Chemotherapy of chronic haematological malignancies

10

Chemotherapy of chronic haematological malignancies ANTHONY

D. HO

Despite advances in the immunology, molecular biology, virology and genetics of haematological diseases, little progress has been made in the treatment of chronic haematological malignancies. Current therapies have thus far failed to substantially influence survival in the most common chronic malignancies such as B cell chronic lymphocytic leukaemia and chronic myeloid leukaemia. Conventional treatment has been administered with palliative intent. In the last years, a few new agents based on novel principles of action have been developed for the treatment of chronic lymphoproliferative diseases. This review will focus on the roles of these agents in current chemoiherapeutic management and on directions for future research. B CELL CHRONIC LYMPHOCYTIC LEUKAEMIA The natural history of B cell chronic lymphocytic leukaemia (B-CLL) is diverse, with a median survival ranging from about 10 years for patients at early stages to less than 2 years at advanced stages (Rai et ai, 1975; Binet et al, 1981). The majority of patients with B-CLL present with limited disease and do not require immediate therapy. Systemic therapy is usually reserved for patients with symptomatic and advanced disease. W h e n to treat

Patients at early stages (Rai 0-II, Binet A and B, see Table 1) can usually be safely observed until there is evidence of disease progression. According to a recent study of the Cancer and Leukemia Group B, the survival of 23 Rai stage I-II patients randomized to chlorambucil therapy was not different from that of 25 patients randomized to observation alone (Shustik et al, 1988). The French Cooperative Group on CLL (1987) has conducted a unique randomized trial in patients with B-CLL stratified according to clinical stages. Of those with Binet stage A, 230 patients were randomized t.o initial observation and 223 were treated at presentation with chlorambucil 0.1 mg/kg daily for an indefinite period. The untreated patients tended to Baillibre's Clinical Haematology--

Vol. 4, No. 1, January 1991 ISBN0--7020-1531-8

197 Copyright9 1991,byBailli6reTindall -Allrightsof reproductionin any formreserved

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Table 1. Staging systems for chronic lymphocytic leukaemia. Stage Rai system 0 I

II HI IV Binet system A

B C

Clinical characteristics

Median survival (years)

Lymphocytosis only Lymphocytosis with lymphadenopathy Lymphadenopathy + splenomegaly + hepatomegaly Lymphocytosis + anaemia Lymphocytosis + thrombocytopenia

> 12.5 8.5 6 1.5 1.5

Less than three involved nodes, no anaemia or thrombocytopenia Three or more involved nodes, no anaemia or thrombocytopenia Anaemia and/or thrombocytopenia

2>10 5 2

progress to a more advanced stage, but more deaths were observed in the treated group, resulting in no difference in survival between the two arms. The results of a recent update of this group (French Cooperative Group on CLL, 1988) even suggested a harmful effect of chlorambucil through selection of resistant clones or an increased incidence of epithelial neoplasias. The recommended strategy is therefore to restrict chemotherapy to patients with bone marrow failure (i.e. patients in Rai stages III and IV or Binet C), or disease-related morbidity, such as infections, haemorrhage or problems arising from lymphadenopathy or hepatosplenomegaly. Treatment in the earlier stages is also justified under the following circumstances: lymphocyte doubling time of less than 10 months, autoimmune haemolytic anaemia or thrombocytopenia poorly responsive to glucocorticoid therapy, progressive splenomegaly and lymphadenopathy, or disease-related symptoms such as weight loss of >--10%, extreme fatigue, fever or night sweats (Theml and Ziegler-Heitbrock, 1984; Cheson et al, 1988). Chemotherapy of B-CLL

The most widely used agent is chlorambucil, which can be administered as daily dose of 0.1-0.2 mg/kg (Ezdinli and Stutzman, 1965; Han et al, 1973). The dosage is reduced by 50% when lymphocyte counts are reduced by 50%. Responses can be expected after 2-3 weeks and maximal effect after 8 weeks. Intermittent therapy with chlorambucil may be preferable since similar response rates could be achieved with less toxicity; chlorambucil is given initially at 0.4 mg/kg at biweekly intervals and the dosag e is increased by 0.1 mg/kg until response is achieved or bone marrow toxicity occurs (Sawitsky et al, 1977). Response rates associated with these chlorambucil regimens are approximately 70%, although complete remission (CR) is achieved in less than 10% of patients. Cyclophosphamide is an acceptable alternative and may occasionally be active in chlorambucil failures. Glucocorticoids alone may

