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Hairy-cell leukemia variant: Recent view on diagnosis, biology and treatment
Cancer Treatment Reviews 37 (2011) 3–10
Contents lists available at ScienceDirect
Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv
Anti-Tumor Treatment
Hairy-cell leukemia variant: Recent view on diagnosis, biology and treatment q Tadeusz Robak * Department of Hematology, Medical University of Lodz, Copernicus Memorial Hospital, 93-510 Lodz, Ul. Ciolkowskiego 2, Poland
a r t i c l e
i n f o
Article history: Received 12 March 2010 Received in revised form 20 May 2010 Accepted 25 May 2010
Keywords: Hairy-cell leukemia variant Japanese variant Molecular biology Purine nucleoside analogs Rituximab Immunotoxins
a b s t r a c t Hairy-cell leukemia variant (HCl-V) is a district clinico-pathological entity with intermediate features between classical HCl (HCl-C) and B-cell prolymphocytic leukemia. HCl-V is now included in the World Health Organization (WHO) classification as a provisional entity. It is an uncommon disorder accounting for approximately 0.4% of chronic lymphoid malignancies and 10% of all HCl cases. In contrast to HCl-C, HCl-V is a more aggressive disease and according to the new WHO classification it is no longer considered to be biologically related to HCl-C. Patients with HCl-V have an elevated white blood count, easy-to-aspirate bone marrow and weak reactivity to tartrate – resistant acid phosphatase (TRAP). Immunophenotypically, HCl-V cells are positive for CD103 and CD11c and negative for CD25. The HCl-V cells express also the B-cell antigens, CD19, CD20 and CD22. The HCl-V patients have frequently an unmutated Ig gene configuration. Currently, the principles of therapy for this rare disease derive from uncontrolled single institutional studies, or even single case reports. In contrast to HCl-C, the HCl-V response to purine nucleoside analogs (PNA) is limited to partial responses in approximately 50% of patients. However, complete responses were observed in patients treated with rituximab and anti-CD22 immunotoxins. In Japan, a distinct subtype of HCl known as HCl-Japanese variant (HCl-JV) has been identified. As with HCl-V, patients with HCl-JV have leukocytosis, weak TRAP activity in leukemic cells, and lack of CD25 antigen. In this review, the biology, diagnostic criteria, and current therapeutic options in HCl-V and HCl-JV are presented. Ó 2010 Elsevier Ltd. All rights reserved.
Introduction Hairy-cell leukemia variant (HCl-V) is an uncommon B-cell neoplasm accounting for 10–20% of HCl patients and 0.4% of chronic lymphoid malignancies, representing about 60–75 new HCl-V patients each year in the US.1–3 The disease affects the elderly population without sexual predominance. Its features are intermediate between those of classical HCl (HCl-C) and prolymphocytic leukemia.4,5 The median age of the patients is 71 years. HCl-V was first identified by Cawley et al.1 and was later described as prolymphocytic variant of HCl. Unlike HCl-C, HCl-V is resistant to most conventional treatments, including interferon-a (IFN-a) and purine nucleoside analogs (PNA).6–8 HCl-V is now included in the World Health Organization (WHO) classification as a provisional entity and is no longer considered to be biologically related to HCl-C.6 The clinical course of HCl-V is variable but usually more aggressive than HCl-C.7,8 In one study, median survival was approximately 9 years with only 15% survival over 15 years.8,9 In this study, 42% of patients died of unrelated causes.8 However, the
q Presented in part at Conference ‘Treatment of Hairy-Cell Leukemia in its Second Half-Century’ April 26–27, 2010, National Institutes of Health, Bethesda, MD, USA. * Tel.: +48 42 689 51 91; fax: +48 42 689 51 92. E-mail address: [email protected]
0305-7372/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2010.05.003
median survival of HCl-V patients is significantly shorter than that of HCl-C.3 Diagnosis HCl-V patients are characterized by splenomegaly, a high white blood cell count without neutropenia or monocytopenia and hyper-cellular marrow that can be easy aspirated.10,11 Morphologically, HCl-V cells are similar to leukemic cells of B-cell prolymphocytic leukemia and HCl-C cells.12,13 They contain abundant villi, an intensely basophilic cytoplasm and central, round, occasionally bilobed, indented hyperchromatic nuclei with prominent nucleoli.14 In comparison to HCl-C, HCl-V cells are smaller, have higher nuclear cytoplasmic ratios and no ribosome-lamella complexes.12 In contrast with HCl-C, leukemic cells of patients with HCl-V only infrequently demonstrate reactivity to tartrate resistant acid phosphate (TRAP).3,12,13 In HCl-V, the immunophenotype of the leukemic cells is CD11c+, CD10, CD23, CD24, CD25, CD27 and CD5 and have variable expression of CD103. In addition, antigens of mature Blymphocytes, CD19, CD20 and CD22 and FMC-7 with light chain restriction are present.12,15–20 In a study by Del Giudice et al.19 peripheral blood leukemic cells expressed CD123 antigen only in 9% of the patients with HCl-V. CD52 antigen was detected on 99%
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T. Robak / Cancer Treatment Reviews 37 (2011) 3–10
of neoplastic cells from the spleen of patients with this disease.21 Unlike HCl-C, immunophenotyping of HCl-V cells usually reveals negativity for Annexin A1 (ANXA1).5 Cytogenetic abnormalities in HCl-V have been occasionally reported in patients with HCl-V.22,23 In a study by Brito-Babapulle et al. two of six cases with HCl-V had abnormalities of chromosome 17p.22 The majority of the HCl-V patients have interstitial bone marrow infiltration with scattered hairy cells lying within sinusoids.8 However, approximately 20% of the patients have a mixed, interstitial and nodular pattern. In addition, pure sinusoidal and intrasinusoidal bone marrow involvement was also occasionally reported.10,14 The histological features of HCl-V in the spleen are similar to those found in HCl-C with primary involvement of the red pulp.12,13,15 HCl-C and HCl-V are rare in Japan.24,25 However, another distinct variant of HCl known as HCl-Japanese variant (HCl-JV) has been identified in this country.24,25 HCl-JV was proposed as a provisional subtype of HCl by Katayama et al.25 in a review of literature regarding 36 Japanese patients diagnosed as atypical HCl with some findings not usually seen in HCl.25 Subsequently, Machii et al.24 reported a series of 29 Japanese patients with similar symptoms, and further defined this subtype of HCl. HCl-JV is more frequent in females. Patients with HCV-JV possess splenomegaly without peripheral lymphadenopathy. However, in contrast to HCl-C, but similar to HCl-V, HCl-JV patients usually demonstrate leukocytosis and an easily aspirable bone marrow.26–28 The HClJV cells have an abundant pale cytoplasm with long microvilli, round hyperchromatic nuclei, inconspicuous nucleoli and rarely contain ribosome-lamella complexes.24,25 HCl-JV, like HCl-V, is characteristically CD11c and CD22 positive, always CD24 and CD25 negative, and usually CD103 negative.16,20,26 The leukemic cells are also CD22+, CD10, CD24 and sIg negative or weekly positive. A marked high ratio j + type to k + type has been also found.29 TRAP staining is negative in up to one-half of cases. Similarly, HCl-C and HCl-V leukemic cells preferentially infiltrate splenic red pulp.20 However, HCl-JV shows rather an indolent clinical course as in the cases of HCl-C. A form of polyclonal B-cell lymphocytosis with features resembling HCl-JV has also been reported.30,31 Machii et al.30 described four patients with persistent lymphocytosis and cell morphology
similar to that of leukemia cells of HCl-JV. The surface CD11c+, CD22+, CD24+, CD25, IgG and CD5-phenotype and the weak TRAP activity in the lymphoid cells were identical to those of the HCl-JV. However, studies of Ig gene rearrangements and expression showed the polyclonal proliferation of B-cells. It is suggested that the B-cells of these patients are the nonmalignant counterparts of leukemic cells in HCl-JV.
Differential diagnosis HCl-C, HCl-V, HCl-JV and splenic marginal zone lymphoma (SMZL) have some common features including splenomegaly, peripheral blood and bone marrow infiltration by villous lymphoid cells and B-lymphocyte immunophenotype (Table 1).31,32 Leukopoenia, neutropenia or monocytopenia are frequent in HCl-C. In HCl-V, HCl-JV and SMZL patients were shown to have a moderate degree of leukocytosis.30 The circulating cells of HCl-V have morphological features similar to HCl-C and prolymphocytes, and contain the abundant villous cytoplasm and the round nucleus with prominent nucleolus.12 The morphological findings in HCl-V and SMZL can be similar.33 However, in SMZL, the neoplastic cells are smaller than in HCl-V and have more condensed chromatin. In addition, the villous cytoplasm is usually moderate in amount and can be more basophilic.8,33 A small distinct nucleolus is observed in half of the SMZL patients.33 Flow cytometry analysis of the immunophenotype of leukemic cells has the most important value in differential diagnosis. HClC is always CD11c+, CD25 + and CD103+. HCl-V and HCl-JV are always CD25 and usually CD11c + and occasionally CD103+. In SMZL, CD25 can be negative or positive and CD103 is negative and CD27 positive.27 HCl-V without both CD25 and CD103 may be difficult to differentiate from SMZL. However, the immunoprofile should be correlated with other available pathological studies and clinical data. In HCl-C, strong TRAP activity occurs in contrast to HCl-V where TRAP inactivity is present. TRAP staining is negative in up to one-half of HCl-JV cases. The bone marrow is typically aspirable in HCl-V, HCl-JV and SLVL. In contrast to these disorders, the ‘‘dry tap” is often encountered on bone marrow aspiration in HCl-C patients.27 SMZL has a characteristic intrasinusoidal bone marrow involvement. However
Table 1 Comparison of clinical and laboratory characteristics of classical hairy-cell leukemia (HCl-C), hairy-cell leukemia variant (HCl-V), hairy-cell leukemia Japanese variant (HCl-JV) and splenic marginal zone lymphoma (SMZL). Characteristics
HCl-C
HCl-V
HCl-JV
SMZL
Median age (y) WBC count Cytoplasmic projection
55 Low Unevenly distributed microvilly Oval, indented, bilobed Indistinct Inter sinusoidal
60 High Unevenly distributed microvilli Round Inconspicuous Usually interstitial
69 High Usually polar
Good High CR rate Majority mutated
71 High Unevenly distributed microvilly Round, occasionally bilobed Prominent (60%) Usually interstitial, subtle intersinusoidal Leukemic infiltration of red pulp Negative Negative CD11c +/ , CD25, CD103+/, HC2, CD123, CD10+/ SIgG j
Majority negative
Majority positive
Nuclei Nucleoli Histology of bone marrow involvement Histology of spleen TRAP activity Annexin A1 Immunophenotype of leukemic cells Surface Ig Light chain restriction Response to IFN Response to PNA Mutational status of IGHV gene VH4-34 expression
Leukemic infiltration of red pulp Positive Positive CD11c+, CD25+, CD103+, HC2+, CD123+, CD10/+ SIgM
j=k
Red pulp infiltration
Round Small (50% distinct) Predominantly intersinusoidal White pulp infiltration
Absent to week NR CD11c+, CD25, CD10
Weak NR CD11c+, CD25+/, CD103
SIgG
SIgM
j>k
j>k
Poor Low CR rate Majority mutated
Poor Low CR rate Majority mutated
NR
NR
Abbreviations: Ig – immunoglobulin; NR – not reported; tartrate resistant acid phosphate; CR complete response; PR – partial response.
