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Hairy Cell Leukemia

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An indolent, chronic, B-cell lymphoproliferative disease involving the bone marrow and spleen.

The family of HCLs are chronic B-cell malignancies that account for approximately 2% of all diagnosed leukemias.

HCL B cells tend to accumulate in the bone marrow, splenic red pulp, and in some cases the peripheral blood.

Incidence rate is 0.3 cases per hundred thousand population per year.

Incidence higher in Caucasians than blacks.

There is a 4:1 male predominance.

Caucasians are more frequently affected than other ethnic groups with HCL.

HCL occurs more frequently in farmers and in persons exposed to pesticides and/or herbicides, petroleum products, and ionizing radiation.

There is sufficient evidence of an association between herbicides and chronic lymphoid leukemias, including HCL to consider these diseases linked to exposure.

Familial forms have also been described that are associated with specific HLA haplotypes, indicating a possible hereditary component.

It is likely, a combination of environmental and genetic factors ultimately contributes to the development of HCL.

Cause of HL is not known.

Average age at diagnosis 52 years.

Etiology remains unknown.

Not curable.

A rare chronic lymphoproliferative disorder, with only approximately 2000 new cases diagnosed in the United States each year.

There are 2 distinct categories of HCL, classic HCL (cHCL) and variant HCL (vHCL).

The 2 entities bear clinical and microscopic similarities and because of this were originally indistinguishable.

Differentiating between the classic and variant disease subtypes is sometimes difficult.

For cHCL the median age of diagnosis is 55 years.

vHCL occurring in patients who are somewhat older.

HCL has been described only in the adult population.

cHCL B cells have elevated MAPK signaling, leading to enhancement of growth and survival.

The characteristic immunophenotype of cHCL is a population of monoclonal B lymphocytes which co-express CD19, CD20, CD11c, CD25, CD103, and CD123.

Variant HCL is characterized by a very similar immunophenotype but is usually negative for CD25 and CD123.

CD25 positivity may be lost following treatment, and the absence of this marker should not be used as the sole basis of a cHCL versus vHCL diagnosis.

vHCL often lacks expression of CD25 and CD123.

The B-cell receptor (BCR) is expressed on hairy cells and its activation promotes proliferation and survival of cells.

Changes to the patient’s original immunophenotype have been observed following treatment and upon disease recurrence.

Testing for BRAF V600E by polymerase chain reaction or immunohistochemical staining is now routinely performed when HCL is suspected.

While BRAF V600E is identified in nearly all cases of cHCL, it is rare in vHCL.

The BRAF V600E mutation status is a key feature of cHCL and is absent in vHCL, it is important to perform this testing at the time of diagnosis.

The variant type of HCL can now often be distinguished from cHCL on the basis of BRAF mutational status.

In the rare cases of BRAF V600E–negative cHCL, other mutations in BRAF or downstream targets as well as ab2241ant activation of the RAF-MEK-ERK signaling cascade are observed, indicating that this pathway is critical in HCL.

Expression of the IGHV4 immunoglobulin rearrangement, is more common in vHCL.

IGHV4-immunoglobulin rearrangement has been identified in 10% of cHCL cases and appears to confer poor prognosis.

Other mutated genes that have been identified in HCL include CDKN1B, TP53, U2AF1, ARID1A, EZH2, and KDM6A.20

Male:female predominance of 4:1 with a higher incidence in Ashkenazi Jews and a median age of 52 years.

Rare in persons of African or Asian descent.

Typically present with peripheral blood cytopenias, splenomegaly, and circulating hairy cells.

Most frequent laboratory abnormalities reveal anemia, leukopenia, monocytopenia, and neutropenia.

Other laboratory findings include thrombocytopenia and hypocholesterolemia.

Autoimmune hemolytic anemia and ITP also have been observed.

Usually lack lymphadenopathy.

Associated with an absolute monocytopenia.

Can cause life-threatening conditions such as infections, hemorrhage, and anemia.

It only rarely results in lymphadenopathy.

Has a distinct appearance of the malignant hairy cells.

HCL cells are mature, small lymphoid B-cells with a round or oval nucleus and abundant pale blue cytoplasm.

It’s irregular projections of cytoplasm and microvilli give the cells a s2241ated, “hairy” appearance.

