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Alemtuzumab in T-cell lymphoproliferative disorders
Best Practice & Research Clinical Haematology Vol. 19, No. 4, pp. 795e810, 2006 doi:10.1016/j.beha.2006.05.005 available online at http://www.sciencedirect.com
11 Alemtuzumab in T-cell lymphoproliferative disorders Claire E. Dearden*
BSc, MD, FRCP, FRCPath
Consultant Haematologist
Estella Matutes
MD, PhD, FRCPath
Consultant Haematologist Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK
The humanized monoclonal antibody alemtuzumab binds to the CD52 antigen, a glycoprotein which is widely expressed on normal and malignant B and T lymphocytes. Recently it has been demonstrated in a number of clinical trials that alemtuzumab has clinical activity in mature T-cell diseases such as T-prolymphocytic leukaemia and cutaneous T-cell lymphoma, inducing responses in up to two thirds of heavily pre-treated relapsed/refractory patients. Response was associated with improved survival. The toxicity profile for the antibody is manageable. The major complications are infusional reactions associated with initial injections, and prolonged lymphopenia associated with reactivation of viruses. Future studies will be directed towards alternative (subcutaneous) routes and schedules of administration, use as first-line therapy, combination strategies, and role of alemtuzumab to purge minimal residual bone-marrow disease prior to stem-cell transplantation. Key words: T cell; alemtuzumab.
Over the past 10 years unmodified monoclonal antibodies have become established as an effective therapy for a number of lymphoid malignancies. CD52 is a non-modulating antigen which is expressed at high density on >95% of all normal and malignant B and T lymphocytes, monocytes and macrophages1, but not on haemopoietic stem cells.2 A range of rat anti-CD52 antibodies was developed in the 1980s for ex-vivo T-cell depletion of haemopoietic stem cells prior to transplantation, thus reducing graft-versus-host disease (GVHD). Campath-1H (alemtuzumab) was the first fully humanized anti-CD52 monoclonal antibody to be used therapeutically in 1988 to treat a patient with a B-cell non-Hodgkins lymphoma.3 In vitro, alemtuzumab is active in complement-mediated * Corresponding author. Tel.: þ44 20 8661 3655; Fax: þ44 20 8642 9634. E-mail address: [email protected] (C.E. Dearden). 1521-6926/$ - see front matter ª 2006 Elsevier Ltd. All rights reserved.
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lysis4, antibody-dependent cell cytotoxicity (ADCC)5, and apoptosis.6 It is unclear which mechanism is most important for the therapeutic activity of this antibody in vivo. CD52þ cells vary in their sensitivity to alemtuzumab-induced lysis, and this may be related to the antigen site density on different cell types.7 The CD52 antigen is expressed at a particularly high density (>500,000 receptors per cell) on most malignant T lymphocytes, making alemtuzumab a good candidate for novel therapy in T-cell malignancies. The mature T-cell malignancies are rare, accounting for approximately 10% of all lymphoid neoplasms. This is a heterogeneous group of disorders resulting from clonal proliferation of post-thymic lymphocytes. The different diseases within this group are distinguished by their clinical, morphological, immunophenotypic and cytogenetic characteristics8, and can be broadly categorized into those with leukaemic, cutaneous, nodal or extra-nodal presentation (Table 1). There is racial and geographic variability of subtypes which is in some cases related to an association with viruses. Although some of the diseases in this group e such as T-cell large granular lymphocyte (T-LGL) leukaemia and early-stage mycosis fungoides (MF) e may follow a relatively benign protracted course, others have an aggressive clinical behaviour and a poor response to conventional chemotherapy. These malignancies are rarely curable, and for many patients survival is short (median of 6e8 months).9 There is a lack of consensus regarding treatment, and new therapeutic strategies are needed to improve this bleak prognosis. To date, clinical experience with alemtuzumab treatment in this group has been limited to a few small series, and there have been no prospective randomized trials. The results of these studies are summarized in the Tables 2e4 and discussed in the relevant sections of the text. However, recent experience has shown that alemtuzumab has remarkable activity in T-prolymphocytic leukaemia (T-PLL)10,11, an aggressive disease with a poor prognosis, achieving overall and complete response rates of 76% and 60% respectively. This evidence provides a rationale for exploring the activity of alemtuzumab in other poor-prognosis T-cell malignancies.
Table 1. WHO classification of mature T-cell and NK-cell neoplasms. Leukaemic: T-cell prolymphocytic leukaemia T-cell large granular lymphocytic leukaemia Aggressive NK-cell leukaemia Adult T-cell lymphoma/leukaemia Cutaneous: Mycosis fungoides/Se´zary syndrome Primary cutaneous anaplastic large-cell lymphoma Nodal: Anaplastic large-cell lymphoma Angioimmunoblastic T-cell lymphoma Peripheral T-cell lymphoma unspecified Extranodal: Extranodal NK/T-cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Blastic NK-cell lymphoma
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Table 2. Disease features of T-cell leukaemias.
Clinical
Morphology
T-PLL
LGL leukaemia
ATLL
SS
Splenomegaly, high white blood cell count Prolymphocytes
Cytopenia
Hypercalcaemia HTLV-I-positive
Skin
LGL
‘Flower’ cell
CD8þ CD4e CD57þ CD16þ
CD4þ CD25þ
Cerebriform nucleus CD4þ CD8e
Immunophenotype
CD4þ CD8e or CD4þ CD8þ
Cytogenetics
Inv14(q11; q32) þ8, iso 8q
Complex
Hypo- or hyperdiploid
T-PLL, T-cell prolymphocytic leukaemia; LGL, large granular lymphocyte; ATLL, adult T-cell lymphoma/ leukaemia; SS, Se´zary syndrome; HTLV, human T cell lymphotropic virus.
T-PROLYMPHOCYTIC LEUKAEMIA T-PLL is a disease affecting adults (median age 63 years) and is slightly commoner in men than in women (M:F ratio of 1.3).9 Patients usually present with splenomegaly, lymphadenopathy, and a high white blood cell count, which in half the patients is Table 3. Studies of single-agent alemtuzumab in T-cell malignancies. Study
Disease
n
Results ORR
Dearden et al10 Keating et al11 Dearden et al19 Lundin et al52 Foukanelli et al53 Kennedy et al55 Capabalo et al54 Lenihan et al56 Enblad et al62 Zinzani et al63
Previously treated T-PLL Relapsed/ refractory T-PLL Previously untreated T-PLL Relapsed/ refractory CTCL Relapsed/ refractory CTCL Relapsed MF/SS Relapsed MF/SS Relapsed MF/SS Refractory PTCL Relapsed PTCL and CTCL (low-dose alemtuxumab)
CR
Response duration (months)
Median OS (range) (months)
Not reached
13 (24 for CR) 7.5 (14.8 for CR) Not reached
39
76%
60%
10 (3e45)
76
50%
37.5%
4.5
11
100%
100%
22
55%
32%
12
e
3
100%
66%
3, 8 and 27
e
e
e
e 2, 6, 12
e
8 8 14 10 [4 CTCL]
38% 66% 37.5% 36% 60%
0 33% 0 21% 20% [33% in PTCL]
ORR, overall response rate; CR, complete remission; OS, overall survival; T-PLL, T-cell prolymphocytic leukaemia; CTCL, cutaneous T-cell lymphoma; MF/SS, mycosis fungoides/Se´zary syndrome; PTCL, peripheral T-cell lymphoma.
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Table 4. Studies of alemtuzumab in combination on T-cell malignancies. Study
Disease
n
Hopfinger et al20
T-PLL
16
Ravandi and Faderl40 Weder et al58 Gallamini et al64
ATLL
1
MF
1
Treatment regimen
Results
FCM followed by alemtuzumab (12) Alemtuzumab þ pentostatin
68% after 50% FCM 90% after alemtuzumab 100% 100%
ORR
Alemtuzumab 100% þ gemcitabine CHOP þ 67% alemtuzumab
PTCL 9 (previously treated) Weidmann PTCL 21 (11 FCD þ et al65 previously alemtuzumab untreated)
62%
CR
e 61%
Response Median duration OS (months) (range) (months) 10.6
13.4
e
e
e
e
9.1
10% for 2þ relapsed/ refractory 73% for 17þ previously untreated
15.2
e
ORR, overall response rate; CR, complete remission; OS, overall survival; T-PLL, T-cell prolymphocytic leukaemia; FCM, fludarabine cyclophosphamide mitrozantrone; ATLL, adult T-cell leukaemia/lymphoma; MF, mycosis fungoides; PTCL, peripheral T-cell lymphoma; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisolone; FCD, fludarabine cyclophosphamide doxorubicin.
>200 109/L. Other organs and skin may also be involved. The circulating prolymphocytes have distinctive morphology, with irregular basophilic cytoplasm and a prominent single nucleolus (Figure 1). They express a mature T-cell immunophenotype (TdTe, CD2þ, weak CD3þ, CD5þ, strong CD7þ) with variable expression of CD4 and CD8 (CD4þ/CD8e 63%, CD4þ/CD8þ 23%, CD4e/CD8þ 13%) (Table 2). Cell-surface antigens linked to T-cell activation e such as CD25, CD38, and class II HLA-DR e are variably expressed, and the antigen CD52 is expressed at a high density.7 In most cases, T-PLL patients express the TCRab phenotype, although rare instances of TCRgd have been reported. Cytogenetic abnormalities of chromosome 14 are common, the most frequent being inv (14) (q11;q32.1) which is seen in 75% of cases.12 Chromosomal abnormalities at the 14q32.1 and Xq28 regions13,14 lead to the over-expression of two proto-oncogenes of similar structure: TCL1a/b and p13 MTCP1, respectively. TCL1 has been shown to associate with protein kinase B (Akt), resulting in the promotion of Akt-induced cell survival and proliferation. The TCL1 oncoprotein is expressed in approximately 70% of T-PLL cases. Abnormalities of chromosome 8 (iso(8q), trisomy 8, t(8;8)) are seen in more than half the cases. Molecular methods have shown that the ATM gene, which maps to 11q23, is frequently involved in T-PLL, and this may be important in the pathogenesis of the disease.15
Alemtuzumab in T-cell lymphoproliferative disorders 799
Figure 1. Medium-sized lymphocytes with scanty basophilic and irregular cytoplasm and a single nucleolus, features characteristic of T-cell prolymphocytic leukaemia (T-PLL).
