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Novel Therapies in Hairy Cell Leukemia
Tadeusz Robak*
Department of Hematology, Medical University of Lodz, Poland
Volume 1 Issue 5- 2018
Received Date: 15 July 2018
Accepted Date: 31 Aug 2018
Published Date: 01 Sep 2018
1. Editorial
Hairy Cell Leukemia (HCL) is a rare subtype of B-cell chronic lymphoid leukemia which was
first described by Bertha Bouroncle in 1958 [1]. The annual incidence of HCL is approximately
0.3 cases per 100,000 and the disease comprises 2-3% of all leukaemia’s in the Western world
[2,3]. Its diagnosis is based on the identifying the distinctive morphology of hairy cells, and eval-
uating bone marrow histology and immunological profile (CD19+, CD20+, CD11c+, CD25+,
CD103+, CD123+, CD200+, CD27-, and light chain restriction) [4,5]. HCL cells have strong
positivity for tartrate-resistant acid phosphatase (TRAP) [5]. In addition, molecular studies
have shown that almost all cases of HCL are associated with a point mutation in the signalling
protein BRAF (V600E) [6]. The disease usually has an indolent course, and some patients with
asymptomatic disease do not require therapy until progression. The first active agent for HCL
was interferon-a (IFN-a), which can produce a Complete Response (CR) in approximately 10%
of HCL patients and a Partial Response (PR) in the majority of the remainder [7]. Although its
use in the treatment of HCL is currently limited, IFN-α may still have a place in treating HCL
in patients who are pregnant or are highly neutropenic. Otherwise, Purine Nucleoside Analogs
(PNA), cladribine (2-chlorodeoxyadenosine, 2-CdA) and pentostatin (deoxycoformycin, DCF)
have become gold standards in the treatment of this disease [8]. Piro et al. [9] were the first to
describe sustained CR in HCL patients who had undergone splenectomy and received a single
continuous intravenous infusion of 2-CdA for seven days [9]. Further multiple studies on larger
groups of patients have demonstrated that 2-CdA induces durable and unmaintained CR in
about 80% of patients after a single course of therapy [10-12]. Cladribine is administered either
as a continuous i.v. infusion at a dose of 0.09 mg/kg over a five- to seven-day period, once a week
for six weeks. Similar results were achieved when the drug was given as subcutaneous injection.
A 1984 study by Spiers et al. [13] first demonstrated that pentostatin is also a highly active agent
in HCL [13], and since then, a randomized study found that pentostatin produced higher CR
and PR rates than IFN-a with more durable responses in HCL [14]. Purine nucleoside analogs
are well tolerated in HCL, especially when neutropenia is not severe or there is no history of life-
threatening infections. Myelosuppression is the main toxicity and may require delays in planned
chemotherapy schedule. Purine nucleoside analogs dramatically improved the outcome of HCL,
achieving 10-year OS rates close to 90%. Cladribine and pentostatin seem to induce similar high
response rates but only a large randomized trial with the two agents will be able to evaluate the
CR rates, duration of response, recurrence rates and adverse events that have appeared to be
comparable so far [15,16]. Nevertheless, cladribine affords the convenience of a single course of
administration.
Although purine nucleoside analogs are still recommended as first line therapy for HCL, pa-
tients treated with PNAs do still relapse and the OS curves have not yet reached a plateau, sug-
gesting that a cure remains elusive. Purine nucleoside analogs are also effective in re-induction
therapy; however, novel therapies are needed for many patients who ultimately relapse or go on
Clinics of Oncology
Citation: Tadeusz Robak, Novel Therapies in Hairy Cell Leukemia. Clinics of Oncology. 2018; 1(5): 1-4.