T. Robak / Cancer Treatment Reviews 37 (2011) 3–10
this type of marrow involvement is also found in HCl-C and occasionally in HCl-V.8,10,34,35 In HCl-V, most cases have interstitial infiltration with scattered hairy cells lying within the sinusoids.8 However, approximately 20% of HCl-V patients have mixed nodular and interstitial pattern. The pathological analysis of the spleen in HCl-C and HCl-V patients revealed leukemic infiltration of red pulp without white pulp involvement.10 In contrast, white pulp splenic involvement occurs in SMZL.33 Spleen histology is the gold standard approach to establish a clear-cut diagnosis of SMZL. In cases which do not need a splenectomy, or which are not suitable for a surgical procedure, a combination of bone marrow histology and neoplastic cell phenotype can be useful to establish proper diagnosis of SMZL.31,34 According to the recent criteria of the SMZL working group, the minimum diagnostic criteria for SMZL are either spleen histology plus immunophenotype or typical blood and bone marrow morphology and immunophenotype, plus intrasinusoidal infiltration of the bone marrow by CD20-positive cells.31 The evaluation of immunoglobulin heavy chain isotype expression can also differentiate HCl-V from SMZL.7 SMZL cells characteristically express IgM with IgD and lack of IgG or IgA.35 In HCl-V, IgG expression or coexpression of preswitched (IgM/IgD) and postswitched (IgM/IgD) is observed by the cell isotypes.7
Molecular biology P53 allele loss through monosomy or monoallelic deletion was noted in all 12 patients with HCl-V reported by Vallianatou et al.23 In addition, a higher percentage of cells with p53 deletion correlates well with a greater tendency for transformation and poorer response to therapy. During B-cell differentiation, the VH, DH and JH gene segments of the immunoglobulin (Ig) gene locus are rearranged following a strict hierarchical order in generating the Ig repertoire.36 Recent reports indicate that the vast majority of leukemic cells from HCl-C cells derive from mature B-cells.37 Hochley et al.38 analyzed IGH rearrangements in 41 cases with HCl-V, 30 with HCl-C, and 113 with SMZL. In this study, genes displaying the IGHV mutational status of HCl-V were more similar to SMZL than to HCl-C. No evidence of somatic hypermutation in IGHV genes was found in 22% of HCl-V and 15% of SMZL. In contrast, although somatic hypermutation was seen in the majority of cases with HCl-C, 10% of these cases are not mutated. The Ig gene configuration and expression in HCl-JV partially overlap with those described for immature B-cell leukemia.21 Yamaguchi et al.20 investigated Ig gene rearrangements in 12 patients with HCl-JV and in an HCl-JV derived cell line. The Ig light chain was undetected in nine patients and the remaining four cases expressed the kappa chain. Rearranged bands in the Ig heavy chain gene were recognized in all 12 cases. Martín-Jiménez et al.37 analyzed the VH, DH and JH gene segments of the Ig gene locus in the leukemic cells of patients with HCl-C and HCl-V. The somatic mutations were present in the monoclonal VDJH rearrangements in 38 previously untreated patients with CD25 positive HCl-C cells or CD25 negative cases, a phenotype associated with HCl-V.37 All 38 patients displayed a monoclonal amplification of Pone VDJH or DJH rearrangement. In this study, JH3 segments were selected in two out of five CD25 negative cases, while they were never selected in 33 remaining CD25 + cases. This study supports the existence of molecular differences between CD25 and CD25 + cases. Three of five CD25 negative cases in this analysis were unmutated in contrast to cases with a CD25 positive immunophenotype. In addition, 100% homology to the germ line sequence was demonstrated by the 3 CD25 negative cases but none of the CD25 positive cases. Earlier studies indicated that in HCl-C the leukemic cells have usually one or two different rearrangements for Ig heavy chain.39,40
5
In the majority of HCl-C patients, the expressed tumor IGHV is mutated and only in some patients unmutated IGHV was noted.39,41,42 In SMZL, as in CLL, the mutation status of the Ig genes is heterogenous.43 Whereas the majority of SMZL cases displayed somatic hypermutations in Ig genes, one-third had unmutated Ig genes. In HCl-JV, the rearranged bands in Ig heavy chain genes were recognized in all 12 tested patients.20 In CLL, the unmutated status of IGHV is associated with a poor prognosis and a shorter survival in comparison with CLL, characterized by the mutated status of IGHV.44 Recently, Forconi et al. analyzed clinical significance of the mutational status of the leukemic cells for the prognosis in HCl-C patients.45 They investigated clinical and molecular parameters predicting the response and event-free survival after treatment with cladribine (2-CdA) in 58 HCl patients. Among them, 52 expressed mutated IGHV and six unmutated IGHV. Treatment failures were observed in five patients with unmutated IGHV and all patients with mutated IGVH responded to 2-CdA treatment. The diagnosis of HCl-C was established according to the WHO 2001 Classification of Tumours of Haematopoietic and Lymphoid Tissues3 and patients with HCl-V were not included in this study. All five unmutated IGHV patients not benefiting from 2-CdA were CD25 and CD103 positive and ANXA1 positive. In a simultaneously published report by Arons et al.46 Ig rearrangements were studied in 82 patients diagnosed with HCl, including 20 patients with HCl-V and 62 with HCl-C. They found that VH4-34, the most common VH gene used in HCl-V, had very high homology to its germ line sequence and was associated with symptoms characteristic to HCl-V, such as advanced age, higher leukocytosis, poor response to 2-CdA therapy, and shorter survival. In addition, patients with HCl-C who were VH4-34 positive had also poorer overall survival than VH4-34 negative patients. The median survival for VH4-34 positive patients was 8.6 years and for VH4-34 negative patients – 26.2 years. In addition, this study documented that poor prognosis in HCl is less closely related to unmutated status than to VH4-34 rearrangements. The results of this important study indicate that VH4-34 + HCl represent a disorder overlapping with HCl-V and distinct from typical HCl. Treatment The therapeutic approach to HCl-V is still debated. Various treatment approaches active in HCl-C achieve partial or no response in HCl-V and remission is usually shorter than in HClC.47–50 In addition, HCl-V seems to be resistant to therapeutic modalities usually highly effective in the treatment of HCl-C such as splenectomy, interferon a (IFN-a), and PNA. Clinical responses to splenectomy, IFN-a and PNA in HCl-JV are also inferior to those seen in HCl-C.24,25,29 Splenectomy and splenic irradiation Approximately 90% of HCl-C patients have splenomegaly, and splenectomy has been the first effective treatment in this disease.52 In HCl-C over 80% of patients show hematological improvement and at least 40% achieved a CR.47 Good clinical and hematological responses after splenectomy has been observed in 13 out of 19 patients (74%) with HCl-V, reported by Matutes et al.8 The median response duration was 4 years (1–10+). However, in other studies, less than 1/3 of HCl-V patients obtained a PR and no CR was observed.1 Some authors suggest that previous splenectomy may improve the response to chlorambucil and PNA in HCl-V patients.11,49 These results suggest that splenectomy should be considered in HCl-V because it corrects the cytopenias and removes a significant bulk of the disease.
6
T. Robak / Cancer Treatment Reviews 37 (2011) 3–10
ing for 60 + and 29 + months.48,57 The mean number of 2-CdA cycles was 3.5. Tetreault et al.58 administered 2-CdA to four patients with HCl-V over a 7 year period. Of these 4 patients, one achieved a CR and two a PR. However, these results are also inferior to those achieved with 2-CdA in HCl-C. More recently, Palomera et al.59 reported three patients with HCl-V who were treated with 2-CdA at a daily dosage of 0.1 mg/kg by continuous intravenous infusion for 7 days. One of them was previously treated with splenectomy and IFN-a and two patients were untreated. The patients received from one to three 2-CdA courses. Two PR and one CR were achieved lasting from 15+ to 127 + months. These reports indicate that 2-CdA is significantly less active in HCl-V than in HCl-C. The analysis of 19 cases published so far shows a response rate of 55% including only two CR.48,57–59 This is in contrast to spectacular CR rates in HCl-C treated with 2-CdA, in which of overall CR rate over 80% is obtained with a single cycle.47 In addition, the majority of HCl-V patients required more than one cycle to maintain PR. Three cases of HCl-JV were also treated with 2-CdA 0.09 mg/kg/ day by continuous infusion for 7 days and no response was noted.60 Of three other patients with HCl-VJ treated with 2-CdA in two reports there was one CR and one PR.61 In one multi-center study, the remission rate was only 35.7%.29 However, the effectiveness of 2-CdA in HCl-JV is unclear. In spite of this, a CR was achieved in some patients treated with this agent.28,29,61 Low efficacy of 2-CdA in the treatment of SMZL has been also reported.62 Pentostatin is also less active in HCl-V than in HCl-C.63 Of 12 patients treated with this agent in 3 reports, there were 7 PR and no CR.64–66 Similarly, in a group of 15 patients with HCl-V reported by Matutes et al.8 pentostatin induced only a PR in 8 of 15 (54%) patients and no CR was achieved. On the other hand, a case has been recently presented of a patient with the aplastic variant of HCl successfully treated with pentostatin.67 Hematological improvement was also observed in HCl-V in Japan in a patient refractory to 2CdA and subsequently treated with pentostatin.68 Another patient reported by Ribeiro et al.69 achieved a PR after pentostatin treatment. These cases demonstrate that similar to 2-CdA, HCl-V patients treated with pentostatin have a poorer clinical outcome and a lower response rate than those patients with HCl-C. The data on the use of fludarabine in HCl-V in a similar way to HCl-C is limited. In HCl-C, fludarabine is not as effective as 2-CdA or pentostatin.70 According to Matutes et al.,9 only one out of three patients with HCl-V treated with fludarabine achieved a PR. An additional PR in a patient with HCl-V was reported by Kantarjian et al.70
Splenic irradiation may be also useful, especially in elderly patients with high surgical risk.51,52 Sgarabotto et al.52 reported the case of a 79-year old man with HCl-V treated with splenic radiotherapy in whom a CR was achieved. Two other patients with HCl-V obtained a PR after splenic irradiation9,51 but this treatment was not effective in three other patients.9 In another patient the treatment was fractionated into 10 weekly doses for a total of 10 Gy.52 Three months after radiotherapy, the spleen returned to its normal size, the WBC count was normal and the bone marrow biopsy showed almost total disappearance of the lymphoid infiltration. More recently, Sasaki et al. reported a patient with HCl-V, treated with splenic irradiation and subsequently with alemtuzumab.53 The irradiation attenuated splenomegaly from 12 to 4 cm below the left costal margin and reduced the number of circulating leukemic cells. These results indicate that splenic irradiation may have a beneficial effect in some patients with HCl-V, especially in elderly patients with massive splenomegaly and poor performance status. Interferon a Interferon a is an effective agent in HCl-C.54,55 However, at present its use in the treatment of HCl is limited because PNAs produce higher and durable remissions. Moreover, IFN-a is less convenient to the patient than PNA. Unlike HCl-C, patients with HCl-V are resistant to IFN-a. All 7 patients with HCl-V treated with IFN-a by Sainati et al.12 showed no objective response. In the group of 14 patients treated with IFN-a reported by Matutes et al.8 only two (14%) of them achieved a temporary partial response (PR). These poor results may relate to a low number of IFN-a receptors, which are abundant in typical HCl.56 However, IFN-a seems to be more effective in HCl-JV. In patients with HCl-JV, an overall 35% response to INF-a has been reported.24
Purine nucleoside analogs The purine nucleoside analogs, cladribine (2-CdA) and pentostatin (DCF), are the drugs of choice in the treatment of HCl-C.47 These drugs induce a similar high response rate and a long overall survival in HCl-C. However, the results of the treatment of HCl-V with PNA are poor (Table 2). In our study, 2-CdA was given in 2-h infusions for 5 days in a daily dose of 0.12 mg/kg.48,57 Four of 6 patients did not respond to 2-CdA treatment and only two entered a PR last-
Table 2 Purine nucleoside analogs in the treatment of hairy-cell leukemia-variant. Treatment
No. of courses
No. of patients
CR No. of pts.