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also induce responses in B-CLL and are of particular value in controlling the autoimmune haemolytic anaemia or thrombocytopenia associated with this disease (Ezdinli et al, 1969). However, the response rate associated with glucocorticoids is lower than with alkylating agents and they should not be used as a single agent as primary therapy. The combination of chlorambucil and prednisone seems to result in a response r~ate superior to either agent alone (Han et al, 1973; Knospe et ai, 1974; Sawitsky et al, 1977). However, randomized trials have not been of adequate size to provide a definite answer (Han et al, 1973). The CVP or COP regimen (cyclophosphamide, vincristine and prednisone) has been used extensively as primary or salvage therapy. This regimen induced CR in 40% of patients and partial remission (PR) in a further 28% (Liepman and Votaw, 1978). However, several randomized trials have failed to demonstrate an advantage of this regimen over chlorambucil and prednisone or chlorambucil alone (Montserrat et al, 1985; Bennett et al, 1987; French Cooperative Group on CLL, 1988). The Eastern Cooperative Oncology Group (ECOG) compared chlorambucil plus prednisone with CVP (cyclophosphamide 300 mg/m2 daily by mouth for 5 days, vincristine 1.4mg/m z i.v. on day 1, and prednisone 100mg/m 2 by mouth daily for 5 days) as primary treatment. Response rates were identical for both regimens, with 25% achieving CR and an additional 52% PR. There was also no difference in survival between the two groups. However, five of six toxic deaths, and eight of the ten grade 4 haematological toxicities were on the CVP arm (Bennett et al, 1987). A similar trial was conducted by a Spanish Cooperative Group in 96 patients with Binet stage C disease. A significantly higher overall response rate (59 versus 31%) was observed in the CVP group, but overall survival and CR rates were similar (Montserrat et al, 1985). In the French Cooperative Trial on CLL (1988) 289 patients with stage B disease were randomized to receive either daily chlorambucil (0.1 mg/kg) or 12 cycles of CVP (i.e. cyclophosphamide 300 mg/m2 daily by mouth on days 1 to 5, vincristine 1.0 mg/m2 i.v. on day 1, and prednisone 40mg/m 2 daily by mouth on days 1 to 5, repeated monthly for the first 6 months). Overall survival was the same in the two groups ( P = 0.88). The survival rates were 71% at 3 years and the median survival was 57 months. The possibility that stage B patients may not require systemic therapy was unfortunately not tested. Hence, chlorambucil with or without prednisone remains the standard treatment in most centres. Quite a number of more intensive regimens have also been explored. By using the M2 protocol (cyclophosphamide, BCNU [carmustine], vincristine, melphalan and prednisone), Kempin et al (1982) achieved a CR rate of 17% and a PR rate of 44% in 63 patients. The median survival was 47, 20 and 19 months for Rai stages II, III and IV, respectively. Thus no advantage over less toxic regimens could be demonstrated. The addition of doxorubicin to CVP has not produced convincing results. The POACH regimen (prednisone, vincristine [Oncovin], cytarabine [ara-C], cyclophosphamide and doxorubicin) yielded a CR rate of 21% and an overall response rate of 50% for 34 previously untreated patients (Keating et al, 1988a). Hence, response and survival rate were not different

200

A.D.

uo

from those reported for chlorambucil and prednisone alone. In the French Cooperative Study on CLL (1986), stage C patients were randomized to receive either CVP or CHOP, which contains doxorubicin 25 mg/m 2 i.v. on day 1 of each cycle in addition to CVP. In the first interim analysis (French Cooperative Study on CLL, 1986), a statistically significant overall survival advantage was observed for the doxorubicin group. A recent update of 70 patients after a mean follow-up of 58 months confirmed that the overall survival was significantly improved in the CHOP group (French Cooperative Study on CLL, 1989). The 3-year survival rates were 71% in the CHOP group and 28% in the CVP group, and the median survival durations were 62 and 22 months, respectively. However, the dose intensity of CVP used in this trial is moderate and the median survival of 22 months in the CVP group appeared to be lower than in other trials. In the ECOG study, for example, CVP was applied every 21 days (with higher doses of prednisone--100 mg/m 2 instead of 40 mg/m 2) to patients in Rai stages III and IV, and a survival curve comparable to the CHOP group in the French study was achieved (Bennett et al, 1987). Jaksic and Brugiatelli (1988) have compared high-dose continuous chlorambucil with intermittent chlorambucil plus prednisone. They introduced the concept of total turnout mass ('I~M), which was based upon scoring for the size of major tumour mass compartments in bone marrow and peripheral blood, lymph nodes and spleen. In the arm for high-dose chlorambucil (regimen A), the drug was administered at I5 mg daily for 6 months, or until remission or toxicity occurred. Prednisone was added for patients with persistent adenopathy or splenomegaly but with a drop in blood lymphocytosis to levels below 5.0/nl. In the other arm (regimen B), chlorambucil was given at 75 mg once every 4 weeks and prednisone 50 mg daily for 2 weeks, then 25 mg for a further 2 weeks and 15 mg for the next 2 weeks. A CR rate of 91 out of 129 patients (70%) was reported for regimen A, whereas only 16 out of 52 patients (31%) treated with regimen B achieved CR. The survival probability also seemed to be superior for regimen A. However, the majority of patients were in early stages (69 in Binet stage A and 73 in stage B) and no differences in response and survival could be demonstrated in stage C patients. Definitions of responses are different from the other studies and confirmation from other study groups is clearly needed. The impact of consolidation or maintenance therapy on survival after initial response has also not been defined. The Southeastern Cancer Study Group has compared maintenance with cyclophosphamide and cytarabine to additional chlorambucil and prednisone after primary response and found no difference in survival (Keller et al, 1986). In the recent ECOG study, patients treated for 9 months had a shorter median survival (2.62 years) than those treated for 18 months (4.15 years), suggesting an adyantage for maintenance treatment (Bennett et al, 1987). Biological agents such as interferon-a, monoclonal antibodies or interleukin-2 have thus far not produced any results which would suggest an advantage over conventional chemotherapy (Foon et al, 1985; O'Connell et al, 1986; Rozman et al, 1988).

201

CHEMOTHERAPY OF HAEMATOLOG1CALMALIGNANCIES

NH2

OH

N

NH2 N

PH204--CHOH 0 l

OH

OH

OH

Fludarabine

Pentostatin (deoxycoformycin)

2'-Chlorodeoxyadenosine

Figure 1. Three new agents for the treatment of chronic lymphoid malignancies, all purine analogues.