United Prime Publications: http://unitedprimepub.com
*Corresponding Author (s): Tadeusz Robak, Department of Hematology, Medical Uni-
versity of Lodz, Poland, Tel: +48 42 689-51-91; Fax: + 48 42 689-51-92; E-mail: robak-
tad@csk.umed.lodz.pl
Short Communication
Copyright ©2018 Tadeusz Robak et all This is an open access article distributed under the terms of the Creative Commons Attribution
License, which permits unrestricted use, distribution, and build upon your work non-commercially. 2
Volume 1 Issue 5 -2018 Short Communication
to develop refractory disease despite initial very high response
rates. Rituximab, a chimeric mouse-human anti-CD20 Monoclo-
nal Antibody (MAb), seems to be a promising agent for patients
with HCL [17,18] which can be used as a single agent or in com-
bination with PNA. Its use has been associated with an OR in
up to 80% of relapsed or refractory patients, and occurrence and
duration of response rates can be increased by combining rituxi-
mab with PNA. Ravandi et al. [19] demonstrated a 100% CR rate
using a regimen consisting of cladribine followed by eight doses
of rituximab [19]. Another anti-CD20 antibody, obinutuzumab,
also has demonstrated potential in treating HCL, but further
studies are needed [20,21]. Recent progress in the understanding
of the molecular biology of HCL has stimulated the development
of new active drugs, particularly immunotoxins, BRAF inhibitors
and B-Cell Receptor (BCR) pathway inhibitors [22]. Immunotox-
ins may play a role in the treatment of HCL, especially in patients
with limited responses or treatment failure after conventional
therapy. Moxetumomab pasudotox (CAT-8015, HA22, Med Im-
mune LLC /Cambridge Antibody Technology/Astra Zeneca) is a
new generation of CD22-specific targeted immunotoxins com-
posed of the Fv fragment of an anti-CD22 monoclonal antibody
fused to a 38-kDa fragment of Pseudomonas exotoxin A, called
PE38 [23,24].
Moxetumomab pasudotox is highly active in relapsed/refractory
HCL. A Phase 1 trial in 28 patients with refractory/relapsed HCL
[25] identified an OR rate of 86% and CR 46% among 26 evalu-
able patients. In one patient, CR lasted less than one year and the
median disease-free survival time was not reached at 26 months.
The long-term follow-up results of this study were recently pub-
lished [26]. In total, 33 patients received 50 µg/kg every other day
for three doses in four-week cycles. The combined 33-patient co-
hort achieved 64% CR and 88% OR rates, with a median CR du-
ration of 42.4 months. Moxetumomab pasudotox can eliminate
MRD in a significant percentage of HCL patients. An evaluation
of MRD in 32 patients by bone marrow aspirate flow cytometry
found median CR duration to be 13.5 months in nine MRD-pos-
itive patients and 42.1 months in 11 MRD-negative patients (P <
0.001). At the end of the study, 10 patients among MRD-negative
CRs, had ongoing CR and nine of them without MRD. Repeated
dosing, despite the early neutralization of antibodies, increased
active drug levels without detectable toxicity associated with im-
munogenicity. Recently, the results were reported of a pivotal,
multicenter, open-label study of moxetumomab pasudotox in
80 patients with relapsed/ refractory HCL who had undergone
two or more prior systemic therapies [27]. Moxetumomab pasu-
dotox was given at a dose 40 µg/kg intravenously on days 1, 3,
and 5 every 28 days for six cycles, or less if not tolerated. The
objective response rate was 75% and CR rate 41%. Immunohis-
tochemistry identified MRD negativity in 85% of the patients
with CR. Treatment was generally well tolerated. The most
frequent adverse events (AEs) were peripheral edema (39%),
nausea (35%), fatigue (34%) and headache (33%) [27]. It has
been documented that inhibitors of BRAF V600E and/or mi-
togen-activated protein kinase (MEK), including vemurafenib,
cause HCL cell death [28]. Vemurafenib (Zelboraf™, Roche) is
an ATP-competitive BRAF V600 inhibitor that has been shown
to have potent antitumor activity in HCL. Vemurafenib has
shown remarkable activity in multiple relapsed and refractory
disease [29-33]. Patients treated with vemurafenib experienced
rapidly decreased splenomegaly, increased platelet counts, and
normalization of hemoglobin and granulocyte counts. In some
studies, patients achieved morphologic and molecular remis-
sions as early as one month after starting the therapy.