PR No. of pts.
Response duration
Survival from the beginning of treatment
References
2-CdA 0.12 mg/kg/ d i.v. 2-h inf. d1–5 2-CdA 0.1 mg/kg/d 2-CdA 0.1 mg/kg/d c.i. i.v./d,ds1–7 2-CdA DCF DCF 4 mg/m2 i.v. every 2 weeks DCF 4 mg/m2 i.v. every 2 weeks DCF FA 30 mg/m2 i.v.; ds 1–5 FA
1–3
6
0
2
60 + m, 29 + m
NR
Robak et al.48 Blasinska-Morawiec et al.57
2–5 1–3
4 3
1 1
2 2
108 + m, 12 m, 8 m NR
108 + m, 32 + m, 18 m, 36 m 127 + m, 31 + m, 15 + m
Tetreault et al.58 Palomera et al.59
NR NR 10
8 15 1
0 0 0
4 8 1
NR NR 15 m
NR NR NR
Matutes et al.8,9 Matutes et al.8,9 Dunphy et al.49
8
1
1
0
69 + m
69 + m
Ng et al.67
NR 3; re-treatment 8 courses NR
3 1
0 0
2 1
NR 18 m; 15 + m
NR NR
Sainati et al.12 Kantarjian et al.70
3
0
1
NR
NR
Mutates et al.8,9
Abbreviations: 2-CdA – cladribine, 2-chlorodeoxyadenosine; DCF – pentostatin, deoxycoformycin; FA – Fludarabine; NR – not reported; m –month; d – day; iv – intravenously; ci – continuous infusion.
7
T. Robak / Cancer Treatment Reviews 37 (2011) 3–10
Several clinical trials indicate that the anti-CD20 monoclonal antibody, rituximab, is active in HCl-C.71–74 Single case reports suggest that alemtuzumab is also an active agent in HCl-C, even relapsing after rituximab therapy.75 Recently, some reports indicate that both monoclonal antibodies are active in HCl-V (Table 3).28,76–80 Promising results have been also obtained with immunotoxin BL22 targeting CD22 .
18 months after treatment. Another patient with HCl-VJ refractory to pentostatin, 2-CdA, and INF-a also responded to 8 courses of rituximab at a dose of 375 mg/m2 per course.78 These results suggest that rituximab may be an effective method of treatment for refractory HCl-V and HCl-JV. Moreover, rituximab combined with PNA may be more effective than these agents alone. In one recent report, a patient with HCl-V received rituximab 375 mg/m2 followed by cladribine 0.1 mg/kg for 7 days. Treatment resulted in a remarkable recovery of blood count.
Rituximab
Alemtuzumab
Compared with PNA, rituximab does not induce long-term bone marrow hypoplasia, and the degree of immunosuppression is much less. It is possible that immunochemotherapy with rituximab with PNA will be the most effective treatment of HCl-V, similar to the current treatment of chronic lymphocytic leukemia and other B-cell malignances.81,82 Recent observations indicate that patients with HCl-V can be successfully treated with rituximab.5,76–80 Narat et al.5 reported the case of a 53-year-old man who had refractory HCl-V for 8 years. He was given weekly rituximab (375 mg/m2) for 4 weeks and achieved a CR. At the time of publication, the patient continued to remain well in CR 19 months after rituximab treatment. Quach et al.79 also described a patient with HCl-V, whose course was previously complicated by pure red cell aplasia and who achieved a CR after treatment with rituximab. Another patient diagnosed as having advanced-stage HCl-V, with blastoid variant transformation, was also successfully treated with this agent.77 The above reports indicate that rituximab is a promising therapy for patients with HCl-V, and can be combined with 2-CdA. However, further clinical studies are required before rituximab can be considered as a frontline therapy for HCl-V. Rituximab seems to be also an active drug in HCl-JV. Imamura et al. reported a 76-year-old patient with HCl-JV who received rituximab 375 mg/m2 i.v. weekly for 4 cycles.80 Disappearance of hairy cells from the peripheral blood was observed on the day after the first administration of rituximab, and the bone marrow aspiration performed one week after the fourth dose of rituximab did not reveal any hairy cells. The patient was in CR, which continued for
Alemtuzumab is another monoclonal antibody active in lymphoid malignancies.83 This is a humanized IgG1 anti-CD52 antibody that binds to the cell membrane of normal and malignant lymphocytes. CD52 expression was documented in 92–100% of the malignant cells in HCl and HCl-V.84 Single case reports suggest that alemtuzumab is an active agent in HCl-C and HCl-V even relapsing after rituximab.75,85 Telek et al.85 reported a case of a 58-year-old male with HCl-V and p53 mutation who was treated successfully with alemtuzumab. The monoclonal antibody was given at a dose 3 30 mg/week s.c. for 12 weeks. After 8 weeks of therapy hematologic remission was achieved. In the second patient with HCl-V, alemtuzumab was given after splenic pre-irradiation.53 Treatment with 24 mg of alemtuzumab eradicated leukemic cells from the blood by day 9, splenomegaly disappeared and a CR was confirmed. Activity of alemtuzumab in this patient was confirmed in the in vitro study, showing that alemtuzumab induced leukemic cell death in the complement dependent cytotoxicity mechanism.
Monoclonal antibodies
Immunotoxins In HCl-C with resistance to PNA, promising results have been obtained with two immunotoxins, BL22 and LMP-2 targeting CD22 and CD25 respectively.86,87 BL-22 (RFB4 (dsFv)-PE38) is a 63-kDa recombinant immunotoxin containing truncated Pseudomonas exotoxin and variable domains from anti-CD22. BL22 seems to be a very effective treatment for HCl-V. Kreitman et al.86 treated 3 patients refractory to 2-CdA and all of them achieved a CR after
Table 3 Monoclonal antibodies and immunotoxins in the treatment of hairy-cell leukemia variant. Previous treatment
No. of patients
CR No. of pts.
PR No. of pts.
Response duration
Survival from the beginning of treatment
References
375 mg/m2/wk 4
No
1
1
0
19 + m
19 + m
Narat et al.5
375 mg/m2/wk 6
No
1
0
1
4+m
4+m
Knight et al.91
375 mg/m2/wk 4
DCF, 2-CdA
1
1
0
18 + m
18 + m
Imamura et al.28
375 mg/m2 i.v./w 4 375 mg/m2/wk 4
2-CdA, IFN-a, splenectomy 2-CdA, IFN-a, VACOP-B, Dexa-BEAM, Splenectomy, 2-CdA, DCF, CHOP
1 1
1 0
0 1
13 m, 10 mb 12 m
24 m 55 mc
Quach et al.79 Busemann et al.90
1
0
1
4m
NR
Sasaki et al.53
1
0
1
NR
NR
Sasaki et al.53
3
3
0
8 > 3; 12 > 4; >13
NR
Kreitman et al.86
Treatment
Rituximab wks Rituximab wks Rituximab wksa Rituximab Rituximab
Rituximab 900 mg in 3 wks ? 375 mg/m2 every 3 wks as maintenance Alemtuzumab 1 mg, 3 mg, 10 mg 3, 30 mg trice weekly 8 wks BL 22 30–50 mg/kg 3–14 cycles
2-CdA;DCF; CHOP; Rituximab; IFNa; splenic irradiation 2-CdA; IFN-a; splenectomy; DCF; chlorambucil
Abbreviations: CR – complete response; PR – partial response; 2-CdA- cladribine, 2-chlorodeoxyadenosine; DCF- pentostatin, deoxycoformycin; IFN-a – interfer– ona; CHOP – cyclophosphamide, doxorubicin, vincristin, prednisone. a HCl-JV. b Second CR after re-treatment. c Survival after subsequent stem cell transplantation; wk – week.
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T. Robak / Cancer Treatment Reviews 37 (2011) 3–10
therapy with this agent lasting 8, 12 and >13 months respectively. In these patients, circulating hairy cells began to decrease within 24 h after the first dose of immunotoxins. In addition, two patients had a second CR after re-treatment when relapsed. No patients ever had a CR with 2-CdA chemotherapy. Moreover, two were ineffectively treated with IFN-a and one was previously splenectomiced. The low level of BL22 toxicity made the administration of multiple cycles possible. These encouraging results suggested that BL22 may be a very effective agent in the treatment of refractory HCl-V. CAT-8015 (HA22) is a new generation of CD22-specific targeted immunotoxin composed of anti-CD22 antibody fused to the modified form of Pseudomonas exotoxin.88 This agent has a novel mechanism of action as compared to other anti-CD22 monoclonal antibodies. HA 22 is internalized upon binding to CD22, inhibiting protein translation and promoting apoptosis. Preliminary results of HA22 in patients with refractory/relapsed HCl-C have been recently reported.88 A total of 26 patients have received HA22 to date including 14 treated previously with rituximab. No DLT has been established so far and MTD has not been reached. Nineteen patients (73.1%) responded with a CR rate of 34.6% (9 patients) and a PR rate of 38.5% (10 patients). These data indicate that HA22 is a promising new agent for patients with HCl-C and supports further investigation in patients with HCl-C and HCl-V. Hematopoietic cell transplantation The poor prognosis of patients with HCl-V has led some clinicians to consider hematopoietic cell transplantation (HCT).89,90 However, the data to support this approach is limited to case reports. We identified in the literature two patients treated with this procedure. Busemann et al.90 reported a 60-year-old man initially treated with 2-CdA, IFN-a, VACOP-B, Dexa-BEAM and splenectomy which resulted only in a PR. Subsequently, the patient received 4 doses of rituximab (375 mg/m2) and then single doses of this drug because of the progressive disease, and obtained a dramatic reduction in the circulating leukemic cells. Thereafter the patient was allografted with unmanipulated CD34 + cells from a matched unrelated donor. The patient achieved a clinical and molecular remission lasting for about 3.5 years. Another patient with HCl-V reported in the literature was treated with autologous HCT.89 The patient with aggressive relapsed disease received DHAP (cisplatin, cytarabine, dexamethasone) followed by high-dose chemotherapy supported by autologous peripheral blood stem cells. Clinical and molecular CR was documented three months after transplantation and persisted for 16 months. These two case reports may indicate that both allogeneic and autologous stem cell transplantation are a possible therapeutic approach in selected cases with HCl-V.