New promising agents Recently three agents, all purine analogues, have shown major activity in .B-CLL (Figure 1). Pentostatin

Pentostatin (deoxycoformycin) is a structural analogue of adenosine and a potent inhibitor of the purine degradative enzyme adenosine deaminase (ADA). Hereditary deficiency of this enzyme is associated with severe combined immunodeficiency (SCID) and lymphopenia, whereas other organ systems function normally (Giblett et al, 1972). This observation has provided evidence for the specific role of A D A in lymphocytes and has led to the use of pharmacological inhibition of A D A as a therapeutic tool against lymphoid cells (O'Dwyer et al, 1988). In a group of 28 patients with pretreated B-CLL or diffuse welldifferentiated lymphocytic lymphoma, Grever et al (1985) reported that one CR, four PRs and four clinical improvements (CIs) were achieved with pentostatin. The drug was given at a dosage of 4 mg/m z weekly in nine patients and biweekly in the other 18. Except for infectious episodes, other toxicities were mild. Among 39 patients with B-CLL pretreated maximally with one regimen, Dillman et al (1989) recently showed that a response rate (CR + PR) of 26% could be attained. In this study pentostatin was administered at 4 mg/m z daily once a week for the first 3 weeks, then once every 2 weeks for a maximum of six months. The side-effects were relatively severe. Fatal infections were recorded in 5% of patients and life-threatening or severe infections in another 29%. Moreover, the rates of drug-related thrombocytopenia and anaemia were reported to be fairly high (54% and 43%, respectively). In a phase II trial of the European Organization for Research and Treatment of Cancer (EORTC), pentostatin was used to treat 26 patients with advanced (all in stage III and IV) B-CLL resistant to one to three

202

A.D. ttO

conventional regimens (Ho et al, 1990b). An overall response rate of 46% was achieved, with seven out of 26 (27%) patients demonstrating PR and five (19%) experiencing CI. The median duration of PR until relapse or death was 210 days. The median survival of PR patients was not yet reached at 500 days and that for CI patients was 465 days, compared with a median survival of 210 days for non-responders. Myelosuppression was minor and transient in responsive patients, indicating some degree of lymphocyte selectivity. Thus, according to our experience, pentostatin is highly active as salvage therapy in B-CLL, and the frequency of severe infection (16%) with pentostatin treatment did not seem to be high compared with other clinical trials involving patients with advanced and pretreated B-CLL. Due to the limited supply of this drug, experience in B-CLL has otherwise not been extensive. Once pentostatin becomes available, its efficacy should be tested as primary therapy, either alone or in combination, or in less pretreated patients.

Fludarabhte Fludarabine is a fuorinated analogue of adenine that is relatively resistant to deamination by ADA. This agent has demonstrated reproducible activity in previously treated CLL patients. Grever et al (1986) were the first to show that nine (35%) out of 26 patients with pretreated B-CLL responded to fludarabine. Fludarabine was administered at a daily dose of 20 mg/m 2 for 5 consecutive days at 4-week intervals. In a larger series, Keating et al (1989) reported nine (13%) CRs and 30 (44%) PRs among 68 patients with B-CLL, using the same 5-day schedule but with a daily dose of 25-30 mg/m a given every 3-4 weeks. Seventeen (43%) of the 40 Rai stage I-III and four (19%) of the Rai stage IV patients returned to Rai stage 0. The response to fludarabine was rapid, with 36 (92%) of the 39 responders achieving PR following the first three courses. The number of prior treatments and the time from initial diagnosis to the start of fludarabine therapy were not significantly associated with response or survival. Toxicity was mild. Major infections occurred in 9% of evaluable courses and minor episodes in another 12%. Myelosuppression and infection were more common in patients with initial Rai stages III and IV and in non-responsive patients. Grever et al (1988) have recently updated their experience with ftudarabl~ne and reported one CR, three PRs and 15 CIs among 32 evaluable patients. Thus fludarabine has an unequivocal activity in previously treated B-CLL. Considering the low CR rates and poor response rates in patients pretreated with conventional regimens, this agent seems to be promising.

2'-Chlorodeoxyadenosine 2'-Chlorodeoxyadenosine (CdA) is a substrate analogue resistant to the action of A D A but is not by itself an enzyme inhibitor of ADA. Piro et al (1988) treated 18 patients with advanced B-CLL resistant to conventional treatment with CdA administered at a dosage of 0.05-0.2 mg/kg' daily as a continuous infusion for 7 days. Patients were given between two and four

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203

Table 2. Results of therapy with pentostatin, fludarabine and 2'-chlorodeoxyadenosine for patients with B-CLL. Response Reference

Dose and schedule

n

CR

PR

CI

4 mg/m2 weekly or every 2 weeks 4 mg/m2 weekly • 3, then every 2 weeks 4mg/m2 weekly • 3, then every 2 weeks • 3, then monthly

28 39 26

1 1 0

4 9 7

4 11 5

32 68 19

1 9 6

3 30 8

15 NA NA

18

0

4

6

Pentostatin

Grever et al, 1985 Dillmann et al,"1989 Ho et al, 1990b Fludarabine Grever et al, 1988

20 mg/m2 daily • 5, every month Keating et al, 1989 25-30 mg/m2 daily x 5, every month Keating et al, 1988b* 30 mg/m2 daily • 5, every month 2'-Chlorodeoxyadenosine

Piro et al, 1 9 8 8

0.05-0.15 mg/kg daily x 7, every month

n = numbers of evaluable patients; NA = not applicable. * Patients without previous treatment. courses. An overall response rate of 55% was achieved, with four patients " d e m o n s t r a t i n g PR and six patients CI. Only minor myelosuppression occurred during treatment, indicating a high degree of lymphocyte selectivity. Duration of responses ranged from 2 to 15 months without maintenance therapy. Thus three new agents with mechanisms of action involving the purine degradative enzyme A D A have been shown to be active in B - C L L (Table 2). Responses can be achieved even if the disease is refractory to other cytostatic drugs. Some degree of lymphocyte selectivity seems to be associated with pentostatin and CdA. Although pentostatin has been associated with immunosuppression and with a high frequency of infections in some studies ( O ' D w y e r et al, 1986; U r b a et al, 1989), other authors could not confirm the clinical relevance of such adverse effects ( G r e v e r et al, 1985; H o et al, 1990c). With fludarabine, a relatively high C R rate was achieved in previously treated patients. It is now being evaluated in untreated patients. Lacking c o m p a r a t i v e trials, the relative merits of these three new agents are unknown. The roles of these drugs in the overall concept of treatment of B - C L L also need to be defined and demonstrated by further trials.