Investigators from Italy and the United States designed a single-
arm phase 2 studies in patients with HCL who were refractory
to purine analogues [33]. Vemurafenib was administered at a
dose of 960 mg twice daily for a median of 16 weeks in the Ital-
ian study and 18 weeks in the U.S. study. In the Italian study,
the OR rates were 96% and CR rates 35% after a median of eight
weeks. The median relapse-free survival was 19 months among
patients with a CR and six months among patients with a PR,
with median treatment-free survival being 25 months and 18
months, respectively. In the U.S. study, OR rates were found
to be 100% and CR rates 42%, after a median treatment of 12
weeks. At one year, the PFS rate was 73% and the OS rate was
91%. The treatment was well tolerated. However, skin changes,
arthralgia and pancreatitis were relatively frequent events, all
of them being grade 1 or 2. Lower doses of vemurafenib are
also effective in HCL. In the study by Dietrich et al, 21 patients
were treated with vemurafenib at doses 240-1920 mg per day
with a median treatment duration of 90 days [32]. All patients
responded to vemurafenib, with platelet count, neutrophil
count and hemoglobin level recovering within 28, 43 and 55
days (median), respectively. Complete remission was observed
in 40% of 15 evaluable patients and median event-free survival
was 17 months. No significant difference in CR rate was found
between lower and higher doses of vemurafenib, and CR did
not translate into longer Evidence-Free Survival (EFS). As the
response duration after vemurafenib is relatively short, further
studies are needed to determine the optimal dosing and treat-
ment duration.
Two other BRAF inhibitors which may be potentially useful in
the treatment of HCL are Dabrafenib (Tafinlar®, GlaxoSmith-
Kline) and encorafenib (LGX818, Novartis). These compounds
have entered clinical trials and shown promising results [34-
36]. Further prospective studies are needed to optimize the
doses of BRAF inhibitors and treatment duration against HCL.
Ibrutinib (PCI-32765, IMBRUVICA®, Pharmacyclics, Janssen)
is an inhibitor of Bruton’s Tyrosine Kinase (BTK), which also
demonstrates antitumor activity in HCL. Sivina et al. report that
ibrutinib reduces the survival and proliferation of HCL cells in
vitro [37]. Other encouraging results are presented by Jones et al.,
who report the preliminary data obtained by a study of 13 pa-
tients undergoing a median of four (range: 1-11) prior therapies:
eleven relapsed, one untreated and one with HCL-variant [38].
The presented data concerning the initial dose 420mg/day cohort
found an overall response rate of 46% including one MRD-nega-
tive CR and five partial responses. Four additional patients have
since experienced clinical benefit and continue on treatment. At a
median follow-up of 14.5 months, nine patients (69%) remained
progression-free on treatment with ibrutinib, and responses have
improved with continued treatment. Grade 3/4 adverse effects in-
cluded hypophosphatemia (30%), neutropenia (23%) and infec-
tions (23%). In conclusion, in the coming years, new agents will
probably replace standard therapy of HCL, especially for patients
who have suboptimal results after treatment with PNAs. For these
patients, novel therapies, especially those based around immuno-
toxins and BRAF inhibitors, show promising results.
2. Acknowledgment
We thank Edward Lowczowski from the Medical University of
Lodz for editorial assistance This work was supported in part by
grant funding from the Medical University of Lodz, Poland: No.
503/1-093-01/503-11-004
3. Declaration of interest
The author has no conflicts of interest that are directly relevant to
the content of this article.