addition, VH4-34 gene expression is associated with symptoms characteristic of HCl-V. The clinical course of HCl-V is chronic, usually benign, but survival time of HCl-V patients is usually shorter than HCl-C. Currently, principles of therapy of this rare disease derive from uncontrolled single institutional studies, or even single case reports. For these reasons, the outcome of therapy is unsatisfactory with no standard therapy established. Unfortunately, randomized controlled trials are not feasible because of an insufficient number of cases. Good clinical and hematological responses after splenectomy or splenic irradiation have been observed. Splenectomy can be considered in some patients with HCl-V because it corrects cytopenias and removes a significant bulk of disease. Splenic irradiation may be also useful especially in elderly patients with a high surgical risk. HCl-V seems to be resistant to therapeutic modalities usually highly effective in the treatment of HCl-C such as IFN-a and PNA. However, IFN-a seems to be more effective in the of HCl-JV. Recent studies suggest that rituximab and anti-CD-22 immunotoxin BL22 may be effective agents in the treatment of HCl-V. In the opinion of the author of this review rituximab combined with PNA should be considered as the treatment of choice in previously untreated patients. In addition, some case reports indicate that stem cell transplantation can be a useful therapeutic approach in selected cases with HCl-V. HCl-V remains an incurable disease and the introduction of new drugs and new therapeutic strategies is awaited. The organization of a basic and translational research program focusing on rare chronic lymphoid leukemias based on multidisciplinary teams, tumor banking and tumor registries would be very helpful in better understanding the biology of this disease and progress in the treatment. Progress in the knowledge concerning molecular genetics, immunology and intracellular signaling of HCl-V should translate
Diagnosis and Staging
Symptomatic HCL-V
Asymptomatic HCL-V
2-CdA or DCF +/- Rituximab (if splenomegaly major symptom consider splenectomy or
Response
Observation
splenic irradiation)
Conclusions HCl-V is a distinct clinico-pathological entity. However, distinguishing HCl-V from classical HCl and SMZL which are both associated with pronounced splenomegaly and circulating neoplastic cells with ‘hairy’ projections remain a problem. Patients with HCl-V are usually older, splenomegaly is less common and leucopenia with granulocytopenia and monocytopenia are usually not seen. Bone marrow is typically easily aspirable, hyper-cellular with mild myelofibrosis. However, several markers including CD11c, CD25, CD27, CD103, CD123, ANXA1 and TRAP are claimed to distinguish HCl-V from HCl-C and SMZL. HCl-V cases lack CD-25, CD27 and ANXA1 and might lack CD103 but express other HCl-associated antigens. The analysis of IGHV mutational status of HCl-V cells has shown that most patients are unmutated in contrast to HCl-C. In
Refractory or progression <12 months
Progression >12 months
Clinical trial or alemtuzumab or immunotoxin or SCT
Retreatment
Fig. 1. Proposed treatment algorithm for HCl-V patients.
T. Robak / Cancer Treatment Reviews 37 (2011) 3–10
into the development of new, more specific and more effective drugs. A proposed flow-chart for therapeutic decision-making in the treatment of HCl-V is outlined in Fig. 1. Conflict of interest statement I declare no conflict of interest directly relevant to this review. Acknowledgements This work was supported in part by a Grant from the Medical University of Lodz (No. 503-1093-1) and by the Foundation for the Development of Diagnostics and Therapy, Warsaw, Poland. References 1. Cawley JC, Burns GF, Hayhoe FG. A chronic lymphoproliferative disorder with distinctive features: a distinct variant of hairy-cell leukaemia. Leuk Res 1980;4:547–59. 2. Cannon T, Mobarek D, Wegge J, Tabbara IA. Hairy cell leukemia: current concepts. Cancer Invest 2008;26:860–5. 3. Foucar K, Catovsky D. Hairy cell leukemia. In: Jaffe S, Harris NL, Stein H, Wardman JW ED. WHO classification of haematopoietic and lymphoid tumors. Lyon: IARC Press, 2001. p. 138–41. 4. Ott G, Balague-Ponz O, de Leval L, de Jong D, Hasserjian RP, Elenitoba-Johnson KS. Commentary on the WHO classification of tumors of lymphoid tissues: indolent B cell lymphomas. J Hematopathol 2009;2:77–81. 5. Narat S, Gandla J, Dogan A, Mehta A. Successful treatment of hairy cell leukemia variant with rituximab. Leuk Lymphoma 2005;46:1229–32. 6. Piris M, Foucar K, Mollejo M, Campo E, Falini B. Splenic B-cell lymphoma/ leukemia unclassifiable. In: Swerdlow SH, Campo E, Harris NL et al., editors. World Health Organization classification of tumors of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008. p. 191–2. 7. Cessna MH, Hartung L, Tripp S, Perkins SL, Bahler DW. Hairy cell leukemia variant: fact or fiction. Am J Clin Pathol 2005;123:132–8. 8. Matutes E, Wotherspoon A, Brito-Babapulle V, Catovsky D. The natural history and clinico-pathological features of the variant form of hairy cell leukemia. Leukemia 2001;15:184–6. 9. Matutes E, Wotherspoon A, Catovsky D. The variant form of hairy-cell leukaemia. Best Pract Res Clin Haematol 2003;16:41–56. 10. Ya-In C, Brandwein J, Pantalony D, Chang H. Hairy cell leukemia variant with features of intrasinusoidal bone marrow involvement. Arch Pathol Lab Med 2005;129:395–98. 11. Zinzani PL, Lauria F, Buzzi M, Raspadori D, Gugliotta L, Bocchia M, et al. Hairy cell leukemia variant: a morphologic, immunologic and clinical study of 7 cases. Haematologica 1990;75:54–7. 12. Sainati L, Matutes E, Mulligan S, de Oliveira MP, Rani S, Lampert IA, et al. A variant form of hairy cell leukemia resistant to alpha-interferon: clinical and phenotypic characteristics of 17 patients. Blood 1990;76:157–62. 13. Razaq M, Perumandla S, Mankan N, et al. Hairy cell leukemia variant transforming into aggressive lymphoma with prostatic involvement in a patient with polycythemia vera. Leuk Lymphoma 2006;47:754–7. 14. Hounieu H, Chittal SM, al Saati T, et al. Hairy cell leukemia. Diagnosis of bone marrow involvement in paraffin-embedded sections with monoclonal antibody DBA.44. Am J Clin Pathol 1992;98:26–33. 15. Matutes E. Immunophenotyping and differential diagnosis of hairy cell leukemia. Hematol Oncol Clin North Am 2006;20:1051–63. 16. Wu ML, Kwaan HC, Goolsby CL. Atypical hairy cell leukemia. Arch Pathol Lab Med 2000;124:1710–3. 17. Matutes E, Morilla R, Owusu-Ankomah K, Houliham A, Meeus P, Catovsky D. The immunophenotype of hairy cell leukemia (HCL). Proposal for a scoring system to distinguish HCL from B-cell disorders with hairy or villous lymphocytes. Leuk Lymphoma 1994;14(Suppl. 1):57–61. 18. Robbins BA, Ellison DJ, Spinosa JC, et al. Diagnostic application of two-color flow cytometry in 161 cases of hairy cell leukemia. Blood 1993;82:1277–87. 19. Del Giudice I, Matutes E, Morilla R, et al. . The diagnostic value of CD123 in Bcell disorders with hairy or villous lymphocytes. Haematologica 2004;89:303– 08. 20. Yamaguchi M, Machii T, Shibayama H, et al. Immunophenotypic features and configuration of immunoglobulin genes in hairy cell leukemia-Japanese variant. Leukemia 1996;10:1390–4. 21. Quigley MM, Bethel KJ, Sharpe RW, Saven A. CD52 expression in hairy cell leukemia. Am J Hematol 2003;74:227–30. 22. Brito-Babapulle V, Matutes E, Oscier D, Mould S, Catovsky D. Chromosome abnormalities in hairy cell leukaemia variant. Genes Chromosomes Cancer 1994;10:197–202. 23. Vallianatou K, Brito-Babapulle V, Matutes E, Atkinson S, Catovsky D. p53 gene deletion and trisomy 12 in hairy cell leukemia and its variant. Leuk Res 1999;23:1041–5. 24. Machii T, Tokumine Y, Inoue R, Kitani T. Predominance of a distinct subtype of hairy cell leukemia in Japan. Leukemia 1993;7:181–6.
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25. Katayama I, Mochino T, Honma T, Fukuda M. Hairy cell leukemia: a comparative study of Japanese and non-Japanese patients. Semin Oncol 1984;11(4 Suppl. 2):486–92. 26. Sasaki M, Aritaka N, Tsukune Y, Kawahara S, Masuda A, Tsutsui M, et al. Establishment of a hairy cell leukemia variant cell line, HCLv-07. Acta Haematol 2009;121:63–6. 27. Traverse-Glehen A, Baseggio L, Callet-Bauchu E, et al. Hairy cell leukaemiavariant and splenic red pulp lymphoma: a single entity? Br J Haematol 2010 Mar 11. [Epub ahead of print] PubMed PMID: 20230408. 28. Imamura T, Ohtsuka E, Ogata M, et al. Successful induction of long-term remission using rituximab in a patient with refractory hairy cell leukemiaJapanese variant. Int J Hematol 2004;80:432–4. 29. Kitani T, Machii T, Inoue R, Kanakura Y. Hairy cell leukemia: a report of 10 cases in Japan and characterization of anti-hairy cell sera. Jpn J Clin Oncol 1983;13: 497–509. 30. Machii T, Yamaguchi M, Inoue R, et al. Polyclonal B-cell lymphocytosis with features resembling hairy cell leukemia-Japanese variant. Blood 1997;89: 2008–14. 31. Matutes E, Oscier D, Montalban C, Splenic marginal zone lymphoma proposals for a revision of diagnostic, staging and therapeutic criteria. Leukemia 2008;22:487–95. 32. Dong HY, Weisberger J, Liu Z, Tugulea S. Immunophenotypic analysis of CD103+ B-lymphoproliferative disorders: hairy cell leukemia and its mimics. Am J Clin Pathol 2009;131:586–95. 33. Sun T, Dittmar K, Koduru P, Susin M, Teichberg S, Brody J. Relationship between hairy cell leukemia variant and splenic lymphoma with villous lymphocytes: presentation of a new concept. Am J Hematol 1996;51:282–8. 34. Arcaini L, Paulli M. Splenic marginal zone lymphoma: a hydra with many heads? Haematologica 2010;95:534–7. 35. Kent SA, Variakojis D, Peterson LC. Comparative study of marginal zone lymphoma involving bone marrow. Am J Clin Pathol 2002;117:698–708. 36. Matsuda F, Ishii K, Bourvagnet P, et al. The complete nucleotide sequence of the human immunoglobulin heavy chain variable region locus. J Exp Med 1998;188:2151–62. 37. Martín-Jiménez P, García-Sanz R, González D, et al. Molecular characterization of complete and incomplete immunoglobulin heavy chain gene rearrangements in hairy cell leukemia. Clin Lymphoma Myeloma 2007;7:573–9. 38. Hockley SL, Giannouli S, Morilla A, et al. Insight into the molecular pathogenesis of hairy cell leukaemia, hairy cell leukaemia variant and splenic marginal zone lymphoma, provided by the analysis of their IGH rearrangements and somatic hypermutation patterns. Br J Haematol 2009 October 22. [Epub ahead of print]. 39. Arons E, Sunshine J, Suntum T, Kreitman RJ. Somatic hypermutation and VH gene usage in hairy cell leukaemia. Br J Haematol 2006;133:504–12. 40. Arons E, Margulies I, Sorbara L, et al. Minimal residual disease in hairy cell leukemia patients assessed by clone-specific polymerase chain reaction. Clin Cancer Res 2006;12:2804–11. 41. Maloum K, Magnac C, Azgui Z, et al. VH gene expression in hairy cell leukaemia. Br J Haematol 1998;101:171–8. 42. Thorsélius M, Walsh SH, Thunberg U, Hagberg H, Sundström C, Rosenquist R. Heterogeneous somatic hypermutation status confounds the cell of origin in hairy cell leukemia. Leuk Res 2005;29:153–8. 43. Tierens A, Delabie J, Malecka A, et al. Splenic marginal zone lymphoma with villous lymphocytes shows on-going immunoglobulin gene mutations. Am J Pathol 2003;162:681–9. 44. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999;94:1848–54. 45. Forconi F, Sozzi E, Cencini E, et al. Hairy cell leukemias with unmutated IGHV genes define the minor subset refractory to single-agent cladribine and with more aggressive behavior. Blood 2009;114:4696–702. 46. Arons E, Suntum T, Stetler-Stevenson M, Kreitman RJ. VH4-34+ hairy cell leukemia, a new variant with poor prognosis despite standard therapy. Blood 2009;114:4687–95. 47. Robak T. Current treatment options in hairy cell leukemia and hairy cell leukemia variant. Cancer Treat Rev 2006;32:365–76. 48. Robak T, Błasin´ska-Morawiec M, Błon´ski J, et al. 2-Chlorodeoxyadenosine (cladribine) in the treatment of hairy cell leukemia and hairy cell leukemia variant: 7-year experience in Poland. Eur J Haematol 1999;62:49–56. 49. Dunphy CH, Petruska PJ. Atypical prolymphocytic variant of hairy-cell leukemia: case report and review of the literature. Am J Hematol 1996;53:121–5. 50. Mercieca J, Matutes E, Emmett E, Coles H, Catovsky D. 2-Chlorodeoxyadenosine in the treatment of hairy cell leukaemia: differences in response in patients with and without abdominal lymphadenopathy. Br J Haematol 1996;93: 409–11. 51. Dunn P, Shih LY, Ho YS, Tien HF. Hairy cell leukemia variant. Acta Haematol 1995;94:105–8. 52. Sgarabotto D, Vianello F, Radossi P, et al. Remission in hairy cell leukemiavariant following splenic radiotherapy alone. Leuk Lymphoma 1997;26:395–8. 53. Sasaki M, Sugimoto K, Mori T, Karasawa K, Oshimi K. Effective treatment of a refractory hairy cell leukemia variant with splenic pre-irradiation and alemtuzumab. Acta Haematol 2008;119:45–8. 54. Polliack A. Hairy cell leukemia and allied chronic lymphoid leukemias: current knowledge and new therapeutic options. Leuk Lymphoma 1997;26(Suppl. 1): 41–51.
