Chronic myeloid leukemia coexisting with non-Hodgkin’s lymphoma: An uncommon presentation of bilineage hematological malignancy

Augustine Benjamin; Adebayo Adeshola; Abdulrahman M Fatima; Johnson John; Akinrinmade A Akintunde; Ibrahim Mohammed; Amalimeh Benedict; Abdullahi A Jatau; Muktar M Haruna

doi:10.4103/ejh.ejh_1_22

CASE REPORT

Year : 2022 | Volume : 47 | Issue : 3 | Page : 227-231

Chronic myeloid leukemia coexisting with non-Hodgkin’s lymphoma: An uncommon presentation of bilineage hematological malignancy

Augustine Benjamin¹, Adebayo Adeshola², Abdulrahman M Fatima², Johnson John², Akinrinmade A Akintunde², Ibrahim Mohammed³, Amalimeh Benedict⁴, Abdullahi A Jatau², Muktar M Haruna¹
¹ Department of Haematology, Ahmadu Bello University, Zaria, Nigeria; Department of Haematology and Blood Transfusion, Ahmadu Bello University Teaching Hospital, Zaria, Nigeria
² Department of Haematology and Blood Transfusion, Ahmadu Bello University Teaching Hospital, Zaria, Nigeria
³ Department of Medical Microbiology and Immunology, Federal Teaching Hospital, Gombe, Nigeria
⁴ Department of Maxillofacial Surgery, Ahmadu Bello University Teaching Hospital, Zaria, Nigeria

Date of Submission	05-Jan-2022
Date of Acceptance	10-Jan-2022
Date of Web Publication	03-Jan-2023

Correspondence Address:
Augustine Benjamin
Department of Haematology and Blood Transfusion, Ahmadu Bello University Zaria and Ahmadu Bello University Teaching Hospital, Zaria, Kaduna State
Nigeria

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/ejh.ejh_1_22

Abstract

The incidence of hematological malignancies is on the rise particularly in developing countries as a result of newer diagnostic technologies and skills. However, the coexistence of chronic myeloid leukemia (CML) and non-Hodgkin lymphoma (NHL) in a single patient simultaneously is extremely rare, with an overall incidence of less than 1%, while the majority of cases (66%) have sequential presentations. We report a 36-year old Nigerian man, who was diagnosed in our facility initially in chronic phase CML, but progressed through accelerated phase to blastic phase CML and was subsequently diagnosed with NHL within weeks of starting hydroxyurea. He also received cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisolone (CHOP) for the NHL. However, he subsequently succumbed to the disease. CML is a triphasic disease with the tendency to acquire new cytogenetic abnormalities particularly transformation to extramedullary disease during its blastic phase. These events may be associated with NHL in the setting of blast crisis. Our case report adds to the growing literature on the coexistence of two separate hematological malignancies in a single patient.

Keywords: blastic phase, chronic myeloid leukemia, coexisting, non-Hodgkin lymphoma

How to cite this article:
Benjamin A, Adeshola A, Fatima AM, John J, Akintunde AA, Mohammed I, Benedict A, Jatau AA, Haruna MM. Chronic myeloid leukemia coexisting with non-Hodgkin’s lymphoma: An uncommon presentation of bilineage hematological malignancy. Egypt J Haematol 2022;47:227-31

How to cite this URL:
Benjamin A, Adeshola A, Fatima AM, John J, Akintunde AA, Mohammed I, Benedict A, Jatau AA, Haruna MM. Chronic myeloid leukemia coexisting with non-Hodgkin’s lymphoma: An uncommon presentation of bilineage hematological malignancy. Egypt J Haematol [serial online] 2022 [cited 2023 Mar 30];47:227-31. Available from: http://www.ehj.eg.net/text.asp?2022/47/3/227/366857

Introduction

Chronic myeloid leukemia (CML) is a clonal stem cell disorder of myeloid origin, resulting in uncontrolled and unregulated proliferation of the granulocytic lineage [1]. Its incidence is rising steadily, and the 2017 documented prevalence in Africa, Latin America, lower-income Asia Pacific countries, high-income Asia Pacific countries, Europe, and North America is 3, 5, 6, 10, 11, and 15 cases per 100 000, respectively [2]. The incidence of CML has variously been reported to be 27.7 and 36.6% of all malignancies from centers in Nigeria [3,4]. It is also more prevalent in males though females have a better survival outcome [5].