B CELL PROLYMPHOCYTIC LEUKAEMIA Prolymphocytic leukaemia (PLL) is a rare chronic lymphoid malignancy characterized by a high white blood cell count (usually >__100.0/hi), massive splenomegaly without lymphadenopathy, and large lymphocytes with m o d e r a t e amounts of cytoplasm, a prominent nucleolus and strong expression of surface i m m u n o g l o b u l i n (Galton et al, 1974). The majority of patients are anaemic and thrombocytopenic, and the clinical course is m o r e aggressive than B - C L L so that few patients survive m o r e than 1 year.

204

A.D. HO

Treatment modalities used in CLL, such as chlorambucil, prednisone and CVP, have not been effective in patients with PLL (Galton et al, 1974; Catovsky et al, 1977). The benefits of splenic irradiation in combination with leukapheresis are controversial (Taylor et al, 1982), and the role of splenectomy in B cell PLL (B-PLL) is unclear. Chemotherapy with the CHOP regimen seemed to be effective in some cases, a few patients achieving a stable PR of 26-30 months (Catovsky, 1977; KOnig et al, 1979; Taylor et al, 1982). In a phase II protocol of the EORTC, pentostatin was used either as primary therapy or as salvage therapy in previously treated patients with PLL (Ho et al, 1989b). Preliminary evaluation has shown that of 17 patients, eight achieved PR, some of which were durable (unpublished results). The role of the other new agents, fludarabine and CdA, in B-PLL are being investigated and are not yet known. HAIRY CELL LEUKAEMIA The availability of a few effective agents in hairy cell leukaemia (HCL) has aroused much interest in the treatment of this rare disease. When to treat

The clinical course of some patients with HCL can be indolent and no therapy may be required at the time of diagnosis (Golomb et al, 1986b). Up to 10% of patients never require therapy. Such patients tend to be older and to have less splenomegaly and fewer circulating malignant cells. Severe pancytopenia and its consequences--infections, haemorrhage and frequent transfusion requirements--are the main symptoms and life-limiting factors in HCL. Pancytopenia is considered to be a result of the interplay between sequestration of blood in the spleen and suppression of myelopoiesis in the bone marrow. The latter may be caused by hairy cell infiltration or myelofibrosis, or a combination of both (Golomb, 1987). There is as yet no agreement between the major study groups of HCL on the indication for treatment. The following guidelines have been proposed (Catovsky et al, 1987). Treatment is not indicated if: (a) there is an absence of infections, (b) the granulocyte count is stable and is > 1.5/nl, (c) there is no transfusion requirement or significant anaemia (haemoglobin > 12 g/dl), and (d) there is no bleeding tendency (platelets of > 100.0/nl). Treatment may be required for massive splenomegaly, for spleen infarction or rupture, or for other symptoms commonly associated with HCL such as vasculitis or frequency of infections. Splenectomy

Before the introduction of interferon-~t and pentostatin in 1984, splenectomy had been the only treatment universally accepted to be effective. An improvement in one or more of the blood count components can be achieved

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205

in 90% of patients (Golomb et al, 1986b; Golomb, 1987). However, less than half of the patients show improvement in all the blood cell counts. After splenectomy, approximately 10% of the patients remain in a durable 'haematological' remission, i.e. with normal peripheral blood cell counts, although there is no reduction in hairy cell infiltration of the bone marrow. Our own investigations have shown that normalization of peripheral blood counts after s.plenectomy is associated with a normalization or reduction of soluble CD8 (suppressor) antigen concentration in serum, which might reflect a reduction in suppressor/cytotoxic cell activity (Ho et al, 1990a). After splenectomy, approximately 50% of patients eventually have disease progression and are in need of additional treatment (Golomb et al, 1986b; Ratain et al, 1988). The interval postsplenectomy until further treatment is required ranges from 1 to 120 months or more, with a median of 18.8 months (Ratain et al, 1988). No parameter has been shown to reliably predict the prognosis postsplenectomy and the need for further treatment. Spleen size alone is not a direct indicator of improvement in blood cell counts. In general, splenectomy seems to be successful in patients with enlarged spleens (>5 cm below the costal margin), cytopenia and less than 50% hairy cells in the bone marrow ..(Catovsky et al, 1987). Patients with splenomegaly and > 50% bone marrow infiltration might also benefit from the operation, but they usually require further treatment measures. Recently, Ratain et al (1988) reported that bone marrow cellularity and platelet count were the only significant independent predictors of failure-free survival. Whether the response to new treatment modulaties such as interferon-o~ and pentostatin can be positively or negatively influenced by splenectomy is still unknown or controversial (Pralle et a.l, 1987). Interferon-~

In 1984 Quesada et al first described their experiences in treating seven patients with HCL with leukocyte interferon-~ (IFN-e0. Bone marrow CR was shown in three out of seven patients and PR in the other four patients. Since then, the effectiveness of IFN-,x in HCL has been confirmed by numerous other studies (see Table 3). Different subtypes of recombinant IFN-e~ (ct-2a, tx-2b, a-2c) have been shown to be equally effective as natural IFN-et derived from leukocytes or lymphoblastoid cell lines. Similar remission rates seem to be achieved whether IFN-et is administered intramuscularly or subcutaneously, at a dosage of 2 or 3 • 106u/m 2, daily or three times a week. Dosages as low as • 105u given daily can also be effective, but with much lower response rates (Thompson et al, 1989). The remarkable results achieved with IFN-ct have virtually altered the definition of remissions in HCL. The following guidelines to assess the response to treatment in HCL have been proposed (Catovsky et al, 1987). CR is defined as: (a) regression to normal of organomegaly, (b) haemoglobin _> 12 g/dl, platelets > 100/nl, neutrophils > 1.5/nl and no circulating hairy cells in peripheral blood, and (c) no discernible hairy cells in bone