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55. Ahmed S, Rai KR. Interferon in the treatment of hairy-cell leukemia. Best Pract Res Clin Haematol 2003;16:69–81. 56. Dadmarz R, Evans T, Secher D, Marshall N, Cawley JC. Hairy cell possess more interferon receptors than other lymphoid cell types. Leukemia 1987;1:357–61. 57. Blasin´ska-Morawiec M, Robak T, Krykowski E, Hellmann A, Urban´ska-Rys´ H. Hairy cell leukemia-variant treated with 2-chlorodeoxyadenosine – a report of three cases. Leuk Lymphoma 1997;25:381–5. 58. Tetreault SA, Robbins BA, Saven A. Treatment of hairy cell leukemia-variant with cladribine. Leuk Lymphoma 1999;35:347–54. 59. Palomera L, Domingo JM, Sola C, Azaceta G, Calvo MT, Gutierrez M. Cladribine (2-chlorodeoxyadenosine) therapy in hairy cell leukemia variant. A report of three cases. Haematologica 2002;87:107–8. 60. Machii T, Chou T, Suzuki M, et alCladribine Study Group. Phase II clinical study of cladribine in the treatment of hairy cell leukemia. Int J Hematol 2005;82:230–5. 61. Miyazaki M, Taguchi A, Sakuragi S, Mitani N, Matsuda K, Shinohara K. Hairy cell leukemia, Japanese variant, successfully treated with cladribine. Rinsho Ketsueki 2004;45:405–7. 62. Lefrère F, Hermine O, François S, et al. Lack of efficacy of 2chlorodeoxyadenoside in the treatment of splenic lymphoma with villous lymphocytes. Leuk Lymphoma 2000;40:113–7. 63. Grever MR, Doan CA, Kraut EH. Pentostatin in the treatment of hairy-cell leukemia. Best Pract Res Clin Haematol 2003;16:91–9. 64. Catovsky D, Matutes E, Talavera JG, et al. Long-term results with 20 deoxycoformycin in hairy cell leukemia. Leuk Lymphoma 1994;14(Suppl. ):108–13. 65. Dunphy CH, Petrusk PJ. Atypical prolymphocytic variant of hairy cell leukemia: case report and review of the literature. Am J Hematol 1996;53:121–5. 66. Sanati L, Matutes E, Mulligan S, et al. Variant form of hairy cell leukemia resistant to interferon-a: clinical and phenotypic characteristics of 17 patients. Blood 1990;76:157–62. 67. Ng JP, Nolan B, Chan-Lam D, Coup AJ, McKenna D. Successful treatment of aplastic variant of hairy-cell leukaemia with deoxycoformycin. Hematology 2002;7:259–62. 68. Nagai T, Izumi T, Noborio K, et al. Successful treatment of hairy cell leukemia prolymphocytic variant with 20 -deoxycoformycin. Rinsho Ketsueki 2002;43: 583–5. 69. Ribeiro P, Bouaffia F, Peaud PY, et al. Long term outcome of patients with hairy cell leukemia treated with pentostatin. Cancer 1999;85:65–71. 70. Kantarjian HM, Schachner J, Keating MJ. Fludarabine therapy in hairy cell leukemia. Cancer 1991;67:1291–3. 71. Nieva J, Bethel K, Saven A. Phase 2 study of rituximab in the treatment of cladribine-failed patients with hairy cell leukemia. Blood 2003;102:810–3. 72. Hagberg H, Lundholm L. Rituximab, a chimaeric anti-CD20 monoclonal antibody, in the treatment of hairy cell leukaemia. Br J Haematol 2001;115:609–11. 73. Thomas DA, O’Brien S, Bueso-Ramos C, et al. Rituximab in relapsed or refractory hairy cell leukemia. Blood 2003;102:3906–11.
74. Angelopoulou MK, Pangalis GA, et al. Outcome and toxicity in relapsed hairy cell leukemia patients treated with rituximab. Leuk Lymphoma 2008;49:1817– 20. 75. Fietz T, Rieger K, Schmittel A, Thiel E, Knauf W. Alemtuzumab (Campath 1H) in hairy cell leukaemia relapsing after rituximab treatment. Hematol J 2004;5:451–2. 76. Robak T. Monoclonal antibodies in the treatment of chronic lymphoid leukemias. Leuk Lymphoma 2004;45:205–19. 77. Hadzi-Pecova L, Stojanovik A, Petrusevska G, Panovska I. Rituximab in the treatment of the variant of hairy cell leukaemia: a case report. Prilozi 2008;29:355–60. 78. Makita M, Nakamura K, Kono A. Successful rituximab treatment in a patient with refractory hairy cell leukemia-Japanese variant and suffering from acute respiratory distress. Rinsho Ketsueki. 2005;46:1196–201. 79. Quach H, Januszewicz H, Westerman D. Complete remission of hairy cell leukemia variant (HCL-v) complicated by red cell aplasia post treatment with rituximab. Haematologica 2005;90 Suppl.:EO CR26. 80. Imamura T, Ohtsuka E, Ogata M, et al. Successful induction of long-term remission using rituximab in a patient with refractory hairy cell leukemiaJapanese variant. Int J Hematol 2004;80:432–34. 81. Robak T. Improving FCR immunochemotherapy in CLL. Blood 2010;115: 437–8. 82. Robak T, Jamroziak K, Robak P. Current and emerging treatments for chronic lymphocytic leukaemia. Drugs 2009;69:2415–49. 83. Robak T. Alemtuzumab for B-cell chronic lymphocytic leukemia. Expert Rev Anticancer Ther 2008;8:1033–51. 84. Quigley MM, Bethel KJ, Sharpe RW, Saven A. CD52 expression in hairy cell leukemia. Am J Hematol 2003;74:227–30. 85. Telek B, Batár P, Udvardy M. Successful alemtuzumab treatment of a patient with atypical hairy cell leukaemia variant. Orv Hetil 2007;148:1805–7. 86. Kreitman RJ, Wilson WH, Bergeron K, et al. Efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy-cell leukemia. N Engl J Med. 2001;345:241–7. 87. Kreitman RJ, Pastan I. Immunobiological treatments of hairy-cell leukaemia. Best Pract Res Clin Haematol. 2003;16:117–33. 88. Kreitman RJ, Tallman MS, Coutre S, et al. Phase I dose-escalation study of CAT-8015 (HA22), a CD22-specific targeted immunotoxin, in relapsed or refractory hairy cell leukemia. Blood (ASH Annual Meeting Abstracts) 2009;114:888. 89. Goldaniga M, Guffanti A, Gianelli U, et al. Clinical and molecular complete remission in a case of variant hairy cell leukemia treated with DHAP followed by high-dose chemotherapy plus rituximab. Haematologica 2004;89:ECR41, e138–9. 90. Busemann C, Schüler F, Krüger W, et al. Late extramedullary relapse after allogeneic transplantation in a case of variant hairy cell leukaemia. Bone Marrow Transplant 2009 Oct 12. [Epub ahead of print]. 91. Knight C,Lee EJ. Rituxan is an effective agent in variant hairy cell leukemia. Blood 2002;100:311b (Abstract 4786).
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Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv
Anti-Tumor Treatment
Hairy-cell leukemia variant: Recent view on diagnosis, biology and treatment q Tadeusz Robak * Department of Hematology, Medical University of Lodz, Copernicus Memorial Hospital, 93-510 Lodz, Ul. Ciolkowskiego 2, Poland
a r t i c l e
i n f o
Article history: Received 12 March 2010 Received in revised form 20 May 2010 Accepted 25 May 2010
Keywords: Hairy-cell leukemia variant Japanese variant Molecular biology Purine nucleoside analogs Rituximab Immunotoxins
a b s t r a c t Hairy-cell leukemia variant (HCl-V) is a district clinico-pathological entity with intermediate features between classical HCl (HCl-C) and B-cell prolymphocytic leukemia. HCl-V is now included in the World Health Organization (WHO) classification as a provisional entity. It is an uncommon disorder accounting for approximately 0.4% of chronic lymphoid malignancies and 10% of all HCl cases. In contrast to HCl-C, HCl-V is a more aggressive disease and according to the new WHO classification it is no longer considered to be biologically related to HCl-C. Patients with HCl-V have an elevated white blood count, easy-to-aspirate bone marrow and weak reactivity to tartrate – resistant acid phosphatase (TRAP). Immunophenotypically, HCl-V cells are positive for CD103 and CD11c and negative for CD25. The HCl-V cells express also the B-cell antigens, CD19, CD20 and CD22. The HCl-V patients have frequently an unmutated Ig gene configuration. Currently, the principles of therapy for this rare disease derive from uncontrolled single institutional studies, or even single case reports. In contrast to HCl-C, the HCl-V response to purine nucleoside analogs (PNA) is limited to partial responses in approximately 50% of patients. However, complete responses were observed in patients treated with rituximab and anti-CD22 immunotoxins. In Japan, a distinct subtype of HCl known as HCl-Japanese variant (HCl-JV) has been identified. As with HCl-V, patients with HCl-JV have leukocytosis, weak TRAP activity in leukemic cells, and lack of CD25 antigen. In this review, the biology, diagnostic criteria, and current therapeutic options in HCl-V and HCl-JV are presented. Ó 2010 Elsevier Ltd. All rights reserved.