Treatment T-PLL is often resistant to conventional chemotherapy, and patients in historical series have had a poor median survival (7.5 months).9 Although some patients may initially present with indolent disease, they eventually progress, and the outcome is then similar. In recent years the survival of patients with T-PLL has improved following the introduction of new therapies, including deoxycoformycin (pentostatin) and alemtuzumab. Early studies on a range of lymphoid malignancies included one patient with T-PLL who went into a complete remission (CR) after Campath-1G.16 This prompted a larger phase-II study to examine the role of the humanized antibody alemtuzumab in this disease.10 This series included 39 T-PLL patients treated with alemtuzumab using the standard protocol of 30 mg, 3 times per week, intravenously (or subcutaneously in one case), until maximum response was achieved (median of 35 days). Most patients had received prior therapy with a variety of agents, including pentostatin, and had relapsed or refractory disease. The overall response rate was 76% (60% CR and 16% PR), including patients who had been resistant to other therapies. These response rates are significantly higher than those reported for conventional therapies such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone), with which a third of patients achieve short-lived partial responses (3 months), or pentostatin with a 40% overall response (12% CR) lasting 3e12 months (median 6 months).17 In patients responding to alemtuzumab clearance of cells from the peripheral blood was rapid. However, despite the often very high white counts (>100 109/L), in no case was this complicated by tumour lysis or ‘cytokine release’ syndrome. Resolution of skin infiltration, lymphadenopathy and/or splenomegaly occurred in half the affected patients. However, patients with serous effusions, hepatic or central nervous system involvement, or bulky lymph nodes were more resistant to treatment. Experience using alemtuzumab in the treatment of non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia (CLL) has shown that, whilst clearance of disease from blood and bone marrow may be complete, bulky nodal, liver or CNS disease may be resistant.18
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This differential pattern of response may reflect poor accessibility of the antibody to tumour cells in different sites and/or to reduced or impaired effector-cell function in these locations. In the case of CNS disease the absence of local effector cells may be important. Most CRs were durable, with a median disease-free interval (DFI) of 10 months (up to 45 months). Survival was significantly prolonged in patients achieving CR (median 24 months, compared to 9 months for PR and 4 months for NR). Of 12 patients retreated with alemtuzumab at relapse, five (42%) achieved a second CR and one had a PR. In two patients CD52 expression was lost from the malignant cells at relapse. In a retrospective analysis of 76 patients with T-PLL who were enrolled in a compassionate-use programme in the United States and who had received one or more lines of chemotherapy, alemtuzumab was administered for 4e12 weeks (30 mg 3 times weekly following dose escalation from 5 mg to 30 mg in the first week).11 In this study the objective response rate was 50%, with 37.5% CR (Table 3); among these, 43% had a CR in skin, 39% in bone marrow, 33% in spleen, 32% in lymph nodes, and 30% in the liver. In these heavily pre-treated patients, the median time to progression was 4.5 months and the median overall survival was 7.5 months, and in patients who achieved a CR it was 14.8 months. These results were superior to those achieved with prior therapy. The positive results obtained using alemtuzumab to treat patients with relapsed/ refractory T-PLL have prompted the evaluation of this monoclonal antibody in therapynaive patients. In a preliminary study of 11 patients, 100% achieved a CR, with 7/11 patients (64%) still alive at a median follow-up of 12 months (range 4e17 months).19 An alternate treatment strategy is to debulk tumour with chemotherapy followed by alemtuzumab consolidation with the aim of maintaining CR or improving the response to induction chemotherapy, i.e., converting a PR or stable disease (SD) to a CR. The German CLL study group are conducting a prospective trial with four 4-weekly cycles of FCM (fludarabine 25 mg/m2 and cyclophosphamide 200 mg/m2, days 1e3, plus mitoxantrone 8 mg/m2 on day 1), followed by alemtuzumab 30 mg intravenously 3 times weekly 1e3 months after completion of chemotherapy. Of 16 patients treated with induction chemotherapy, eight had a CR (50%), three had a PR (19%), and two had SD. Twelve patients (one PD, two SD, two PR, and seven CR) received consolidation therapy with alemtuzumab, increasing the OR to 90% including converting the two patients with PR to CR.20 The patient with SD converted to a CR.21 In the 50 T-PLL patients we have treated with alemtuzumab alone, it has been possible to collect stem cells from some patients achieving CR following therapy that were uncontaminated with T-PLL cells as demonstrated by dual colour flow cytometry and/ or polymerase chain reaction (PCR). Sixteen patients have proceeded to high-dose therapy with stem-cell transplantation (SCT) e 11 autologous, five allogeneic e in first or second remission.22 Conditioning for both auto- and allo-graft was with cyclophosphamide and total body irradiation (TBI) in most cases. Two of the allografts were with reduced-intensity conditioning. Seven patients remain alive with a median follow-up of 60 months (24e78 months). Median disease-free survival (DFS) was 20 months (8e78 months) for the autograft patients and 26 months (21 days to 60 months) for those allografted. In the latter group transplant-related mortality (TRM) was high (40%), in both cases full-intensity conditioning was given. SCT appears to prolong DFS and overall survival, although relapses still occur, presumably from ‘sanctuary sites’. For those patients unable to receive a transplant, alemtuzumab maintenance therapy should be considered. These data suggest alemtuzumab therapy can improve outcome in T-PLL, a haematological malignancy with an otherwise dismal prognosis. Despite this success, disease
Alemtuzumab in T-cell lymphoproliferative disorders 801
progression appears inevitable, and therefore SCT in first remission should be the recommended therapeutic option for eligible patients. T-CELL LARGE GRANULAR LYMPHOCYTE LEUKAEMIA Clonal disorders of large granular lymphocytes (LGLs) are rare (<3% of all cases of small lymphocytic leukaemias) and consist of two separate entities. Most (80e90%) belong to a mature CD3þ lineage that progresses slowly and mostly affects older patients.21 These LGLs have pale cytoplasm with cytoplasmic granules that contain cytolytic proteins; the characteristic phenotype is CD3þ, CD4e, CD8þ, CD16þ, CD57þ, CD56e, with rearrangement of the TCRab in most cases. The remaining 10e20% of LGLs have an NK cell phenotype (CD2þ, CD3e CD4e, CD8e, CD16þ, CD56þ, CD57e), occurring preferentially in younger adults and usually associated with a more aggressive disease course. NK-LGLs display a morphology similar to T-LGL. Both T- and NK-LGLs have very strong expression of membrane CD52.23 For the majority of patients with T-LGL leukaemia the disease follows an indolent course with infections secondary to neutropenia being the most common clinical feature. A variety of autoimmune disorders e including haemolytic anaemia, red-cell aplasia, thrombocytopenia and rheumatoid arthritis e may be associated. Splenomegaly is seen in about two thirds of patients, but lymph nodes are not usually enlarged. NK- leukaemia is characterized by cytopenias, hepatosplenomegaly and marrow infiltration; lymphadenopathy may be observed in 25% of cases. Chromosomal abnormalities are rare in CD3þ LGL leukaemia but are more commonly seen in NK-cell leukaemias. Breakpoints in the TCRa and TCRd gene loci have been reported.24 Recent DNA microarray analysis from nine T-LGLs demonstrated genomic changes at more than five loci in four out of nine (44%).25 It has been suggested that the indolent clonal expansion of T-LGL may be an extreme manifestation of a large CD8þ effector clone which produces cytokines that dysregulate the immune system, causing autoimmunity and FasL-mediated neutropenia.26 Treatment T-LGL leukaemia is often asymptomatic, and approximately half of the patients may not need therapy. Symptomatic patients have been treated successfully with cyclosporine A or weekly low-dose oral methotrexate.27,28 Various other agents have been used, including cyclophosphamide, purine analogues and growth factors. There are some patients, however, in whom the disease is clinically aggressive and resistant to conventional chemotherapy. Alemtuzumab may have efficacy in this disease in a variety of clinical settings. There have recently been two case reports of T-LGL patients treated with alemtuzumab. One patient with acquired pure red-cell aplasia secondary to T-LGL leukaemia who had failed multiple regimens of chemotherapy and was transfusion-dependent was treated with alemtuzumab intravenously 30 mg twice weekly, following dose escalation in the first week (total administered dose: 463 mg). Five months after completion of treatment the patient maintained a reduced lymphocyte count and improved haemoglobin and reticulocyte counts of 14.4 g/dL and 43.5 109/L, respectively. The duration of this remission remains to be determined.29 In another case, a 53-year-old woman with T-LGL in whom chemotherapy had failed to achieve disease control, alemtuzumab administered for 6 weeks and maintained thereafter with 1 dose of alemtuzumab every 3
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weeks resulted in stable remission and transfusion independence.30 We have also used alemtuzumab in a patient with T-LGL leukaemia to eliminate residual bone-marrow disease prior to autologous stem-cell transplantation.31 ADULT T-CELL LEUKAEMIA/LYMPHOMA (ATLL) Adult T-cell leukaemia/lymphoma (ATLL) is caused by the retrovirus human T-cell lymphotropic virus 1 (HTLV1) which is endemic in Japan, the Caribbean, Africa, South America, and parts of the south-eastern USA. In Europe the disease is seen in AfroCaribbean immigrants. HTLV-1 infection affects 15e20 million individuals worldwide, although 95% of individuals infected with HTLV-1 are likely to remain asymptomatic carriers.32 Expression of the viral protein encoded by the tax gene in CD4þ T-cell DNA causes clonal expansion driven by viral promoter-directed transcription, cellcycle disruption, and inhibition of apoptosis.33 ATLL is divided into four different clinical subtypes: acute (leukaemic), lymphomatous, chronic and smouldering. The acute form is characterized by a rapidly increasing WBC, lymphadenopathy, hepatosplenomegaly, skin lesions, and hypercalcaemia. ATLL cells are characterized by a variable size and a flower-shaped nucleus. The mature T cells are almost invariably CD4þ and CD25þ and also express CD2þ and CD3þ (weak). Genetic abnormalities are frequent in the acute and lymphomatous types of ATLL and involve trisomy 3, 7, and 21, monosomy X, and chromosome Y deletion. Translocations at 14q32 and 14q11 or 6q deletion are also common.34 These abnormalities arise because of the dysregulation of gene expression in HTLV1-infected cells driven by integrated viral genome promotors. Treatment Various therapies have been used, including combinations of standard chemotherapy with antiretroviral drugs35, arsenic trioxide36, and conjugated and unconjugated monoclonal antibodies (anti-CD25, anti-CD4). CD25 is the a-chain of the interleukin 2 (IL-2) receptor, interruption of which prevents the IL-2-dependent stimulation of cellular proliferation. Humanized anti-CD25 in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) is currently under investigation. Responses to conventional treatments are generally less than 50% and of short duration, and few therapies have proved of any long-term benefit in this aggressive malignancy. The chimeric anti-CCR4 antibody has been shown to induce antibody-dependent cellular cytotoxicity (ADCC) in ATLL cells in vitro and will now be explored in phase-I clinical trials.37 Alemtuzumab has also been evaluated in preclinical studies with immunodeficient mice bearing human ATLL cells. The animals were treated with alemtuzumab, humanized anti-Tac (CD25), or anti-CD2. Whereas anti-Tac prolonged the survival of tumour-bearing mice, alemtuzumab provided significantly longer survival than antiTac (P < 0.001), with treated mice surviving as long as tumour-free animals.38 Clinical experience with alemtuzumab in this group of patients is limited. In a recent case report, a refractory chronic ATL patient in transformation achieved a prolonged (>1 year) remission following 12 weeks of treatment with subcutaneous alemtuzumab.39 This response was associated with suppression of HTLV1 viral load, even after recovery of T cells, and may therefore indicate a possible role for alemtuzumab
Alemtuzumab in T-cell lymphoproliferative disorders 803
maintenance treatment to control viral expansion. Further investigation of alemtuzumab in this disease is warranted, and results of a phase-II study are awaited. In another case report, a 55-year-old woman with ATLL who progressed after chemotherapy and antivirals achieved a complete remission after combination therapy with alemtuzumab and pentostatin.40 CUTANEOUS T-CELL LYMPHOMA (CTCL) The CTCLs include mycosis fungoides (MF), Se´zary syndrome (SS), and a number of rarer entities, and comprise about 1% of all non-Hodgkin’s lymphomas.41 Early stages of MF consist of focal skin patches and plaques resulting from epidermal infiltration. Advanced disease may involve wider skin involvement with the development of tumours and spread to extracutaneous sites such as lymph nodes and viscera. Se´zary syndrome is a distinct variant characterized by exfoliative erythroderma and circulating cerebriform clonal T cells in the peripheral blood (Figure 2). The neoplastic cells of MF/SS are of helper T-cell origin, CD4þ, CD2þ, CD3þ, CD5þ, CD7e. Few studies have been carried out to investigate chromosomal abnormalities. Deletions of p53 are seen, particularly in patients with advanced, refractory or transformed disease.42 Treatment Various strategies have been used to treat CTCL. In patients with patches or minimally infiltrating plaques, phototherapy alone or in combination with photosensitizing agents such as psoralen, and biologics such as bexarotene or interferon-a all have efficacy.43,44 For more advanced-stage disease, combination chemotherapy (anthracycline-based regimens) or purine analogues e including combination therapy with biologics such as interferon-a e have also resulted in high response rates.45e48 However, relapse usually occurs within 1 year, and virtually all patients eventually become refractory to conventional therapy. There is no evidence that any form of treatment is curative.