HCL B cells are most similar to splenic marginal zone B cells and memory B cells by gene expression profiling.

Its cell of origin is the hematopoietic stem cell.

Identification of characteristic cells remains the diagnostic sine qua non, by reviewing air dried Wright’s stain material.

Characterized by circumferential cytoplasmic projections (hairlike projections) on lymphocytes.

Immunophenotyping by flow cytometry and immunohistochemical staining of tissues are predominant diagnostic methods at this time.

Immunophenotyping by flow cytometry is characterized by B-cell antigens CD19, CD20 and CD22, and coexpress surface antigens CD11c, CD25, and CD103.

Classic HCL is characterized by the immunophenotypic expression of CD11c, CD25, CD103, and CD123, with kappa or lambda light chain restriction indicating clonality.

HCL B cells are generally negative for CD5, CD10, CD21, CD23, CD27, and CD79b.

Excessive B cells in hairy cell leukemia have an over expression of the protein CD 22 on their services and that provides a means of therapeutically targeting the cells.

Immunohistochemical stains for DBA44 and annexin A1 confirm the diagnosis.

Cyclin D1, annexing A1, monoclonal antibody DBA 44 and BRAF V600E are usually expressed.

BRAF V600E is the genetic lesion that underlies hairy cell leukemia.

Hairy cells are 1.5-2 times the size of mature lymphocytes and the nucleus occupies one half to two thirds of the cell’s area, with monotonous appearance of population of cells.

Nuclear membrane is nearly always smooth in appearance clearly demarcating it from the surrounding cytoplasm.

Cytoplasm of the cells are distinctive with indistinct border described as s2241ated, frayed or wind blown.

Extremely low proliferative rate with virtually absent transformed cells.

Bone marrow biopsy reveals hypercellularity in most cases, with Gary cells having nuclei widely separated by abundant cytoplasm with a fried egg appearance

Infiltration of the bone marrow is usually accompanied by reticulin and collagen fibrosis and it causes difficulty in the ability to aspirate the marrow.

Bone marrow fibrosis in HCL may prevent a marrow aspirate from being obtained, require key diagnostic studies be performed on the core biopsy, including morphological evaluation and immunohistochemical stains such as CD20 (a pan-B cell antigen), annexin-1 (an anti-inflammatory protein expressed only in cHCL), and VE1 (a BRAF V600E stain).

Dry taps on attempted bone marrow aspiration common.

Touch preparations of core biopsy can permit identification of cytologically typical hairy cells and cytochemical staining for TRAP can make the diagnosis in most patients.

Electron microscopy readily demonstrates hairy distinctive hair like cytoplasmic projections, nuclear findings of peripherally arrayed heterochromatin and presence of a small nucleolus.

Occasional patients have atypical cellular features but have clinical, morphologic and immunophenotypic features that are otherwise characteristic.

Leukemic hairy cells found in the blood, bone marrow and splenic red pulp with associated atrophy of the white pulp.

Cells infiltrate the red pulp of the spleen and hepatic sinusoids and portal tracts and usually spare lymph nodes.

The liver is nearly always involved with infiltrate of the hepatic sinusoids and portal tracts.

Peripheral enlargement of lymph nodes is rare but involvement of splenic hilar nodes is common and occasionally abdominal and retroperitoneal nodes are involved.

Infiltrating cells cause bone marrow fibrosis and form vascular lakes, especially in the splenic red pulp.

Moderate to marked splenomegaly in almost all patients due to the expanded red pulp.

Such cells infiltrate the sinus endothelium of the spleen and cause degeneration of the sinus basement membrane resulting in the dilation of the red blood cell filled vascular space creating a “blood lake” appearance.

The white pulp is frequently hypoplastic.

Extramedullary hematopoiesis is infrequent and not a prominent feature of the disease.

Occasional patients present with a process that simulated aplastic anemia with hypocellularity.

Marrow often found to have an increase in polyclonal plasma cells, and increased numbers of mast cells.

Involve activated B cells related more closely to CLL and normal memory B cells than other B cell types.

Prominent surface projections seen on cells on peripheral blood smear.

Highly active cells with distinctive surface morphology.

Cells express light chain restricted immunoglobulin (Slg) and receptors for the Fc of IgG (γFcR) at the cell surface.

Pancytopenias is present in half the cases.

