Chronic lymphocytic leukemia/small lymphocytic lymphoma arising in the pituitary gland: illustrative case

Hang Zhou Departments of Neurological Surgery, and

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Xiaowei Zhang Departments of Neurological Surgery, and

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Xin Jia Pathology, The Second Hospital of Hebei Medical University, Hebei, China

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Liang Jia Departments of Neurological Surgery, and

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Qingjiu Zhang Departments of Neurological Surgery, and

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BACKGROUND

The authors describe a 60-year-old female who underwent a correlative examination for an accidental scalp injury, revealing a sellar mass, which was surgically excised and pathologically confirmed to be a non-Hodgkin’s small B-cell lymphoma. These findings in combination with the immunophenotype led to a final diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma. Previous studies have shown that hematological solid tumors occurring in the pituitary gland are extremely rare, and there are only approximately three other cases of living patients with similarities to this case, all of which had ambiguous expression of subsequent hematological treatment.

OBSERVATIONS

In this case, the authors used an endoscopic approach to completely excise the tumor. Follow-up of the patient was continued after surgery, and the patient is currently receiving standardized treatment with zanubrutinib.

LESSONS

This patient did not have any previous history of tumor, had a good postoperative recovery with a normal quality of life, and still receives hormone replacement and zanubrutinib on a standardized basis. This is a complete case that has not been previously reported and reveals the diagnostic and therapeutic process of rare diseases in the sellar area.

ABBREVIATIONS

BTK = Bruton’s tyrosine kinase; CLL = chronic lymphocytic leukemia; CT = computed tomography; MRI = magnetic resonance imaging; SLL = small lymphocytic lymphoma

BACKGROUND

The authors describe a 60-year-old female who underwent a correlative examination for an accidental scalp injury, revealing a sellar mass, which was surgically excised and pathologically confirmed to be a non-Hodgkin’s small B-cell lymphoma. These findings in combination with the immunophenotype led to a final diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma. Previous studies have shown that hematological solid tumors occurring in the pituitary gland are extremely rare, and there are only approximately three other cases of living patients with similarities to this case, all of which had ambiguous expression of subsequent hematological treatment.

OBSERVATIONS

In this case, the authors used an endoscopic approach to completely excise the tumor. Follow-up of the patient was continued after surgery, and the patient is currently receiving standardized treatment with zanubrutinib.

LESSONS

This patient did not have any previous history of tumor, had a good postoperative recovery with a normal quality of life, and still receives hormone replacement and zanubrutinib on a standardized basis. This is a complete case that has not been previously reported and reveals the diagnostic and therapeutic process of rare diseases in the sellar area.

ABBREVIATIONS

BTK = Bruton’s tyrosine kinase; CLL = chronic lymphocytic leukemia; CT = computed tomography; MRI = magnetic resonance imaging; SLL = small lymphocytic lymphoma

Among occupying lesions in the sellar region, pituitary adenomas are the most common, with clinical manifestations of endocrine symptoms caused by hyperfunction or hypofunction of the pituitary gland or target glands and mass effect on adjacent structures such as the optic nerve, whose compression is elevated when the tumor is large. In large retrospective studies, the etiology of sellar region masses was overwhelmingly pituitary adenomas (84.6%), followed by craniopharyngiomas (3.2%), cystic nonneoplastic lesions (2.8%), inflammatory lesions (1.1%), meningiomas (0.94%), metastatic tumors (0.6%), and chordomas (0.5%), although other rare lesions have also been detected (6.0% in total).1–3

Primary central nervous system lymphoma is relatively rare. Because of the absence of intracranial lymphoid structures, it is now generally accepted that the lesions originate from primitive mesenchymal cells of the ventricular ectoderm, soft meningeal histiocytes, and microglia and that they are predominantly non-Hodgkin’s lymphomas, most often of B-cell origin. The majority of lesions occur in the brain parenchyma, spinal cord, cerebral nerves, meninges, and/or eyes, and the brain parenchyma is the most common site of lesions.