Figure 2. Peripheral-blood film from a patient with Se´zary syndrome showing three lymphocytes with highly convoluted cerebriform nuclei.
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More recently various new targeted treatments have become available which have shown some activity in heavily pre-treated patients with advanced and refractory disease. These include a diphtheria toxineIL-2-linked fusion protein (denileukin diftitox; ONTAK)49, a fully humanized monoclonal antibody targeting the CD4 antigen (HuMax-CD4)50, and alemtuzumab. In an early multicentre phase-II clinical trial of alemtuzumab monotherapy in patients with B- and T-cell malignancies, four of eight MF patients responded to treatment (2 CR, 2 PR).51 These results led to a phase-II study of single-agent alemtuzumab in 22 patients with advanced MF or SS.52 The overall response rate (ORR) was 55% (32% CR, 23% PR), with better efficacy in patients with erythroderma (69% ORR) than those with plaques or skin tumours (ORR: 40%). The median time to treatment failure was 12 months. There has been a number of other small studies in which alemtuzumab 30 mg has been administered intravenously 3 times per week to patients with advanced MF and/ or SS refractory to conventional treatment. In the first of these, all three patients responded (2 CR and 1 PR) with response duration of 27, 3, and 8 months, respectively.53 One of the patients, who originally achieved a CR and relapsed, experienced a second CR after retreatment with alemtuzumab. This patient had an overall survival of 3 years.54 In another phase-II study of eight patients with MF/SS, seven of whom were refractory to previous therapy, three patients (38%) achieved a partial response.55 In a third study, one out of three patients had a CR and another a PR. The third patient achieved clinical improvement of SS but died during the third week of treatment due to ischaemic heart disease and diabetes.54 Although alemtuzumab has not been commonly linked to cardiac side-effects in patients treated for CLL, it has been reported recently that four of eight patients (50%) who were treated with alemtuzumab for MF/SS at MD Anderson Cancer Center developed significant arrhythmia or heart failure. The symptoms resolved on discontinuation of the antibody.56 A review of 30 European patients with MF/SS receiving alemtuzumab found no cardiac complications during or after alemtuzumab therapy.57 A recent case of familial MF resistant to various treatment modalities has shown a remarkable response of skin lesions and disappearance of lymphadenopathy after sequential gemcitabine and alemtuzumab therapy, suggesting that such combination chemo-immunotherapy may be beneficial in the treatment of MF/SS.58 PERIPHERAL T-CELL LYMPHOMA (PTCL) PTCLs are derived from post-thymic cells and include a number of distinct clinicopathological entities such as angio-immunoblastic T-cell lymphoma, anaplastic largecell lymphoma (ALCL), enteropathy-type intestinal T-cell lymphoma, hepatosplenic g/dT-NHL, and subcutaneous panniculitis-like T-cell lymphoma. The remainder cannot be categorized as any specific clinical or pathological syndrome and are designated as PTCL unspecified. The correlation between cytomorphological features and prognosis is poor. Apart from a subgroup of ALCLs which are positive for the anaplastic lymphoma kinase (ALK) protein, the outlook for this group of malignancies is very poor, with 3-year survival rates of around 20%. In a study by the Italian group 48.5% of the patients with PTCL (excluding ALCL and CTCL) died within 1 year of diagnosis.59 Patients often present at older age (median 60 years) with advanced-stage disease, and have unfavourable IPI scores (high lactate dehydrogenase, bulky disease), B symptoms, and poor performance status. A third of patients with PTCL and nearly all with NK-cell tumours have extranodal disease.
Alemtuzumab in T-cell lymphoproliferative disorders 805
Most peripheral T-cell lymphomas display the phenotype: CD2þ, CD3þ, CD4þ, CD5þ, CD7e. Additionally, CD30 and CD45 or CD15 may be expressed, and the TCRg gene is often rearranged. The t(2;5) translocation leads to over-expression of the gene for anaplastic lymphoma kinase (ALK ) in patients with anaplastic large-cell lymphoma of T-cell type and is associated with a good prognosis. In PTCL unspecified, a number of different numerical and structural chromosomal abnormalities has been detected.60 NK-cell-derived malignancies usually present in non-nodal sites and can be separated into three groups depending on whether they are found in the nasal area (nasal NK-cell lymphoma) in the upper respiratory tract, GI tract, or skin (nasal-like NK-cell lymphoma), or are disseminated (NK-cell lymphoma/leukaemia). This group of malignancies occurs more often in Oriental populations than in the West (5:1), and is associated with EpsteineBarr virus infection.61 Treatment With the exception of ALKþ anaplastic large-cell lymphoma, PTCLs do not respond well to conventional combination chemotherapy regimens; CR rates are usually <20% and of short duration. Outcome is related to the PTCL subtype, stage at presentation, histology, age, and the presence of B symptoms. In a recent prospective study, 14 patients with advanced, refractory PTCL were treated with alemtuzumab 30 mg intravenously 3 times weekly for 12 weeks following escalation from 3 mg to 30 mg in the first week.62 Five of 14 patients responded (36%; 3CR, 2PR) with a duration of response of 2, 6, and 12 months for each of the CR patients. In this heavily pre-treated population, therapy was accompanied by significant toxicity, including six cases of cytopmegalovirus (CMV) reactivation, two cases of aspergillosis, and four cases of pancytopenia. Zinzani et al have treated ten patients with advanced-stage relapsed cutaneous (4) or peripheral (6) T-cell lymphomas using low-dose (10 mg 3 per week for 4 weeks) alemtuzumab.63 They reported an ORR of 60% with 20% CR. The CR rate was higher (33%) in the PTCL group. CMV reactivation was seen in one patient, but this schedule was otherwise well tolerated with no grade 3/4 haematological toxicity as has been seen with conventional dosing. With the success of chemo-immunotherapy combinations in the B-NHLs, this approach is now being explored in PTCL. CHOP plus alemtuzumab has demonstrated activity as first-line therapy in PTCL patients. One dose of alemtuzumab (30 mg subcutaneously) was administered with each of 8 courses of CHOP-21. Nine out of 12 patients completed the therapeutic regimen and were available for evaluation. Five of the patients achieved CR, one PR and one MR. After a median follow-up of 298 days, five out of nine treated patients were alive.64 The Hovon group are also exploring the addition of alemtuzumab to CHOP for previously untreated patients, in this case using a more intensive CHOP-14 schedule. The German aggressive lymphoma study group are currently testing the value of 4 weeks of therapy with alemtuzumab given as consolidation following induction therapy with 6 cycles of CHOEP-14. Results from these trials are awaited. An alternative combination using doxorubicin, cyclophosphamide, fludarabine and alemtuzumab as initial therapy or after first or second relapse in 21 evaluable patients demonstrated an OR of 62%.65 Among newly diagnosed patients seven out of nine (78%) achieved CR. Grade IIeIV leukopenia developed in 81% of the evaluable treatment cycles. The significantly higher response rates in previously untreated patients
806 C. E. Dearden and E. Matutes
receiving this regimen suggest that the addition of alemtuzumab to induction chemotherapy may be valuable. Purine analogues e such as pentostatin and gemcitabine e which have efficacy as single agents in PTCL may also be suitable for combination therapy with alemtuzumab. Early experience suggests that these combinations are tolerated and may offer another therapeutic option, particularly for patients who have become resistant to standard approaches. Alemtuzumab has also been combined with platinum-based regimens used as salvage therapy at relapse and prior to SCT. Wulf et al have reported the success of a regimen incorporating standard ICE (ifosfamide, carboplatin, etoposide) with alemtuzumab, given for 2 cycles prior to proceeding with reduced-intensity allograft. Of ten patients, seven achieved CR with a survival of 4e13 months.66 Indeed, SCT e either autograft or allograft e should be considered for all patients in high-risk categories in first remission, and for all patients in chemosensitive relapse.67 Alemtuzumab may be of benefit used as part of a chemo-immunotherapy induction pre-transplant, as an agent to purge residual disease prior to autograft, or as part of the preparative regimen for allograft. TOXICITY AND SIDE-EFFECTS OF ALEMTUZUMAB Alemtuzumab is a generally well-tolerated therapy. Intravenous administration is almost always associated with first-dose reactions characterized by fever, rigors and nausea due to release of cytokines such as tumour necrosis factor and interleukin-6. These acute infusion-related effects are only associated with initial therapy or with dose increments and are usually well controlled by premedication with acetominophen and antihistamines. Systemic side-effects may also be reduced by subcutaneous administration of alemtuzumab. No serious allergic reactions or antiglobulin responses have been observed in our patients. The dose schedule of 30 mg 3 times a week was selected following results of a phase-I study. However, the optimal dose and dose interval are not yet clearly established and need to be further evaluated. In addition, doses and schedules selected for combination have not been determined. The most significant side-effect is prolonged lymphopenia associated with reactivation of viruses (such as CMV and herpes) and other opportunistic infections, particularly in heavily pre-treated patients. Use of antibacterial and antiviral prophylaxis is important and should probably be continued for at least 3 months after completion of therapy. In addition, monitoring for reactivation of CMV by PCR is advisable during therapy, particularly in the first 6 weeks. Transient haematological toxicity occurs in a minority of cases and is not usually severe. There have been cases of bone-marrow aplasia which may be related to viral reactivation, although this remains unproven. In some cases the hypoplasia is due to haemophagocytosis. CD52 is not expressed on haemopoietic progenitors, and alemtuzumab would therefore not be expected to cause direct toxicity to stem cells.2 CONCLUSION Except for ALKþ anaplastic large-cell lymphoma, early-stage MF and T-LGL leukaemia, T-cell malignancies have a poor prognosis with conventional therapy. Few patients achieve CR, relapse is common and usually associated with chemo-resistance. The almost ubiquitous presence of the CD52 antigen on the tumour cells suggests that
Alemtuzumab in T-cell lymphoproliferative disorders 807
immunotherapy with the anti-CD52 monoclonal antibody alemtuzumab may be a valuable addition to the treatment of these diseases. Durable remissions have been seen in heavily pre-treated patients, up to two thirds with T-PLL, the largest disease group studied. These results show a significant improvement over previous therapy and offer the hope of improved survival for many patients. We would consider alemtuzumab to be the first-line treatment in T-PLL. The role of alemtuzumab in the other T-cell diseases has yet to be established, but preliminary results would suggest that the antibody has clinical activity which may translate into survival benefit as more data become available. However, alemtuzumab therapy alone does not appear to be curative. Alternative strategies e such as combinations with other agents either simultaneously or sequentially, consolidation of responses with SCT, and the use of maintenance therapy e need to be further explored if the natural history of these aggressive malignancies is to be improved.