Approximately 1/4 of patients are asymptomatic at presentation, and/or evaluated because of an abnormal complete blood cell count.

Patients previously were diagnosed with HCL when they presented with splenomegaly, infections, or complications of anemia or thrombocytopenia.

Presently, patients are more likely to be incidentally diagnosed when they are found to have an abnormal value on a CBC.

Patients may have pancytopenia or isolated cytopenias.

Patients may be symptomatic with fatigue, dyspnea, bruisability, mucosal cutaneous bleeding, malaise, or weight loss.

Patients with massive splenomegaly may have early satiety and increased abdominal girth.

Cytopenias may also be caused by splenomegaly, and symptomatic splenomegaly with or without cytopenias is an indication for treatment.

Approximately 10% of patients do not require immediate therapy after diagnosis and are monitored until treatment is indicated.

Purine nucleoside analog is usually the recommended first-line therapy.

This includes either cladribine or pentostatin, either agent appears to be equally effective

Peripheral blood flow cytometry can frequently suggested diagnosis, but a bone marrow biopsies essential for confirmation of the diagnosis, and to quantify bone marrow infiltration degree.

A complete assessment of the immunophenotype, molecular profile, and cytogenetic features is required to arrive at this diagnosis.

Evaluation includes: examination of the peripheral blood for morphology and immunophenotyping, obtaining bone marrow core and aspirate biopsy samples for immunophenotyping via immunohistochemical staining and flow cytometry.

Treatyment is initiated with symptomatic patients, but for asymptomatic patients there are no absolute criteria for treatment.

Patients should be treated when declining trend in hematologic parameters are present or the patient experiences symptoms from the disease.

Guidelines recommend treatment when hemoglobin less than 11 g/dL, platelet count less than 100 × 103/µL, or absolute neutrophil count less than 1000/µL. indicating compromised bone marrow function.

The majority of patients with HCL in the modern era will be diagnosed prior to reaching stage 3.

Because there is no curative treatment for either cHCL or vHCL outside allogeneic transplantation.

It is not clear that early treatment leads to better outcomes in HCL.

Treatment at the time of diagnosis or relapse is not always required.

No standard therapy exists, and about 50% of patients relapse after responding to initial treatment.

Although no curative treatment options exist outside of allogeneic transplantation, therapeutic improvements have resulted in patients with cHCL having a life expectancy similar to that of unaffected patients.

The choice of therapy is determined by the treating physician based on his or her experience.

Cladribine administration intravenous continuous infusion (0.1 mg/kg) for 7 days, intravenous infusion (0.14 mg/kg/day) over 2 hours on a 5-day regimen, or alternatively subcutaneously (0.1–0.14 mg/kg/day) on a once-per-day or once-per-week regimen.

Pentostatin is administered intravenously (4 mg/m2) in an outpatient setting once every other week.

The best outcomes are seen in patients who have received combination chemo-immunotherapy such as purine nucleoside analog therapy plus rituximab or bendamustine plus rituximab.

In a study of bendamustine plus rituximab in 12 patients found an overall response rate of 100%, with the majority of patients achieving a complete response.

For patients who achieved a complete response, the median duration of response had not been reached.

Myelosuppressive chemotherapy is not recommended for patients with active infections, and an alternative agent may need to be selected in these cases.

vHCL remains difficult to treat and early disease progression is common, unlike classical hairy cell leukemia.

No accepted standard for minimal residual disease (MRD) monitoring in HCL exists, and quantitative monitoring of marrow involvement by HCL, immunohistochemical staining of the bone marrow core biopsy is usually required.

Relapse could be predicted by evaluating MRD by percentage of positive cells in the marrow by immunohistochemical staining, with less than 1% involvement having the lowest risk for disease relapse and greater than 5% having the highest risk for disease relapse.

About 25% of patients have no signs or symptoms at the initial presentation.

Most individuals have fatigue and generalized weakness and may have unexplained weight loss, left upper quadrant pain, recurrent infections and bruisability.

Examination may reveal hepatosplenomegaly and lymphadenopathy.

Skin manifestations are common and include ecchymoses, purpura, zoster, cellulitis, abscesses, pyoderma, and dermatophytosis.

Asymptomatic patients can be monitored closely before initiation of treatment.

