myeloma is 62, 6%,
radiological signs. against 32,3% of chronic lymphocytic leukaemia , 3% of
Sezary syndrome, and prolymphocytic and hairy cell
Exclusion criteria leukemia are ranked last with 1% each (Figure 1).
Hyper lymphocytosis due to viral infections and chronic
polyclonal hyperlymphocytosis were excluded from the
present study.

RESULTS
Of the 99 registered cases, the median age of the patients
is 61 years (41 to 80 years). There is 76 males (76%) and
23 females (24%) Male-to-female sex ratio is 3.

Figure 1: Distribution of chronic lymphoproliferative syndromes by type.

Myelomas are the most frequently encountered in our Among 62 myelomas, 78% have bone pain, 6% vertebral
series. The average age is 55 with extremes of 41 to 80 compression and 7% have chronic renal failure. The
years. The sex ratio is 2.5. sedimentation rate is less than 30 mm at the first hour in
35% of patients, between 30 and 100 mm in 60% and
very accelerated exceeding 100 mm in 5%. (Table I)

Table I: Clinical signs of Multiple Myeloma diagnosis.

Circumstances of discovery Number of patients Percentage
Bone pain 48 78 %
VS between 100 and 130 at 1st hour 3 5%
Incidental discovery of a monoclonal peak in EPP 3 4%
Vertebral settlement 4 6%
Chronic Renal Insufficiency 4 7%

Monoclonal gammopathy with kappa-type IgG is found Peripheral lymphadenopathy was the most frequent
in 60% of cases, IgG lambda in 26% of cases, IgA kappa discovery, revealing the disease in 16 cases (50%). They
in 5% of cases, IgM kappa in 4% of cases and kappa were associated with splenomegaly in 2 cases (5%). the
light chains in 5% of cases. rest were clinically asymptomatic (45%) (Figure 2).

The diagnosis of myeloma is confirmed by the bone

marrow smear, which showed between 10 and 98% of
dystrophic plasma cells (central-core plasma cells,
multinucleated cells, flamed cytoplasm, Mott cells). A
rare case of association of myeloma with megaloblastosis
is reported in this series.

After myeloma, chronic lymphocytic leukaemia comes in

second place. The average age of patients is 65 years
with extremes of 45 and 78 years. The sex ratio is 5.

www.wjpls.org │ Vol 8, Issue 4, 2022. │ ISO 9001:2015 Certified Journal │ 33

Nakhli et al. World Journal of Pharmaceutical and Life Science

Figure 2: Circumstances of discovery of the LLC.

The diagnosis of CLL is made by a complete blood count dl in 19 cases (54,5%), a platelet count between 70 and
that showed a hyperlymphocytosis of variable 130 G / l in 1 case (3%), and an association between an
importance, always greater than 5G / l. anemia and thrombocytopenia in 12 cases ( 34,5%).
(Table II)
The other lines were also affected in 32 patients (91%),
with a hemoglobin level varying between 8 and 11.5 g /

Table II: Distribution of anemia and thrombocytopenia in patients with CLL.

Anemia and thrombocytopenia Number of cases Percentage
Isolated anemia 19 54,5 %
Anemia+Thrombocytopenia 12 34,5 %
Thrombocytopenia 1 3%
No anemia or thrombocytopenia 3 9%