Practice points alemtuzumab is the recommended first-line therapy for T-PLL, inducing higher response rates and improved survival compared to other treatments patients with bulky nodal disease may respond less well to single-agent alemtuzumab, and combinations with chemotherapy e concurrently or sequentially e should be evaluated infusion-related side-effects of alemtuzumab are predictable and manageable, and may be reduced by subcutaneous administration all patients treated with alemtuzumab should receive anti-infective prophylaxis and CMV monitoring during and after therapy relapse rates for patients with T-cell malignancies are high, and eligible patients should be considered for SCT in their first remission REFERENCES 1. Leeumann A, Lifely MR, Schneider P et al. Primary Structure of CD52. Journal of Biological Chemistry 1995; 270: 6088e6099. 2. Gilleece MH & Dexter TM. Effects of CAMPATH-1H antibody on human haemopoietic progenitors in vitro. Blood 1993; 82: 807e812. 3. Hale G, Dyer MJ, Clark MR et al. Remission induction in non-Hodgkin lymphoma with reshaped human monoclonal antibody Campath-1H. Lancet 1988; 2: 1394e1399. 4. Heit W, Bunjes D, Wiesneth M et al. Ex vivo T-cell depletion with the monoclonal antibody Campath1H plus human complement effectively prevents acute graft-versus-host disease in allogeneic bone marrow transplantation. British Journal of Haematology 1986; 64: 479e486. 5. Dyer MJ, Hale G, Hayhoe FG et al. Effects of Campath 1-H antibodies in vivo in patients with lymphoid malignancies: influence of antibody isotype. Blood 1989; 73: 1431e1439. 6. Rowan W, Tite J, Topley P et al. Cross-linking of the Campath 1-H antigen (CD52) mediates growth inhibition in human B- and T-lymphocytes cell lines and subsequent emergence of CD52-deficient cells. Immunology 1998; 95: 427e436. 7. Ginaldi L, De Martinis M, Matutes E et al. Levels of expression of CD52 in normal and leukemic B and T cells: correlation with in vitro therapeutic responses to Campath-1H. Leukemia Research 1998; 22: 1185e1191. *8. Jaffe ES, Harris N, Stein H et al. Tumours of Haematopoietic and lymphoid tissues. World Health Organization Classification of Tumours Lyon. France: IARC Press, 2001.
808 C. E. Dearden and E. Matutes 9. Matutes E, Brito-Babapulle V, Swansbury J et al. Clinical and laboratory features of 78 cases of T-prolymphocytic leukaemia. Blood 1991; 78: 3269e3274. *10. Dearden CE, Matutes E, Cazin B et al. High remission rate in T-cell prolymphocytic leukemia with Campath-1H. Blood 2001; 98(6): 1721e1726. 11. Keating MJ, Cazin B, Coutre S et al. Campath-1H Treatment of T-cell prolymphocytic leukemia in patients for whom at least one prior chemotherapy regimen has failed. Journal of Clinical Oncology 2002; 20: 205e213. 12. Brito-Babapulle V & Catovsky D. Inversions and tandem translocations involving chromosome 14q11 and 14q32 in T-prolymphocytic leukemia and T-cell leukemias in patients with ataxia telangiectasia. Cancer Genetics and Cytogenetics 1991; 55: 1e9. 13. Virgilio L, Narducci MG, Isobe M et al. Identification of the TCL1 gene involved in T-cell malignancies. Proceedings of the National Academy of Sciences of the USA 1994; 91: 12530e12534. 14. Madani A, Choukroun V, Soulier J et al. Expression of p13MTCP1 is restricted to mature T-cell proliferations with t(X;14) translocations. Blood 1996; 87: 1923e1927. 15. Stoppa-Lyonnet D, Soulier J, Lauge A et al. Inactivation of the ATM gene in T-cell prolymphocytic leukemias. Blood 1998; 91: 3920e3926. 16. Dyer MJS, Hale G, Marcus RE et al. Remission induction in patients with lymphoid malignancies using unconjugated CAMPATH-1 monoclonal antibodies. Leukemia and Lymphoma 1990; 2: 179e190. 17. Mercieca J, Matutes E, Dearden C et al. The role of pentostatin in the treatment of T-cell malignancies: analysis of response rate in 145 patients according to disease subtype. Journal of Clinical Oncology 1994; 12: 2588e2593. 18. Lim SH, Davey G & Marcus R. Differential response in a patient treated with Campath-1H monoclonal antibody for refractory non-Hodgkin lymphoma. Lancet 1993; 341: 432e433. 19. Dearden C, Matutes E, Cazin B et al. Very high response rates in previously untreated T-cell prolymphocytic leukaemia patients receiving alemtuzumab (Campath-1H) therapy. Blood 2003; 102 [Abstract 2378]. 20. Hopfinger G, Busch R, Eichorst B et al. T-PLL-1 Protocol of the German CLL Study Group (GCLLSG) e a prospective phase II trial of fludarabine phosphate, mitoxantrone and cyclophosphamide (FMC) followed by alemtuzumab consolidation in T-PLL. Blood 2005; 106 [Abstract 2130]. *21. Lamy T & Loughran Jr. TP. Current concepts: large granular lymphocyte leukemia. Blood Reviews 1999; 13: 230e240. 22. Krishnan B, Swansbury J, Cazin B et al. Clinical outcome of Stem Cell Transplantation (SCT) in patients with T Cell Prolymphocytic Leukaemia(T-PLL) previously treated with Alemtuzumab: a multicentre experience. Blood 2005; 106: 285-I [Abstract 2005]. 23. Osuji N, Matutes E, Dearden C et al. Pregnancy improves neutropenia in T-cell large granular lymphocyte leukaemia. British Journal of Haematology 2005; 128(5): 645e648. 24. Wong KF, Chan JC, Liu HS et al. Chromosomal abnormalities in T-cell large granular lymphocyte leukaemia: report of two cases and review of the literature. British Journal of Haematology 2002; 116: 598e600. 25. Skacel M, Maciejewski J, Kandil D et al. Recurrent genomic imbalances in T-cell Large Granular Lymphocytes (T-LGL) leukemia detected by array-based comparative genomic hybridization (CGH). Blood 2003; 102 [Abstract 4768]. 26. Bigouret V, Hoffmann T, Arlettaz L et al. Monoclonal T-cell expansions in asymptomatic individuals and in patients with large granular leukemia consist of cytotoxic effector T cells expressing the activating CD94:NKG2C/E and NKD2D killer cell receptors. Blood 2003; 101: 3198e3204. *27. Loughran Jr. TP, Kidd PG & Starkebaum G. Treatment of large granular lymphocyte leukemia with oral low-dose methotrexate. Blood 1994; 84: 2164e2170. 28. Osuji N, Del Giudice I, Matutes E et al. Treatment of T-cell large granular lymphocytic leukaemia: The role for methotrexate and cyclosporine A in new, relapsed and refractory cases. Blood 2003; 102 [Abstract 1467]. 29. Ru X & Liebman HA. Successful treatment of refractory pure red cell aplasia associated with lymphoproliferative disorders with the anti-CD52 monoclonal antibody alemtuzumab (Alemtuzumab-1H). British Journal of Haematology 2003; 123: 278e281. *30. Rosenblum MD, LaBelle JL, Chang CC et al. Efficacy of alemtuzumab treatment for refractory T-cell large granular lymphocytic leukemia. Blood 2004; 103: 1969e1971.
