Priority Report
Therapeutic Advances in Hairy Cell Leukemia
Volume 1
Issue 1

Treatment of Hairy Cell Leukemia: Overview and First-Line Options


Hairy cell leukemia is a rare malignancy for which treatment has progressed significantly in recent years.

Hairy cell leukemia (HCL) is a rare malignancy for which treatment has progressed significantly in recent years. Patients with HCL were once limited to survival times of approximately 4 years following diagnosis, but current and developing treatments are allowing these patients to lead normal lives with life expectancies that are similar to those of the general population.1,2 This article provides a historical overview of treatment options that have been effective in combating HCL, and it discusses the progression that culminated in the current and emerging first-line HCL therapies.

Historical Perspective and Treatment Options

HCL was first recognized as a clinical entity in a 1958 paper describing a series of patients with leukemic reticuloendotheliosis.3 In this report, nearly every patient presented with an enlarged spleen, and the authors detailed the cytoplasmic projections of the characteristic “hairy” cells that were detected in blood samples.3 In this era, patients often died of infectious complications and cytopenia.1

Hairy cells typically infiltrate the bone marrow and spleen; these sites are frequently symptomatic in patients with HCL. Splenomegaly is historically a common presenting feature of HCL; however, modern early detection abilities may be causing this statistic to decline.4 The bone marrow of these patients is typically difficult to aspirate, frequently resulting in a dry tap.4 Patients with HCL also often develop opportunistic infections.5

Some patients with HCL are asymptomatic and can be monitored for symptom development without undergoing treatment, as no studies have indicated benefits to early treatment initiation.6 The National Comprehensive Cancer Network (NCCN) guidelines recommend using clinical judgment when electing to begin treatment based on physician preference, patient comfort, and hematological parameters. Treatment is indicated in patients who are symptomatic, including those who experience excessive fatigue, pancytopenia, recurrent infections, or symptomatic splenomegaly (early satiety, difficulty breathing, rupture).7 Patients who exhibit declining hematologic parameters are also recommended to initiate treatment. Most patients with HCL will require treatment upon initial presentation.


Initially, splenectomy was the preferred therapy for patients who experienced progressive cytopenia, recurrent infections, or discomfort associated with an enlarged spleen.2 This was the standard of care for patients with HCL for years, based on data from a few key retrospective studies and the belief that chemotherapy was dangerous to patients previously suffering from pancytopenia.8 Several analyses reported that splenectomy led to positive outcomes for many patients, including palliation of symptoms, longer survival times, and improved blood counts.8 Although splenectomy had positive impacts on pancytopenia, it failed to address the impacts of circulating hairy cells and bone marrow infiltration, ultimately allowing the disease to progress.9

Several studies throughout the 1970s and 1980s illustrated the positive impact of splenectomy as an HCL intervention. One 1979 study reported a 5-year actuarial survival rate of 72% in 26 patients with HCL who underwent splenectomy as an initial therapy.10 Of these patients, 42% experienced a complete response (CR) and 58% exhibited a partial response (PR). The 5-year actuarial survival for the CR and PR groups was 86% and 47%, respectively. This study reported that even patients with minimal spleen enlargement had the potential to benefit from splenectomy.10

In 1981, a large retrospective study evaluated 391 patients across 22 different medical centers who underwent splenectomy for symptomatic HCL.8 When compared with those who did not undergo splenectomy, patients who were treated with splenectomy survived for significantly longer (P <.0001). In addition, this analysis found that patients aged >60 years did not benefit from the procedure.8

Another group reported the outcomes of 63 patients with HCL who underwent splenectomy; 67% of measurable patients had a CR at 6 months post procedure.9 Ultimately, 44% of these patients experienced disease progression, and the overall survival (OS) rate for this group was 61% at 5 years.9 In addition to measuring outcomes, this study attempted to determine predictive factors that could identify patients who would respond to splenectomy, including sex, age, and hematologic parameters, but the investigators were unable to pinpoint any effective indicator.9 Although several studies have attempted to define predictive markers, no consensus exists on how a patient with HCL will respond to this therapy.