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marrow aspirate or biopsy. PR is defined as: (a) reduction of organomegaly by at least 50% of the initial values as assessed by clinical examination (measurements should be recorded in centimetres below the costal margin for spleen and liver and the largest diameter of lymph nodes and/or other tumour masses), (b) values for haemoglobin, platelets and granulocytes as for CR, (c) reduction of hairy cells in the bone marrow by at least 50%, and (d) circulating hairy cells --<5%. Minor response is defined as: (a) reduction of hairy cells in the peripheral blood by at least 50%, and (b) improvement in one or more of the peripheral blood elements: haemoglobin, neutrophils, platelets or number of hairy cells. Haematological responses to IFN-~ are rapid, with a return of platelet counts to the normal range within 2 months. The haemoglobin and neutrophil counts return more slowly, within 4 and 6 months, respectively. Splenomegaly usually regresses within a few weeks. Despite the haematological remission, hairy cell infiltrations in the bone marrow persist in the majority of patients. A few studies have shown that a gradual decrease in the hairy cell index can be achieved by continuing INF-a therapy for up to 1 year (Castaigne et al, 1986; Cheson and Martin, 1987; Ratain et al, 1987; Thompson et al, 1987). The optimal duration of IFN-a therapy in HCL remains to be defined. Current recommendations are for at least 1 year of treatment. After cessation of therapy, relapses often occur within 12 months and most patients respond again if IFN-a therapy is reinstituted. The advantage of maintenance therapy over reinduction also needs to be assessed. Pentostatin

The evaluation of pentostatin in HCL has proceeded almost simultaneously with the IFN-oc trials (Spiers et al, 1984, 1987; Cheson and Martin, 1987). Due to the limited supply of this drug, experience is considerably less extensive. Spiers et al (1984) were the first to report their experience with pentostatin in three patients with HCL, and shortly thereafter (Spiers et al, 1987) confirmed the efficacy in 37 further patients treated with 5 mg/m 2 daily for 2 days every 2 weeks. Of 27 patients evaluable for response, 16 achieved CR and 10 PR. In the meantime, these encouraging results have been confirmed by other authors and study groups (see Table 4). Responses to pentostatin seem to be extremely rapid, usually within days to weeks. According to our own experience, the median interval between the beginning of pentostatin therapy and the best response was 3.9 months, with a range from 2.0 to 7.0 months (Ho et al, 1989a). CRs can be achieved in 30% of patients pretreated with IFN-~ and up to 90% in untreated patients. Relapses after CR appear uncommon. Spiers et al (1987) had not observed any relapses after a follow-up of 7 months to 3 years. Other authors have reported anecdotal relapses after cessation of pentostatin therapy. Pentostatin has also shown activity in patients who failed to respond to IFN-c~ treatment (Foon et al, 1986). Our EORTC trial has shown that even in patients with progressive disease under IFN-cx therapy or with stable disease after adequate treatment with IFN-oL (median duration of IFN-o~

208

A.D. HO

Table 4. Results of treatment with pentostatin and 2'-chlorodeoxyadenosinein patients with HCL. Response Reference Pentostatin Spiers et al, 1987

Dose and schedule

Treatment duration

5 mg/m2 • 2 days every UntilCR 2 weeks Kraut et al, 1986 4 mg/m2 every 2 weeks Until CR Johnston et al, 1988 4mg/m2/weekx 3 Until CR, then every 8 weeks 2 more cycles Grem et al, 1989 Variable* Variable Ho et al, 1989a 4mg/m2/weekx 3, then 6-9 months every 2 weeks x 3, then monthly 2'-Chlorodeoxyadenosine Piro et al, 1990 0.1 mg/kg/day x 7 One course continuous infusion

n

CR

PR

MR

27

16

10

0

18 28

15 25

1 3

0 0

66 33

37 11

15 15

10 4

12

11

1

0

n = number of evaluable patients; MR = minor response. * Results in patients treated with pentostatin under the Special Exception mechanism of the Division of Cancer Treatment, NCI. The dosage and duration of treatment were variable. therapy was 14.7 months), a C R rate of 33% and an overall response rate of 78% can be achieved (Ho et al, 1989a). The rapidity of responses, the high frequency of CR and the apparently durable remissions without maintenance seem to be the advantages of pentostatin over IFN-et therapy. In addition, a treatment period of 3 to 6 months is sufficient to achieve CR, instead of the 12 months or more required with IFN-ot therapy. Nevertheless, the side-effects of pentostatin treatment may be more severe than with IFN-et. A high frequency of severe infections upon treatment with pentostatin was reported in a retrospective study of 300 patients with diverse lymphoproliferative diseases, and two thirds of these infections were fatal ( O ' D w y e r et al, 1986). However, the dosages administered in these patients were much higher than those currently used for H C L and none of the patients in this report had HCL. According to our experience, the rate of severe (9.1%) infections with pentostatin was not different from that in patients with comparable advanced disease treated with IFN-et. Severe infections, if present, seem to occur within the first four weeks of treatment, and are probably dependent on the performance status of the patient. Pentostatin may cause initial myelotoxicity in some patients, but neutropenia usually resolves rapidly in those who respond. Pentostatin has also been reported to cause impairment of helper lymphocytes ( C D 4 + ) and of the proliferative response to phytohaemagglutinin (Urba et al, 1989). We have evaluated the immunological parzlmeters in our patients at follow-up periods of 10 to 27 months after the last administration of pentostatin (Ho et al, 1990c). Although we could confirm a persistent reduction in C D 4 + cells and proliferative response to phytohaemagglutinin, the capacity to produce cytokines was not impaired and no increased