Alemtuzumab in T-cell lymphoproliferative disorders 809 31. Dearden CE, Matutes E & Catovsky D. Alemtuzumab in T-cell malignancies. Medical Oncology 2002; 19(supplement): S27eS32. *32. Mahieux R & Gessain A. HTLV-1 and associated adult T-cell leukemia/lymphoma. Reviews in Clinical and Experimental Hematology 2003; 7: 336e361. 33. Iwanaga R, Ohtani K, Hayashi T et al. Molecular mechanism of cell cycle progression induced by the oncogene product Tax of human T-cell leukemia virus type I. Oncogene 2001; 20: 2055e2067. 34. Kamada N, Sakurai M, Miyamoto K et al. Chromosome abnormalities in adult T-cell leukemia/lymphoma: a karyotype review committee report. Cancer Research 1992; 52: 1481e1493. 35. Matutes E, Taylor GP, Cavenagh J et al. Interferon alpha and zidovudine therapy in adult T-cell leukaemia lymphoma: response and outcome in 15 patients. British Journal of Haematology 2001; 113: 779e784. 36. Hermine O, Dombret H, Poupon J et al. Phase II trial of arsenic trioxide and alpha interferon in patients with relapsed/refractory adult T-cell leukemia/lymphoma. The Hematology Journal 2004; 5: 130e134. 37. Ishida T, Lida S, Akatsua Y et al. CCR4: chemokine receptor as a novel molecular target for immunotherapy in adult T-cell leukemia/lymphoma (ATLL). Blood 2003; 102 [Abstract 3348]. 38. Zhang Z, Zhang M, Goldman CK et al. Effective therapy for a murine model of adult T-cell leukemia with the humanized anti-CD52 monoclonal antibody, Alemtuzumab-1H. Cancer Research 2003; 63: 6453e6457. *39. Mone A, Puhalla S, Whitman S et al. Durable hematologic complete response and suppression of HTLV1 viral load following alemtuzumab in zidovudine/IFN-a-refractory adult T-cell leukaemia. Blood 2005; 106(10): 3380e3382. 40. Ravandi F & Faderl S. Complete response in a patient with adult T-cell leukaemia (ATL) treated with combination of alemtuzumab and pentostatin. Leukemia Research 2006; 30(1): 103e105. 41. Kim YH & Hoppe RT. Mycosis Fungoides and the Sezary syndrome. Seminars in Oncology 1999; 26: 276e289. 42. Scarisbrick JJ, Woolford AJ, Russell-Jones R et al. Allelotyping in mycosis fungoides and Sezary syndrome: common regions of allelic loss identified on 9p, 10q, and 17p. The Journal of Investigative Dermatology 2001; 117: 663e670. 43. Kuzel TM, Roenigk Jr. HH, Samuelson E et al. Effectiveness of interferon alfa-2a combined with phototherapy for mycosis fungoides and the Sezary syndrome. Journal of Clinical Oncology 1995; 13: 257e263. 44. Duvic M, Hymes K, Heald P et al. Bexarotene is effective and safe for treatment of refractory advancedstage cutaneous T-cell lymphoma: multinational phase II-III trial results. Journal of Clinical Oncology 2001; 19: 2456e2471. 45. Wollina U, Dummer R, Brockmeyer NH et al. Multicenter study of pegylated liposomal doxorubicin in patients with cutaneous T-cell lymphoma. Cancer 2003; 98: 993e1001. 46. Dearden C, Matutes E & Catovsky D. Pentostatin treatment of cutaneous T-cell lymphoma. Oncology (Huntingt) 2000; 14: 37e40. 47. Kuzel TM, Hurria A, Samuelson E et al. Phase II trial of 2-chlorodeoxyadenosine for the treatment of cutaneous T-cell lymphoma. Blood 1996; 87: 906e911. 48. Foss FM, Ihde DC, Linnoila IR et al. Phase II trial of fludarabine phosphate and interferon alfa-2a in advanced mycosis fungoides/Sezary syndrome. Journal of Clinical Oncology 1994; 12: 2051e2059. 49. Saleh MN, LeMaistre CF, Kuzel TM et al. Antitumor activity of DAB389IL-2 fusion toxin in mycosis fungoides. Journal of the American Academy of Dermatology 1998; 39: 63e73. 50. Obitz E, Kim YH, Iversen L et al. HuMax-CD4, a fully human monoclonal antibody: early results of an ongoing phase II trial in cutaneous T cell lymphoma (CTCL). Blood 2003; 102 [Abstract 2383]. *51. Lundin J, Osterborg A, Brittinger G et al. CAMPATH-1H monoclonal antibody in therapy for previously treated low-grade non-Hodgkin’s lymphomas: a phase II multicenter study. European Study Group of Campath-1H Treatment in Low-Grade Non-Hodgkin’s Lymphoma. Journal of Clinical Oncology 1998; 16: 3257e3263. 52. Lundin J, Hagberg H, Repp R et al. Phase 2 study of alemtuzumab (anti-Cd52 monoclonal antibody) in patients with advanced mycosis Fungoides/Sezary syndrome. Blood 2003; 101(11): 4267e4272. 53. Foukaneli T, Marsh J, Pettengell R et al. Sezary syndrome responds to treatment with Alemtuzumab-1H. Blood 2001; 98 [Abstract 556]. 54. Capalbo S, Delia M, Dargenio M et al. Mycosis fungoides/Sezary syndrome: a report of three cases treated with Alemtuzumab-1H as salvage treatment. Medical Oncology 2003; 20: 389e396.
810 C. E. Dearden and E. Matutes 55. Kennedy GA, Seymour JF, Wolf M et al. Treatment of patients with advanced mycosis fungoides and Sezary syndrome with alemtuzumab. European Journal of Haematology 2003; 71: 250e256. 56. Lenihan DJ, Alencar AJ, Yang D et al. Cardiac toxicity of alemtuzumab in patients with mycosis fungoides/Sezary syndrome. Blood 2004; 104(3): 655e658. 57. Lundin J, Kennedy B, Dearden C et al. No cardiac toxicity associated with alemtuzumab therapy for mycosis fungoides/Se´zary syndrome. Blood 2005; 105(10): 4148e4149. 58. Weder P, Anliker M, Itin P et al. Familial cutaneous mycosis fungoides: successful treatment with a combination of gemcitabine and alemtuzumab. Dermatology 2004; 208: 281e283. 59. Gallamini A, Stelitano C, Calvi R et al. Peripheral T-cell lymphoma unspecified (PTCL-U): a new prognostic model from a retrospective multicentric clinical study. Blood 2004; 103(7): 2474e2479. 60. Zettl A, Rudiger T, Konrad MA et al. Genomic profiling of peripheral T-cell lymphoma, unspecified, and anaplastic large T-cell lymphoma delineates novel recurrent chromosomal alterations. The American Journal of Pathology 2004; 164: 1837e1848. 61. Dutcher JP. The role of Epstein-Barr virus and elevated levels of tumor necrosis factor in determining prognosis in Asian peripheral T-cell lymphomas. Leukemia Research 2003; 27: 467e469. *62. Enblad G, Hagberg H, Erlanson M et al. A pilot study of alemtuzumab (anti-CD52 monoclonal antibody) therapy for patients with relapsed or chemotherapy-refractory peripheral T-cell lymphomas. Blood 2004; 103(8): 2920e2924. 63. Zinzani PL, Alinari L, Tani M et al. Preliminary observations of a phase II study of reduced-dose alemtuzumab treatment in patients with pretreated T-cell lymphoma. Haematologica 2005; 90(5): 702e703. 64. Gallamini A, Zaja F, Gargantini L et al. CHOP chemotherapy plus Alemtuzumab-1H (CHOP-C) as first line treatment in patients with peripheral T-cell lymphoma (PTCL). Annals of Oncology 2005; 16 [Abstract 321]. 65. Weidmann E, Hess G, Krause SW et al. Alemtuzumab, fludarabine, cyclophosphamide, and doxorubicin; An effective first-line treatment in peripheral T-cell lymphomas. Annals of Oncology 2005; 16 [Abstract 232]. *66. Wulf GG, Hasenkamp J, Jung W et al. Reduced intensity conditioning and allogeneic stem cell transplantation after salvage therapy integrating alemtuzumab for patients with relapsed peripheral T-cell nonHodgkin’s lymphoma. Bone Marrow Transplantation 2005; 36(3): 271e273. 67. Kahl C, Leithauser M, Wolff D et al. Treatment of peripheral T-cell lymphomas (PTCL) with high-dose chemotherapy and autologous or allogeneic hematopoietic transplantation. Annals of Hematology 2002; 81: 646e650.
11 Alemtuzumab in T-cell lymphoproliferative disorders Claire E. Dearden*
BSc, MD, FRCP, FRCPath
Consultant Haematologist
Estella Matutes
MD, PhD, FRCPath
Consultant Haematologist Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK
The humanized monoclonal antibody alemtuzumab binds to the CD52 antigen, a glycoprotein which is widely expressed on normal and malignant B and T lymphocytes. Recently it has been demonstrated in a number of clinical trials that alemtuzumab has clinical activity in mature T-cell diseases such as T-prolymphocytic leukaemia and cutaneous T-cell lymphoma, inducing responses in up to two thirds of heavily pre-treated relapsed/refractory patients. Response was associated with improved survival. The toxicity profile for the antibody is manageable. The major complications are infusional reactions associated with initial injections, and prolonged lymphopenia associated with reactivation of viruses. Future studies will be directed towards alternative (subcutaneous) routes and schedules of administration, use as first-line therapy, combination strategies, and role of alemtuzumab to purge minimal residual bone-marrow disease prior to stem-cell transplantation. Key words: T cell; alemtuzumab.
Over the past 10 years unmodified monoclonal antibodies have become established as an effective therapy for a number of lymphoid malignancies. CD52 is a non-modulating antigen which is expressed at high density on >95% of all normal and malignant B and T lymphocytes, monocytes and macrophages1, but not on haemopoietic stem cells.2 A range of rat anti-CD52 antibodies was developed in the 1980s for ex-vivo T-cell depletion of haemopoietic stem cells prior to transplantation, thus reducing graft-versus-host disease (GVHD). Campath-1H (alemtuzumab) was the first fully humanized anti-CD52 monoclonal antibody to be used therapeutically in 1988 to treat a patient with a B-cell non-Hodgkins lymphoma.3 In vitro, alemtuzumab is active in complement-mediated * Corresponding author. Tel.: þ44 20 8661 3655; Fax: þ44 20 8642 9634. E-mail address: [email protected] (C.E. Dearden). 1521-6926/$ - see front matter ª 2006 Elsevier Ltd. All rights reserved.
796 C. E. Dearden and E. Matutes
lysis4, antibody-dependent cell cytotoxicity (ADCC)5, and apoptosis.6 It is unclear which mechanism is most important for the therapeutic activity of this antibody in vivo. CD52þ cells vary in their sensitivity to alemtuzumab-induced lysis, and this may be related to the antigen site density on different cell types.7 The CD52 antigen is expressed at a particularly high density (>500,000 receptors per cell) on most malignant T lymphocytes, making alemtuzumab a good candidate for novel therapy in T-cell malignancies. The mature T-cell malignancies are rare, accounting for approximately 10% of all lymphoid neoplasms. This is a heterogeneous group of disorders resulting from clonal proliferation of post-thymic lymphocytes. The different diseases within this group are distinguished by their clinical, morphological, immunophenotypic and cytogenetic characteristics8, and can be broadly categorized into those with leukaemic, cutaneous, nodal or extra-nodal presentation (Table 1). There is racial and geographic variability of subtypes which is in some cases related to an association with viruses. Although some of the diseases in this group e such as T-cell large granular lymphocyte (T-LGL) leukaemia and early-stage mycosis fungoides (MF) e may follow a relatively benign protracted course, others have an aggressive clinical behaviour and a poor response to conventional chemotherapy. These malignancies are rarely curable, and for many patients survival is short (median of 6e8 months).9 There is a lack of consensus regarding treatment, and new therapeutic strategies are needed to improve this bleak prognosis. To date, clinical experience with alemtuzumab treatment in this group has been limited to a few small series, and there have been no prospective randomized trials. The results of these studies are summarized in the Tables 2e4 and discussed in the relevant sections of the text. However, recent experience has shown that alemtuzumab has remarkable activity in T-prolymphocytic leukaemia (T-PLL)10,11, an aggressive disease with a poor prognosis, achieving overall and complete response rates of 76% and 60% respectively. This evidence provides a rationale for exploring the activity of alemtuzumab in other poor-prognosis T-cell malignancies.