Splenectomy remained the standard of care for HCL until the emergence of interferon-based therapies in the 1980s. Although it is not currently listed as a treatment option in the NCCN guidelines, selected patients may benefit from splenectomy, including those who are pregnant or have symptomatic splenomegaly, active infection, or thrombocytopenia with bleeding.1,11

Interferon Therapy

Although splenectomy was beneficial and increased longevity in some patients, the outcomes of this procedure were often unsatisfactory, and an unmet need remained for better intervention methods.9 The emergence of interferon-based therapies in the early 1980s dramatically altered the treatment landscape for patients with HCL. Prompted by an HCL workshop at the University of Chicago in 1983, a large collection of studies was performed that reported CRs in patients with HCL.2 These data, in addition to higher response rates, extended remission, and longer survival times, rapidly pushed interferon therapy to the frontline of HCL treatment.

Interferons are a class of cytokines that promote immune function. These agents play a role in cellular defense against viruses and malignant cells, and they have antiproliferative activity as well. This antiproliferative function has supported the successful deployment of interferon-based therapies against malignancies, including HCL.12 Several interferon agents have been effective in combating different cancer types, but interferon-&#593; agents have been most successful in treating HCL.12 The mechanism of action of interferon &#593; in treating HCL involves inducing apoptosis in malignant cells, hindering cell division, and interfering with growth factor signaling.6

The significance of interferon &#593; therapy was rapidly and widely appreciated, with several studies reporting overall response rates (ORRs) ranging from 69% to 87%.12,13 An early study reviewed more than 200 patients with HCL who had received interferon therapy, and it reported that hairy cells disappeared and platelet levels were normalized in most patients.13 Another study followed 30 patients who were treated with interferon &#593;-2a and reported that 30% of patients had a CR, 57% had a PR, and all patients exhibited improved blood counts.14 These results indicated that interferon therapy could provide drastic improvements for patients with HCL, and they shed light on the potential for achieving long-term remission following diagnosis. Recombinant interferon &#593;-2a and &#593;-2b, forms that differ by 1 amino acid, were both approved by the FDA in 1986 for the treatment of patients with HCL.12

Although many patients benefited from treatment with interferon therapy, most eventually relapsed after discontinuing treatment. Median time-to-treatment failure ranged from 6 to 25 months following therapy discontinuation, with 2-year disease-free survival rates ranging from 25% to 60%.12 Fortunately, however, patients often respond to readministration of interferon therapy, making long-term survival possible through maintenance therapy.12 The high incidence of relapse remained a significant unmet need for patients with HCL. Additional studies pushed to identify better therapies with durable long-term efficacy.

Since the early 1980s, when interferon therapy became a treatment option and remission appeared attainable, the therapeutic options and management of HCL have greatly improved, particularly with the development and approval of purine nucleoside analogues (PNAs).6 Although interferon &#593; therapy has since been replaced as a first-line therapy, certain patient populations may still benefit from this treatment.1,7 Current NCCN guidelines suggest interferon &#593; therapy for patients with HCL who have experienced relapse after treatment with PNAs, especially for those who may require maintenance therapy.7 For patients who are pregnant or who are unable to risk the immunosuppression that accompanies treatment with PNAs, interferon &#593; may also be a safer initial treatment option.6

Standard First-Line Treatment of HCL: Purine Nucleoside Analogues

The advent of PNAs was the next major advancement to impact HCL treatment. Purine analogues for the treatment of HCL began to emerge in the late 1980s, with studies showing the promising efficacy of pentostatin. These were quickly followed by promising data supporting the use of cladribine.15-17 Currently, cladribine and pentostatin remain the first-line therapeutic options for treating patients with HCL.7


Cladribine (2-chlorodeoxyadenosine) is a synthetic PNA that mimics adenosine. As a prodrug, cladribine must be phosphorylated by deoxyadenosine kinase prior to activation. A key feature of cladribine is its resistance to adenosine deaminase, which is an enzyme required for purine metabolism in lymphocytes. Resistant to breakdown, active phosphorylated-cladribine accumulates in lymphocytes where it is incorporated into DNA, causes DNA strand breakage, and decreases RNA synthesis. These nucleic acid disruptions ultimately drive apoptosis within lymphocytes while minimizing off-target effects.17,18