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frequency of infections was observed at long-term follow-up. Pentostatin is also frequently associated with nausea and vomiting, skin rash and conjunctivitis. Central nervous system toxicity, lethargy and renal toxicity, common at high doses, are rare at current dose ranges. CdA CdA is anotl~er purine analogue that may be promising in the treatment of HCL. Piro et al (1990) recently reported their experience in 12 patients, five of whom were pretreated with IFN-a. Patients received CdA 0.1 mg/kg daily by continuous infusion for 7 days. All 12 patients responded to one single course and 11 of them achieved a pathological CR lasting for 4 to 43 months. Transient fever of 3 to 10 days' duration was observed in seven of the 12 patients and myelotoxicity in six patients. Thus, in addition to IFN-a, pentostatin and CdA are also highly active against HCL. Numerous trials are being conducted to define the roles of these drugs relative to each other and to splenectomy. Although experience with pentostatin is less extensive than with IFN-a and the drug is not widely available, the preliminary response rates of 80 to 95% with CRs of 30 to 90% and the durability of responses render this drug a prominent place in the "overall strategy of treatment of HCL. Large phase III trials are underway to investigate the relative efficacy and toxicity of these two agents, as well as their effect on the quality of life and survival. Experience with CdA in HCL has thus far been reported from one single institution. However, the fact that this disease could be cured with one 7-day course of chemotherapy is intriguing. Additional studies with this interesting .new agent are certainly warranted. T CELL CHRONIC LEUKAEMIA The T cell variants of chronic lymphocytic leukaemia (T-CLL), prolymphocytic leukaemia and hairy cell leukaemia are rare, and their pathomorphological features have been described in detail recently (Bennett et ai, 1989). T-CLL accounts for about 5% of cases of chronic lymphocytic leukaemia (CLL) in the Western World. Other than an increased frequency of skin involvement, its symptoms and clinical course are similar to B-CLL. About 20% of patients with the morphological features of PLL have a T cell variant (T-PLL). Like B-PLL, the white blood cell count is usually high (> 100/nl) at presentation, but there are usually also lymphadenopathy, skin lesions and serous effusions. The course is usually aggressive. Adult T cell leukaemia/lymphoma (ATCL) is another aggressive disease characterized by high leukocyte counts, hepatosplenomegaly, lymphadenopathy, skin lesions, hypercalcaemia and bone lesions (Bunn et al, 1983). Most cases have been found in south-western Japan, the Caribbean region, the south-eastern United States and in Caribbean immigrants who reside in other countries. This disease has been associated with the human type C retrovirus HTLV-1.

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The treatment of these mature T cell leukaemias has been disappointing. Chemotherapy regimens effective in B-CLL may produce temporary improvement, but no data are available on whether chemotherapy prolongs survival or improves life quality. For ATCL, intensive combination therapy using the CHOP regimen showed a temporary effect (Bunn et al, 1983). A few reports have shown that some patients with T-PLL or ATCL may respond to pentostatin (Daenen et al, 1984; El'Agnaf et al, 1986). Dearden et'al (1987) recently reported their experience with pentostatin in mature T cell malignancies. Pentostatin was given in a dosage of 4 mg/m a i.v. weekly or twice weekly with a range of two to 20 injections and was stopped when CR or best response was achieved. Two out of eight patients with T-PLL, one of two with T-CLL, one out of four with ATCL and one of three with S6zary syndrome achieved CR. Responses were observed only in patients with the C D 4 + , C D 8 - phenotype. In contrast, our own experience showed that patients with CD8+ or CD4+,CDS+ phenotypes also responded to pentostatin (Ho et al, 1988). Nevertheless, pentostatin seems to be promising in T-PLL and ATCL, and further trials on a larger number of patients are required to provide a definite answer. The roles of the other new agents such as fludarabine and CdA have yet to be evaluated, although the latter has already been shown to be active in T cell cutaneous lymphoma (Saven et al, 1989).

CHRONIC MYELOID LEUKAEMIA Chronic myeloid leukaemia (CML) is a clonal disorder in which the malignant pluripotent stem cell gives rise not only to neutrophils, but also to red cells, eosinophils, basophils, monocyte/macrophages, platelets and probably B cells. Three stages of the disease are recognized: a chronic phase, an accelerated phase and a blast crisis phase.

Management of the chronic phase The treatment of CML has traditionally been palliative in intent. During the chronic phase, the growth of the malignant cells can be suppressed by a number of alkylating agents or antimetabolites. The two most commonly, used drugs are busulphan and hydroxyurea (Haut et al, 1961; Kennedy, 1972). Busulphan affects primitive stem cells and has a prolonged duration of effect. It is not known whether busulphan therapy is more effective if administered continuously throughout the chronic phase or intermittently when the leukocyte count rises to some arbitrary level. There is also no evidence that treatment administered to symptomless patients whose disease has been diagnosed by chance is beneficial (Champlin and Golde, 1985). At dosages of 4 to 6 mg/day it is primarily very effective in controlling the leukocytosis within 2-4 weeks. The administration of single large doses of busulphan at intervals of several weeks is as effective as conventional treatment, but no advantage is evident (Sullivan et al, 1977). The efficacy of maintenance is also not known. During busulphan therapy the blood counts