The myelogram carried out in 8 patients, shows a hyperleukocytosis at 200 G / L. The lymphoid cells on
lymphocyte infiltration of 30% to 91%, the other lines the blood smear are large with a dense chromatin
are quantitatively diminished. The lymphoid cells rounded nucleus and a prominent nucleolus. The
observed on blood smear and bone marrow smear had a percentage of these cells is 75%.
small size with normal morphology , with a nucleus
surrounded by a regular border of cytoplasm but little The prevalence of hairy cell leukemia is 1%. We
extended and weakly basophilic without granulations. reported a case of a patient with hepatosplenomegaly, a
hemorrhagic syndrome due to deep thrombocytopenia at
In our series, Sezary syndrome has a prevalence of 3% of 40 G / L, an infectious syndrome and normochromic
total chronic lymphoproliferative syndromes. The skin normocytic anemia. The successive haemograms of this
lesions are the most frequent sign, 2 of the 3 patients patient showed pancytopenia with 3% of hairy cells, the
present desquamating erythroderma with bone marrow smear showed poor material with 5% of
polyadenopathy, the other patient have parapsoriasiform hairy cells. The diagnosis is based on the morphological
lesions. Sezary cells represent 5 to 50% of the total identification of hairy cells, Flow Cytometry data
lymphocytes, which corresponds to 0.5-35 G / L in showed a combination of the three markers CD11c,
absolute numbers these atypical lymphocytes are of CD25 and CD103
variable size, mature, the nucleocytoplasmic ratio is high
with a nucleus hyperconvolute or "cerebriform" DISCUSSION
characteristic and a scanty cytoplasm, discreetly
Chronic lymphoproliferative syndromes(CLPD)represent
basophilic and without granulationsof the cases recorded,
a heterogeneous set of malignant hemopathies more
60% have normochromic normocytic anemia.
frequently encountered in the elderly, with an incidence
that increases with age.[2] The diagnosis requires a
A single case of prolymphocytic leukemia B is reported,
multidisciplinary approach including both clinical,
the patient presented a splenomegaly without peripheral
histological, immunophenotypic and cytogenic aspects.[2]
lymphadenopathy, anemia, thrombocytopenia and

www.wjpls.org │ Vol 8, Issue 4, 2022. │ ISO 9001:2015 Certified Journal │ 34

Nakhli et al. World Journal of Pharmaceutical and Life Science

There is a significant heterogeneity of clinical the average prevalence of light chain myeloma in our
presentation and prognosis between the different hospital.[10]
(CLPD).
The Salmon and Durie classification is the gold standard
Multiple myeloma for prognostic evaluation. Stage III is the most frequent
According to the American Cancer Society, there are in most series (50 to 96.5%).[11,12] Our results are
approximately 12,000 new cases of MM and about 9,000 consistent with the data in the literature (82%).
MM-related deaths each year in the United States (10%
of malignant hemopathy).[4] The diagnosis is based on Chronic lymphocytic leukemia (CLL)
the presence of ≥10% clonal bone marrow plasma cells Chronic lymphocytic leukemia (CLL) is the most
or a biopsy proven plasmacytoma associated to one or common of the Chronic lymphoproliferative syndromes,
more CRAB criteria (renal failure, hypercalcemia, lytic it is considered as an indolent disease, common in adults
bone lesions and anemia). The main manifestations of and accounts for 12% of all hematological diseases,[13]
myeloma result from the accumulation of malignant 6% in Japan, 1.5% in Korea.[14] The crudeincidence rate
plasma cells in the bone marrow, which leads to the per 100,000 individuals is 0.11in Korea.
production and secretion of a monoclonal protein in the
blood and/or urine, bone lesions, bone marrow failure Patients are initially asymptomatic and symptoms appear
with anemia and/or leukopenia and thrombocytopenia, as the disease progresses, a third of patients will never
immunosuppression with inhibition of normal need to be treated with a treatment, a third is
immunoglobulin production and increased susceptibility symptomatic and requires treatment, the last third will be
to infection. processed during the follow-up, it is recognized by its
clinical but also prognostic heterogeneity. The etiologies
In this series, the prevalence of myeloma is 62,6%. This are not well known.[15] CLL is defined by the presence
alteration of the general condition was often due to the and accumulation of small mature lymphocytosis in the
delay in consultation and mainly concerned the elderly. bone marrow, blood and lymphoid organs, more than 5
Bone manifestations (pain, pathological fractures) G/L clonal cells, lasting more than three months, with
frequently dominate the clinical picture. monotypic proliferation. CLL cells are small
lymphocytes with dense chromatin, a nucleus that
The frequency of osteoarticular manifestations is virtually fills the cell with no nucleoli.[16] The diagnosis
variable from one series to another, but they are almost of CLL is confirmed by the study of lymphocyte
constant (65-90%). In our study, bone pain was the main membrane markers and a Matutes score greater than or
revealing sign of the pathology (47 patients (78%), equal to 4 when examined by immunophenotyping, a
which concurs with the other series: Makni,[3] Bouataya score strictly inferior to 3 points towards another
and al.[4] Renal failure is found with a frequency of 7% in lymphoproliferative B syndrome.[17] The median age at
our series. Frequencies of (22% and 31%) were found in diagnosis ranges from 70 to 72 years.[18,19] The average
two large series of Blade and al,[5] and Hippe and al.[6] age in our series is 55 years old withextremes ranging
from 45 to 78 years which is in line with the results of
For the 3 cases with a peak at electrophoresis, it is most international series, in the Young-Woo series the median
often of type γ, regarding the isotypic distribution, the age is 59 with extremes from 60 to 80 years old. In the
IgG type is predominant. The prominent place occupied Young-Woo series the median age is 59 with extremes
by IgG in our series is also found in major international from 60 to 80 years old.[17] Patients at diagnosis are often
series where their proportion varies from 48 to 65%. In asymptomatic.[20] Two characteristics stand out in the
our series IgA ranks second with 5% of cases. This result study of our series, the sex ratio raised to 5 (1.5 to 2 in
is found in the Tunisian series of Mseddiet al.[7] and in Europe) (1 to 1.4 in korea).[17] and the late discovery of
the Spanish series of Giraldo et al.[8] where IgA accounts the disease at the stage of ganglionic and splenic
for more than 18% of cases. invasion in more than 90% of patients.[21]

