Cancer, Hairy Cell Leukemia


Article Author:
Phyu Thin Naing


Article Editor:
Utkarsh Acharya



Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Kyle Blair
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
9/9/2019 10:47:58 PM

Introduction

Hairy cell leukemia (HCL) is a relatively rare chronic B-cell malignancy that involves the bone marrow, spleen, and peripheral blood. The complete blood count may reveal pancytopenia including monocytopenia. Median age at diagnosis is approximately 55. Poor prognostic features, while somewhat variable in the literature, may include age, hemoglobin less than 10  g/dL, platelets less than 100, ANC less than 1000, the presence of lymphadenopathy, and massive splenomegaly. Differential diagnosis includes other B-cell lymphoproliferative disorders, including splenic marginal zone lymphoma. A distinct entity is known as hairy cell leukemia variant (HCL-V), which is biologically unique from HCL also exists. Response to typical HCL in this disease is poor. The variant can be identified by immunophenotypic differences, lack of BRAF mutation, and lack of monocytopenia.[1][2]

HCL accounts for 2% of all leukemias with approximately 1000 new cases being reported in the United States each year.

Etiology

The etiology of hairy cell leukemia is not well elucidated. However, previous exposure to various chemicals may play a role in its development. Most cases are postulated to be derived from V600E BRAF gene mutation of late activated memory B cells.

Epidemiology

Hairy cell leukemia is a rare neoplasm representing 2% of lymphoid leukemias. Median age at diagnosis is 55 years old. Although it may occur in younger individuals, it is almost never seen in children. Males are disproportionately affected compared to females, with a ratio of 4:1.

Pathophysiology

As a lymphoproliferative neoplasm, Hairy cell leukemia is a clonal disorder. The relatively recent discovery of the presence of the V600E BRAF mutation in the vast majority of cases of classic Hairy cell leukemia has suggested that the pathogenesis of this disorder lies in the RAS-RAF-MAPK signaling pathway. Constitutive activity of this pathway leads to increased cellular proliferation and survival, and, ultimately, malignancy. A recent study by Sascha Dietrich et al. also found CDKN1B inactivation in 16% of patients with classical HCL. It is the second most commonly mutated gene in HCL.

Histopathology

Diagnosis of HCL is based on morphological evidence of hairy cells under microscopic examination. The HCL cell is a mononuclear cell that is usually 1 to 2 times the size of a mature lymphocyte. HCL cells can be identified in Romanowsky-stained peripheral blood films from approximately 90% of patients as mononuclear cells that are usually 1 to 2 times the size of a mature lymphocyte. The nuclei are most commonly ovoid but may be round, oval, or horseshoe-shaped. The cytoplasm is variable in amount but usually abundant, pale blue to blue-gray, and occasionally described as "fluffy" or "hairy." The hairy projections are more easily visualized under the electron microscope.

History and Physical

Affected patients often have non-specific symptoms including fatigue and weakness, as well as symptoms related to cytopenias and splenomegaly. Eighty percent of patients will have significant cytopenias on presentation, with severe pancytopenia in less than 10%. While splenomegaly is a predominant feature, massive, symptomatic splenomegaly is less frequent, perhaps due to earlier detection on routine complete blood count (CBC). Autoimmune thrombocytopenia and hemolytic anemia can occur along with hairy cell leukemia, rarely. Infectious complications are common, due to both the underlying immunosuppression from cytopenias and myelosuppressive therapy.

Evaluation

Diagnosis is achieved by studies on peripheral blood, including flow cytometry and review of peripheral smear, along with bone marrow biopsy. A “dry tap,” or, inability to perform bone marrow aspiration is frequently encountered with hairy cell leukemia although not with HCL-V. The hairy cell has characteristic-appearing mononuclear cells which are typically large with circumferential hair-like cytoplasmic projections and a round, well-defined nucleus. The flow cytometry markers positive in hairy cell leukemia include CD11c, CD25, CD103, and CD123, along with typical B-cell markers such as CD19, CD20, or CD22. The cyclin-d1 expression is usually present, but it is weak or focal (in contrast to mantle cell lymphoma). HCL-V is negative for CD25 and CD123. BRAF-mutation V600E is seen in nearly all cases of classic hairy cell leukemia (although it is not present in HCL-V). CT should be considered to assess the degree of lymphadenopathy.[3][4][5]

Treatment / Management

Given its incurable nature, hairy cell leukemia treatment is reserved for symptomatic patients, including significant fatigue, symptomatic splenomegaly, and significant cytopenias (hemoglobin less than 12 g/dL, platelets, 100000/mcL, ANC less than 1000/mcL). Asymptomatic individuals should be monitored closely for disease progression with history and physical and CBC approximately every 3 to 6 months.

Cladribine and pentostatin, 2 purine analogs, are the first-line treatment for hairy cell leukemia. They are equally effective in inducing and maintaining remission. Nonetheless, cladribine is regarded as first-line chemotherapy among most hematologists due to its favorable toxicity profile. A single course of cladribine induces complete response in approximately 90% of individuals after one cycle (5 to 7 days). It is important to note that these patients will be immunosuppressed for many months following therapy, and attention to possible infectious complications is critical. A recent meta-analysis conducted by Andrasiak et al. showed that the most effective therapy in patients who are treatment-naive and in the first relapse was cladribine with rituximab maintenance. Vemurafenib was also shown to be similarly efficacious; however, it is usually used for refractory or progressive cases.