Solid tumors of the hematological system occurring in the pituitary gland are very rare; according to a 17-year single-center study, hematological malignancies of the sellar region accounted for 0.36% of all sellar region tumors. This coupled with the complexity of the hematological disease typology has led to a wide variety of diagnostic and therapeutic modalities for a solid tumor of the hematological system occurring in the pituitary gland.4–6 In this report, we describe a 60-year-old female who was examined for an accidental scalp injury, which revealed an abnormal mass in the sellar region. The mass was surgically removed and pathologically confirmed as non-Hodgkin’s small B-cell lymphoma. These findings combined with immunophenotyping resulted in a final diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Other cases of hematological solid tumors of the same site and type as in this patient and treated with standardized hematological first-line targeted agents have not been previously reported. In this case, we discuss the rare diagnosis and treatment of CLL/SLL occurring in the pituitary gland.

Illustrative Case

History and Presentation

A 60-year-old female presented to a local healthcare facility with a scalp injury, where cranial imaging was refined and pituitary magnetic resonance imaging (MRI) suggested a space-occupying lesion in the saddle area. Physical examination showed no blurring of vision, no visual field defects, no acromegaly changes, no abdominal striae or other signs of Cushing’s disease, and no fever. The patient had regular premenopausal menstruation and no breast fluid. There was no prior history of tumor. The patient was then referred to our hospital for neurosurgical treatment.

She complained of no discomfort at the time of admission and underwent 3.0-T pituitary-enhanced MRI at our institution, which confirmed a mass with isotropic T1 and isotropic T2 signals in the intrasellar and suprasellar areas, with definite inhomogeneous enhancement on enhanced scans and a well-defined lesion approximately 1.9 × 1.4 × 1.5 cm in size (left-right × anteroposterior × superoanterior; Fig. 1). Associated pituitary hormones such as growth hormone, thyroid-stimulating hormone, prolactin, gonadotropins, and adrenocorticotropic hormone were within normal reference ranges (Table 1). In the peripheral blood, the white blood cell count was slightly elevated, the lymphocyte percentage was 61.5% (reference range 20%–50%), and the absolute lymphocyte value was 6.5 × 109/L (reference range 1.1–3.2 × 109/L). During hospitalization, the patient also underwent chest and abdominal computed tomography (CT) scanning. The abdominal CT suggested multiple small lymph nodes in the abdominal cavity. However, at the time of clinical diagnosis, the likelihood of a nonfunctioning pituitary adenoma was still favored.

FIG. 1
FIG. 1

Preoperative pituitary MRI showed dilation of the sella turcica, sagging of the sellar floor, and a mass visible in the intrasellar and suprasellar region. A: Coronal T1-weighted image, the lesion is isosignal. B: On a coronal T2-weighted image, the lesion has an isosignal. C: Coronal enhancement scan with definite inhomogeneous enhancement of the lesion. D: Sagittal T1-weighted image. E: Sagittal enhancement scan. F: Axial enhancement scan.

TABLE 1

Laboratory findings of pituitary-related hormones

MeasurePRLACTHTSHFree T4IGF-1am Cortisol
Reference range2.27–19.64 ng/mL6.00–56.00 pg/mL0.55–4.78 mIU/L11.5–22.7 pmol/L43–220 ng/mL5.27–22.45 μg/dL
Preop16.3015.901.9512.26168.0011.64
Postop3.1822.301.338.7783.4017.73

ACTH = adrenocorticotropic hormone; IGF-1 = insulin-like growth hormone 1; PRL = prolactin; TSH = thyroid-stimulating hormone; T4 = thyroxine.

Operation and Postoperative Course

According to preoperative pituitary MRI, the mass was large, had invaded adjacent structures, compressed the optic chiasm and encircled part of the right internal carotid artery, and had a Knosp grade of 2 to 3, which was indicative of surgery. After informing the patient of her condition, she requested that the lesion be removed to prevent progression of the mass and to further define the nature of the pathology. Considering that her lesion was located in the sellar area, we performed a single-nostril endoscopic transnasal transsphenoidal pituitary surgery. After grinding the bone of the sellar floor and clipping the dura mater, the tumor was exposed, which was light red, tough, and extremely rich in blood supply. During the operation, we observed that the tumor had invaded the diaphragma sellae and that there was cerebrospinal fluid outflow after the resection of the tumor (Fig. 2). The patient’s autologous thigh broad fascia, fat, and muscle were taken for reconstruction of the skull base. Her coagulation function did not show any abnormality throughout the operation. Total tumor resection was achieved endoscopically, and the tumor was sent for pathological analysis. The pathology results showed a non-Hodgkin’s small B-cell lymphoma, which, combined with the immunophenotyping, led to a final diagnosis of CLL/SLL (Fig. 3).

