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 Table of Contents  
CASE REPORT
Year : 2021  |  Volume : 12  |  Issue : 3  |  Page : 172-175

A case of chronic lymphocytic leukemia with unmutated variable region of the immunoglobulin heavy chain gene with markedly high lactate dehydrogenase responding to ibrutinib


Department of Medicine, King Saud University, Riyadh, Saudi Arabia

Date of Submission20-Feb-2021
Date of Decision26-Mar-2021
Date of Acceptance26-Mar-2021
Date of Web Publication21-Oct-2021

Correspondence Address:
Dr. Musa Alzahrani
Department of Medicine, King Saud University, Saudi Arabia, P.O. Box: 55068(37), Riyadh 12372
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joah.joah_17_21

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  Abstract 

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Several prognostic factors exist that help stratify patients into different risk categories. Unmutated status of the immunoglobulin heavy chain (IGHV) gene has been shown to be among the most important high-risk prognostic factors in CLL. Elevated serum level of lactate dehydrogenase has also been shown to be associated with worst outcomes. Recently, the management of CLL has progressed favorably and improved outcomes were seen with the use of the small-molecule Bruton's tyrosine kinase inhibitor, ibrutinib, when compared with traditional chemotherapy. Here, we present a CLL case with an unmutated IGHV gene status presenting with markedly elevated LDH and responding dramatically to ibrutinib.

Keywords: Chronic lymphocytic leukemia, ibrutinib, lactate dehydrogenase


How to cite this article:
Alzahrani M. A case of chronic lymphocytic leukemia with unmutated variable region of the immunoglobulin heavy chain gene with markedly high lactate dehydrogenase responding to ibrutinib. J Appl Hematol 2021;12:172-5

How to cite this URL:
Alzahrani M. A case of chronic lymphocytic leukemia with unmutated variable region of the immunoglobulin heavy chain gene with markedly high lactate dehydrogenase responding to ibrutinib. J Appl Hematol [serial online] 2021 [cited 2021 Dec 2];12:172-5. Available from: https://www.jahjournal.org/text.asp?2021/12/3/172/328714




  Introduction Top


Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults accounting for up to 35% of all leukemia cases.[1] CLL is a B-cell neoplasm that is characterized by accumulation of monoclonal mature B-lymphocytes in the bone marrow and peripheral blood and may involve other tissues or organs.[2]

Serum lactate dehydrogenase (LDH) is commonly elevated in lymphoproliferative disorders and has been shown to be associated with worse prognosis.[3],[4],[5]

In CLL, like other lymphoproliferative disorders, LDH has been found to be prognostically important and it may as well reflect the proliferative burden of the disease.[6],[7]

Furthermore, published data suggest that serum LDH may predict progression-free survival, treatment-free survival, and overall survival in patients with CLL.[6]

On the other hand, one of the most important prognostic markers in CLL is the mutational status of the variable region of the immunoglobulin heavy chain (IGHV) gene which has been shown to be associated with worse outcomes and increased rate of relapse.[8],[9]

Ibrutinib is a small-molecule drug that blocks Bruton's tyrosine kinase, an important enzyme in B-cell signaling pathway, that when compared to traditional chemotherapy in CLL has been shown to be superior.[10],[11]

Markedly high LDH in unmutated immunoglobulin H (IgH) CLL could predict a high-risk disease. Impressive response to ibrutinib was noted in the case presented herein who had unmutated IGHV status and remarkably high LDH. This proves the remarkable effect of ibrutinib in controlling high-risk CLL disease.


  Case Report Top


Our case is a 64-year-old Saudi woman who was referred to hematology on December 17, 2019, because of asymptomatic peripheral blood lymphocytosis that was discovered incidentally in a routine blood work. She denied any shortness of breath, chest pain, fatigue, weight loss, sweating, or fever. Her performance status was 0 as per Eastern Cooperative Oncology Group performance status.[12] Her examination revealed multiple palpable nonbulky lymph nodes above and below the diaphragm. Thyroid examination was normal and abdominal examination failed to reveal signs of organomegaly.

Her blood work showed white blood cells (WBCs) of 143.3 × 109/L with 90% lymphocytes, hemoglobin 114 g/L, and platelet 160 × 109/L. Her last previous complete blood count was in September 1, 2018, with WBC of 13.2 × 199/L, hemoglobin 130 g/L, and platelet of 173 × 109/L. Blood film revealed a marked increase in mature lymphocytes with multiple smudge cells. LDH was reported as >1000 units/L (normal range: 84–246). Creatinine, electrolytes, calcium, serum albumin, and liver enzymes were all within normal range. Total bilirubin was 4.46 (normal range: 3–17 umol/L), haptoglobin 1.8 g/L (normal range: 0.3–2), and reticulocyte 1.4% (normal range: 0.2–2) with negative direct Coombs test.

The peripheral blood sample was processed for four-color immunophenotyping and analyzed with CD45 versus side scattered. It was noted that 78% of total gated events are located in the CD45-bright/low scatter (lymphocyte gate); 70% of them are monoclonal B-lymphocytes expressing kappa light chain, dim CD20, CD19, CD5, CD23, CD22, and CD43. They are negative for CD10 and lambda light chain. Molecular IGVH test was done in Bioscientia Laboratory in Germany and showed a detection of a productive IgH-rearranged sequence with unmutated IGVH status with 100% homology with germline sequence.

Because the patient did not have an indication for treatment as per the International Workshop on Chronic Lymphocytic Leukemia guidelines,[13] treatment was delayed and the patient was put on watchful waiting. However, since LDH was markedly elevated with no evidence of hemolysis, a concern of Richter transformation was raised and imaging was obtained.