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must be carefully monitored since overdosage may produce protracted or even irreversible pancytopenia. Hydroxyurea is a cell-cycle-specific antagonist of DNA synthesis and is equally effective in suppressing myelopoiesis. It is relatively short-acting, is less toxic than busulphan and is preferred by some haematologists (Bolin et al, 1982). This agent can initially be given in a daily oral dosage of 20--30 mg/kg.and the dose can be adjusted according to the effect on blood counts and organ size. An on-going randomized trial of the German Cooperative Group is comparing the relative merits of busulphan, hydroxyurea and INF-a as primary therapy in CML (Hehlmann et al, 1988a). Since 1985, 326 patients have been randomized: 150 each for busulphan and hydroxyurea and 26 for INF-a. At present, no significant difference in survival can be observed between the busulphan and the hydroxyurea group. Other alkylating agents and phosphorus-32 are also effective in suppressing leukocytosis in CML, but have not shown any advantage over busulphan or hydroxyurea (Champlin and Golde, 1985; Hehlmann et al, 1988a). All these agents suppress the growth of the malignant clone but cannot eradicate the disease. Despite achievement of normal blood counts, predominantly Philadelphia (Ph ~) chromosome positive cells persist in the bone marrow. Chemotherapy does relieve the symptoms of the disease, but there is no evidence that treatment delays the development of blast crisis or prolongs survival. A number of investigators have evaluated the effect of intensive combination chemotherapy as applied in acute myeloid leukaemia, with the aim of erhdicating the Phi-positive cells (Smalley et al, 1977; Hester et al, 1984; Ciarkson, 1985). Although this could be achieved with cytarabine, daunorubicin and cyclophosphamide based regimens in a few patients, it was short-lived and associated with severe myelosuppressive toxicity. There is no evidence that the duration of the chronic phase is prolonged or that survival is improved. Since blastic transformation may originate in the spleen, elective splenectomy has also been proposed as a treatment for CML. Unfortunately, several large controlled trials have failed to show any evidence that splenectomy prolongs the chronic phase (Ihde et al, 1976; Medical Research Council Working Party for Therapeutic Trials in Leukaemia, 1983; Italian Cooperative Study Group on CML, 1984). IFN-et has been extensively evaluated for the treatment of CML in recent years. Thus far, human recombinant IFN-c~ has produced a clinical response in 70-80% of patients and in 50-60% a suppression, usually partial, of the 9PhLpositive cells could be attained (Talpaz et al, 1983, 1986). The response rate appears to be higher in patients with recently (less than I year) diagnosed CMLthan those with a longer history. Cytogeneticimprovements are seldom in patients whose disease has been diagnosed for more than 1 year. The efficacy of IFN-ot seems to depend on the dosage. Higher response rates are achieved with doses of 5 x 106u/m z every other day than with 2 • 106u/m 2 every other day (Morra et al, 1987). Dosages of 5 • 10 6 u / m 2 daily given intramuscularly apparently have produced a higher rate of CR compared

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with lower dosages (Talpaz et al, 1986; Alimena et al, 1989). Treatment with IFN-a is associated with flu-like illness (fever, chills, myalgia, headache and fatigue). With repeated administration, tachyphylaxis to fever usually occurs, but fatigue and anorexia increase with dosage and duration of treatment. Other minor side-effects include myelosuppression, elevated liver enzymes, paraesthesias, anosmia, confusion, somnolence and impotence. The effect of IFN-~t on overall survival is uhknown. In view of the encouraging results with IFN-o~, hydroxyurea has been combined with IFN
Patients who progress to the accelerated and acute phases of CML have an extremely poor prognosis. The dosage of hydroxyurea may be increased or bolus therapy with busulphan may be tried when CML enters an accelerated phase, but the response is usually unsatisfactory (Champlin and Golde, 1985). Allogeneic bone marrow transplantation in the accelerated phase is less effective, but may still produce remissions and long-term survival in 15-20% of patients who are eligible (Goldman et al, 1988; Thomas and Clift, 1989). Patients in myeloid blast crisis respond poorly to treatment: less than 30% achieve remission with intensive chemotherapy, and these remissions are generally very brief. Different aggressive regimens, such as high-dose cytarabine and mitoxantrone (Kantarjian et al, 1988) or plicamycin plus hydroxyurea (Koller and Miller, 1986), have been reported to achieve exciting results in small numbers of patients. Similar to many other previously reported regimens (Spiers et al, 1977; Iacoboni et al, 1986), these early results could not be confirmed by other groups. Approximately 60% of patients who develop lymphoid blast crisis achieve remission after treatment with vincristine and prednisone (Canellos et al, 1971; Marks et al, 1978). Unfortunately, the median duration of remissionts only 4-6 months and <20% survive for I year (Champlin and Golde, 1985). Despite all the efforts to find a better treatment for CML, the results have been disappointing. For 40 years, the median duration of survival has remained at 3-4 years. There was good reason to attempt very high dose 'myeloablative' chemoradiotherapy followed by bone marrow transplantation to restore haemopoiesis (Thomas and CIift, 1989). Some authors have used cryopreserved autologous peripheral blood or bone marrow ceils collected during the chronic phase and have reinfused the autologous cells in patients who progressed to the acute phase (Goldman et al, 1978). The objective of this approach is to restore the chronic phase. Although most patients achieved a second chronic phase, they usually relapsed within 4 months and < 20% survived for 1 year. This approach was of marginal benefit.

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Encouraging results have been obtained with high-dose chemoradiotherapy followed by allogeneic or synergeneic bone marrow transplantation (Thomas and Clift, 1989). The best results have been achieved in patients treated while in the chronic phase. The disease-free survival among patients followed for 7 to 12 years is almost 65%. Therefore, for patients younger than 50 years with CML who have an HLA-identical sibling donor, bone marrow transplantation offers the best prospect for long-term survival. IDIOPATHIC MYELOFIBROSIS (AGNOGENIC MYELOID METAPLASIA) Idiopathic myelofibrosis (IMF) is characterized clinically by a massively enlarged spleen, a leukoerythroblastic peripheral smear showing 'tear drop' erythrocytes, nucleated red cells, giant platelets and immature myeloid cells. Bone marrow cannot be aspirated and a marrow biopsy shows fibrosis. There is no causal therapy for this disorder and management must be directed toward specific clinical problems. Prognosis is not determined by 9 the number of immature myeloid cells in the peripheral blood, the size of the liver or spleen, or the degree of marrow cellularity or fibrosis (Manoharan, 1988). If the patient has symptoms related to the splenomegaly, therapy with busulphan 2--4mg daily may reduce the size of the spleen or liver. Hydroxyurea given at a dosage of 20-30 mg/kg daily may achieve the same effect. However, such treatment usually causes a deterioration in the anaemia, neutropenia and thrombocytopenia. Small doses of local irradiation, e.g. a total of 200-500 cGy, can also reduce the spleen size and relieve symptoms. However, irradiation will also cause significant pancytopenia and its effects are only short-lived. Splenectomy can also be performed, but it is associated with a high mortality in patients with IMF (between 11 and 28%) (Benbassat et al, 1979; Silverstein, 1984). Prophylactic splenectomy has not been shown to be effective in improving survival (Mulder et al, 1977). Other symptoms such as unexplained fever, weight loss or night sweats may respond to busulphan or hydroxyurea in the dosages given above. Haemorrhage associated with thrombocytopenia or excessive thrombocythaemia can be a problem in patients with myeloproliferative diseases. It can be treated symptomatically by platelet transfusions. Thromboembolic complications are more difficult to manage (see below). IMF may enter an aggressive phase in 10-25% of patients, similar to the 16last crisis in CML (Ward and Block, 1971); treatment of this aggressive phase is equally unsatisfactory. ESSENTIAL THROMBOCYTHAEMIA Essential thrombocythaemia is a chronic myeloproliferative disorder in which the number of colony-forming units for megakaryocytes in the