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United Prime Publications: http://unitedprimepub.com 4
Volume 1 Issue 5 -2018 Short Communication

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Novel Therapies in Hairy Cell Leukemia

  • 1. Novel Therapies in Hairy Cell Leukemia Tadeusz Robak* Department of Hematology, Medical University of Lodz, Poland Volume 1 Issue 5- 2018 Received Date: 15 July 2018 Accepted Date: 31 Aug 2018 Published Date: 01 Sep 2018 1. Editorial Hairy Cell Leukemia (HCL) is a rare subtype of B-cell chronic lymphoid leukemia which was first described by Bertha Bouroncle in 1958 [1]. The annual incidence of HCL is approximately 0.3 cases per 100,000 and the disease comprises 2-3% of all leukaemia’s in the Western world [2,3]. Its diagnosis is based on the identifying the distinctive morphology of hairy cells, and eval- uating bone marrow histology and immunological profile (CD19+, CD20+, CD11c+, CD25+, CD103+, CD123+, CD200+, CD27-, and light chain restriction) [4,5]. HCL cells have strong positivity for tartrate-resistant acid phosphatase (TRAP) [5]. In addition, molecular studies have shown that almost all cases of HCL are associated with a point mutation in the signalling protein BRAF (V600E) [6]. The disease usually has an indolent course, and some patients with asymptomatic disease do not require therapy until progression. The first active agent for HCL was interferon-a (IFN-a), which can produce a Complete Response (CR) in approximately 10% of HCL patients and a Partial Response (PR) in the majority of the remainder [7]. Although its use in the treatment of HCL is currently limited, IFN-α may still have a place in treating HCL in patients who are pregnant or are highly neutropenic. Otherwise, Purine Nucleoside Analogs (PNA), cladribine (2-chlorodeoxyadenosine, 2-CdA) and pentostatin (deoxycoformycin, DCF) have become gold standards in the treatment of this disease [8]. Piro et al. [9] were the first to describe sustained CR in HCL patients who had undergone splenectomy and received a single continuous intravenous infusion of 2-CdA for seven days [9]. Further multiple studies on larger groups of patients have demonstrated that 2-CdA induces durable and unmaintained CR in about 80% of patients after a single course of therapy [10-12]. Cladribine is administered either as a continuous i.v. infusion at a dose of 0.09 mg/kg over a five- to seven-day period, once a week for six weeks. Similar results were achieved when the drug was given as subcutaneous injection. A 1984 study by Spiers et al. [13] first demonstrated that pentostatin is also a highly active agent in HCL [13], and since then, a randomized study found that pentostatin produced higher CR and PR rates than IFN-a with more durable responses in HCL [14]. Purine nucleoside analogs are well tolerated in HCL, especially when neutropenia is not severe or there is no history of life- threatening infections. Myelosuppression is the main toxicity and may require delays in planned chemotherapy schedule. Purine nucleoside analogs dramatically improved the outcome of HCL, achieving 10-year OS rates close to 90%. Cladribine and pentostatin seem to induce similar high response rates but only a large randomized trial with the two agents will be able to evaluate the CR rates, duration of response, recurrence rates and adverse events that have appeared to be comparable so far [15,16]. Nevertheless, cladribine affords the convenience of a single course of administration. Although purine nucleoside analogs are still recommended as first line therapy for HCL, pa- tients treated with PNAs do still relapse and the OS curves have not yet reached a plateau, sug- gesting that a cure remains elusive. Purine nucleoside analogs are also effective in re-induction therapy; however, novel therapies are needed for many patients who ultimately relapse or go on Clinics of Oncology Citation: Tadeusz Robak, Novel Therapies in Hairy Cell Leukemia. Clinics of Oncology. 2018; 1(5): 1-4. United Prime Publications: http://unitedprimepub.com *Corresponding Author (s): Tadeusz Robak, Department of Hematology, Medical Uni- versity of Lodz, Poland, Tel: +48 42 689-51-91; Fax: + 48 42 689-51-92; E-mail: robak- tad@csk.umed.lodz.pl Short Communication