Introduction Hairy-cell leukemia variant (HCl-V) is an uncommon B-cell neoplasm accounting for 10–20% of HCl patients and 0.4% of chronic lymphoid malignancies, representing about 60–75 new HCl-V patients each year in the US.1–3 The disease affects the elderly population without sexual predominance. Its features are intermediate between those of classical HCl (HCl-C) and prolymphocytic leukemia.4,5 The median age of the patients is 71 years. HCl-V was first identified by Cawley et al.1 and was later described as prolymphocytic variant of HCl. Unlike HCl-C, HCl-V is resistant to most conventional treatments, including interferon-a (IFN-a) and purine nucleoside analogs (PNA).6–8 HCl-V is now included in the World Health Organization (WHO) classification as a provisional entity and is no longer considered to be biologically related to HCl-C.6 The clinical course of HCl-V is variable but usually more aggressive than HCl-C.7,8 In one study, median survival was approximately 9 years with only 15% survival over 15 years.8,9 In this study, 42% of patients died of unrelated causes.8 However, the
q Presented in part at Conference ‘Treatment of Hairy-Cell Leukemia in its Second Half-Century’ April 26–27, 2010, National Institutes of Health, Bethesda, MD, USA. * Tel.: +48 42 689 51 91; fax: +48 42 689 51 92. E-mail address: [email protected]
0305-7372/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2010.05.003
median survival of HCl-V patients is significantly shorter than that of HCl-C.3 Diagnosis HCl-V patients are characterized by splenomegaly, a high white blood cell count without neutropenia or monocytopenia and hyper-cellular marrow that can be easy aspirated.10,11 Morphologically, HCl-V cells are similar to leukemic cells of B-cell prolymphocytic leukemia and HCl-C cells.12,13 They contain abundant villi, an intensely basophilic cytoplasm and central, round, occasionally bilobed, indented hyperchromatic nuclei with prominent nucleoli.14 In comparison to HCl-C, HCl-V cells are smaller, have higher nuclear cytoplasmic ratios and no ribosome-lamella complexes.12 In contrast with HCl-C, leukemic cells of patients with HCl-V only infrequently demonstrate reactivity to tartrate resistant acid phosphate (TRAP).3,12,13 In HCl-V, the immunophenotype of the leukemic cells is CD11c+, CD10, CD23, CD24, CD25, CD27 and CD5 and have variable expression of CD103. In addition, antigens of mature Blymphocytes, CD19, CD20 and CD22 and FMC-7 with light chain restriction are present.12,15–20 In a study by Del Giudice et al.19 peripheral blood leukemic cells expressed CD123 antigen only in 9% of the patients with HCl-V. CD52 antigen was detected on 99%
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T. Robak / Cancer Treatment Reviews 37 (2011) 3–10
of neoplastic cells from the spleen of patients with this disease.21 Unlike HCl-C, immunophenotyping of HCl-V cells usually reveals negativity for Annexin A1 (ANXA1).5 Cytogenetic abnormalities in HCl-V have been occasionally reported in patients with HCl-V.22,23 In a study by Brito-Babapulle et al. two of six cases with HCl-V had abnormalities of chromosome 17p.22 The majority of the HCl-V patients have interstitial bone marrow infiltration with scattered hairy cells lying within sinusoids.8 However, approximately 20% of the patients have a mixed, interstitial and nodular pattern. In addition, pure sinusoidal and intrasinusoidal bone marrow involvement was also occasionally reported.10,14 The histological features of HCl-V in the spleen are similar to those found in HCl-C with primary involvement of the red pulp.12,13,15 HCl-C and HCl-V are rare in Japan.24,25 However, another distinct variant of HCl known as HCl-Japanese variant (HCl-JV) has been identified in this country.24,25 HCl-JV was proposed as a provisional subtype of HCl by Katayama et al.25 in a review of literature regarding 36 Japanese patients diagnosed as atypical HCl with some findings not usually seen in HCl.25 Subsequently, Machii et al.24 reported a series of 29 Japanese patients with similar symptoms, and further defined this subtype of HCl. HCl-JV is more frequent in females. Patients with HCV-JV possess splenomegaly without peripheral lymphadenopathy. However, in contrast to HCl-C, but similar to HCl-V, HCl-JV patients usually demonstrate leukocytosis and an easily aspirable bone marrow.26–28 The HClJV cells have an abundant pale cytoplasm with long microvilli, round hyperchromatic nuclei, inconspicuous nucleoli and rarely contain ribosome-lamella complexes.24,25 HCl-JV, like HCl-V, is characteristically CD11c and CD22 positive, always CD24 and CD25 negative, and usually CD103 negative.16,20,26 The leukemic cells are also CD22+, CD10, CD24 and sIg negative or weekly positive. A marked high ratio j + type to k + type has been also found.29 TRAP staining is negative in up to one-half of cases. Similarly, HCl-C and HCl-V leukemic cells preferentially infiltrate splenic red pulp.20 However, HCl-JV shows rather an indolent clinical course as in the cases of HCl-C. A form of polyclonal B-cell lymphocytosis with features resembling HCl-JV has also been reported.30,31 Machii et al.30 described four patients with persistent lymphocytosis and cell morphology
similar to that of leukemia cells of HCl-JV. The surface CD11c+, CD22+, CD24+, CD25, IgG and CD5-phenotype and the weak TRAP activity in the lymphoid cells were identical to those of the HCl-JV. However, studies of Ig gene rearrangements and expression showed the polyclonal proliferation of B-cells. It is suggested that the B-cells of these patients are the nonmalignant counterparts of leukemic cells in HCl-JV.
Differential diagnosis HCl-C, HCl-V, HCl-JV and splenic marginal zone lymphoma (SMZL) have some common features including splenomegaly, peripheral blood and bone marrow infiltration by villous lymphoid cells and B-lymphocyte immunophenotype (Table 1).31,32 Leukopoenia, neutropenia or monocytopenia are frequent in HCl-C. In HCl-V, HCl-JV and SMZL patients were shown to have a moderate degree of leukocytosis.30 The circulating cells of HCl-V have morphological features similar to HCl-C and prolymphocytes, and contain the abundant villous cytoplasm and the round nucleus with prominent nucleolus.12 The morphological findings in HCl-V and SMZL can be similar.33 However, in SMZL, the neoplastic cells are smaller than in HCl-V and have more condensed chromatin. In addition, the villous cytoplasm is usually moderate in amount and can be more basophilic.8,33 A small distinct nucleolus is observed in half of the SMZL patients.33 Flow cytometry analysis of the immunophenotype of leukemic cells has the most important value in differential diagnosis. HClC is always CD11c+, CD25 + and CD103+. HCl-V and HCl-JV are always CD25 and usually CD11c + and occasionally CD103+. In SMZL, CD25 can be negative or positive and CD103 is negative and CD27 positive.27 HCl-V without both CD25 and CD103 may be difficult to differentiate from SMZL. However, the immunoprofile should be correlated with other available pathological studies and clinical data. In HCl-C, strong TRAP activity occurs in contrast to HCl-V where TRAP inactivity is present. TRAP staining is negative in up to one-half of HCl-JV cases. The bone marrow is typically aspirable in HCl-V, HCl-JV and SLVL. In contrast to these disorders, the ‘‘dry tap” is often encountered on bone marrow aspiration in HCl-C patients.27 SMZL has a characteristic intrasinusoidal bone marrow involvement. However
Table 1 Comparison of clinical and laboratory characteristics of classical hairy-cell leukemia (HCl-C), hairy-cell leukemia variant (HCl-V), hairy-cell leukemia Japanese variant (HCl-JV) and splenic marginal zone lymphoma (SMZL). Characteristics
HCl-C
HCl-V
HCl-JV
SMZL
Median age (y) WBC count Cytoplasmic projection
55 Low Unevenly distributed microvilly Oval, indented, bilobed Indistinct Inter sinusoidal
60 High Unevenly distributed microvilli Round Inconspicuous Usually interstitial
69 High Usually polar
Good High CR rate Majority mutated
71 High Unevenly distributed microvilly Round, occasionally bilobed Prominent (60%) Usually interstitial, subtle intersinusoidal Leukemic infiltration of red pulp Negative Negative CD11c +/ , CD25, CD103+/, HC2, CD123, CD10+/ SIgG j
Majority negative
Majority positive
Nuclei Nucleoli Histology of bone marrow involvement Histology of spleen TRAP activity Annexin A1 Immunophenotype of leukemic cells Surface Ig Light chain restriction Response to IFN Response to PNA Mutational status of IGHV gene VH4-34 expression
Leukemic infiltration of red pulp Positive Positive CD11c+, CD25+, CD103+, HC2+, CD123+, CD10/+ SIgM
j=k
Red pulp infiltration
Round Small (50% distinct) Predominantly intersinusoidal White pulp infiltration
Absent to week NR CD11c+, CD25, CD10
Weak NR CD11c+, CD25+/, CD103
SIgG
SIgM
j>k
j>k
Poor Low CR rate Majority mutated
Poor Low CR rate Majority mutated
NR
NR
Abbreviations: Ig – immunoglobulin; NR – not reported; tartrate resistant acid phosphate; CR complete response; PR – partial response.