Patients are susceptible to infections due to neutropenia, monocytopenia and associated immunocompromised state.

Alfa-interferon produces a partial remission in 30-70% of patients and a complete remission in 50%.

Splenomegaly almost universal.

Abnormal peripheral blood is seen in nearly all patients with pancytopenia being common and neutropenia usually out of proportion to the degree of anemia and thrombocytopenia.

Dearth of circulating monocytes is a consistent finding and thrombocytopenia diagnosis is unlikely if significant monocytes are present on the review of the blood smear.

Monocytopenia is a common finding in cHCL.

Typical cells of cHCL do not usually circulate in the peripheral blood, but if present would appear as mature lymphocytes with villous cytoplasmic projections, pale blue cytoplasm, and reniform nuclei with open chromatin.

Circulating large granulocytes may be present, and significant leukoerythroblastosis is usually not seen.

Circulating hairy cells are present usually in low numbers.

Rarely associated with lytic bone lesions.

Up to one third of patients have internal lymphadenopathy.

TRAP (tartrate resistant acid phosphatase ) positive.

HCL B cells also typically express CD19, CD20, CD22, CD79a, CD200, CD1d, and annexin A1.

Tartrate-resistant acid phosphatase (TRAP) positivity by immunohistochemistry is a hallmark of cHCL.

Isoenzyme 5 of acid phosphatase resistant to treatment with tartaric acid seen in virtually all cases.

TRAP (tartrate resistant acid phosphtase) seen occasionally in other lymphoproliferative disorders including B cell lymphoma, Sezary syndrome, T cell prolymphocytic leukemia and Human T cell lymphotrophic virus related T cell leukemia.

Acid phosphatase stains are technically difficult, and such cells are heterogeneous so many cells are TRAP negative.

Only a few positive mononuclear cells with cytologic features of hairy cells are required for a positive TRAP study.

Antibodies to Cyclin D seen in nearly all cases.

The BRAF V600E mutation is invariably associated with this disease.

The BRAF V600E Is present in the entire spectrum of patients, including those with leukocytosis or without splenomegaly and those evaluated after treatment, and it is present in the entire tumor cell clone in virtually all patients with hairy cell leukemia.

No recurrent chromosomal translocations have been identified.

HCL genomic profile is relatively stable, with few chromosomal defects or translocations observed.

BRAF V600E is a hallmark mutation in cHCL.

The BRAF V600E gain-of-function mutation results in constitutive activation of the serine-threonine protein kinase B-Raf, which regulates the mitogen-activated protein kinase (MAPK)/RAF-MEK-ERK pathway.

Differential diagnosis: CLL, small lymphocytic lymphoma (SLL), prolymphocytic leukemia (PLL), splenic marginal zone lymphomas (SMZL), HCL variant, myelodysplastic syndrome (MDS), and primary myelofibrosid.

Watchful waiting is appropriate for asymptomatic patients without significant cytopenias.

Poor prognosis factors include: advanced age, hemoglobin <12gm/dL, and presence of splenomegaly.

No proven benefit to treating asymptomatic patients.

No absolute guidelines exist for when to initiate treatment, but therapy is recommended for symptomatic splenomeagly, including early satiety, abdominal discomfort, and difficulty breathing.

In asymptomatic patients treatment is offered for severe cytopenias.

Treatment may be offered if the patient develops an opportunistic infection.

Prior to effective therapy, the median duration of survival after diagnosis was approximately four years, with patients dying of complications related to pancytopenia, hemorrhage and infections.

Disease complications include: anemia, thrombocytopenia, neutropenia, monocytopenia, platelet dysfunction, lytic bone lesions, arthritis, vasculitis, T cell dysfunction, and splenic rupture.

Infections of the most common cause of death.

Before modern chemotherapy, splenectomy was the treatment with a five year survival rate of 68%.

Presently splenectomy is reserved for patients with primary splenic HCL, for those who are refractory to medical therapy, patients with splenic rupture, or for diagnostic purposes.

Splenectomy is associated with a significant risk of hemorrhage, which is the second most common cause of death in patients with HCL.

Treatment initiation precipitated by severe weakness and fatigue, symptomatic splenomegaly, , lymphadenopathy, signs of bone marrow failure with hemoglobin <10 g/dL, a platelet count <100,000/microL, and absolute neutrophil count <1000/microL, and frequent infections.