Interferon-alpha is the treatment of choice during pregnancy when treatment is warranted. It may be preferred for the initial treatment in patients with severe pancytopenia and/or active infection to improve blood counts and allow for subsequent therapy with purine analogs. However, patients with HCL who express the CD5 antigen appear to respond poorly to IFN-a.

Splenectomy may be considered in patients with symptomatic massive splenomegaly, severe pancytopenia due to splenic sequestrations and as a temporizing measure in symptomatic pregnant women.

Repeat bone marrow biopsy should be performed after treatment to confirm complete remission. Complete remission is defined as the absence of hairy cells in blood and bone marrow, resolution of splenomegaly, and recovery of peripheral blood counts (Hgb greater than 12, platelet greater than 100, ANC greater than 1500). Partial response is defined as normalization of peripheral blood counts along with a 50% decrease in splenomegaly, and less than 5% of circulating hairy cells remain. Currently, the clinical implications for minimal residual disease (MRD) are poorly defined. Many patients MRD will still have prolonged, complete hematologic remissions.

Relapsed disease can be treated with either another course of purine analog (if relapse is more than 1 year from initial treatment); however, response rates are often lower, and remissions shorter after relapse. Many other options for relapsed or refractory disease exist, including a combination of cladribine or pentostatin with rituximab, fludarabine alone or in combination with rituximab, bendamustine, and interferon-alpha. The BRAF mutation in hairy cell leukemia can be targeted by the oral BRAF inhibitor vemurafenib, which has been shown to be efficacious in both the relapsed and refractory settings.

Supportive care measures such as antimicrobial prophylaxis for viral and pneumocystis pneumonia should be considered for those with significant cytopenias. Transfused blood products, if necessary, should be irradiated to prevent transfusion-associated graft-versus-host disease.

Differential Diagnosis

Differential diagnoses include:

  • HCL variant: Typically has prominent nucleoli and less marrow infiltration. It is often associated with extreme leukocytosis, often without the neutropenia, monocytopenia, anemia, and thrombocytopenia seen in HCL.
  • Splenic diffuse red pulp small B cell lymphoma: Typically does not express annexin A1, CD25, CD103, CD123, and CD11c.
  • Splenic marginal zone lymphoma: Typically does not express CD103, CD11c, and CD25.
  • Other unclassifiable splenic lymphomas
  • Mantle cell lymphoma: Expresses CD5 and has strong expression of cyclin D1; it does not express CD25, CD103, or annexin A1. It also does not demonstrate hairy cytoplasm in lymphocytes.
  • Chronic lymphocytic leukemia: Expresses CD5 and lacks expression of CD103. It involves both red pulp and white pulp of the spleen while HCV predominantly involves red pulp.
  • Prolymphocytic leukemia: Marked the elevation of the white blood cell count, with the characteristic morphology of prolymphocytes and lack of hairy cytoplasmic projections.

Medical Oncology

Many investigational therapeutic agents are underway for the treatment of hairy cell leukemia. At least 3 monoclonal antibodies, directed against CD22, CD20, or CD25, have been evaluated in the treatment of resistant or relapsed HCL. However, except for rituximab, the anti-CD20 antibody, the other monoclonal antibodies are still considered experimental at this point.

Prognosis

The median survival is usually 4 years without treatment. VH4-34 positive HCL cases are associated with poor prognosis.

Complications

Several studies have reported cases of secondary malignancies in patients with hairy cell leukemia. It could be explained by the immunosuppression caused by the disease itself or the use of chemotherapeutic agents.

Enhancing Healthcare Team Outcomes

Hairy cell leukemia is a relatively rare hematological malignancy and is best managed by an interdisciplinary team that includes an oncologist, hematologist, internist, and an infectious disease expert. There is no cure for hairy cell leukemia and without treatment life expectancy is about 4 years. [6] (Level V)Only symptomatic patients are treated with chemotherapy. Once treated, these patients need to be followed by the oncology nurse and primary care physician with regular monitoring of blood work.

The interprofessional team can optimize the treatment of these patients through communication and coordination of care. Oncologists provide diagnoses and care plans. Nurse practitioners implement care and monitor treatment. Specialty care oncologic nurses should work with the team for coordination of care and are involved in patient education. Oncologic pharmacists should evaluate medications prescribed, recognize drug-drug interactions, provide patient education, and monitor compliance. The interdisciplinary team can thus improve outcomes for patients with HCL. [Level V]

Supportive care measures such as antimicrobial prophylaxis for viral and pneumocystis pneumonia should be considered for those with significant cytopenias. Patients should be educated about personal hygiene and the importance of handwashing.


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Cancer, Hairy Cell Leukemia - Questions

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A 55-year-old patient undergoes a workup for low-grade fever, weight loss, and general malaise. Blood work reveals the presence of cells positive for tartrate-resistant acid phosphatase. What is the most likely diagnosis?