From the first identification of the characteristic small chromosome in neoplastic cells from patients with CML by Nowell and Hungerford in 1960s [6] to the elucidation of the translocation and subsequent cytogenetic changes, we have come a long way in understanding the biology of CML. The genetic alteration in CML is one of the most extensively studied and best understood models in human cancer, and the treatment of CML with tyrosine kinase inhibitors has been one of the most successful stories in oncology [6]. The 2008 WHO Classification of Haematopoietic Tumors, classified CML into three clinical presentations, consisting of chronic phase (CP), accelerated phase (AP), and blast phase (BP) [7]. Lymph node enlargement in CML may represent an extramedullary blast crisis. Extramedullary BP CML is an extremely infrequent finding and there are few cases described in the literature [7]. Most patients are diagnosed in the CP, which is characterized by anemia, splenomegaly with concomitant abdominal discomfort and infections, thrombocytosis, and increased white blood count (WBC) made up of mature granulocytes and their precursors. Until relatively recently, the natural history of the disease evolved from the CP which usually lasts several years before the ultimately fatal AP and BP [1].

CML is characterized by a chromosomal reciprocal t (9; 22) (q34; q11) translocation, the abnormal chromosome 22 being referred to as the Philadelphia (Ph) chromosome. This translocation is the most commonly seen, accounting for about 85% of all cases. Other minor variant translocations include [t (v; 22)] or cryptic rearrangement [8]. The crucial pathogenetic consequence of this translocation is the creation of an aberrant chimeric BCR-ABL1 fusion gene, resulting in a constitutively active tyrosine kinase with high proliferative potential. Three different types of BCR-ABL proteins have been identified: they are the classical 210 kD protein seen in almost all CML patients, and approximately one-third of patients with Ph+ acute lymphoblastic leukemia; and a 190 kD type seen in the remainder of Ph+ acute lymphoblastic leukemia patients and rarely Ph+ chronic neutrophilic leukemia. There is also a 230 kD type associated with the rare Ph+ chronic neutrophilic leukemia [5].

The aberrant BCR-ABL gene is involved in neoplastic transformation through stimulation of multiple downstream signaling cross-connections. Some of the multiple pathways signaled by the BCR/ABL kinase are JAK/STAT, PI3K/AKT, and Ras/MEK, and these pathways drive CML pathogenesis [6]. This aberrant BCR-ABL signaling has also been linked to five events that play key roles in leukemogenesis and disease progression: These include induction of cell proliferation through activation of a number of mitogenic pathways, inhibition of the adhesion of hematopoietic progenitor cells to stromal cells and the extracellular matrix in the bone marrow, inhibition of apoptosis, degradation of regulatory protein (potentially including p53), and impaired DNA repair. The latter two effects have been hypothesized to cause or contribute to genetic instability in Ph+ CML in blast crisis (responsible for additional chromosomal aberrations or mutations frequently seen in blast crisis) [6].

Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy in the world, and is ranked as the seventh most common cancer among males and the sixth most common cancer among females, and accounts for 2.7% of all cancers. The incidence of NHL subtypes also varies by age, sex, ethnicity, and geographic region [9,10]. It comprised numerous biologically and clinically heterogeneous subtypes, with more than 40 major subtypes identified, each having distinct genetic, morphologic, and clinical features [9]. This heterogeneity is associated with the various clinical, pathological, immunological, and cytogenetic presentations, and thus the prognoses are quite variable. NHL originates from precursor cells in primary lymphoid organs or from mature cells located in the peripheral lymphoid organs, as a result of clonal expansion of B lymphocyte or T lymphocyte transformed during the pathways of lymphocyte differentiation and may involve any organ that contains lymphoid tissue [11].