Imaging included an 18F-fluorodeoxyglucose (FDG) positron emission tomography scan (PET) and a computer tomography scan for the neck, chest, abdomen, and pelvis (CT-CAP).

The PET scan was done on April 27, 2020, and showed multiple FDG-avid bilateral cervical and bilateral supraclavicular lymphadenopathies in addition to involvement of the right thyroid lobe with maximum standard unit value (SUVmax) of 20.8 at right thyroid lobe. No hypermetabolic cervical or supraclavicular lymphadenopathy was seen. Extensive FDG-avid lymphadenopathy at the subpectoral and axillary regions bilaterally (SUVmax: 6.8 on the right side) was also seen. No hypermetabolic mediastinal lymph nodes or pulmonary nodules were seen. Extensive FDG-avid lymphadenopathy at the upper abdomen, retroperitoneal, mesenteric, pelvic, and bilateral inguinal regions (SUVmax: 8.4 at right hemipelvis) were detected.

Hepatosplenomegaly was seen but with no FDG-avid lesion. Other major organs were unremarkable.

CT-CAP was done on June 3, 2020, and showed a diffuse enlargement of the right lobe of the thyroid with multiple calcification associated with a right thyroid heterogeneous hypodense nodule with foci of calcification measuring about 3.5 cm × 2.7 cm × 4 cm. Another small hypodense nodule was seen in the inferior pole of the left thyroid lobe. There were multiple bilateral cervical, intraparotid, retropharyngeal, supraclavicular, bilateral axillary, mesenteric, retroperitoneal, bilateral pelvic, bilateral inguinal lymph nodes, the largest measured 2.5 cm in long axis located in the pelvic area. Mild hepatosplenomegaly was also seen.

After the finding of thyroid nodule, a fine-needle aspiration was arranged and revealed evidence of papillary thyroid carcinoma (Bethesda category: 6). She was subsequently evaluated by endocrine surgery team.

Upon follow-up, her lymphocyte count was rising very quickly and was associated with progressive drop in hemoglobin. The patient also started complaining of fatigue and shortness of breath related to her anemia. Workup for anemia showed no evidence of immune hemolysis with negative direct Coombs test. Because of her anemia, a decision was to start her on medical therapy and she commenced on ibrutinib monotherapy at a dose of 420 mg daily on July 23, 2020. It was expected to have transient increase in her lymphocyte count following initiation of therapy with ibrutinib, however, the opposite was observed. The patient responded dramatically and swiftly to ibrutinib with improvements in symptoms, lymphocyte count, hemoglobin, platelet count, and LDH [Figure 1].
Figure 1: Diagrammatic representation of the patient's laboratory parameters. On the Y-axis shown: WBCs, Hgb, and LDH, respectively. On the X-axis shown: the date. Ibrutinib started on July 23, 2020, with dramatic responses. WBC = White blood cell; Hgb = Hemoglobin; LDH = Lactate dehydrogenase

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On September 28, 2020, the patient underwent a total thyroidectomy with right lateral neck dissection and central neck dissection after ibrutinib was held for 1 week. Postoperative pathologic examination of lymph nodes obtained by neck dissection from the right cervical region on levels II,III and IV, revealed that 13 out of 64 lymph nodes were positive for metastatic papillary thyroid carcinoma (13/64).

After temporary holding ibrutinib for surgery, a transient increase in her lymphocyte counts was seen, but 3 days postoperatively, the drug was restarted with a quick response observed in lymphocytosis.

Currently, she remains on ibrutinib for about 7 months and she continues to be in a good response. Her last blood work on January 31, 2021, showed WBC of 9 × 109/L, hemoglobin 129 g/L, platelet 256 × 109/L, and LDH of 228 units/L (normal range: 84–246).

The patient remains well and stable in very good remission until the writing of this report.


  Discussion Top


Our case has many important teaching points. First, the case demonstrates that markedly elevated LDH can happen with CLL even in the absence of Richter transformation or bulky masses.[14]

It is important to note that marked elevation of LDH in CLL, especially if it is otherwise unexplained, should raise the suspicion for Richter transformation and a search for the maximum area of uptake on PET scan can help to identify the site for an optimal tissue biopsy.

Second, 100% unmutated IGVH cases would typically represent the upper end of the bad prognostic spectrum of the unmutated status, however, despite that, a dramatic response was seen with the use of ibrutinib. Mutated IGHV genes are typically defined as a >2% difference in nucleotide sequence compared with germline sequences, i.e., <98% homology.[8]

Third, unlike the usual observation of transient worsening of peripheral blood lymphocytosis, this case did not go through this typical pattern and response happened right away.[15],[16]

Fourth, temporary interruption of ibrutinib for surgery is needed to avoid bleeding complications, but resumption of effective therapy is possible and safe after surgery.[17],[18],[19]

Fifth, incidental thyroid cancer detected by PET scan is common upon the workup for lymphoproliferative disorders.[20],[21],[22]

Finally, the case demonstrates how second cancers can be more aggressive in CLL and required aggressive management when compared to patients with the same diagnosis but lacking CLL.[23],[24] There are several reasons behind this observation, but importantly, tumor cell evasion of the immune system resulting from dysfunctional CLL lymphocytes can lead to development of second cancers.[25],[26]


  Conclusion Top


We believe that this case has a unique presentation with markedly high LDH that demonstrated an excellent response to ibrutinib in the setting of 100% homology of the IGVH gene to the germline sequence. Futures research could study the association between lowering LDH and outcomes and the use of LDH as a marker of disease response to ibrutinib.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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