Cladribine was first introduced as a potential HCL treatment in 1990 with striking study results. Of 12 patients with HCL who were treated with a 7-day continuous infusion of cladribine, 11 achieved CR and 1 exhibited a PR.17 These results were later confirmed by Saven et al in a larger study group, in which 349 patients with HCL were treated with single-agent cladribine. The authors reported an ORR of 98%, with 91% of the evaluable patients achieving CR and 7% exhibiting a PR.19 At a median of 29 months, 26% of patients had relapsed, but the majority of patients (62%) who were treated after relapsing attained CR.19 The OS for this retreated population was 96% at 48 months.19 Several other studies have reported similar ORRs with cladribine ranging from 98% to 100%, with relapse rates from 20% to 30%.1

Major adverse events (AEs) associated with cladribine treatment were grade 3/4 neutropenia (up to 87%), febrile neutropenia (42%), grade 3/4 thrombocytopenia (20%), grade 3/4 anemia (22%), and infection (13%).19 Although fever is common, <15% of febrile patients had a documented infection.19

The typical cladribine dosing regimen is relatively short: daily 0.1 mg/kg via 2-hour intravenous (IV) infusion over 7 days. Alternative administration routes and dosing strategies have been tested, including subcutaneous injections and treatment lengths ranging from 5 days to 6 weeks. No difference in efficacy is reported among these methods, but 1 retrospective trial found that IV administration was associated with an increased risk of infection and mucositis when compared directly with the subcutaneous administration route.20

A 2010 follow-up to the 358 patients evaluated by Saven et al reported that of the 19 patients who maintained a continuous and complete hematologic response, 47% of patients had no detectable minimal residual disease.21 Consistent high response and survival rates indicate the potential for patients to experience durable remission following a single 7-day course of cladribine.1


Pentostatin is a natural adenosine mimetic produced by the bacterium Streptomyces antibioticus. While cladribine function hinges on its ability to resist breakdown by adenosine deaminase, pentostatin binds to adenosine deaminase and inhibits enzymatic activity. As a result of this inhibition, dATP levels increase and single-strand DNA breaks accumulate in lymphocytes. The accumulation of DNA damage can trigger an apoptotic signaling cascade in lymphocytic cells, but an analysis of HCL patient biochemical features suggests errors with this model for pentostatin’s effect on HCL.15 Thus, the mechanism behind the potent effect of pentostatin on HCL remains unclear.22

Based on the successful use of pentostatin in other malignancies, Spiers et al tested pentostatin treatment in 2 patients with HCL in 1984, reporting CR in both patients.16 A review of subsequent pentostatin trials for HCL treatment reported similarly encouraging outcomes, with ORRs ranging from 84% to 100%, CRs as high as 89%, and 10-year relapse-free survival rates in 67% to 76% of responders.1

The phase III, randomized SWOG 8691 trial compared pentostatin treatment with interferon therapy in 313 patients with previously untreated HCL.23 In the interferon cohort, 38% of patients achieved complete or partial remission, whereas 79% of patients in the pentostatin group achieved these outcomes (P <.0001). A total of 104 of 158 patients in the interferon group crossed over to pentostatin treatment after failing to respond to their initial regimen.23 Of the evaluable crossover patients, 66% experienced CR and 9% achieved a PR. The authors reported that pentostatin was well tolerated by most patients.23 The emergence of these promising data catapulted pentostatin to the forefront of the HCL treatment algorithm.6

The most recent long-term pentostatin study followed patients from SWOG 8691 who were treated with pentostatin either as an initial therapy or following interferon therapy failure. The estimated OS at 5 years was reported to be 90% (95% CI, 87%-94%) and 81% (95% CI, 75%-86%) at 10 years. For the patients with confirmed CRs, these values were 85% (95% CI, 80%-91%) and 67% (95% CI, 58%-76%), respectively.24 Patients who had undergone pentostatin treatment as an initial therapy and those who had switched therapy from failed interferon had similar results. These lengthy survival times indicate improvements in the treatment of this rare disease, but the reported 10-year relapse-free survival rate of 67% indicates that better treatment options are still needed.24

Pentostatin is administered every other week through IV doses at 4 mg/m2.22 The total number of reported doses required to achieve CR ranges from 4 to 15.25 Reduced dosing (2-3 mg/m2) may be safer for patients with infections, renal dysfunction, or poor performance status, as myelosuppression and immunosuppression are dose-dependent effects.7,25 Patients are recommended to receive hydration prior to and following treatment.22 The most common toxicities associated with pentostatin administration include myelosuppression and infections that may require systemic antibiotic treatment (27%).23