Table 1. WHO classification of mature T-cell and NK-cell neoplasms. Leukaemic: T-cell prolymphocytic leukaemia T-cell large granular lymphocytic leukaemia Aggressive NK-cell leukaemia Adult T-cell lymphoma/leukaemia Cutaneous: Mycosis fungoides/Se´zary syndrome Primary cutaneous anaplastic large-cell lymphoma Nodal: Anaplastic large-cell lymphoma Angioimmunoblastic T-cell lymphoma Peripheral T-cell lymphoma unspecified Extranodal: Extranodal NK/T-cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Blastic NK-cell lymphoma
Alemtuzumab in T-cell lymphoproliferative disorders 797
Table 2. Disease features of T-cell leukaemias.
Clinical
Morphology
T-PLL
LGL leukaemia
ATLL
SS
Splenomegaly, high white blood cell count Prolymphocytes
Cytopenia
Hypercalcaemia HTLV-I-positive
Skin
LGL
‘Flower’ cell
CD8þ CD4e CD57þ CD16þ
CD4þ CD25þ
Cerebriform nucleus CD4þ CD8e
Immunophenotype
CD4þ CD8e or CD4þ CD8þ
Cytogenetics
Inv14(q11; q32) þ8, iso 8q
Complex
Hypo- or hyperdiploid
T-PLL, T-cell prolymphocytic leukaemia; LGL, large granular lymphocyte; ATLL, adult T-cell lymphoma/ leukaemia; SS, Se´zary syndrome; HTLV, human T cell lymphotropic virus.
T-PROLYMPHOCYTIC LEUKAEMIA T-PLL is a disease affecting adults (median age 63 years) and is slightly commoner in men than in women (M:F ratio of 1.3).9 Patients usually present with splenomegaly, lymphadenopathy, and a high white blood cell count, which in half the patients is Table 3. Studies of single-agent alemtuzumab in T-cell malignancies. Study
Disease
n
Results ORR
Dearden et al10 Keating et al11 Dearden et al19 Lundin et al52 Foukanelli et al53 Kennedy et al55 Capabalo et al54 Lenihan et al56 Enblad et al62 Zinzani et al63
Previously treated T-PLL Relapsed/ refractory T-PLL Previously untreated T-PLL Relapsed/ refractory CTCL Relapsed/ refractory CTCL Relapsed MF/SS Relapsed MF/SS Relapsed MF/SS Refractory PTCL Relapsed PTCL and CTCL (low-dose alemtuxumab)
CR
Response duration (months)
Median OS (range) (months)
Not reached
13 (24 for CR) 7.5 (14.8 for CR) Not reached
39
76%
60%
10 (3e45)
76
50%
37.5%
4.5
11
100%
100%
22
55%
32%
12
e
3
100%
66%
3, 8 and 27
e
e
e
e 2, 6, 12
e
8 8 14 10 [4 CTCL]
38% 66% 37.5% 36% 60%
0 33% 0 21% 20% [33% in PTCL]
ORR, overall response rate; CR, complete remission; OS, overall survival; T-PLL, T-cell prolymphocytic leukaemia; CTCL, cutaneous T-cell lymphoma; MF/SS, mycosis fungoides/Se´zary syndrome; PTCL, peripheral T-cell lymphoma.
798 C. E. Dearden and E. Matutes
Table 4. Studies of alemtuzumab in combination on T-cell malignancies. Study
Disease
n
Hopfinger et al20
T-PLL
16
Ravandi and Faderl40 Weder et al58 Gallamini et al64
ATLL
1
MF
1
Treatment regimen
Results
FCM followed by alemtuzumab (12) Alemtuzumab þ pentostatin
68% after 50% FCM 90% after alemtuzumab 100% 100%
ORR
Alemtuzumab 100% þ gemcitabine CHOP þ 67% alemtuzumab
PTCL 9 (previously treated) Weidmann PTCL 21 (11 FCD þ et al65 previously alemtuzumab untreated)
62%
CR
e 61%
Response Median duration OS (months) (range) (months) 10.6
13.4
e
e
e
e
9.1
10% for 2þ relapsed/ refractory 73% for 17þ previously untreated
15.2
e
ORR, overall response rate; CR, complete remission; OS, overall survival; T-PLL, T-cell prolymphocytic leukaemia; FCM, fludarabine cyclophosphamide mitrozantrone; ATLL, adult T-cell leukaemia/lymphoma; MF, mycosis fungoides; PTCL, peripheral T-cell lymphoma; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisolone; FCD, fludarabine cyclophosphamide doxorubicin.
>200 109/L. Other organs and skin may also be involved. The circulating prolymphocytes have distinctive morphology, with irregular basophilic cytoplasm and a prominent single nucleolus (Figure 1). They express a mature T-cell immunophenotype (TdTe, CD2þ, weak CD3þ, CD5þ, strong CD7þ) with variable expression of CD4 and CD8 (CD4þ/CD8e 63%, CD4þ/CD8þ 23%, CD4e/CD8þ 13%) (Table 2). Cell-surface antigens linked to T-cell activation e such as CD25, CD38, and class II HLA-DR e are variably expressed, and the antigen CD52 is expressed at a high density.7 In most cases, T-PLL patients express the TCRab phenotype, although rare instances of TCRgd have been reported. Cytogenetic abnormalities of chromosome 14 are common, the most frequent being inv (14) (q11;q32.1) which is seen in 75% of cases.12 Chromosomal abnormalities at the 14q32.1 and Xq28 regions13,14 lead to the over-expression of two proto-oncogenes of similar structure: TCL1a/b and p13 MTCP1, respectively. TCL1 has been shown to associate with protein kinase B (Akt), resulting in the promotion of Akt-induced cell survival and proliferation. The TCL1 oncoprotein is expressed in approximately 70% of T-PLL cases. Abnormalities of chromosome 8 (iso(8q), trisomy 8, t(8;8)) are seen in more than half the cases. Molecular methods have shown that the ATM gene, which maps to 11q23, is frequently involved in T-PLL, and this may be important in the pathogenesis of the disease.15
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Figure 1. Medium-sized lymphocytes with scanty basophilic and irregular cytoplasm and a single nucleolus, features characteristic of T-cell prolymphocytic leukaemia (T-PLL).
Treatment T-PLL is often resistant to conventional chemotherapy, and patients in historical series have had a poor median survival (7.5 months).9 Although some patients may initially present with indolent disease, they eventually progress, and the outcome is then similar. In recent years the survival of patients with T-PLL has improved following the introduction of new therapies, including deoxycoformycin (pentostatin) and alemtuzumab. Early studies on a range of lymphoid malignancies included one patient with T-PLL who went into a complete remission (CR) after Campath-1G.16 This prompted a larger phase-II study to examine the role of the humanized antibody alemtuzumab in this disease.10 This series included 39 T-PLL patients treated with alemtuzumab using the standard protocol of 30 mg, 3 times per week, intravenously (or subcutaneously in one case), until maximum response was achieved (median of 35 days). Most patients had received prior therapy with a variety of agents, including pentostatin, and had relapsed or refractory disease. The overall response rate was 76% (60% CR and 16% PR), including patients who had been resistant to other therapies. These response rates are significantly higher than those reported for conventional therapies such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone), with which a third of patients achieve short-lived partial responses (3 months), or pentostatin with a 40% overall response (12% CR) lasting 3e12 months (median 6 months).17 In patients responding to alemtuzumab clearance of cells from the peripheral blood was rapid. However, despite the often very high white counts (>100 109/L), in no case was this complicated by tumour lysis or ‘cytokine release’ syndrome. Resolution of skin infiltration, lymphadenopathy and/or splenomegaly occurred in half the affected patients. However, patients with serous effusions, hepatic or central nervous system involvement, or bulky lymph nodes were more resistant to treatment. Experience using alemtuzumab in the treatment of non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia (CLL) has shown that, whilst clearance of disease from blood and bone marrow may be complete, bulky nodal, liver or CNS disease may be resistant.18
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This differential pattern of response may reflect poor accessibility of the antibody to tumour cells in different sites and/or to reduced or impaired effector-cell function in these locations. In the case of CNS disease the absence of local effector cells may be important. Most CRs were durable, with a median disease-free interval (DFI) of 10 months (up to 45 months). Survival was significantly prolonged in patients achieving CR (median 24 months, compared to 9 months for PR and 4 months for NR). Of 12 patients retreated with alemtuzumab at relapse, five (42%) achieved a second CR and one had a PR. In two patients CD52 expression was lost from the malignant cells at relapse. In a retrospective analysis of 76 patients with T-PLL who were enrolled in a compassionate-use programme in the United States and who had received one or more lines of chemotherapy, alemtuzumab was administered for 4e12 weeks (30 mg 3 times weekly following dose escalation from 5 mg to 30 mg in the first week).11 In this study the objective response rate was 50%, with 37.5% CR (Table 3); among these, 43% had a CR in skin, 39% in bone marrow, 33% in spleen, 32% in lymph nodes, and 30% in the liver. In these heavily pre-treated patients, the median time to progression was 4.5 months and the median overall survival was 7.5 months, and in patients who achieved a CR it was 14.8 months. These results were superior to those achieved with prior therapy. The positive results obtained using alemtuzumab to treat patients with relapsed/ refractory T-PLL have prompted the evaluation of this monoclonal antibody in therapynaive patients. In a preliminary study of 11 patients, 100% achieved a CR, with 7/11 patients (64%) still alive at a median follow-up of 12 months (range 4e17 months).19 An alternate treatment strategy is to debulk tumour with chemotherapy followed by alemtuzumab consolidation with the aim of maintaining CR or improving the response to induction chemotherapy, i.e., converting a PR or stable disease (SD) to a CR. The German CLL study group are conducting a prospective trial with four 4-weekly cycles of FCM (fludarabine 25 mg/m2 and cyclophosphamide 200 mg/m2, days 1e3, plus mitoxantrone 8 mg/m2 on day 1), followed by alemtuzumab 30 mg intravenously 3 times weekly 1e3 months after completion of chemotherapy. Of 16 patients treated with induction chemotherapy, eight had a CR (50%), three had a PR (19%), and two had SD. Twelve patients (one PD, two SD, two PR, and seven CR) received consolidation therapy with alemtuzumab, increasing the OR to 90% including converting the two patients with PR to CR.20 The patient with SD converted to a CR.21 In the 50 T-PLL patients we have treated with alemtuzumab alone, it has been possible to collect stem cells from some patients achieving CR following therapy that were uncontaminated with T-PLL cells as demonstrated by dual colour flow cytometry and/ or polymerase chain reaction (PCR). Sixteen patients have proceeded to high-dose therapy with stem-cell transplantation (SCT) e 11 autologous, five allogeneic e in first or second remission.22 Conditioning for both auto- and allo-graft was with cyclophosphamide and total body irradiation (TBI) in most cases. Two of the allografts were with reduced-intensity conditioning. Seven patients remain alive with a median follow-up of 60 months (24e78 months). Median disease-free survival (DFS) was 20 months (8e78 months) for the autograft patients and 26 months (21 days to 60 months) for those allografted. In the latter group transplant-related mortality (TRM) was high (40%), in both cases full-intensity conditioning was given. SCT appears to prolong DFS and overall survival, although relapses still occur, presumably from ‘sanctuary sites’. For those patients unable to receive a transplant, alemtuzumab maintenance therapy should be considered. These data suggest alemtuzumab therapy can improve outcome in T-PLL, a haematological malignancy with an otherwise dismal prognosis. Despite this success, disease