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marrow is elevated. Clinically it is characterized by episodes of acromelalgia, palmo-plantar burns, headaches, flushes, and by frequent bruising. Recurrent haemorrhages or thrombo-embolic episodes may occur, especially when there is an enormous increase in the number of platelets. There is evidence that such complications can be successfully treated by lowering the number of platelets (Barburi et al, 1983; Case, 1984; Hehlmann et al, 1988b). Marked increase in symptoms seems to occur if the platelet count exceeds 650/ni (LaHuerta-Palacios et al, 1988). Although there is no evidence that controlling the platelet count may prolong survival, reduction of platelet numbers is associated with the relief of symptoms. Four treatment modalities are available to reduce platelet counts: (a) plateletapheresis, (b) administration of radioactive phosphorus, (c) cytotoxic therapy with alkylating agents, and (d) biological therapy with IFN-et. Plateletapheresis is an effective, but expensive and invasive procedure which is suitable only for acute and short-term treatment. Radioactive phosphorus administration is associated with a high risk of carcinogenesis and leukaemogenesis (Berk et al, 1981). A number of cytotoxic agents such as busulphan or hydroxyurea can lower the platelet counts (Case, 1984; Kaplan et al, 1986). These drugs are myelosuppressive and their use requires careful monitoring of the blood counts. IFN-a given in dosages similar to that used for CML has been reported to be effective in controlling thrombocytosis (Gisslinger et al, 1989; Lazzarino et al, 1989; Talpaz et al, 1989). However, this agent is also associated with toxicity and has to be administered continually to maintain the response. No long-term advantage for IFN-a over conventional cytotoxic agents is evident yet.

Anagrelide Anagrelide, originally developed as an antiaggregating agent, has recently been shown to suppress platelet numbers selectively. The reduction in platelet number occurs at doses below those required for inhibition of aggregation. Silverstein et al (1988) evaluated this agent in the treatment of thrombocytosis. Induction doses of 1-1.5mg given orally every 6 hours produced a rapid decrease in the platelet counts within 5 to 12 days and side-effects were minimal. The platelet count was reduced successfully in'15 out of 17 patients with essential thrombocythaemia, two patients with polycythaemia vera and one patient with CML. Recently, Silverstein and Petitt (1989) have extended this study and reported their experience in 119 patients. A response was achieved in 114 out of 119 patients, with return of platelet counts to normal or near normal. The most frequent side-effects were headache, nausea, palpitations or forceful pulse, fluid retention and severe diarrhoea. Only One of the 119 patients was removed from study because of life-threatening toxicity. No significant changes were observed in haemoglobin levels, white blood cell counts or coagulation parameters. Our own preliminary experience with anagrelide has also shown a rapid response in all patients. Pending further confirmation, anagrelide may eventually turn out to be the treatment of

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choice in thrombocytosis associated with myeloproliferative diseases. However, the relative merits of these new agents: anagrelide and IFN-t2 remain to be evaluated in the next few years. SUMMARY After years of stagnation in the treatment of chronic haematological malignancies, some interesting agents have emerged which might improve the prognosis of these diseases. For chronic leukaemias of lymphoid lineage, three new chemical agents, all purine analogues, seem to be of particular interest. Pentostatin is a specific inhibitor of ADA and has been shown to be highly efficient in producing CR in patients with HCL. Its relative merit compared with IFN-ot for the treatment of HCL is being studied in ongoing randomized trials. Pentostatin is also active in B-CLL and promising activities have been demonstrated in T- or B-PLL and ATCL. Fludarabine is an analogue of adenine which is resistant to the deamination of ADA. It has been reported to be highly active for patients with both pretreated or non-treated B-CLL. CR rates of 13% with overall response rates of 57% can be achieved, even in heavily pretreated patients. Its activity in the other i~,mphoid malignancies is not yet known. CdA, a substrate analogue of ADA, has also produced encouraging results in B-CLL, HCL and T cell malignancies, and in some patients with just one single course. Thus far, experience with this drug comes from one institution and requires further confirmation. For chronic myeloproliferative diseases, little progress has yet been made. Although IFN-ct seems to be active in CML and to result in cyto'genetic remissions in bone marrow, a definite advantage of this biological agent over conventional chemotherapy as regards survival and life quality has not yet been proven. Allogeneic bone marrow transplantation is beneficial for those patients who are eligible. No remarkable advances have been made in the treatment of myeloproliferative disorders except for the development of an antiplatelet drug, anagrelide. This agent seems to be highly effective in controlling thrombocytosis. The relative merit of this agent as compared with IFN-et, as well as the impact of this agent on the survival and on life-quality of patients with myeloproliferative disorders, have yet to be defined.

Acknowledgements The excellent assistance of Mrs Cornelia Schuster in preparing the manuscript is acknowledged.

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