Hairy Cell Leukaemia Prognosis – Abstract: Hairy cell leukemia (HCL) is a B-cell lymphoproliferative disorder characterized by pancytopenia, splenomegaly, and characteristic cytoplasmic hairy projections. Accurate diagnosis is essential to distinguish classic forms from HCL variants, such as the HCL variant and VH4-34 molecular variants, which are more resistant to available treatments. The current standard of care is treatment with purine analogues (PAs) such as cladribine or pentostatin, which provide high rates of long-term clinical remission. However, ~30%-40% of patients relapse, and in addition, some of these refractory cases are difficult to treat. The use of the monoclonal antibody rituximab in combination with PA appears to produce even higher responses, and is often used to reduce or eliminate residual disease. Currently, research in the field of HCL is focused on identifying new therapeutic targets and potential agents that are safe and can cure the disease globally. The discovery of BRAF mutations and advances in understanding the biology of the disease have allowed the scientific community to discover new therapeutic targets. Ongoing clinical trials are evaluating different treatment strategies such as combinations of PA and anti-CD20 monoclonal antibodies, CD22-targeted recombinant immunotoxins, BRAF inhibitors, and B-cell receptor signaling inhibitors.
According to the World Health Organization classification, hairy cell leukemia (HCL) is defined as a mature peripheral B-cell neoplasm that accounts for 2%–3% of all adult leukemias.
Hairy Cell Leukaemia Prognosis
It is characterized by infiltration of the bone marrow, liver and spleen by malignant B cells with hair-like cytoplasmic projections and an indolent course. HCL is more common in men, with an overall male to female ratio of 4:1, and a mean age of onset of 52 years.
Hairy Cell Leukemia
Hair cells have a characteristic immunophenotype profile showing positivity for CD11c, CD25, and CD103 markers, in addition to the B cell antigens CD20 and CD22. However, recurrent chromosomal translocations have not been identified. Recently, a BRAF V600E mutation was identified to activate the MEK-ERK pathway in patients with classical HCL (HCL-c).
Accurate diagnosis and detailed workup are imperative because the clinical profile of HCL can mimic other chronic B-cell lymphoproliferative disorders that are treated differently. Variants of HCL, such as HCL-Variants (HCL-v) and VH4-34 molecular variants, have a different immunophenotype and specific usage of the VH gene and are more resistant to available treatments. BRAF mutations are absent in both variants.
Before the introduction of purine analogs (PAs), splenectomy and treatment with interferon alfa led to clinical and hematological responses; However, these were rarely completed and median survival was only 4 years.
Frontline treatment of HCL is currently based on the purine nucleoside analogues pentostatin or cladribine. Both agents yield high and durable response rates, but 30%–40% of patients will eventually relapse 5–10 years after their first treatment.
Dissection Of The Bone Marrow Microenvironment In Hairy Cell Leukaemia Identifies Prognostic Tumour And Immune Related Biomarkers
In this disease, the main challenge is the treatment of patients with multiple clinical cases as well as those with HCL variants who are refractory to standard PA therapies.
This article provides an update on currently available treatment options and reviews the results of clinical trials with new molecules that may change the future therapeutic landscape of this rare disease.
The main indications for treatment are symptomatic cytopenia or painful splenomegaly. If a patient is asymptomatic and cytopenia is minimal, a watch-and-wait policy is appropriate. It should be noted that patients with monocytopenia, with or without neutropenia, are at high risk for opportunistic infections. Therefore, even asymptomatic patients can be considered for early treatment.
Since the effects of the PAs pentostatin and cladribine have been detected in HCL patients, treatment with these drugs is currently the standard of care. Both agents induce complete remission (CR) in a high proportion of patients (>80%), and most studies show a median disease-free survival of >10 years.
Hairy Cell Leukemia
However, pentostatin and cladribine have not been compared in large randomized trials and most available data on response and toxicity come from published retrospective series. A long-term follow-up study by Else et al showed no difference in outcome between the two agents.
Overall response rates (ORRs) were 96%–100%, CR around 80%, and 10-year overall survival between 85% and 100%, with no statistically significant differences. Relapse rates were similar for both groups (44% for pentostatin and 38% for cladribine). In another retrospective study, 107 patients treated with pentostatin or cladribine were evaluated and a CR was observed with 92% in pentostatin-treated patients and 88% in cladribine-treated patients with a 100% ORR in both groups. Minimal residual disease (MRD) was positive in 52% and 47% (
= 0.016), and the median treatment-free interval (TFI) was 95 months for pentostatin and 144 months for cladribine, with no significant differences. Considering both groups, the data showed a TFI of 44 months compared to 170 months for patients with CR versus partial remission (PR).