FIG. 2
FIG. 2

A: The dura mater of the sellar floor was opened to expose the tumor. B: Invasion of the diaphragma sellae was seen after resection of part of the tumor. C: The right cavernous sinus was invaded. D: The intrasellar state after complete resection of the tumor.

FIG. 3
FIG. 3

A: Hematoxylin and eosin staining showed a large number of tumor cells with marked vascular proliferation and background inflammatory cells. B: CD23-positive expression. C: CD20-positive expression. D: CD10-negative expression.

The patient subsequently received relevant treatment, and a complete bone marrow biopsy suggested active myeloproliferative activity (approximately 60%) with markedly increased lymphocytes and small cytosol, which was considered to be lymphoproliferative disease. Given these findings in combination with the surgical pathology, the patient was treated with the targeted drug zanubrutinib. After surgery, the patient recovered well and was given oral levothyroxine sodium replacement therapy after a 1-month postoperative review of low thyroid function (Table 1).

Patient Informed Consent

The necessary patient informed consent was obtained in this study.

Discussion

Observations

CLL/SLL is a clonal proliferative neoplasm of mature B-lymphocytes with specific immunophenotypical features occurring predominantly in middle-aged and older adults and is characterized by aggregation of lymphocytes in the peripheral blood, bone marrow, spleen, and lymph nodes. The disease has an insidious onset, and sometimes the diagnosis is discovered after obtaining a blood count for other reasons. Enlarged lymph nodes are its most common symptom.7

The probability of this disease occurring in the pituitary is extremely rare. Previously, there have been case reports of lymphoma cells infiltrating the pituitary gland during surgery for pituitary apoplexy in patients who have been diagnosed with CLL, and a small number of similar cases have been reported in some autopsy findings, which are not instructive for the treatment of this disease.8,9 However, there is no clear report of a case such as ours, which was found by accident on examination, had a good postoperative recovery, was clearly diagnosed, and is now being treated with targeted drugs and can be followed up with a sustainable prognosis. CLL/SLL of the pituitary usually expresses both CD5 and CD23, and other related immunophenotypes such as CD43 and CD20 are also positively expressed, whereas CD10 and cyclin D1 are negatively expressed. In our case, the final diagnosis of CLL/SLL of the pituitary was confirmed in combination with an absolute preoperative peripheral blood lymphocyte value of 6.5 × 109/L ≥ 5 × 109/L.6,7,10 CLL/SLL is readily diagnosed on the basis of a markedly elevated peripheral blood lymphocyte count, typical lymphocyte morphology, and immunophenotypic features, but it still needs to be differentiated from other disorders, particularly mantle cell lymphoma, marginal zone lymphoma in the leukemic stage, and lymphoplasmacytic lymphoma, which also express CD5 but in most cases dos not express CD23.11 For such tumors occurring in the sellar region, it is very easy to confuse them with pituitary adenomas on imaging analysis alone until pathological results are available.12

In our case, endoscopic total tumor resection was achieved, and the patient was promptly treated with first-line targeted drugs for the hematological system postoperatively, and recurrence is not currently considered in the short term. Given the absence of intracranial lymphoid structures in our case, we considered the sellar region lesion to be due to extracranial focal invasion; after all, the patient’s abdominal CT had confirmed the presence of multiple lymph node enlargements in the abdominal cavity. Although this disease is a malignant hematological disease, the patient did not have any prior history of tumor or self-sensory discomfort, and there are many clinical causes of elevated lymphocyte counts and enlarged lymph nodes, the most common of which is the result of the immune response to systemic or local infections. Therefore, we considered that the sellar mass was more likely to be a nonfunctioning pituitary adenoma. We did not perform tumor embolization, administer oral bromocriptine or cabergoline, or perform puncture biopsy of the enlarged lymph nodes before surgery, and we routinely used endoscopic transnasal transsphenoidal pituitary surgery to resect the sellar region mass.13 The patient recovered well after the operation, but her thyroid function was low when she was rechecked 1 month after the operation and was given oral levothyroxine sodium replacement therapy. Hypofunction caused by similar related diseases has been reported, and supplementation with the appropriate hormones is sufficient.14,15