Myeloid leukemia and lymphoma are different malignancies originating from two lineages and possess disparate cytogenetic, cell phenotype, and biological process [11]. The coexistence of CML and NHL is an uncommon entity, and there are limited reports of this relationship in the literatures and from our environment. CML has been associated with NHL in the setting of blast crisis, and may be misdiagnosed as an extramedullary lymphoid blast transformation. [5, 12, 13] extramedullary disease (EMD) including nodal involvement typically occurs in the AP or BP, and accounts for 15% of newly diagnosed CML, with the commonly affected sites being the central or peripheral nervous system (12–83%), bone (37–57%), lymph node (17–29%), skin, and soft tissue (14–29%) [5,14]. In most cases, the blasts are of myeloid origin, expressing granulocytic markers (CD13, CD33); in 10–20% of cases the blasts are of lymphoid origin expressing lymphoid B-markers (CD10, CD19, CD20) or T-markers (CD3, CD7); rarely blast crisis is bilineage (myeloblasts and lymphoblasts) or biphenotypic (both markers of myeloblasts and lymphoblasts) [5].

The occurrence of two hematological malignancies in a single patient has been reported to occur in the younger patients with the majority of them being males. Most presentations are on account of fever, fatigue, and splenomegaly and enlarged lymph nodes [11].

The pathophysiology of the occurrence of two or more simultaneous hematologic malignancies is not well understood, and thus there have been multiple suggested theories. There is no clear evidence of the pathogenetic association between CML and NHL. The genomic instability characteristic of CML may play a role in the subsequent occurrence of NHL [5, 6, 13, 14]. Studies have found a significantly higher number of BCR-ABL transcripts in association with higher expression of cyclin D1 in AP of CML than in CP [5]. It has also been shown that the activated ABL oncogene could signal through cyclin D1, and induce malignant transformation. It has been suggested that one of the possible mechanism involved in blast crisis could result from accumulation of genetic and/or epigenetic changes including changes in the activity of cyclin D/Rb pathway. These pathophysiological mechanisms associated with the activation of the BCR-ABL oncogene may possibly contribute to cyclin D1 overexpression, which can drive B-cell lymphomagenesis and potentially account for a possible biological link between CML and lymphoma [5,13]. Other hypothesis includes the possibility of the two diseases originating from common progenitors; this hypothesis would be supported by the presence of the JAK2V617F mutation in both myeloid cells and B lymphocytes; another hypothesis is that these are two independent diseases occurring from different progenitors, and having different etiopathogenetic routes. The rarity of simultaneous diagnoses of CML and NHL explains the difficulty in finding consistent explanations that may apply to all cases [15].

