Hairy cell leukemie

Hairy cell leukemia (HCL): uncommon chronic B-cell leukemia

  • classic form: hairy cell leukemia (HCLc) with specific mutation, BRAFV600E

  • rarer variant: hairy cell leukemia variant (HCLv), without BRAFV600E mutation. WHO 5: deze entiteit komt te vervallen!

Presentatie

Patients often present with symptoms of fatigue and infection. Although patients in the past often presented with an enlarged spleen (approximately 90%), this finding appears to be much less frequent as a result of earlier detection of disease. More commonly, patients present because of incidental findings of pancytopenia.

The initial evaluation should include careful review of the peripheral blood smear with a differential count; monocytopenia is a relatively sensitive and specific manifestation of HCLc. Leukemic cells are often rare.

Immunofenotypering perifeer bloed: Check for positivity for CD19, CD20, CD11c, CD25, CD103, CD123, CD200, and immunoglobulin light chain restriction of the circulating mononuclear cells for confirmation of diagnosis. In contrast, leukemic cells in patients with HCLv are most often CD25 NEG and CD123 NEG, and most of these patients will not be monocytopenic

Beenmerg pathologie: IHC for CD20, annexin-1, DBA.44, VE1 (for BRAFV600E). It is important to note that, in order to avoid false-negative results, highly sensitive techniques (eg, allele-specific polymerase chain reaction or next-generation sequencing) should be preferred over less sensitive techniques (eg, Sanger sequencing, pyrosequencing, or melting curve analysis). If access to sufficient leukemic cells or to highly sensitive molecular techniques for genomic profiling is not readily achievable, then application of immunohistochemical stain (eg, VE1) to the bone marrow biopsy may enable detection of this mutation.

NB. At diagnosis, a successful bone marrow aspirate is often not attainable because of a dry tap, in which extensive fibrosis precludes the ability to obtain a cellular aspirate. Approximately 10% of patients will also have a hypocellular bone marrow biopsy at diagnosis reflecting a decrease in normal hematopoiesis.

Differentiaal diagnose HCLc: splenic B-cell lymphoma/leukaemia with prominent nucleoli (SBLPN), splenic diffuse red pulp small B-cell lymphoma (SDRPL), splenic marginal zone lymphoma (SMZL).

Hairy cells are medium in size with moderately abundant pale blue cytoplasm, reniform nuclei, open chromatin, absent nucleoli, and a characteristic serrated cytoplasmic border

Therapie

Indicatie behandeling

Although the majority of patients with HCL require treatment, a small number (about 10%) may not require immediate therapy and may be closely observed until therapy is needed.

  • Hematologic parameters consistent with initiating treatment: Include at least one of the following: Hb <6.60 mmol/L, platelet count <100/μL, or absolute neutrophil count <1.0/μL.

  • Clinical features or symptoms for which therapy may be considered: Include symptomatic organomegaly, progressive lymphocytosis, or lymphadenopathy, unexplained weight loss (>10% within prior 6 months). Symptomatic splenomegaly may serve as an indication for treatment.

Behandeling

In the absence of renal impairment or active infection, therapy should consist of a standard regimen of a purine nucleoside analog.

In general, the therapeutic agents used to treat HCL are quite effective, but they are immunosuppressive. After the administration of a purine nucleoside analog, there is a further decline in neutrophils before recovery. Initiating therapy before the blood parameters have declined to a dangerous level or before a patient has an active infection is advised.

Primary nucleoside analog induction therapy for HCL involves either cladribine. The administration of cladribine has been effective in several different schedules and by different routes (eg, intravenous continuous infusion for 7 days, intravenous infusion over 2 hours on a 5-day regimen, or alternatively subcutaneously on a once-per-day or once-per-week regimen. Subcutaneous administration reduces cost as well as the inconvenience and adverse effects associated with intravenous treatment.

BRAFV600E mutation: Demonstration of the BRAFV600E mutation could also be important for those who do not respond to standard therapy or have multiple relapses. Inhibitors of BRAFV600E (e.g. vemurafenib) have provided responses in patients who are resistant to standard therapy.

Responsbeoordeling

Assessment of response involves inspection of hematologic parameters, complete physical examination, including an evaluation of spleen size, and then a bone marrow biopsy to determine whether normal hematopoiesis has been established with eradication of the leukemia. Assessment of the completeness of the response may provide guidance regarding the future clinical course. Patients who have the longest disease-free interval have usually achieved a complete remission. An assessment of response is an important part of care. In general, it is recommended that a follow-up bone marrow biopsy after cladribine therapy should be delayed for 4 to 6 months after drug administration is complete. Following purine analog therapy, there can be delayed and continuing improvement. The bone marrow biopsy after pentostatin therapy is usually performed after a clinical response that includes near normalization of hematologic parameters. Administering 2 consolidation doses of pentostatin after induction therapy is completed has been the general practice, but this consolidation has not been proven to be necessary. In patients being treated with pentostatin, failure to obtain clinical evidence of an objective response by 6 months indicates that it is time to select another therapeutic approach. In contrast, patients who show objective evidence of a response by 6 months were treated for up to a year in an attempt to achieve an optimal response

Infectie

The most frequent cause of death among patients with HCL is infection. Because these patients often present with pre-existing neutropenia and/or monocytopenia, bacterial, viral, and opportunistic infections should be anticipated. In addition, the primary therapy for HCL is immunosuppressive, and patients may be placed at further risk for infection during treatment. Purine analogs confer prolonged suppression of immune effector cells (eg, CD4+ T cells) and induce profound and prolonged neutropenia.

Patients must be educated about preventing infection and must learn the indications for seeking medical treatment (eg, fever during periods of neutropenia, rash consistent with varicella zoster). Evidence for the use of specific prevention strategies has not been validated in well-controlled clinical trials. Practice patterns vary among groups, and thus evaluation of prevention and treatment strategies is an important area of needed research.

The use of myeloid growth factors needs to be considered on a case-by-case basis in patients with active infection. Patients may receive vaccinations that use killed viral agents, but there are no data showing that patients with this disease respond to vaccines . Live virus vaccines should be avoided.

Because patients with HCL who have previously been treated with purine analogs have profound and persistent lymphopenia, they should probably receive irradiated blood products, if a transfusion is indicated, to prevent transfusion-associated graft-versus-host disease. Furthermore, hepatitis history should be documented with consideration for suppressive anti-viral treatment of those who are positive for hepatitis B surface antigen. Patients have had severe liver toxicity after immunosuppressive therapy if there is a chance that reactivation of viral hepatitis should occur. Therefore, screening for previous exposure to hepatitis before therapy for the disease is highly recommended.

If active infection is present, attempts to control infection should be pursued before instituting the purine nucleoside regimen. If it is not possible to control infection, alternative therapy with interferon alpha, low-dose pentostatin, or newer agents (eg, vemurafenib) not associated with worsening myelosuppression may be used to improve the absolute neutrophil count in an attempt to control infection before using regular-dose purine analogs to secure a durable response.