Due to the high recurrence rate and systemic invasive tumor biology of these hematological malignancies, close follow-up is warranted. In this case, it has been more than 6 months since the operation, and the patient is still available for follow-up. With the advent of the targeted era, she is currently regulated on the first-line targeted drug zanubrutinib. Bruton’s tyrosine kinase (BTK) is a key regulator of the B-cell receptor signaling pathway and plays an important role in B-cell proliferation, apoptosis, differentiation, and development. Zanubrutinib is a selective inhibitor of BTK, which inhibits the activity of BTK by covalently binding to the cysteine at site 481 of the BTK protein, thereby inhibiting its tyrosine phosphorylation at site 223.5,16,17

Lessons

CLL/SLL in the pituitary gland is extremely rare, and our patient did not have any prior history of tumor, had a good postoperative recovery with a normal quality of life, and still receives hormone replacement and zanubrutinib on a standardized basis. Ours is a complete case that has not been previously reported and reveals the diagnostic and therapeutic processes of rare diseases in the sellar area.

Author Contributions

Conception and design: Zhou, X Zhang. Acquisition of data: Zhou, X Zhang. Analysis and interpretation of data: Zhou. Drafting the article: Zhou, X Jia. Critically revising the article: Q Zhang, Zhou. Reviewed submitted version of manuscript: Zhou. Approved the final version of the manuscript on behalf of all authors: Q Zhang. Administrative/technical/material support: Q Zhang, Zhou, L Jia. Study supervision: Q Zhang, Zhou.

References

  • 1

    Saeger W, Lüdecke DK, Buchfelder M, Fahlbusch R, Quabbe HJ, Petersenn S Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry. Eur J Endocrinol. 2007;156(2):203216.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Saeger W Space occupying processes of the sellar region with emphasis on tumor-like lesions. Article in German. Pathologe. 2003;24(4):247254.

  • 3

    Abushamat LA, Kerr JM, Lopes MBS, Kleinschmidt-DeMasters BK Very unusual sellar/suprasellar region masses: a review. J Neuropathol Exp Neurol. 2019;78(8):673684.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Pekic S, Stojanovic M, Manojlovic Gacic E, et al. The sellar region as presenting theater for hematologic malignancies-A 17-year single-center experience. Endocr J. 2022;69(9):10791090.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Wierda WG, Brown J, Abramson JS, et al. NCCN Guidelines® Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 3.2022. J Natl Compr Canc Netw. 2022;20(6):622634.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):27452760.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Hoeller S, Zhou Y, Kanagal-Shamanna R, et al. Composite mantle cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma: a clinicopathologic and molecular study. Hum Pathol. 2013;44(1):110121.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Krisht KM, Palmer CA, Couldwell WT Combined chronic lymphocytic leukemia and prolactinoma: a rare occurrence in a patient presenting with pituitary apoplexy. J Neurosurg. 2013;119(4):924928.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Rye AD, Stitson RN, Dyer MJ Pituitary infiltration in B-cell chronic lymphocytic leukaemia. Br J Haematol. 2001;115(4):718.

  • 10

    Coelho Siqueira SA, Ferreira Alves VA, Beitler B, Otta MM, Nascimento Saldiva PH Contribution of immunohistochemistry to small B-cell lymphoma classification. Appl Immunohistochem Mol Morphol. 2006;14(1):16.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Yoshino T, Tanaka T, Sato Y Differential diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma and other indolent lymphomas, including mantle cell lymphoma. J Clin Exp Hematop. 2020;60(4):124129.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Shin DW, Kim JH, Kim YH, Cho YH, Hong SH Primary central nervous system lymphoma involving the hypothalamic-pituitary axis: a case series and pooled analysis. J Neurooncol. 2020;147(2):339349.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Azab WA, Khan T, Alqunaee M, Al Bader A, Yousef W Endoscopic endonasal surgery for uncommon pathologies of the sellar and parasellar regions. Adv Tech Stand Neurosurg. 2023;48:139205.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Foo SH, Sobah SA Burkitt’s lymphoma presenting with hypopituitarism: a case report and review of literature. Endocrinol Diabetes Metab Case Rep. 2014;2014:140029.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Khan U, Borg A, Beltechi R, et al. Non-Hodgkin lymphoma causing hypopituitarism can imaging help diagnosis and management? Eur J Case Rep Intern Med. 2021;8(12):002980.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Rainone M, Siddiqi T Management of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma in the era of targeted therapies. Curr Hematol Malig Rep. 2022;17(1):3945.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Hillmen P, Brown JR, Eichhorst BF, et al. ALPINE: zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Future Oncol. 2020;16(10):517523.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Collapse
  • Expand
  • FIG. 1