Cladribine Versus Pentostatin

No randomized head-to-head studies have compared the performance of cladribine and pentostatin for treating patients with HCL. A British group published a retrospective study comparing the 2 therapies across 210 patients treated between 1992 and 1997. Both groups exhibited high CR rates (84% for cladribine and 82% for pentostatin).26 Another retrospective study reported similar relapse rates at 15 years post treatment (48% and 47%, respectively).27

Although pentostatin and cladribine share similar progression-free survival and equal potential for relapse, there remain differences in administration and AEs that could make one therapy preferable over the other for specific patients (Table).19,20,22,23 Both therapies are immunosuppressive, but pentostatin has been successfully administered to patients with infections at a lower initial dose.23 Cladribine, however, has a more convenient administration schedule that is completed more quickly and tends to be the preferred treatment approach.11 These factors should be considered when selecting the most appropriate agent for patients with HCL. It is important to note that although these therapies are both PNAs and are regarded as analogous regarding outcomes, they each function through separate mechanisms and one may be used if the other treatment fails.7

Overall, PNAs have had a substantial positive impact on the HCL treatment landscape. Although relapse remains a concern for patients with HCL, many patients do respond to retreatment and have the potential to achieve long-term disease remission. The outlook for patients with this disease will continue to improve as pentostatin and cladribine are integrated into combination therapies.

Rituximab: An Emerging Treatment Option for HCL

The monoclonal antibody rituximab is commonly used for the treatment of several B-cell malignancies, and it is now emerging as a treatment option for patients with HCL.7 This monoclonal antibody has been evaluated as a monotherapy and in combination with PNAs to combat HCL.

The hairy cells that are characteristic of HCL express high levels of the CD20 antigen, making them an intriguing target for anti-CD20 monoclonal antibody therapies such as rituximab.28 Rituximab is a chimeric monoclonal antibody that is composed in part of human fragment crystallizable regions, which bind to immune cells, and murine variable regions, which bind to CD20. Although the interaction between rituximab and CD20 inhibits cell division and can trigger cell death, a detailed understanding of the mechanism of action of rituximab antitumor activity remains elusive.29

Rituximab monotherapy has been shown in limited studies to be effective in patients who have relapsed following treatment with PNAs. A 2003 study evaluated 15 patients with relapsed or refractory HCL who had been treated with cladribine, including some who had also undergone splenectomy or received interferon and/or pentostatin therapy. These patients were treated with weekly doses of 375 mg/m2 of rituximab for ≥8 weeks and up to 12 weeks.30 The ORR for this group was 80%.30 A more recent review reported a wide range of CR rates (10%-55%) and ORRs (25%-80%) to rituximab monotherapy, and the authors attributed this large variation to the heterogeneity of patients enrolled in these studies.1

Rituximab has also been evaluated in combination with cladribine. A 2016 phase II trial evaluated the efficacy of a treatment regimen consisting of cladribine followed by rituximab in 83 patients with newly diagnosed HCL or HCL in first relapse. These patients fell into 3 cohorts: untreated (n = 59), relapsed (n = 14), and HCL variant (n = 7). The CR rates for these groups were 100%, 100%, and 86%, respectively.31 Patients who had previously been treated with cladribine monotherapy as a first-line treatment exhibited significantly improved failure-free survival rates when receiving second-line cladribine followed by rituximab therapy (P = .004).31 A total of 74% of patients in this group were negative for minimal residual disease, including 76% of the untreated patients, 71% of the HCL variant patients, and 64% of the relapsed patients (P = .69).31

The FDA maintains boxed warnings for rituximab for fatal infusion-related reactions, severe mucocutaneous reactions, hepatitis B virus (HBV) reactivation, and progressive multifocal leukoencephalopathy.29 Patients must be monitored for infusion-related reactions; these occur most often within 24 hours of the first infusion and patients are pretreated with antihistamine and acetaminophen as a precaution.29 Because CD20 antibodies are associated with the reactivation of HBV in patients who test positive for certain HBV markers, patients should be screened for these markers prior to receiving rituximab therapy.29