While in most international series, IgM ranks second Patients have a good performance status at diagnosis.
with more than 20 to 33% of monoclonal gammopathies. Lymphadenopathy (cervical and axillary lymph nodes
These differences may in part be explained by the higher bilaterally and symetrical)may be observed in
prevalence of Waldenström disease in Western Europe approximately 80% of cases, in our series, Peripheral
compared to the Mediterranean basin. Other genetic and lymphadenopathy was the most frequent discovery
environmental factors that are not yet well known would revealing disease in 31 cases (50%), They were
be involved.[9] associated with splenomegaly in 2 cases (5%). the rest
were clinically asymptomatic (45%).
The second particularity of our series is the frequency of
light chain gammapathies which represent 5%. In Anemia and thrombocytopenia are observed in 15-30%
international series, the frequency of this type of of patients with CLL.[22] In our case we foundan
gammopathy varies from 2.7 to 14.13%, which shows hemoglobin level varying between 8 and 11.5 g / dl in 19
cases (54,5%), and a platelet count between 70 and 130

www.wjpls.org │ Vol 8, Issue 4, 2022. │ ISO 9001:2015 Certified Journal │ 35

Nakhli et al. World Journal of Pharmaceutical and Life Science

G / l in 1 cases (3%). Some patients may also have a CONCLUSION

small serum monoclonal protein. Although in rare cases
Chronic lymphoproliferative disorders represent a
patients may not have lymphocytosis at diagnosis,
relatively heterogeneous group of malignant blood
peripheral blood and bone marrow are usually involved
diseases affecting mature cells of B and T lymphoid
as the disease progresses.[22]
lineages.
Although some CLL cases may have an atypical
The diagnosis is guided by the clinic, the data of the
immunophenotype, the characteristic profile includes
blood count and blood count formula. And the
CD19/CD5/CD23/CD43/CD200 positivity with weak
examination of blood smears as a first step, which will
CD20 and CD11c positivity and dim surface
eventually be completed by Immunophenotyping of
immunoglobulin expression with restricted light chain
tumor cells, and histological study.
expression.[22]
The management of Chronic lymphoproliferative
Sezary syndrome
disorders needs the collaboration between the
Sezary syndrome comes third in our series. It is
hematologist and the biologist to assure an early
considered by authors as the leukemic variant of mycosis
diagnosis and a good prognosis.
fungoides (MF), but it is classified separately according
to the new WHO classification among cutaneous
REFERENCES
lymphomas,it is a cutaneous T-cell epidermotrophic
lymphoma.[25] Men are more affected than women 1. Vardiman JW, Thiele J, Arber DA, Brunning RD,
(incidence rate ratio: 1.6).[23] The incidence of this Borowitz MJ, Porwit A, Harris NL, Le Beau MM,
disease increases with age with the highest incidence at Hellström-Lindberg E, Tefferi A, Bloomfield CD.
greater than 70 years of age.[24] Due to its rarity and The 2008 revision of the World Health Organization
requirement for careful clinicopathological correlation, (WHO) classification of myeloid neoplasms and