    Preoperative pituitary MRI showed dilation of the sella turcica, sagging of the sellar floor, and a mass visible in the intrasellar and suprasellar region. A: Coronal T1-weighted image, the lesion is isosignal. B: On a coronal T2-weighted image, the lesion has an isosignal. C: Coronal enhancement scan with definite inhomogeneous enhancement of the lesion. D: Sagittal T1-weighted image. E: Sagittal enhancement scan. F: Axial enhancement scan.

  • FIG. 2

    A: The dura mater of the sellar floor was opened to expose the tumor. B: Invasion of the diaphragma sellae was seen after resection of part of the tumor. C: The right cavernous sinus was invaded. D: The intrasellar state after complete resection of the tumor.

  • FIG. 3

    A: Hematoxylin and eosin staining showed a large number of tumor cells with marked vascular proliferation and background inflammatory cells. B: CD23-positive expression. C: CD20-positive expression. D: CD10-negative expression.

  • 1

    Saeger W, Lüdecke DK, Buchfelder M, Fahlbusch R, Quabbe HJ, Petersenn S Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry. Eur J Endocrinol. 2007;156(2):203216.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Saeger W Space occupying processes of the sellar region with emphasis on tumor-like lesions. Article in German. Pathologe. 2003;24(4):247254.

  • 3

    Abushamat LA, Kerr JM, Lopes MBS, Kleinschmidt-DeMasters BK Very unusual sellar/suprasellar region masses: a review. J Neuropathol Exp Neurol. 2019;78(8):673684.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Pekic S, Stojanovic M, Manojlovic Gacic E, et al. The sellar region as presenting theater for hematologic malignancies-A 17-year single-center experience. Endocr J. 2022;69(9):10791090.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Wierda WG, Brown J, Abramson JS, et al. NCCN Guidelines® Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 3.2022. J Natl Compr Canc Netw. 2022;20(6):622634.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):27452760.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Hoeller S, Zhou Y, Kanagal-Shamanna R, et al. Composite mantle cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma: a clinicopathologic and molecular study. Hum Pathol. 2013;44(1):110121.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Krisht KM, Palmer CA, Couldwell WT Combined chronic lymphocytic leukemia and prolactinoma: a rare occurrence in a patient presenting with pituitary apoplexy. J Neurosurg. 2013;119(4):924928.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Rye AD, Stitson RN, Dyer MJ Pituitary infiltration in B-cell chronic lymphocytic leukaemia. Br J Haematol. 2001;115(4):718.

  • 10

    Coelho Siqueira SA, Ferreira Alves VA, Beitler B, Otta MM, Nascimento Saldiva PH Contribution of immunohistochemistry to small B-cell lymphoma classification. Appl Immunohistochem Mol Morphol. 2006;14(1):16.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Yoshino T, Tanaka T, Sato Y Differential diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma and other indolent lymphomas, including mantle cell lymphoma. J Clin Exp Hematop. 2020;60(4):124129.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Shin DW, Kim JH, Kim YH, Cho YH, Hong SH Primary central nervous system lymphoma involving the hypothalamic-pituitary axis: a case series and pooled analysis. J Neurooncol. 2020;147(2):339349.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Azab WA, Khan T, Alqunaee M, Al Bader A, Yousef W Endoscopic endonasal surgery for uncommon pathologies of the sellar and parasellar regions. Adv Tech Stand Neurosurg. 2023;48:139205.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Foo SH, Sobah SA Burkitt’s lymphoma presenting with hypopituitarism: a case report and review of literature. Endocrinol Diabetes Metab Case Rep. 2014;2014:140029.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Khan U, Borg A, Beltechi R, et al. Non-Hodgkin lymphoma causing hypopituitarism can imaging help diagnosis and management? Eur J Case Rep Intern Med. 2021;8(12):002980.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Rainone M, Siddiqi T Management of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma in the era of targeted therapies. Curr Hematol Malig Rep. 2022;17(1):3945.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Hillmen P, Brown JR, Eichhorst BF, et al. ALPINE: zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Future Oncol. 2020;16(10):517523.

    • PubMed
    • Search Google Scholar
    • Export Citation

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