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Which of the following medications is indicated for use in hairy cell leukemia?



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A 60-year-old male with no significant past medical history presents for evaluation after a routine CBC showed a hemoglobin of 9 grams/dL and a platelet count of 76,000 platelets/microliter. On a review of his peripheral smear, mononuclear cells with circumferential hair-like cytoplasmic projections were noted. He has had a several month history of vague left upper quadrant pain and early satiety. Which of the following is most likely to be noted on his bone marrow biopsy or aspirate?



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Which of the following immunophenotypes is most characteristic of classic hairy cell leukemia?



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A 65-year-old male is diagnosed with hairy cell leukemia after further workup from a routine CBC which showed pancytopenia. Which of the following should prompt treatment?



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A 35 year old female G2P1 in her second trimester is diagnosed with hairy cell leukemia after severe cytopenias were noted on her CBC. Which of the following should be considered as first line treatment?



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A 70-year-old male with no medical comorbidities and a Karnofsky performance status of 90 is found to have relapsed hairy cell leukemia 24 months after he was initially treated with cladribine. Which of the following is the best treatment choice?



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A 52-year-old male has been referred to the hematology clinic. He has not been feeling well for the past 4 months and was found to be anemic and thrombocytopenic. A blood smear is shown below. Cytochemical evaluation of the cells revealed positivity for tartrate-resistant acid phosphatase. While other blood work is pending, what is one universal feature that is expected in the majority of patients with this disorder?

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  • Image 6297 Not availableImage 6297 Not available
    Image courtesy S Bhimji MD
Attributed To: Image courtesy S Bhimji MD



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A 50-year-old male with abdominal fullness and discomfort presents to the clinic for evaluation. On examination, splenomegaly without hepatomegaly is detected. Lab work shows a hemoglobin of 11.5 grams/dL, WBC 4500/mm3, and platelet count 110,000/microliter. The absolute neutrophil count is 1500/mm3. After further investigation, a diagnosis of hairy cell leukemia is made. What is the next step in management?



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A 50-year-old male with a history of hairy cell leukemia presents to the clinic with weakness and fatigue for 1 month. He has been in remission for 3 years. He denies fever, shortness of breath, or abdominal discomfort. On examination, the spleen is mildly enlarged. Lab results show hemoglobin 10.5 grams/dL, WBC 4600/mm3 with an absolute neutrophil count of 1550/mm3, and platelet count 120,000/microliter. A peripheral blood smear shows hairy cells. After careful evaluation, diagnosis of relapsed disease is made, and the patient is considered for retreatment. Which of the following is the reason for retreatment?



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Cancer, Hairy Cell Leukemia - References

References

King AC,Kabel CC,Pappacena JJ,Stump SE,Daley RJ, No Loose Ends: A Review of the Pharmacotherapy of Hairy Cell and Hairy Cell Leukemia Variant. The Annals of pharmacotherapy. 2019 Mar 6;     [PubMed]
Kreitman RJ,Dearden C,Zinzani PL,Delgado J,Karlin L,Robak T,Gladstone DE,le Coutre P,Dietrich S,Gotic M,Larratt L,Offner F,Schiller G,Swords R,Bacon L,Bocchia M,Bouabdallah K,Breems DA,Cortelezzi A,Dinner S,Doubek M,Gjertsen BT,Gobbi M,Hellmann A,Lepretre S,Maloisel F,Ravandi F,Rousselot P,Rummel M,Siddiqi T,Tadmor T,Troussard X,Yi CA,Saglio G,Roboz GJ,Balic K,Standifer N,He P,Marshall S,Wilson W,Pastan I,Yao NS,Giles F, Moxetumomab pasudotox in relapsed/refractory hairy cell leukemia. Leukemia. 2018 Aug;     [PubMed]
Wierda WG,Byrd JC,Abramson JS,Bhat S,Bociek G,Brander D,Brown J,Chanan-Khan A,Coutre SE,Davis RS,Fletcher CD,Hill B,Kahl BS,Kamdar M,Kaplan LD,Khan N,Kipps TJ,Lancet J,Ma S,Malek S,Mosse C,Shadman M,Siddiqi T,Stephens D,Wagner N,Zelenetz AD,Dwyer MA,Sundar H, Hairy Cell Leukemia, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network : JNCCN. 2017 Nov;     [PubMed]
Kreitman RJ,Arons E, Update on hairy cell leukemia. Clinical advances in hematology     [PubMed]
Taylor J,Xiao W,Abdel-Wahab O, Diagnosis and classification of hematologic malignancies on the basis of genetics. Blood. 2017 Jul 27;     [PubMed]
Inbar M,Herishanu Y,Goldschmidt N,Bairey O,Yuklea M,Shvidel L,Fineman R,Aviv A,Ruchlemer R,Braester A,Najib D,Rouvio O,Shaulov A,Greenbaum U,Polliack A,Tadmor T, Hairy Cell Leukemia: Retrospective Analysis of Demographic Data and Outcome of 203 Patients from 12 Medical Centers in Israel. Anticancer research. 2018 Nov;     [PubMed]

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