diagnosis of Cutaneous T-cell lymphomas is frequently acute leukemia: rationale and important changes.
challenging and may be delayed. It may resemble benign Blood, 2009 Jul 30; 114(5): 937-51.
inflammatory dermatoses, and the histological features of 2. Daniel A, Attilio O, Robert H, J Thiele , M J
FM may be absent at the onset of the disease, even after Borowitz, The 2016 revision to the World Health
several biopsies. Patient with Sezary syndrome typically Organization classification of myeloid neoplasms
present erythroderma, it is a diffuse erythemaaffecting and acute leukemia,Blood, 2016 May 19; 127(20):
80% of the body surface area.[26,27] 2391-405.
3. Makni S, Zouari R, Barbouch MR, Ayed K, Moalla
In our series, Sézary syndrome has a prevalence of 3% of M, Zakraoui L. Gammapathies monoclonales en
total diagnosed Chronic lymphoproliferative syndromes. Tunisie. Rev Fr Transfus Hem, 1990; 33: 31-8.
There is a clear male predominance a result comparable 4. Bouatay A, et al. Myélome multiple : aspect
to the data in the literature.[28] The average age of clinique, diagnostic biologique et pronostic.
diagnosed cases is 47 years old, in the series of Zinzani ImmunolBiolSpec, 2012. j.immbio.2012.09.001.
et al the average age is between 55 and 60 years old.[29] 5. Blade J, Fernandez-Lama P, Bosch F, Montoliu J,
With an apparent higher incidence in Africans and Lens XM, Mon-toto S, et al. Renal failure in
African-Americans.[30] According to Lutzner et al.[31] multiple myeloma: presenting features and
mycosis fungoides cells vary greatly in size. At times, predictors of outcome in 94 patients from a single
they are small and indistinguishable from small institution. Arch Intern Med, 1998; 158: 1889—93.
lymphocytes.[31] 6. The Nordic Myeloma Study GroupKnudsen LM,
Hippe E, Hjorth M, Holmberg E, Westin J. Renal
Hairy cell leukemia function in newly diagnosed multiple myeloma:
Hairy cell leukemia (HCL) is recognized as an entity by ademographic study of 1353 patients. Eur J
the World Health Organization (WHO 2008).[32] And the Haematol, 1994; 53: 207—12.
2016 revision of the WHO classification of lymphoid 7. Mseddi-Hdiji S, Haddouk S, BenAyed M, et al.
neoplasms.[33] HCL is more frequent in men than women, Gammapathies monoclonales en Tunisie: analyse
the splenomegaly present in 72% of cases is truly épidémiologique, immunochimique et étiologique
voluminous in only 18% of cases; moderate d’une série de 288 cas. PatholBiol, 2005; 53: 19–25.
hepatomegaly is noted in 20% of cases; the signs of 8. Hurez D. Épidémiologie des gammapathies
pancytopenia as initial symptoms are unequally monoclonales. Rev Prat (Paris), 1993; 43: 271–4.
distributed: the infectious manifestations are observed in 9. Kyle RA. Monoclonal gammapathy of undertemined
29 to 30% of cases, the anemic syndrome is noted in 27 significance and sonoldering multiple myeloma. Eur
to 28% of cases, hemorrhagic signs are indicative of the J Haematol, 1989; 43: 70–5.
disease only in 4% of cases.[33] 10. Ong F, Hermans J, Noordijk EM, et al. A
population- based registry onparaportéinaemia in the
netherlands. Br J Haematology, 1997; 99: 914–20.