Fortunately, the results of the aforementioned studies indicate that rituximab therapy is well-tolerated in most patients with HCL. AEs reported for rituximab monotherapy in HCL are minimal, with the majority of the reported toxicities being grade 1 and 2. The majority (60%) of patients who received this therapy experienced grade 1 fever and chills, and 27% of patients reported nausea and vomiting. Of 15 evaluated patients,1 experienced grade 3 myalgia. Other toxicities included heart palpations (n = 1), shortness of breath (n = 1), and fatigue (n =1).30 When administered following cladribine treatment, rituximab therapy was also generally well tolerated. In the 83 patients evaluated by Chihara et al, the most common toxicities were fatigue (n = 2), rash (n = 1), and hyperbilirubinemia (n = 1). Grade 3 and 4 infections occurred in 19 patients.31

The standard dosing for rituximab monotherapy is 375 mg/m2 administered through a weekly IV infusion. Some patients respond to as few as 4 doses, while others could benefit from as many as 12.30,32 Patients typically receive rituximab for 4 weeks.2 Because of the risk of complications, prophylaxis against infection and infusion reactions are crucial steps of rituximab administration.6

Although initial reports describing the utility of rituximab therapy are encouraging, more studies are still needed to determine its role in treating HCL. Rituximab is generally not recommended as an initial treatment for HCL. NCCN guidelines recommend rituximab treatment with PNAs for patients who are experiencing disease relapse 2 or more years after a previous complete recovery ensued from initial PNA treatment; the patient must use a PNA different from the one used in the initial treatment. In addition, patients who are unable to receive purine analogue therapy are also candidates for rituximab monotherapy.7 As with all malignancies, all patients, especially those who do not respond to first-line treatment options, are encouraged to enroll in an ongoing clinical trial.7

Continued Improvement

The rarity of HCL has presented challenges regarding clinical development and research. Nonetheless, several effective therapeutic options have achieved FDA approval. The introduction of interferon therapy to the treatment paradigm of HCL provided a systemic treatment that extended the life expectancy and broadened the population of patients with HCL who could benefit from treatment. Long-term successes with interferon therapies foreshadowed the improved outcomes that modern patients can achieve.

The emergence of PNAs in the 1980s radically improved the outlook for patients with HCL, boasting high overall response and CR rates, while promoting long-term life expectancy approaching that of the general population. The purine analogues, pentostatin and cladribine, remain the first-line options for combating HCL. New therapeutic approaches, including treatment that incorporates rituximab, continue to increase the number of patients achieving durable long-term remission. For an overview of significant historical events in HCL, see Figure.2

Because of the remarkable success of therapeutic developments in treating HCL, many patients are able to lead relatively normal lives, and future therapeutic developments will only extend these benefits to more patients. Still, despite these impactful successes, relapse remains a significant issue for patients with HCL. Improved treatment options that overcome this barrier to maintain remission are needed to combat this rare disease. The next article in this publication focuses on treatment options for relapsed or refractory disease.