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progression appears inevitable, and therefore SCT in first remission should be the recommended therapeutic option for eligible patients. T-CELL LARGE GRANULAR LYMPHOCYTE LEUKAEMIA Clonal disorders of large granular lymphocytes (LGLs) are rare (<3% of all cases of small lymphocytic leukaemias) and consist of two separate entities. Most (80e90%) belong to a mature CD3þ lineage that progresses slowly and mostly affects older patients.21 These LGLs have pale cytoplasm with cytoplasmic granules that contain cytolytic proteins; the characteristic phenotype is CD3þ, CD4e, CD8þ, CD16þ, CD57þ, CD56e, with rearrangement of the TCRab in most cases. The remaining 10e20% of LGLs have an NK cell phenotype (CD2þ, CD3e CD4e, CD8e, CD16þ, CD56þ, CD57e), occurring preferentially in younger adults and usually associated with a more aggressive disease course. NK-LGLs display a morphology similar to T-LGL. Both T- and NK-LGLs have very strong expression of membrane CD52.23 For the majority of patients with T-LGL leukaemia the disease follows an indolent course with infections secondary to neutropenia being the most common clinical feature. A variety of autoimmune disorders e including haemolytic anaemia, red-cell aplasia, thrombocytopenia and rheumatoid arthritis e may be associated. Splenomegaly is seen in about two thirds of patients, but lymph nodes are not usually enlarged. NK- leukaemia is characterized by cytopenias, hepatosplenomegaly and marrow infiltration; lymphadenopathy may be observed in 25% of cases. Chromosomal abnormalities are rare in CD3þ LGL leukaemia but are more commonly seen in NK-cell leukaemias. Breakpoints in the TCRa and TCRd gene loci have been reported.24 Recent DNA microarray analysis from nine T-LGLs demonstrated genomic changes at more than five loci in four out of nine (44%).25 It has been suggested that the indolent clonal expansion of T-LGL may be an extreme manifestation of a large CD8þ effector clone which produces cytokines that dysregulate the immune system, causing autoimmunity and FasL-mediated neutropenia.26 Treatment T-LGL leukaemia is often asymptomatic, and approximately half of the patients may not need therapy. Symptomatic patients have been treated successfully with cyclosporine A or weekly low-dose oral methotrexate.27,28 Various other agents have been used, including cyclophosphamide, purine analogues and growth factors. There are some patients, however, in whom the disease is clinically aggressive and resistant to conventional chemotherapy. Alemtuzumab may have efficacy in this disease in a variety of clinical settings. There have recently been two case reports of T-LGL patients treated with alemtuzumab. One patient with acquired pure red-cell aplasia secondary to T-LGL leukaemia who had failed multiple regimens of chemotherapy and was transfusion-dependent was treated with alemtuzumab intravenously 30 mg twice weekly, following dose escalation in the first week (total administered dose: 463 mg). Five months after completion of treatment the patient maintained a reduced lymphocyte count and improved haemoglobin and reticulocyte counts of 14.4 g/dL and 43.5 109/L, respectively. The duration of this remission remains to be determined.29 In another case, a 53-year-old woman with T-LGL in whom chemotherapy had failed to achieve disease control, alemtuzumab administered for 6 weeks and maintained thereafter with 1 dose of alemtuzumab every 3
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weeks resulted in stable remission and transfusion independence.30 We have also used alemtuzumab in a patient with T-LGL leukaemia to eliminate residual bone-marrow disease prior to autologous stem-cell transplantation.31 ADULT T-CELL LEUKAEMIA/LYMPHOMA (ATLL) Adult T-cell leukaemia/lymphoma (ATLL) is caused by the retrovirus human T-cell lymphotropic virus 1 (HTLV1) which is endemic in Japan, the Caribbean, Africa, South America, and parts of the south-eastern USA. In Europe the disease is seen in AfroCaribbean immigrants. HTLV-1 infection affects 15e20 million individuals worldwide, although 95% of individuals infected with HTLV-1 are likely to remain asymptomatic carriers.32 Expression of the viral protein encoded by the tax gene in CD4þ T-cell DNA causes clonal expansion driven by viral promoter-directed transcription, cellcycle disruption, and inhibition of apoptosis.33 ATLL is divided into four different clinical subtypes: acute (leukaemic), lymphomatous, chronic and smouldering. The acute form is characterized by a rapidly increasing WBC, lymphadenopathy, hepatosplenomegaly, skin lesions, and hypercalcaemia. ATLL cells are characterized by a variable size and a flower-shaped nucleus. The mature T cells are almost invariably CD4þ and CD25þ and also express CD2þ and CD3þ (weak). Genetic abnormalities are frequent in the acute and lymphomatous types of ATLL and involve trisomy 3, 7, and 21, monosomy X, and chromosome Y deletion. Translocations at 14q32 and 14q11 or 6q deletion are also common.34 These abnormalities arise because of the dysregulation of gene expression in HTLV1-infected cells driven by integrated viral genome promotors. Treatment Various therapies have been used, including combinations of standard chemotherapy with antiretroviral drugs35, arsenic trioxide36, and conjugated and unconjugated monoclonal antibodies (anti-CD25, anti-CD4). CD25 is the a-chain of the interleukin 2 (IL-2) receptor, interruption of which prevents the IL-2-dependent stimulation of cellular proliferation. Humanized anti-CD25 in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) is currently under investigation. Responses to conventional treatments are generally less than 50% and of short duration, and few therapies have proved of any long-term benefit in this aggressive malignancy. The chimeric anti-CCR4 antibody has been shown to induce antibody-dependent cellular cytotoxicity (ADCC) in ATLL cells in vitro and will now be explored in phase-I clinical trials.37 Alemtuzumab has also been evaluated in preclinical studies with immunodeficient mice bearing human ATLL cells. The animals were treated with alemtuzumab, humanized anti-Tac (CD25), or anti-CD2. Whereas anti-Tac prolonged the survival of tumour-bearing mice, alemtuzumab provided significantly longer survival than antiTac (P < 0.001), with treated mice surviving as long as tumour-free animals.38 Clinical experience with alemtuzumab in this group of patients is limited. In a recent case report, a refractory chronic ATL patient in transformation achieved a prolonged (>1 year) remission following 12 weeks of treatment with subcutaneous alemtuzumab.39 This response was associated with suppression of HTLV1 viral load, even after recovery of T cells, and may therefore indicate a possible role for alemtuzumab
Alemtuzumab in T-cell lymphoproliferative disorders 803
maintenance treatment to control viral expansion. Further investigation of alemtuzumab in this disease is warranted, and results of a phase-II study are awaited. In another case report, a 55-year-old woman with ATLL who progressed after chemotherapy and antivirals achieved a complete remission after combination therapy with alemtuzumab and pentostatin.40 CUTANEOUS T-CELL LYMPHOMA (CTCL) The CTCLs include mycosis fungoides (MF), Se´zary syndrome (SS), and a number of rarer entities, and comprise about 1% of all non-Hodgkin’s lymphomas.41 Early stages of MF consist of focal skin patches and plaques resulting from epidermal infiltration. Advanced disease may involve wider skin involvement with the development of tumours and spread to extracutaneous sites such as lymph nodes and viscera. Se´zary syndrome is a distinct variant characterized by exfoliative erythroderma and circulating cerebriform clonal T cells in the peripheral blood (Figure 2). The neoplastic cells of MF/SS are of helper T-cell origin, CD4þ, CD2þ, CD3þ, CD5þ, CD7e. Few studies have been carried out to investigate chromosomal abnormalities. Deletions of p53 are seen, particularly in patients with advanced, refractory or transformed disease.42 Treatment Various strategies have been used to treat CTCL. In patients with patches or minimally infiltrating plaques, phototherapy alone or in combination with photosensitizing agents such as psoralen, and biologics such as bexarotene or interferon-a all have efficacy.43,44 For more advanced-stage disease, combination chemotherapy (anthracycline-based regimens) or purine analogues e including combination therapy with biologics such as interferon-a e have also resulted in high response rates.45e48 However, relapse usually occurs within 1 year, and virtually all patients eventually become refractory to conventional therapy. There is no evidence that any form of treatment is curative.
Figure 2. Peripheral-blood film from a patient with Se´zary syndrome showing three lymphocytes with highly convoluted cerebriform nuclei.
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More recently various new targeted treatments have become available which have shown some activity in heavily pre-treated patients with advanced and refractory disease. These include a diphtheria toxineIL-2-linked fusion protein (denileukin diftitox; ONTAK)49, a fully humanized monoclonal antibody targeting the CD4 antigen (HuMax-CD4)50, and alemtuzumab. In an early multicentre phase-II clinical trial of alemtuzumab monotherapy in patients with B- and T-cell malignancies, four of eight MF patients responded to treatment (2 CR, 2 PR).51 These results led to a phase-II study of single-agent alemtuzumab in 22 patients with advanced MF or SS.52 The overall response rate (ORR) was 55% (32% CR, 23% PR), with better efficacy in patients with erythroderma (69% ORR) than those with plaques or skin tumours (ORR: 40%). The median time to treatment failure was 12 months. There has been a number of other small studies in which alemtuzumab 30 mg has been administered intravenously 3 times per week to patients with advanced MF and/ or SS refractory to conventional treatment. In the first of these, all three patients responded (2 CR and 1 PR) with response duration of 27, 3, and 8 months, respectively.53 One of the patients, who originally achieved a CR and relapsed, experienced a second CR after retreatment with alemtuzumab. This patient had an overall survival of 3 years.54 In another phase-II study of eight patients with MF/SS, seven of whom were refractory to previous therapy, three patients (38%) achieved a partial response.55 In a third study, one out of three patients had a CR and another a PR. The third patient achieved clinical improvement of SS but died during the third week of treatment due to ischaemic heart disease and diabetes.54 Although alemtuzumab has not been commonly linked to cardiac side-effects in patients treated for CLL, it has been reported recently that four of eight patients (50%) who were treated with alemtuzumab for MF/SS at MD Anderson Cancer Center developed significant arrhythmia or heart failure. The symptoms resolved on discontinuation of the antibody.56 A review of 30 European patients with MF/SS receiving alemtuzumab found no cardiac complications during or after alemtuzumab therapy.57 A recent case of familial MF resistant to various treatment modalities has shown a remarkable response of skin lesions and disappearance of lymphadenopathy after sequential gemcitabine and alemtuzumab therapy, suggesting that such combination chemo-immunotherapy may be beneficial in the treatment of MF/SS.58 PERIPHERAL T-CELL LYMPHOMA (PTCL) PTCLs are derived from post-thymic cells and include a number of distinct clinicopathological entities such as angio-immunoblastic T-cell lymphoma, anaplastic largecell lymphoma (ALCL), enteropathy-type intestinal T-cell lymphoma, hepatosplenic g/dT-NHL, and subcutaneous panniculitis-like T-cell lymphoma. The remainder cannot be categorized as any specific clinical or pathological syndrome and are designated as PTCL unspecified. The correlation between cytomorphological features and prognosis is poor. Apart from a subgroup of ALCLs which are positive for the anaplastic lymphoma kinase (ALK) protein, the outlook for this group of malignancies is very poor, with 3-year survival rates of around 20%. In a study by the Italian group 48.5% of the patients with PTCL (excluding ALCL and CTCL) died within 1 year of diagnosis.59 Patients often present at older age (median 60 years) with advanced-stage disease, and have unfavourable IPI scores (high lactate dehydrogenase, bulky disease), B symptoms, and poor performance status. A third of patients with PTCL and nearly all with NK-cell tumours have extranodal disease.