Sensitive to α-interferon, nucleosides deoxycoformycin, chlordeoxyadenosine and fludarabine.

Interferon has an overall response rate of 73% with a complete remission rate of 49% and a partial response rate of about 24%, with 83% of treated patients remaining alive at six years: currently interferon alpha is used for patients with relapsed and refractory disease after purine analogs.

Current guidelines suggest interferon Alpha therapy for patients who have experienced relapse of the treatment with purine nucleoside analogues, especially for those who may require maintenance therapy, and for patients who are pregnant or who are unable to risk immunosuppression that accompanies purine nucleoside analogues.

Cells produce large amounts of TNF and possess TNF receptors 1 and 2.

Autocrine TNF increases cell survival but in the presence of alpha interferon apoptosis is promoted.

Purine analogues including pentostatin and cladribine demonstrated improved tolerability and response rate, greater reduction in splenic size and lymphadenopathy and longer time to progression over preexisting agents.

Currently Cladribine is the considered treatment of choice, with short duration of treatment, favorable toxicity profile, durable response rates, and improved disease-free survival.

Multiple studies have shown an overall response rate between 98 and 100% with complete remissions ranging from 76-95%.

Relapsed patients after initial therapy with Cladribine can be retreated with another course of the same agent or switched to pentostatin.

Single infusions of cladribine as a continuous infusion over 7 days induces response in more than 95% of patients, 85% of cases are complete and durable.

The application chlorodeoxyadenosine or pentostatin treatment produced estimated 10 year event free survival rates greater than 60% and survival rates greater than 80%.

Pentostatin and cladribine induce complete remissions in up to 85% of patients and partial responses in 5-25%.

Up to 58% of patients with HCL have a relapse, with the disease becoming progressively less sensitive to purine analogues, which could also cause cumulative hematologic and immunologic toxic effects.

Purine analogues such as cladribine and pentostatin Induce complete responses in approximately 80% of patients, however 30 to 50% of patients undergo relapse and have progressively worse response to purine analogues.

Approximately half of patients treated with purine nucleoside analogues eventually undergo a noticeable relapse within 15 years and require additional therapy.

In patient experiencing a relapse, subsequent purine nucleoside analog therapy is often characterized by lower complete remission rates, shorter durations of response, and a greater risk for treatment related toxicities and infections.

Rituximab has an overall response rate of 80% and a complete remission rate of 53%.

Rituximab in combination with purine analogs in relapsed and refractory setting is effective in eradicating minimally residual disease, that can be detected by immunophenotyping by flow cytometry and PCR.

Alemtuzumab can also in the relapsed setting.

With present management the rate of disease-free survival at eight years is 60-75%.

Radiation is effective for lytic lesions associated with HCL and splenic radiation is considered only in patients with symptomatic splenomegaly and are not good candidates for other therapies.

The risk of developing a second malignancy is 2 times the general population.

Associated with markers of CD19, CD20, CD22, CD25, CD11c, FMC7, CD103, CD72, among others.

Cells lack CD23.

Typically B cell markers CD20 and CD22 very positive and almost never express CD5 and only 10% express CD10.

CD11c expressed in B cell CLL and splenic marginal zone lymphoma but has a 30 fold increased expression in HCL.

Absence of CD25 excludes the diagnosis of HCL.

At least 90% of cases are CD103, CD11c, and CD25 positive.

Antibody DBA-44 expressed in 99% of cases, but is also expressed in 80% of cases of splenic marginal zone lymphoma, 20-40% of cases of follicular lymphoma, mantle cell lymphoma and diffuse large B cell lymphoma.

Cells have mutated VH genes.

No specific or consistent chromosomal abnormalities associated with the disease.

The most frequent cytogenetic abnormalities are gains in parts of chromosome 5, about 20%, or losses of long arm of chromosome 7, about 7%.

After effective therapy 15-50% of patients have minimal residual disease using immunohistochemistry and flow cytometry techniques and such disease is not seen on routine morphologic examination.

Many patients with minimal residual disease do not relapse or do so only after many years, therefore minimal residual disease predictive value is low after treatment.

Hematologic remissions can be maintained for extended periods, yet 18 years after diagnosis, roughly half of all long-term complete responders still have minimal residual disease (Sigal DS et al).

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