www.wjpls.org │ Vol 8, Issue 4, 2022. │ ISO 9001:2015 Certified Journal │ 36

Nakhli et al. World Journal of Pharmaceutical and Life Science

11. El Mezouar I. Myelome multiple a propos de 58 cas. variants. Am J Dermatopathol, 2014; 36(12): 933–
These de medecine N°60, Fes, 2010. 48 [quiz: 949–51].
12. Messmer BT. Albesiano E. Efremov DG. Ghiotto F. 28. Lutzner MA, Jordan HW. The ultrastructure of an
Allen SL. Kolitz J. et al. Multiple distinct sets of abnormal cell in Sézary's syndrome. Blood, 1968;
stereotyped antigen receptors indicate a role for 31: 719–26.
antigen in promoting chronic lymphocytic leukemia. 29. Zinzani PL, A. Ferreri AJM, Cerroni L. Mycosis
J Exp Med, 2004; 200: 519–25. fungoides: Critical Reviews. Oncol Haematol, 2008;
13. Hallek M, Cheson BD, Catovsky D, et al. iwCLL 65: 172-82.
guidelines for diagnosis, indications for treat- ment, 30. CriscioneVD,WeinstockMA. Incidence of cutaneous
response assessment, and supportive management of T-cell lymphoma in the United States, 1973-2002.
CLL. Blood, 2018; 131(25): 2745–60. Arch Dermatol, 2007; 143(7): 854–9.
14. Jung KW, Won YJ, Kong HJ, Oh CM, Seo HG, Lee 31. Lutzner MA, Jordan HW. The ultrastructure of an
JS. Cancer statistics in Korea: incidence, mortality, abnormal cell in Sézary's syndrome. Blood, 1968;
survival and prevalence in 2010. Cancer Res Treat, 31: 719–26.
2013; 45: 1-14. 32. Foucar K, Falini B, Catovsky D, Stein H. Hairy cell
15. Goede V, Fischer K, Engelke A, et al. Obi- leukemia. In: Swerdlow SH, Campo E, Harris NL,
nutuzumab as frontline treatment of chronic eds. WHO Classification of Tumours of
lymphocytic leukemia: updated results of the CLL11 Haematopietic and Lymphoid Tissues.Am J
study. Leukemia, 2015; 29: 1602–4. Hematol, 2017; 92: 1382–1390.
16. Dearden C. B- and T-cell prolymphocytic leukemia: 33. Swerdlow SH, Campo E, Pileri SA, et al. The 2016
antibody approaches. Hematol. Am. Soc. Hematol. revision of the World Health Organization
Educ. Program, 2012; 2012: 645–651. classification of lymphoid neoplasms. Blood, 2016;
17. Nabhan C, Aschebrook-Kilfoy B, Chiu BC, et al. 127(20): 2375–90.
The impact of race, ethnicity, age, and sex on
clinical outcome in chronic lymphocy-tic leukemia:
a comprehensive SEER analysis in the modern era.
Leukemia Lymphoma, 2014; 55: 2778–84.
18. Siegel R, et al. Cancer treatment and survivorship
statistics. CA Cancer J. Clin, 2012; 62: 220–241.
19. Nabhan C, et al. The impact of race, ethnicity, age
and sex on clinical outcome in chronic lymphocytic
leukemia: a comprehensive Surveillance,
Epidemiology, and End Results analysis in the
modern era. Leuk. Lymphoma, 2014; 55: 2778–
2784.
20. Steven H., E Campo, Stefano A.Nancy L,
Swerdlow, S. et al. The revision of the World Health
Organization classification oflymphoid neoplasms,
2016; 127: 2375-2390.
21. Béral HM. Leucémie lymphoïde chronique. Revue
Francophone des Laboratoire, 2006; 379: 3743.
22. Matutes E, Catovsky D. The value of scoring
systems for the diagnosis of biphenotypic leukemia
and mature B-cell disorders. Leuk Lymphoma,
1994; 13: 11–4.
23. Imam MH, Shenoy PJ, Flowers CR, et al. Incidence
and survival patterns of cutaneous T-cell lymphomas
in the United States. Leuk Lymphoma, 2013; 54(4):
752–9.
24. Korgavkar K, Xiong M, Weinstock M. Changing
incidence trends of cutaneous T-celllymphoma.
JAMA Dermatol, 2013; 149(11): 1295–9.
25. WillemzeR, Jaffe ES, Burg G. WHO-EORTC
classification for cutaneous lymphomas, Blood,
2005; 105: 3768–85.
26. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC
classification for cutaneous lymphomas. Blood,
2005; 105(10): 3768–85.
27. Ahn CS, ALSayyah A, Sangueza OP. Mycosis
fungoides: an updated review of clinicopathologic

www.wjpls.org │ Vol 8, Issue 4, 2022. │ ISO 9001:2015 Certified Journal │ 37