T. Robak / Cancer Treatment Reviews 37 (2011) 3–10
this type of marrow involvement is also found in HCl-C and occasionally in HCl-V.8,10,34,35 In HCl-V, most cases have interstitial infiltration with scattered hairy cells lying within the sinusoids.8 However, approximately 20% of HCl-V patients have mixed nodular and interstitial pattern. The pathological analysis of the spleen in HCl-C and HCl-V patients revealed leukemic infiltration of red pulp without white pulp involvement.10 In contrast, white pulp splenic involvement occurs in SMZL.33 Spleen histology is the gold standard approach to establish a clear-cut diagnosis of SMZL. In cases which do not need a splenectomy, or which are not suitable for a surgical procedure, a combination of bone marrow histology and neoplastic cell phenotype can be useful to establish proper diagnosis of SMZL.31,34 According to the recent criteria of the SMZL working group, the minimum diagnostic criteria for SMZL are either spleen histology plus immunophenotype or typical blood and bone marrow morphology and immunophenotype, plus intrasinusoidal infiltration of the bone marrow by CD20-positive cells.31 The evaluation of immunoglobulin heavy chain isotype expression can also differentiate HCl-V from SMZL.7 SMZL cells characteristically express IgM with IgD and lack of IgG or IgA.35 In HCl-V, IgG expression or coexpression of preswitched (IgM/IgD) and postswitched (IgM/IgD) is observed by the cell isotypes.7
Molecular biology P53 allele loss through monosomy or monoallelic deletion was noted in all 12 patients with HCl-V reported by Vallianatou et al.23 In addition, a higher percentage of cells with p53 deletion correlates well with a greater tendency for transformation and poorer response to therapy. During B-cell differentiation, the VH, DH and JH gene segments of the immunoglobulin (Ig) gene locus are rearranged following a strict hierarchical order in generating the Ig repertoire.36 Recent reports indicate that the vast majority of leukemic cells from HCl-C cells derive from mature B-cells.37 Hochley et al.38 analyzed IGH rearrangements in 41 cases with HCl-V, 30 with HCl-C, and 113 with SMZL. In this study, genes displaying the IGHV mutational status of HCl-V were more similar to SMZL than to HCl-C. No evidence of somatic hypermutation in IGHV genes was found in 22% of HCl-V and 15% of SMZL. In contrast, although somatic hypermutation was seen in the majority of cases with HCl-C, 10% of these cases are not mutated. The Ig gene configuration and expression in HCl-JV partially overlap with those described for immature B-cell leukemia.21 Yamaguchi et al.20 investigated Ig gene rearrangements in 12 patients with HCl-JV and in an HCl-JV derived cell line. The Ig light chain was undetected in nine patients and the remaining four cases expressed the kappa chain. Rearranged bands in the Ig heavy chain gene were recognized in all 12 cases. Martín-Jiménez et al.37 analyzed the VH, DH and JH gene segments of the Ig gene locus in the leukemic cells of patients with HCl-C and HCl-V. The somatic mutations were present in the monoclonal VDJH rearrangements in 38 previously untreated patients with CD25 positive HCl-C cells or CD25 negative cases, a phenotype associated with HCl-V.37 All 38 patients displayed a monoclonal amplification of Pone VDJH or DJH rearrangement. In this study, JH3 segments were selected in two out of five CD25 negative cases, while they were never selected in 33 remaining CD25 + cases. This study supports the existence of molecular differences between CD25 and CD25 + cases. Three of five CD25 negative cases in this analysis were unmutated in contrast to cases with a CD25 positive immunophenotype. In addition, 100% homology to the germ line sequence was demonstrated by the 3 CD25 negative cases but none of the CD25 positive cases. Earlier studies indicated that in HCl-C the leukemic cells have usually one or two different rearrangements for Ig heavy chain.39,40
5
In the majority of HCl-C patients, the expressed tumor IGHV is mutated and only in some patients unmutated IGHV was noted.39,41,42 In SMZL, as in CLL, the mutation status of the Ig genes is heterogenous.43 Whereas the majority of SMZL cases displayed somatic hypermutations in Ig genes, one-third had unmutated Ig genes. In HCl-JV, the rearranged bands in Ig heavy chain genes were recognized in all 12 tested patients.20 In CLL, the unmutated status of IGHV is associated with a poor prognosis and a shorter survival in comparison with CLL, characterized by the mutated status of IGHV.44 Recently, Forconi et al. analyzed clinical significance of the mutational status of the leukemic cells for the prognosis in HCl-C patients.45 They investigated clinical and molecular parameters predicting the response and event-free survival after treatment with cladribine (2-CdA) in 58 HCl patients. Among them, 52 expressed mutated IGHV and six unmutated IGHV. Treatment failures were observed in five patients with unmutated IGHV and all patients with mutated IGVH responded to 2-CdA treatment. The diagnosis of HCl-C was established according to the WHO 2001 Classification of Tumours of Haematopoietic and Lymphoid Tissues3 and patients with HCl-V were not included in this study. All five unmutated IGHV patients not benefiting from 2-CdA were CD25 and CD103 positive and ANXA1 positive. In a simultaneously published report by Arons et al.46 Ig rearrangements were studied in 82 patients diagnosed with HCl, including 20 patients with HCl-V and 62 with HCl-C. They found that VH4-34, the most common VH gene used in HCl-V, had very high homology to its germ line sequence and was associated with symptoms characteristic to HCl-V, such as advanced age, higher leukocytosis, poor response to 2-CdA therapy, and shorter survival. In addition, patients with HCl-C who were VH4-34 positive had also poorer overall survival than VH4-34 negative patients. The median survival for VH4-34 positive patients was 8.6 years and for VH4-34 negative patients – 26.2 years. In addition, this study documented that poor prognosis in HCl is less closely related to unmutated status than to VH4-34 rearrangements. The results of this important study indicate that VH4-34 + HCl represent a disorder overlapping with HCl-V and distinct from typical HCl. Treatment The therapeutic approach to HCl-V is still debated. Various treatment approaches active in HCl-C achieve partial or no response in HCl-V and remission is usually shorter than in HClC.47–50 In addition, HCl-V seems to be resistant to therapeutic modalities usually highly effective in the treatment of HCl-C such as splenectomy, interferon a (IFN-a), and PNA. Clinical responses to splenectomy, IFN-a and PNA in HCl-JV are also inferior to those seen in HCl-C.24,25,29 Splenectomy and splenic irradiation Approximately 90% of HCl-C patients have splenomegaly, and splenectomy has been the first effective treatment in this disease.52 In HCl-C over 80% of patients show hematological improvement and at least 40% achieved a CR.47 Good clinical and hematological responses after splenectomy has been observed in 13 out of 19 patients (74%) with HCl-V, reported by Matutes et al.8 The median response duration was 4 years (1–10+). However, in other studies, less than 1/3 of HCl-V patients obtained a PR and no CR was observed.1 Some authors suggest that previous splenectomy may improve the response to chlorambucil and PNA in HCl-V patients.11,49 These results suggest that splenectomy should be considered in HCl-V because it corrects the cytopenias and removes a significant bulk of the disease.
6
T. Robak / Cancer Treatment Reviews 37 (2011) 3–10
ing for 60 + and 29 + months.48,57 The mean number of 2-CdA cycles was 3.5. Tetreault et al.58 administered 2-CdA to four patients with HCl-V over a 7 year period. Of these 4 patients, one achieved a CR and two a PR. However, these results are also inferior to those achieved with 2-CdA in HCl-C. More recently, Palomera et al.59 reported three patients with HCl-V who were treated with 2-CdA at a daily dosage of 0.1 mg/kg by continuous intravenous infusion for 7 days. One of them was previously treated with splenectomy and IFN-a and two patients were untreated. The patients received from one to three 2-CdA courses. Two PR and one CR were achieved lasting from 15+ to 127 + months. These reports indicate that 2-CdA is significantly less active in HCl-V than in HCl-C. The analysis of 19 cases published so far shows a response rate of 55% including only two CR.48,57–59 This is in contrast to spectacular CR rates in HCl-C treated with 2-CdA, in which of overall CR rate over 80% is obtained with a single cycle.47 In addition, the majority of HCl-V patients required more than one cycle to maintain PR. Three cases of HCl-JV were also treated with 2-CdA 0.09 mg/kg/ day by continuous infusion for 7 days and no response was noted.60 Of three other patients with HCl-VJ treated with 2-CdA in two reports there was one CR and one PR.61 In one multi-center study, the remission rate was only 35.7%.29 However, the effectiveness of 2-CdA in HCl-JV is unclear. In spite of this, a CR was achieved in some patients treated with this agent.28,29,61 Low efficacy of 2-CdA in the treatment of SMZL has been also reported.62 Pentostatin is also less active in HCl-V than in HCl-C.63 Of 12 patients treated with this agent in 3 reports, there were 7 PR and no CR.64–66 Similarly, in a group of 15 patients with HCl-V reported by Matutes et al.8 pentostatin induced only a PR in 8 of 15 (54%) patients and no CR was achieved. On the other hand, a case has been recently presented of a patient with the aplastic variant of HCl successfully treated with pentostatin.67 Hematological improvement was also observed in HCl-V in Japan in a patient refractory to 2CdA and subsequently treated with pentostatin.68 Another patient reported by Ribeiro et al.69 achieved a PR after pentostatin treatment. These cases demonstrate that similar to 2-CdA, HCl-V patients treated with pentostatin have a poorer clinical outcome and a lower response rate than those patients with HCl-C. The data on the use of fludarabine in HCl-V in a similar way to HCl-C is limited. In HCl-C, fludarabine is not as effective as 2-CdA or pentostatin.70 According to Matutes et al.,9 only one out of three patients with HCl-V treated with fludarabine achieved a PR. An additional PR in a patient with HCl-V was reported by Kantarjian et al.70
Splenic irradiation may be also useful, especially in elderly patients with high surgical risk.51,52 Sgarabotto et al.52 reported the case of a 79-year old man with HCl-V treated with splenic radiotherapy in whom a CR was achieved. Two other patients with HCl-V obtained a PR after splenic irradiation9,51 but this treatment was not effective in three other patients.9 In another patient the treatment was fractionated into 10 weekly doses for a total of 10 Gy.52 Three months after radiotherapy, the spleen returned to its normal size, the WBC count was normal and the bone marrow biopsy showed almost total disappearance of the lymphoid infiltration. More recently, Sasaki et al. reported a patient with HCl-V, treated with splenic irradiation and subsequently with alemtuzumab.53 The irradiation attenuated splenomegaly from 12 to 4 cm below the left costal margin and reduced the number of circulating leukemic cells. These results indicate that splenic irradiation may have a beneficial effect in some patients with HCl-V, especially in elderly patients with massive splenomegaly and poor performance status. Interferon a Interferon a is an effective agent in HCl-C.54,55 However, at present its use in the treatment of HCl is limited because PNAs produce higher and durable remissions. Moreover, IFN-a is less convenient to the patient than PNA. Unlike HCl-C, patients with HCl-V are resistant to IFN-a. All 7 patients with HCl-V treated with IFN-a by Sainati et al.12 showed no objective response. In the group of 14 patients treated with IFN-a reported by Matutes et al.8 only two (14%) of them achieved a temporary partial response (PR). These poor results may relate to a low number of IFN-a receptors, which are abundant in typical HCl.56 However, IFN-a seems to be more effective in HCl-JV. In patients with HCl-JV, an overall 35% response to INF-a has been reported.24
Purine nucleoside analogs The purine nucleoside analogs, cladribine (2-CdA) and pentostatin (DCF), are the drugs of choice in the treatment of HCl-C.47 These drugs induce a similar high response rate and a long overall survival in HCl-C. However, the results of the treatment of HCl-V with PNA are poor (Table 2). In our study, 2-CdA was given in 2-h infusions for 5 days in a daily dose of 0.12 mg/kg.48,57 Four of 6 patients did not respond to 2-CdA treatment and only two entered a PR last-
Table 2 Purine nucleoside analogs in the treatment of hairy-cell leukemia-variant. Treatment
No. of courses
No. of patients
CR No. of pts.
PR No. of pts.
Response duration
Survival from the beginning of treatment
References
2-CdA 0.12 mg/kg/ d i.v. 2-h inf. d1–5 2-CdA 0.1 mg/kg/d 2-CdA 0.1 mg/kg/d c.i. i.v./d,ds1–7 2-CdA DCF DCF 4 mg/m2 i.v. every 2 weeks DCF 4 mg/m2 i.v. every 2 weeks DCF FA 30 mg/m2 i.v.; ds 1–5 FA
1–3
6
0
2
60 + m, 29 + m
NR
Robak et al.48 Blasinska-Morawiec et al.57
2–5 1–3
4 3
1 1
2 2
108 + m, 12 m, 8 m NR
108 + m, 32 + m, 18 m, 36 m 127 + m, 31 + m, 15 + m
Tetreault et al.58 Palomera et al.59
NR NR 10
8 15 1
0 0 0
4 8 1
NR NR 15 m
NR NR NR
Matutes et al.8,9 Matutes et al.8,9 Dunphy et al.49
8
1
1
0
69 + m
69 + m
Ng et al.67
NR 3; re-treatment 8 courses NR
3 1
0 0
2 1
NR 18 m; 15 + m
NR NR
Sainati et al.12 Kantarjian et al.70
3
0
1
NR
NR
Mutates et al.8,9
Abbreviations: 2-CdA – cladribine, 2-chlorodeoxyadenosine; DCF – pentostatin, deoxycoformycin; FA – Fludarabine; NR – not reported; m –month; d – day; iv – intravenously; ci – continuous infusion.