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Most peripheral T-cell lymphomas display the phenotype: CD2þ, CD3þ, CD4þ, CD5þ, CD7e. Additionally, CD30 and CD45 or CD15 may be expressed, and the TCRg gene is often rearranged. The t(2;5) translocation leads to over-expression of the gene for anaplastic lymphoma kinase (ALK ) in patients with anaplastic large-cell lymphoma of T-cell type and is associated with a good prognosis. In PTCL unspecified, a number of different numerical and structural chromosomal abnormalities has been detected.60 NK-cell-derived malignancies usually present in non-nodal sites and can be separated into three groups depending on whether they are found in the nasal area (nasal NK-cell lymphoma) in the upper respiratory tract, GI tract, or skin (nasal-like NK-cell lymphoma), or are disseminated (NK-cell lymphoma/leukaemia). This group of malignancies occurs more often in Oriental populations than in the West (5:1), and is associated with EpsteineBarr virus infection.61 Treatment With the exception of ALKþ anaplastic large-cell lymphoma, PTCLs do not respond well to conventional combination chemotherapy regimens; CR rates are usually <20% and of short duration. Outcome is related to the PTCL subtype, stage at presentation, histology, age, and the presence of B symptoms. In a recent prospective study, 14 patients with advanced, refractory PTCL were treated with alemtuzumab 30 mg intravenously 3 times weekly for 12 weeks following escalation from 3 mg to 30 mg in the first week.62 Five of 14 patients responded (36%; 3CR, 2PR) with a duration of response of 2, 6, and 12 months for each of the CR patients. In this heavily pre-treated population, therapy was accompanied by significant toxicity, including six cases of cytopmegalovirus (CMV) reactivation, two cases of aspergillosis, and four cases of pancytopenia. Zinzani et al have treated ten patients with advanced-stage relapsed cutaneous (4) or peripheral (6) T-cell lymphomas using low-dose (10 mg 3 per week for 4 weeks) alemtuzumab.63 They reported an ORR of 60% with 20% CR. The CR rate was higher (33%) in the PTCL group. CMV reactivation was seen in one patient, but this schedule was otherwise well tolerated with no grade 3/4 haematological toxicity as has been seen with conventional dosing. With the success of chemo-immunotherapy combinations in the B-NHLs, this approach is now being explored in PTCL. CHOP plus alemtuzumab has demonstrated activity as first-line therapy in PTCL patients. One dose of alemtuzumab (30 mg subcutaneously) was administered with each of 8 courses of CHOP-21. Nine out of 12 patients completed the therapeutic regimen and were available for evaluation. Five of the patients achieved CR, one PR and one MR. After a median follow-up of 298 days, five out of nine treated patients were alive.64 The Hovon group are also exploring the addition of alemtuzumab to CHOP for previously untreated patients, in this case using a more intensive CHOP-14 schedule. The German aggressive lymphoma study group are currently testing the value of 4 weeks of therapy with alemtuzumab given as consolidation following induction therapy with 6 cycles of CHOEP-14. Results from these trials are awaited. An alternative combination using doxorubicin, cyclophosphamide, fludarabine and alemtuzumab as initial therapy or after first or second relapse in 21 evaluable patients demonstrated an OR of 62%.65 Among newly diagnosed patients seven out of nine (78%) achieved CR. Grade IIeIV leukopenia developed in 81% of the evaluable treatment cycles. The significantly higher response rates in previously untreated patients
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receiving this regimen suggest that the addition of alemtuzumab to induction chemotherapy may be valuable. Purine analogues e such as pentostatin and gemcitabine e which have efficacy as single agents in PTCL may also be suitable for combination therapy with alemtuzumab. Early experience suggests that these combinations are tolerated and may offer another therapeutic option, particularly for patients who have become resistant to standard approaches. Alemtuzumab has also been combined with platinum-based regimens used as salvage therapy at relapse and prior to SCT. Wulf et al have reported the success of a regimen incorporating standard ICE (ifosfamide, carboplatin, etoposide) with alemtuzumab, given for 2 cycles prior to proceeding with reduced-intensity allograft. Of ten patients, seven achieved CR with a survival of 4e13 months.66 Indeed, SCT e either autograft or allograft e should be considered for all patients in high-risk categories in first remission, and for all patients in chemosensitive relapse.67 Alemtuzumab may be of benefit used as part of a chemo-immunotherapy induction pre-transplant, as an agent to purge residual disease prior to autograft, or as part of the preparative regimen for allograft. TOXICITY AND SIDE-EFFECTS OF ALEMTUZUMAB Alemtuzumab is a generally well-tolerated therapy. Intravenous administration is almost always associated with first-dose reactions characterized by fever, rigors and nausea due to release of cytokines such as tumour necrosis factor and interleukin-6. These acute infusion-related effects are only associated with initial therapy or with dose increments and are usually well controlled by premedication with acetominophen and antihistamines. Systemic side-effects may also be reduced by subcutaneous administration of alemtuzumab. No serious allergic reactions or antiglobulin responses have been observed in our patients. The dose schedule of 30 mg 3 times a week was selected following results of a phase-I study. However, the optimal dose and dose interval are not yet clearly established and need to be further evaluated. In addition, doses and schedules selected for combination have not been determined. The most significant side-effect is prolonged lymphopenia associated with reactivation of viruses (such as CMV and herpes) and other opportunistic infections, particularly in heavily pre-treated patients. Use of antibacterial and antiviral prophylaxis is important and should probably be continued for at least 3 months after completion of therapy. In addition, monitoring for reactivation of CMV by PCR is advisable during therapy, particularly in the first 6 weeks. Transient haematological toxicity occurs in a minority of cases and is not usually severe. There have been cases of bone-marrow aplasia which may be related to viral reactivation, although this remains unproven. In some cases the hypoplasia is due to haemophagocytosis. CD52 is not expressed on haemopoietic progenitors, and alemtuzumab would therefore not be expected to cause direct toxicity to stem cells.2 CONCLUSION Except for ALKþ anaplastic large-cell lymphoma, early-stage MF and T-LGL leukaemia, T-cell malignancies have a poor prognosis with conventional therapy. Few patients achieve CR, relapse is common and usually associated with chemo-resistance. The almost ubiquitous presence of the CD52 antigen on the tumour cells suggests that
Alemtuzumab in T-cell lymphoproliferative disorders 807
immunotherapy with the anti-CD52 monoclonal antibody alemtuzumab may be a valuable addition to the treatment of these diseases. Durable remissions have been seen in heavily pre-treated patients, up to two thirds with T-PLL, the largest disease group studied. These results show a significant improvement over previous therapy and offer the hope of improved survival for many patients. We would consider alemtuzumab to be the first-line treatment in T-PLL. The role of alemtuzumab in the other T-cell diseases has yet to be established, but preliminary results would suggest that the antibody has clinical activity which may translate into survival benefit as more data become available. However, alemtuzumab therapy alone does not appear to be curative. Alternative strategies e such as combinations with other agents either simultaneously or sequentially, consolidation of responses with SCT, and the use of maintenance therapy e need to be further explored if the natural history of these aggressive malignancies is to be improved.
Practice points alemtuzumab is the recommended first-line therapy for T-PLL, inducing higher response rates and improved survival compared to other treatments patients with bulky nodal disease may respond less well to single-agent alemtuzumab, and combinations with chemotherapy e concurrently or sequentially e should be evaluated infusion-related side-effects of alemtuzumab are predictable and manageable, and may be reduced by subcutaneous administration all patients treated with alemtuzumab should receive anti-infective prophylaxis and CMV monitoring during and after therapy relapse rates for patients with T-cell malignancies are high, and eligible patients should be considered for SCT in their first remission REFERENCES 1. Leeumann A, Lifely MR, Schneider P et al. Primary Structure of CD52. Journal of Biological Chemistry 1995; 270: 6088e6099. 2. Gilleece MH & Dexter TM. Effects of CAMPATH-1H antibody on human haemopoietic progenitors in vitro. Blood 1993; 82: 807e812. 3. Hale G, Dyer MJ, Clark MR et al. Remission induction in non-Hodgkin lymphoma with reshaped human monoclonal antibody Campath-1H. Lancet 1988; 2: 1394e1399. 4. Heit W, Bunjes D, Wiesneth M et al. Ex vivo T-cell depletion with the monoclonal antibody Campath1H plus human complement effectively prevents acute graft-versus-host disease in allogeneic bone marrow transplantation. British Journal of Haematology 1986; 64: 479e486. 5. Dyer MJ, Hale G, Hayhoe FG et al. Effects of Campath 1-H antibodies in vivo in patients with lymphoid malignancies: influence of antibody isotype. Blood 1989; 73: 1431e1439. 6. Rowan W, Tite J, Topley P et al. Cross-linking of the Campath 1-H antigen (CD52) mediates growth inhibition in human B- and T-lymphocytes cell lines and subsequent emergence of CD52-deficient cells. Immunology 1998; 95: 427e436. 7. Ginaldi L, De Martinis M, Matutes E et al. Levels of expression of CD52 in normal and leukemic B and T cells: correlation with in vitro therapeutic responses to Campath-1H. Leukemia Research 1998; 22: 1185e1191. *8. Jaffe ES, Harris N, Stein H et al. Tumours of Haematopoietic and lymphoid tissues. World Health Organization Classification of Tumours Lyon. France: IARC Press, 2001.
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