Case report

A 36-year-old Nigerian man was referred to our specialist clinic in a tertiary health facility on account of 3-month history of progressive splenomegaly, weight loss, and left-sided abdominal pain, which was said to be dragging in nature associated with easy satiety, and a month history of low-grade fever, swellings in the neck, axilla, and groins bilaterally. Physical examination revealed an ill-looking, emaciated man who was pale, not jaundiced. The respiratory and cardiovascular system examinations were unremarkable. Abdominal examination revealed splenomegaly, 14 cm below the left costal margin and hepatomegaly of 8 cm. Complete blood count results showed packed cell volume (PCV) 0.30 l/l, WBC 122.4 × 10⁹/l, and platelet 390 × 10⁹/l. The peripheral blood film and bone marrow aspiration examinations showed all the series of the myeloid lineage consistent with CP CML ([Figure 1] and [Figure 2]). Viral screening was nonreactive to HBsAg, HCV, and HIV. Serum biochemistry and liver function tests were essentially noncontributors. Screening for tuberculosis was negative. He was started on Caps Hydroxyurea 1 g three times daily to achieve cytoreduction, while awaiting a cytogenetic test result before starting tyrosine kinase inhibitors. BCR-ABL fusion gene analysis showed positivity for the Ph chromosome. Other supportive medications include Allopurinol 300 mg daily, vitamin B12, vitamin B6, and diclofenac. The abdominal pain abated a week after starting therapy, though the liver and splenic sizes remained unchanged. Blood parameters were monitored weekly and hydroxyurea tapered to twice daily on achieving a WBC of 32.6 × 10⁹/l. Further comprehensive blood workup 4 weeks after presentation showed PCV 0.29 l/l, WBC 870 × 10⁹/l with a differential count of myeloblast 5%, promyelocyte 7%, myelocyte 48%, metamyelocyte and band 10%, neutrophil 18%, lymphocyte 12%, and platelet 1125 × 10⁹/l. The peripheral blood film examinations showed all series of the myeloid lineage consistent with AP CML and presence of atypical lymphocytes, which arose our suspicion of a lymphoproliferative disorder ([Figure 3]). Six weeks after starting therapy with hydroxyurea, the patient complained of appearance of multiple swellings in the neck, axilla and groin regions, fever and feeling of heaviness in the abdomen. Physical examination showed generalized palpable lymph node enlargement in the cervical, axilla, and inguinal regions measuring 3 × 4, 2 × 2, and 1 × 2 cm, respectively. Complete blood count result showed PCV 20.9%, WBC 135 × 10⁹/l with a differential count of myeloblast 79%, promyelocyte 7%, band 4%, neutrophil 5%, and lymphocyte 5%. The platelet count was 1455 × 10⁹/l ([Figure 4]). An assessment of blastic phase CML with differential of lymphoproliferative disorder was made. Cervical lymph node biopsy was sent for tissue diagnosis. A repeat bone marrow aspiration showed acute myeloblastic leukemia (myeloblast 60% of bone marrow nucleated cells and 20% lymphoblast with increased bone marrow eosinophilic precursors). Hydroxyurea dose was subsequently increased to 2 g six hourly for 36 h with a view to achieving cytoreduction. The lymph node biopsy reported NHL, and an overall assessment of bilineage malignancy [CML (BP) and NHL] was made on the patient ([Figure 5]). The patient was counseled on both disease process and required therapy. He had liver function tests and serum biochemistry, which were within normal limits. Echocardiography revealed an ejection fraction of 50.0 with concentric left ventricular hypertrophy and normal left ventricular systolic function and grade II diastolic dysfunction. He was started on modified cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisolone (CHOP) regimen due to decompensated cardiac function at the following doses, respectively, intravenous Cyclophosphamide 750 mg/m² on day 1 of cycle, intravenous Vincristine 1.4 mg/m² on day 1, intravenous Adriamycin 30 mg/m² days 1–3, and tabs Prednisolone 100 mg/day in three divided doses for 28 days. Premedication with ondansetron and metoclopramide was also administered. G-CSF in the form of Filgrastim 300 μg twice weekly was also prescribed to counteract myelosuppressive effect of chemotherapy. He had blood transfusion, antimicrobials, and other forms of supportive therapy. His clinical and laboratory features were closely monitored. He had two complete cycles of modified cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisolone (CHOP), patient’s condition though deteriorated subsequently after the second cycle, and he succumbed to the disease.

Figure 1: Peripheral blood film showing all stages of myeloid series.

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Figure 2: Section of bone marrow aspirate showing hypercellularity and all stages of myeloid differentiation consistent with chronic myeloid leukemia.

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Figure 3: Blood film showing the presence of atypical lymphocytes.

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Figure 4: Peripheral blood film showing myeloblasts and promyelocytes with marked thrombocytosis.

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Figure 5: Left cervical lymph node showing partial effacement of nodal architecture by a diffuse infiltration of uniform sheets of monomorphic medium-sized round cells having scanty cytoplasm and hyperchromatic nuclei, some with prominent nucleoli.