  • 2. Copyright ©2018 Tadeusz Robak et all This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and build upon your work non-commercially. 2 Volume 1 Issue 5 -2018 Short Communication to develop refractory disease despite initial very high response rates. Rituximab, a chimeric mouse-human anti-CD20 Monoclo- nal Antibody (MAb), seems to be a promising agent for patients with HCL [17,18] which can be used as a single agent or in com- bination with PNA. Its use has been associated with an OR in up to 80% of relapsed or refractory patients, and occurrence and duration of response rates can be increased by combining rituxi- mab with PNA. Ravandi et al. [19] demonstrated a 100% CR rate using a regimen consisting of cladribine followed by eight doses of rituximab [19]. Another anti-CD20 antibody, obinutuzumab, also has demonstrated potential in treating HCL, but further studies are needed [20,21]. Recent progress in the understanding of the molecular biology of HCL has stimulated the development of new active drugs, particularly immunotoxins, BRAF inhibitors and B-Cell Receptor (BCR) pathway inhibitors [22]. Immunotox- ins may play a role in the treatment of HCL, especially in patients with limited responses or treatment failure after conventional therapy. Moxetumomab pasudotox (CAT-8015, HA22, Med Im- mune LLC /Cambridge Antibody Technology/Astra Zeneca) is a new generation of CD22-specific targeted immunotoxins com- posed of the Fv fragment of an anti-CD22 monoclonal antibody fused to a 38-kDa fragment of Pseudomonas exotoxin A, called PE38 [23,24]. Moxetumomab pasudotox is highly active in relapsed/refractory HCL. A Phase 1 trial in 28 patients with refractory/relapsed HCL [25] identified an OR rate of 86% and CR 46% among 26 evalu- able patients. In one patient, CR lasted less than one year and the median disease-free survival time was not reached at 26 months. The long-term follow-up results of this study were recently pub- lished [26]. In total, 33 patients received 50 µg/kg every other day for three doses in four-week cycles. The combined 33-patient co- hort achieved 64% CR and 88% OR rates, with a median CR du- ration of 42.4 months. Moxetumomab pasudotox can eliminate MRD in a significant percentage of HCL patients. An evaluation of MRD in 32 patients by bone marrow aspirate flow cytometry found median CR duration to be 13.5 months in nine MRD-pos- itive patients and 42.1 months in 11 MRD-negative patients (P < 0.001). At the end of the study, 10 patients among MRD-negative CRs, had ongoing CR and nine of them without MRD. Repeated dosing, despite the early neutralization of antibodies, increased active drug levels without detectable toxicity associated with im- munogenicity. Recently, the results were reported of a pivotal, multicenter, open-label study of moxetumomab pasudotox in 80 patients with relapsed/ refractory HCL who had undergone two or more prior systemic therapies [27]. Moxetumomab pasu- dotox was given at a dose 40 µg/kg intravenously on days 1, 3, and 5 every 28 days for six cycles, or less if not tolerated. The objective response rate was 75% and CR rate 41%. Immunohis- tochemistry identified MRD negativity in 85% of the patients with CR. Treatment was generally well tolerated. The most frequent adverse events (AEs) were peripheral edema (39%), nausea (35%), fatigue (34%) and headache (33%) [27]. It has been documented that inhibitors of BRAF V600E and/or mi- togen-activated protein kinase (MEK), including vemurafenib, cause HCL cell death [28]. Vemurafenib (Zelboraf™, Roche) is an ATP-competitive BRAF V600 inhibitor that has been shown to have potent antitumor activity in HCL. Vemurafenib has shown remarkable activity in multiple relapsed and refractory disease [29-33]. Patients treated with vemurafenib experienced rapidly decreased splenomegaly, increased platelet counts, and normalization of hemoglobin and granulocyte counts. In some studies, patients achieved morphologic and molecular remis- sions as early as one month after starting the therapy. Investigators from Italy and the United States designed a single- arm phase 2 studies in patients with HCL who were refractory to purine analogues [33]. Vemurafenib was administered at a dose of 960 mg twice daily for a median of 16 weeks in the Ital- ian study and 18 weeks in the U.S. study. In the Italian study, the OR rates were 96% and CR rates 35% after