The dosing and treatment schedule of PA has recently been published in the revised British Guidelines for the Diagnosis and Management of HCL,
Detection Of Braf Mutations In Patients With Hairy Cell Leukemia And Related Lymphoproliferative Disorders
Which are included in Table 1. Different dosages and schedules have been used with similar results. Roebuck et al showed that if cladribine could be infused over 2 hours instead of 24 hours, 19 of 23 patients achieved a CR. The same study showed that there was no statistically significant difference between CR rates in the group receiving the drug on day 7 compared to day 5, with the 5-day arm presenting fewer infectious complications.
Cladribine was administered at a dose of 0.15 mg/kg per week for 6 weeks. Preliminary results suggested less immunosuppression and similar efficacy in infections.
However, a large follow-up trial involving 138 patients showed that this schedule did not significantly reduce toxicity.
In addition, daily subcutaneous administration of cladribine over 7 consecutive days was studied in 73 patients. Efficacy and toxicity were comparable to studies with intravenous cladribine and plasma concentrations of subcutaneous cladribine were similar to those obtained by the intravenous route.
Therapeutic Algorithm For Relapsed And Refractory Classical Hairy Cell…
Using a 5-day subcutaneous dosing regimen, von Rohr et al treated 62 HCL patients with cladribine 0.14 mg/kg/d. The achieved CR rate was 76% with a response rate of 97%.
Several studies have shown the type of response to PA to be an important prognostic factor, with patients who achieved only a partial response doing significantly worse than those who achieved a CR.
Therefore, achieving a CR is an important goal of treatment. Bone marrow evaluation is recommended after cell count recovery (4–6 months after cladribine therapy or eight to nine courses of pentostatin), and a second course of PA therapy is given if patients do not enter CR.
Although both PAs are highly effective and lead to excellent overall survival, it seems that neither of them is curative as most patients have evidence of MRD despite being in CR. Several authors have studied the presence of MRD using immunohistochemistry, flow cytometry, or polymerase chain reaction techniques.
The 5th Edition Of The World Health Organization Classification Of Haematolymphoid Tumours: Lymphoid Neoplasms
Who detected MRD in 40%–60% of patients who received PA. Flow cytometry is clearly superior to other techniques, but the prognostic implications of MRD detected after HCL treatment can be confounded by several factors: -Variability in the sensitivity of different techniques used for the assessment of MRD, lack of uniformity of criteria. Define MRD, variability in timing of MRD assessment after therapy, and limited number of patients in reported studies.
However, an abundance of data suggests that persistence of MRD after nucleoside analog therapy predicts disease recurrence. Tallman et al
MRD was studied using immunohistochemical techniques in patients treated with PAs. The prevalence of MRD detected after cladribine (13%) was lower than after pentostatin treatment (26%) but was not significantly different. However, the 4-year relapse-free survival rate was significantly lower (55% vs. 88%) if MRD was detected.
MRD positivity (analyzed by immunophenotyping) was detected in 49% of 107 HCL patients treated with PAs, and significant differences were found between the two treatments. The TFI estimated by Kaplan-Meier analysis was 97 months in MRD + patients, while the median TFI in MRD patients was not reached (
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The utility of MRD detection was confirmed using the results of flow cytometry techniques to identify patients at high risk of recurrence.
The rationale for adding rituximab to PAs was based on the efficacy and safety of this combination in patients with recurrent disease.
Reported a phase II clinical trial in 31 patients with previously untreated HCL. Cladribine was administered intravenously at 5.6 mg/m
2 hours/day for 5 consecutive days. Approximately 4 weeks after starting cladribine, eight weekly doses of rituximab (375 mg/m
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Intravenously) was administered. A CR rate of 100% was reported and, after a median follow-up of 25 months, median survival in CR, PFS, and overall survival had not been reached. Patients achieved MRD-negative status after completing rituximab treatment, as demonstrated by flow cytometry and consensus polymerase chain reaction. Despite a marked decrease in CD4 count
No increase in T cells, as well as serum immunoglobulin levels, was observed in the incidence of opportunistic infections. Longer follow-up studies may provide more information on the importance of achieving MRD-negative CR on long-term outcomes.
The results of ten patients who received four cycles of rituximab after the administration of cladribine were analyzed. Before starting anti-CD20 antibody therapy, two patients were in CR, six were in PR, and two had no significant response to cladribine. All cases resulted
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