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Discussion

The coexistence of CML and NHL in a single patient is a rare occurrence, as we encountered in our index patient, which prompted this case report. However, there are increasing reports of this occurrence [1, 2, 5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15], and this finding poses a great challenge to the hemato-oncologists and pathologists involved in the management of these patients. The occurrence of a second malignancy diagnosed in a patient with cancer can be as a result of de novo unrelated oncogenic process, which is nontherapy related or therapy related (related/induced by the type of therapy received).

The peripheral blood findings, bone marrow and cytogenetic analysis results of our patient prompted the diagnosis of CML. However, the presence of atypical lymphocytes on peripheral blood examination with the physical finding of lymphadenopathy aroused our suspicion of either an EMD, a reactive process or a harbinger of a lymphoproliferative disorder. This was the indication for the lymph node biopsy that our patient had, which eventually revealed the overall feature of NHL.

Various pathophysiological models have been proposed to account for the coexistence of two hematological malignancies in a single patient. Among these hypotheses include the creation of an aberrant chimeric BCR-ABL1 fusion gene, which is said to be involved in neoplastic transformation through stimulation of multiple downstream signaling cross-connections. Some of the multiple pathways signaled by the BCR/ABL kinase are JAK/STAT, PI3K/AKT, Ras/MEK, degradation of regulatory protein (potentially including p53), and impaired DNA repair, overexpression of cyclin D1, and these pathways drive CML pathogenesis [6,13]. The occurrence of two hematological malignancies in a single patient has been reported to occur in the younger patients with the majority of them being males. Most presentations are on account of fever, fatigue, and splenomegaly and enlarged lymph nodes [11].

The phasic nature of CML may play a role in the pathogenesis of this phenomenon. The evolution of AP and BP is also not fully understood, but is presumed to be due to the accumulation of more stem cell-like characteristics and additional mutations [6]. The blast crisis in CML may occur in either myeloid or lymphoid cell lines and in 10–20% of cases the blasts are of lymphoid origin expressing lymphoid B-cell markers or T-cell markers [6,11]. The blast crisis may also include EMD, and may involve the nodes. This is said to occur in about 15% of all newly diagnosed CML patients [12]. CML has been reported to be associated with NHL in the setting of blast crisis [5,6]. The genomic instability characteristic of blastic crisis in CML may play a role in the subsequent occurrence of NHL. The occurrence of the two hematological malignancies in our case may be supported by these theories/hypotheses, even though the true nature of the pathophysiological mechanism involved in the development of two hematological malignancies in a single patient is not clearly understood.

In our index case, initial presentation was in the CP, with subsequent progression through AP to the BP. During the course of presentation for our index case, lymphadenopathy was a significant finding. It is possible that during the blastic phase he might have acquired new genetic changes predisposing to the development of NHL. Historical presentation of our case showed that neck, axillary, and groin swellings appeared 2 months after he started having symptoms of splenomegaly and weight loss. It will be extremely difficult to show that the subsequent diagnosis of NHL in our patient could have been present at initial presentation or it developed subsequently.

In well-equipped facilities, using standard cytogenetic analysis, reverse transcription PCR, and fluorescence in situ hybridization, the origin of two disparate hematological malignancies coexisting whether simultaneously or sequentially can be identified.

Conclusion

The occurrence of two separate hematological malignancies has been reported in the literature. But these finding are very rare events, more so the occurrence of CML and NHL in a single patient is a rare occurrence. This finding therefore propelled our case report with its diagnostic dilemma and rarity of occurrence. Occurrence of EMD involving the lymph nodes should arouse suspicion of lymphoma in a patient with CML. With the growing literatures of these findings including this case report, our understanding as hemato-oncologists and pathologists will expand to help in the diagnosis and channeling of therapeutic approach to such rare clinical findings and also add to the existing and growing body of knowledge of cancer pathogenesis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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