7
T. Robak / Cancer Treatment Reviews 37 (2011) 3–10
Several clinical trials indicate that the anti-CD20 monoclonal antibody, rituximab, is active in HCl-C.71–74 Single case reports suggest that alemtuzumab is also an active agent in HCl-C, even relapsing after rituximab therapy.75 Recently, some reports indicate that both monoclonal antibodies are active in HCl-V (Table 3).28,76–80 Promising results have been also obtained with immunotoxin BL22 targeting CD22 .
18 months after treatment. Another patient with HCl-VJ refractory to pentostatin, 2-CdA, and INF-a also responded to 8 courses of rituximab at a dose of 375 mg/m2 per course.78 These results suggest that rituximab may be an effective method of treatment for refractory HCl-V and HCl-JV. Moreover, rituximab combined with PNA may be more effective than these agents alone. In one recent report, a patient with HCl-V received rituximab 375 mg/m2 followed by cladribine 0.1 mg/kg for 7 days. Treatment resulted in a remarkable recovery of blood count.
Rituximab
Alemtuzumab
Compared with PNA, rituximab does not induce long-term bone marrow hypoplasia, and the degree of immunosuppression is much less. It is possible that immunochemotherapy with rituximab with PNA will be the most effective treatment of HCl-V, similar to the current treatment of chronic lymphocytic leukemia and other B-cell malignances.81,82 Recent observations indicate that patients with HCl-V can be successfully treated with rituximab.5,76–80 Narat et al.5 reported the case of a 53-year-old man who had refractory HCl-V for 8 years. He was given weekly rituximab (375 mg/m2) for 4 weeks and achieved a CR. At the time of publication, the patient continued to remain well in CR 19 months after rituximab treatment. Quach et al.79 also described a patient with HCl-V, whose course was previously complicated by pure red cell aplasia and who achieved a CR after treatment with rituximab. Another patient diagnosed as having advanced-stage HCl-V, with blastoid variant transformation, was also successfully treated with this agent.77 The above reports indicate that rituximab is a promising therapy for patients with HCl-V, and can be combined with 2-CdA. However, further clinical studies are required before rituximab can be considered as a frontline therapy for HCl-V. Rituximab seems to be also an active drug in HCl-JV. Imamura et al. reported a 76-year-old patient with HCl-JV who received rituximab 375 mg/m2 i.v. weekly for 4 cycles.80 Disappearance of hairy cells from the peripheral blood was observed on the day after the first administration of rituximab, and the bone marrow aspiration performed one week after the fourth dose of rituximab did not reveal any hairy cells. The patient was in CR, which continued for
Alemtuzumab is another monoclonal antibody active in lymphoid malignancies.83 This is a humanized IgG1 anti-CD52 antibody that binds to the cell membrane of normal and malignant lymphocytes. CD52 expression was documented in 92–100% of the malignant cells in HCl and HCl-V.84 Single case reports suggest that alemtuzumab is an active agent in HCl-C and HCl-V even relapsing after rituximab.75,85 Telek et al.85 reported a case of a 58-year-old male with HCl-V and p53 mutation who was treated successfully with alemtuzumab. The monoclonal antibody was given at a dose 3 30 mg/week s.c. for 12 weeks. After 8 weeks of therapy hematologic remission was achieved. In the second patient with HCl-V, alemtuzumab was given after splenic pre-irradiation.53 Treatment with 24 mg of alemtuzumab eradicated leukemic cells from the blood by day 9, splenomegaly disappeared and a CR was confirmed. Activity of alemtuzumab in this patient was confirmed in the in vitro study, showing that alemtuzumab induced leukemic cell death in the complement dependent cytotoxicity mechanism.
Monoclonal antibodies
Immunotoxins In HCl-C with resistance to PNA, promising results have been obtained with two immunotoxins, BL22 and LMP-2 targeting CD22 and CD25 respectively.86,87 BL-22 (RFB4 (dsFv)-PE38) is a 63-kDa recombinant immunotoxin containing truncated Pseudomonas exotoxin and variable domains from anti-CD22. BL22 seems to be a very effective treatment for HCl-V. Kreitman et al.86 treated 3 patients refractory to 2-CdA and all of them achieved a CR after
Table 3 Monoclonal antibodies and immunotoxins in the treatment of hairy-cell leukemia variant. Previous treatment
No. of patients
CR No. of pts.
PR No. of pts.
Response duration
Survival from the beginning of treatment
References
375 mg/m2/wk 4
No
1
1
0
19 + m
19 + m
Narat et al.5
375 mg/m2/wk 6
No
1
0
1
4+m
4+m
Knight et al.91
375 mg/m2/wk 4
DCF, 2-CdA
1
1
0
18 + m
18 + m
Imamura et al.28
375 mg/m2 i.v./w 4 375 mg/m2/wk 4
2-CdA, IFN-a, splenectomy 2-CdA, IFN-a, VACOP-B, Dexa-BEAM, Splenectomy, 2-CdA, DCF, CHOP
1 1
1 0
0 1
13 m, 10 mb 12 m
24 m 55 mc
Quach et al.79 Busemann et al.90
1
0
1
4m
NR
Sasaki et al.53
1
0
1
NR
NR
Sasaki et al.53
3
3
0
8 > 3; 12 > 4; >13
NR
Kreitman et al.86
Treatment
Rituximab wks Rituximab wks Rituximab wksa Rituximab Rituximab
Rituximab 900 mg in 3 wks ? 375 mg/m2 every 3 wks as maintenance Alemtuzumab 1 mg, 3 mg, 10 mg 3, 30 mg trice weekly 8 wks BL 22 30–50 mg/kg 3–14 cycles
2-CdA;DCF; CHOP; Rituximab; IFNa; splenic irradiation 2-CdA; IFN-a; splenectomy; DCF; chlorambucil
Abbreviations: CR – complete response; PR – partial response; 2-CdA- cladribine, 2-chlorodeoxyadenosine; DCF- pentostatin, deoxycoformycin; IFN-a – interfer– ona; CHOP – cyclophosphamide, doxorubicin, vincristin, prednisone. a HCl-JV. b Second CR after re-treatment. c Survival after subsequent stem cell transplantation; wk – week.
8
T. Robak / Cancer Treatment Reviews 37 (2011) 3–10
therapy with this agent lasting 8, 12 and >13 months respectively. In these patients, circulating hairy cells began to decrease within 24 h after the first dose of immunotoxins. In addition, two patients had a second CR after re-treatment when relapsed. No patients ever had a CR with 2-CdA chemotherapy. Moreover, two were ineffectively treated with IFN-a and one was previously splenectomiced. The low level of BL22 toxicity made the administration of multiple cycles possible. These encouraging results suggested that BL22 may be a very effective agent in the treatment of refractory HCl-V. CAT-8015 (HA22) is a new generation of CD22-specific targeted immunotoxin composed of anti-CD22 antibody fused to the modified form of Pseudomonas exotoxin.88 This agent has a novel mechanism of action as compared to other anti-CD22 monoclonal antibodies. HA 22 is internalized upon binding to CD22, inhibiting protein translation and promoting apoptosis. Preliminary results of HA22 in patients with refractory/relapsed HCl-C have been recently reported.88 A total of 26 patients have received HA22 to date including 14 treated previously with rituximab. No DLT has been established so far and MTD has not been reached. Nineteen patients (73.1%) responded with a CR rate of 34.6% (9 patients) and a PR rate of 38.5% (10 patients). These data indicate that HA22 is a promising new agent for patients with HCl-C and supports further investigation in patients with HCl-C and HCl-V. Hematopoietic cell transplantation The poor prognosis of patients with HCl-V has led some clinicians to consider hematopoietic cell transplantation (HCT).89,90 However, the data to support this approach is limited to case reports. We identified in the literature two patients treated with this procedure. Busemann et al.90 reported a 60-year-old man initially treated with 2-CdA, IFN-a, VACOP-B, Dexa-BEAM and splenectomy which resulted only in a PR. Subsequently, the patient received 4 doses of rituximab (375 mg/m2) and then single doses of this drug because of the progressive disease, and obtained a dramatic reduction in the circulating leukemic cells. Thereafter the patient was allografted with unmanipulated CD34 + cells from a matched unrelated donor. The patient achieved a clinical and molecular remission lasting for about 3.5 years. Another patient with HCl-V reported in the literature was treated with autologous HCT.89 The patient with aggressive relapsed disease received DHAP (cisplatin, cytarabine, dexamethasone) followed by high-dose chemotherapy supported by autologous peripheral blood stem cells. Clinical and molecular CR was documented three months after transplantation and persisted for 16 months. These two case reports may indicate that both allogeneic and autologous stem cell transplantation are a possible therapeutic approach in selected cases with HCl-V.
addition, VH4-34 gene expression is associated with symptoms characteristic of HCl-V. The clinical course of HCl-V is chronic, usually benign, but survival time of HCl-V patients is usually shorter than HCl-C. Currently, principles of therapy of this rare disease derive from uncontrolled single institutional studies, or even single case reports. For these reasons, the outcome of therapy is unsatisfactory with no standard therapy established. Unfortunately, randomized controlled trials are not feasible because of an insufficient number of cases. Good clinical and hematological responses after splenectomy or splenic irradiation have been observed. Splenectomy can be considered in some patients with HCl-V because it corrects cytopenias and removes a significant bulk of disease. Splenic irradiation may be also useful especially in elderly patients with a high surgical risk. HCl-V seems to be resistant to therapeutic modalities usually highly effective in the treatment of HCl-C such as IFN-a and PNA. However, IFN-a seems to be more effective in the of HCl-JV. Recent studies suggest that rituximab and anti-CD-22 immunotoxin BL22 may be effective agents in the treatment of HCl-V. In the opinion of the author of this review rituximab combined with PNA should be considered as the treatment of choice in previously untreated patients. In addition, some case reports indicate that stem cell transplantation can be a useful therapeutic approach in selected cases with HCl-V. HCl-V remains an incurable disease and the introduction of new drugs and new therapeutic strategies is awaited. The organization of a basic and translational research program focusing on rare chronic lymphoid leukemias based on multidisciplinary teams, tumor banking and tumor registries would be very helpful in better understanding the biology of this disease and progress in the treatment. Progress in the knowledge concerning molecular genetics, immunology and intracellular signaling of HCl-V should translate
Diagnosis and Staging
Symptomatic HCL-V
Asymptomatic HCL-V
2-CdA or DCF +/- Rituximab (if splenomegaly major symptom consider splenectomy or
Response
Observation
splenic irradiation)
Conclusions HCl-V is a distinct clinico-pathological entity. However, distinguishing HCl-V from classical HCl and SMZL which are both associated with pronounced splenomegaly and circulating neoplastic cells with ‘hairy’ projections remain a problem. Patients with HCl-V are usually older, splenomegaly is less common and leucopenia with granulocytopenia and monocytopenia are usually not seen. Bone marrow is typically easily aspirable, hyper-cellular with mild myelofibrosis. However, several markers including CD11c, CD25, CD27, CD103, CD123, ANXA1 and TRAP are claimed to distinguish HCl-V from HCl-C and SMZL. HCl-V cases lack CD-25, CD27 and ANXA1 and might lack CD103 but express other HCl-associated antigens. The analysis of IGHV mutational status of HCl-V cells has shown that most patients are unmutated in contrast to HCl-C. In
Refractory or progression <12 months
Progression >12 months
Clinical trial or alemtuzumab or immunotoxin or SCT
Retreatment
Fig. 1. Proposed treatment algorithm for HCl-V patients.
T. Robak / Cancer Treatment Reviews 37 (2011) 3–10
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