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  2. Andritsos LA, Grever MR. Historical overview of hairy cell leukemia. Best Pract Res Clin Haematol. 2015;28(4):166-174. doi: 10.1016/j.beha.2015.10.018.
  3. Bouroncle BA, Wiseman BK, Doan CA. Leukemic reticuloendotheliosis. Blood 1958;13(7):609-630. doi: 10.1182/blood-2016-01-696179.
  4. Grever MR, Abdel-Wahab O, Andritsos LA, et al. Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia. Blood. 2017;129(5):553-560. doi: 10.1182/blood-2016-01-689422.
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  6. King AC, Kabel CC, Pappacena JJ, et al. No loose ends: a review of the pharmacotherapy of hairy cell and hairy cell leukemia variant [published online March 6, 2019]. Ann Pharmacother. doi: 10.1177/1060028019836775.
  7. NCCN Clinical Practice Guidelines in Oncology. Hairy Cell Leukemia, version 3.2019. National Comprehensive Cancer Network website. Published January 31, 2019. Accessed April 4, 2019.
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  10. Mintz U, Golomb HM. Splenectomy as initial therapy in twenty-six patients with leukemic reticuloendotheliosis (hairy cell leukemia). Cancer Res. 1979;39(7 Pt 1):2366-2370.
  11. Naik RR, Saven A. My treatment approach to hairy cell leukemia. Mayo Clin Proc. 2012;87(1):67-76. doi: 10.1016/j.mayocp.2011.09.001.
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  13. Porzsolt F. Primary treatment of hairy cell leukemia: should IFN-therapy replace splenectomy? Blut. 1986;52(5):265-272.
  14. Quesada JR, Hersh EM, Manning J, et al. Treatment of hairy cell leukemia with recombinant alpha-interferon. Blood. 1986;68(2):493-497.
  15. Johnston JB, Begleiter A, Pugh L, et al. Biochemical changes induced in hairy-cell leukemia following treatment with the adenosine deaminase inhibitor 2’-deoxycoformycin. Cancer Res. 1986;46(4 Pt 2):2179-2184.
  16. Spiers AS, Parekh SJ, Bishop MB. Hairy-cell leukemia: induction of complete remission with pentostatin (2’-deoxycoformycin). J Clin Oncol. 1984;2(12):1336-1342.
  17. Piro LD, Carrera CJ, Carson DA, Beutler E. Lasting remissions in hairy-cell leukemia induced by a single infusion of 2-chlorodeoxyadenosine. N Engl J Med. 1990;322(16):1117-1121.
  18. Seto S, Carrera CJ, Kubota M, et al. Mechanism of deoxyadenosine and 2-chlorodeoxyadenosine toxicity to nondividing human lymphocytes. J Clin Invest. 1985;75(2):377-383.
  19. Saven A, Burian C, Koziol JA, Piro LD. Long-term follow-up of patients with hairy cell leukemia after cladribine treatment. Blood. 1998;92(6):1918-1926.
  20. Khorshid O, Namour AE, El-Gammal MM, et al. Efficacy and safety of cladribine: subcutaneous versus intravenous administration in hairy cell leukemia patients. Mediterr J Hematol Infect Dis. 2015;7(1):e2015058. doi: 10.4084/MJHID.2015.058.
  21. Sigal DS, Sharpe R, Burian C, Saven A. Very long-term eradication of minimal residual disease in patients with hairy cell leukemia after a single course of cladribine. Blood. 2010;115(10):1893-1896. doi: 10.1182/blood-2009-10-251645.
  22. NIPENT [prescribing information]. Lake Forest, IL: Hospira, Inc; 2018. Accessed May 21, 2019.
  23. Grever M, Kopecky K, Foucar MK, et al. Randomized comparison of pentostatin versus interferon alfa-2a in previously untreated patients with hairy cell leukemia: an intergroup study. J Clin Oncol. 1995;13(4):974-982.
  24. Flinn IW, Kopecky KJ, Foucar MK, et al. Long-term follow-up of remission duration, mortality, and second malignancies in hairy cell leukemia patients treated with pentostatin. Blood 2000;96(9):2981-2986.
  25. Kraut EH, Bouroncle BA, Grever MR. Pentostatin in the treatment of advanced hairy cell leukemia. J Clin Oncol. 1989;7(2):168-172.
  26. Dearden CE, Matutes E, Hilditch BL, et al. Long-term follow-up of patients with hairy cell leukaemia after treatment with pentostatin or cladribine. Br J Haematol. 1999;106(2):515-519.
  27. Else M, Dearden CE, Matutes E, et al. Long-term follow-up of 233 patients with hairy cell leukaemia, treated initially with pentostatin or cladribine, at a median of 16 years from diagnosis. Br J Haematol. 2009;145(6):733-740. doi: 10.1111/j.1365-2141.2009.07668.x.
  28. Ginaldi L, De Martinis M, Matutes E, et al. Levels of expression of CD19 and CD20 in chronic B cell leukaemias. J Clin Pathol. 1998;51(5):364-369.
  29. RITUXAN [prescribing information]. South San Francisco, CA: Genentech, Inc; 2019. Accessed May 21, 2019.
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  31. Chihara D, Kantarjian H, O’Brien S, et al. Long-term durable remission by cladribine followed by rituximab in patients with hairy cell leukaemia: update of a phase II trial. Br J Haematol. 2016;174(5):760-766. doi: 10.1111/bjh.14129.
  32. Hagberg H, Lundholm L. Rituximab, a chimaeric anti-CD20 monoclonal antibody, in the treatment of hairy cell leukaemia. Br J Haematol. 2001;115(3):609-611.
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