a median of eight weeks. The median relapse-free survival was 19 months among patients with a CR and six months among patients with a PR, with median treatment-free survival being 25 months and 18 months, respectively. In the U.S. study, OR rates were found to be 100% and CR rates 42%, after a median treatment of 12 weeks. At one year, the PFS rate was 73% and the OS rate was 91%. The treatment was well tolerated. However, skin changes, arthralgia and pancreatitis were relatively frequent events, all of them being grade 1 or 2. Lower doses of vemurafenib are also effective in HCL. In the study by Dietrich et al, 21 patients were treated with vemurafenib at doses 240-1920 mg per day with a median treatment duration of 90 days [32]. All patients responded to vemurafenib, with platelet count, neutrophil count and hemoglobin level recovering within 28, 43 and 55 days (median), respectively. Complete remission was observed in 40% of 15 evaluable patients and median event-free survival was 17 months. No significant difference in CR rate was found between lower and higher doses of vemurafenib, and CR did not translate into longer Evidence-Free Survival (EFS). As the response duration after vemurafenib is relatively short, further studies are needed to determine the optimal dosing and treat- ment duration. Two other BRAF inhibitors which may be potentially useful in the treatment of HCL are Dabrafenib (Tafinlar®, GlaxoSmith- Kline) and encorafenib (LGX818, Novartis). These compounds have entered clinical trials and shown promising results [34- 36]. Further prospective studies are needed to optimize the
  • 3. doses of BRAF inhibitors and treatment duration against HCL. Ibrutinib (PCI-32765, IMBRUVICA®, Pharmacyclics, Janssen) is an inhibitor of Bruton’s Tyrosine Kinase (BTK), which also demonstrates antitumor activity in HCL. Sivina et al. report that ibrutinib reduces the survival and proliferation of HCL cells in vitro [37]. Other encouraging results are presented by Jones et al., who report the preliminary data obtained by a study of 13 pa- tients undergoing a median of four (range: 1-11) prior therapies: eleven relapsed, one untreated and one with HCL-variant [38]. The presented data concerning the initial dose 420mg/day cohort found an overall response rate of 46% including one MRD-nega- tive CR and five partial responses. Four additional patients have since experienced clinical benefit and continue on treatment. At a median follow-up of 14.5 months, nine patients (69%) remained progression-free on treatment with ibrutinib, and responses have improved with continued treatment. Grade 3/4 adverse effects in- cluded hypophosphatemia (30%), neutropenia (23%) and infec- tions (23%). In conclusion, in the coming years, new agents will probably replace standard therapy of HCL, especially for patients who have suboptimal results after treatment with PNAs. For these patients, novel therapies, especially those based around immuno- toxins and BRAF inhibitors, show promising results. 2. Acknowledgment We thank Edward Lowczowski from the Medical University of Lodz for editorial assistance This work was supported in part by grant funding from the Medical University of Lodz, Poland: No. 503/1-093-01/503-11-004 3. Declaration of interest The author has no conflicts of interest that are directly relevant to the content of this article. References 1. Bouroncle BA, Wiseman BK, Doan CA: Leukemic reticuloendothelio- sis. Blood 1958;13(7):609-30. 2. Bernstein L, Newton P, Ross RK. Epidemiology of hairy cell leukemia: an update. Curr Opin Hematol. 2003;10:258-66. 3. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013;49(6):1374-403. 4. Robak T, Matutes E, Catovsky D, Zinzani PL, Buske C, ESMO Guide- lines Committee. Hairy cell leukaemia: ESMO Clinical Practice Guide- lines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26 (Suppl 5):v100-7. 5. Grever MR, Abdel-Wahab O, Andritsos LA, Banerji V, Barrientos J, Blachly JS, et al. Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia. Blood. 2017;129:553-60. 6. Tiacci E, Trifonov V, Schiavoni G, Holmes A, Kern W, Martel- li MP, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med. 2011;364(24):2305-15. 7. 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;13:974- 82. 8. Robak T. 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