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Therapy PerspectiveS™ For Rational Drug Use and Disease Management JULY 8,1996

VOLUME 8, NO.1 ISSN 1172-0360

CONTENTS New drugs and therapeutics 1

Tretinoin improves the prognosis of acute promyelocytic leukaemia

5

Nonspecific immunosuppressive therapies still the mainstay forSLE

9

Long-term drug therapy can often be continued in patients undergoing surgery

Drug economics and quality of life 14 The earlier and more widespread use of ACE inhibitors in CHF is likely to be cost effective

Addendum 13 Addendum: results of the

Digitalis Investigation Group (DIG) study

Tretinoin improves the prognosis of acute promyelocytic leukaemia Regimens involving induction of remission with tretinoin and consolidation with further antineoplastic therapy have improved the prognosis of pati nts with acute promyelocytic leukaemia. Tr tinoin is effective in indUCing remis ion in patients with acute promyelocytic leuka rnia who have the t(15;17) chromoomal tran 1 cati n. By inducing terminal differentiation of promyelocytic leukaemic cells, tretinoin i able to induce clinical remi sion without cau ing bone marrow suppression. However, the rate of clinical relapse is high if suitable consolidation therapy i not gi en. Resistance to tretinoin is acquired rapidly and almo t universally with prolonged daily treatment, and the drug has no role as consolidation or maintenance therapy. Unlike standard chemotherapy regimens, tretinoin does not exacerbate coagulopathy. However, tretinoin may cause a retinoic acid syndrome in up to 25% of patients, and this can be fatal if untreated. Acute promyelocytic leukaemia (APL) is caused by failure of promyelocytes to differentiate into mature granulocytes. It is often associated with a severe haemorrhagic diathesis.[1] The retinoid tretinoin t (all-trans-retinoic acid) promotes terminal differentiation in leukaemic promyelocytes, leading to morphological and functional maturation of these cells, without causing bone marrow suppression)!]

Why tretinoin works in APL

·

a~a~IS INTERNATIONAL

APL is uniquely sensitive and responsive to tretinoin, whereas other leukaemias are much less responsive to this agent. This is largely related to the presence of a characteristic chromosomal t( 15; 17) translocation that involves the retinoic acid receptor-a (RAR-a) gene and the promyelocytic leukaemia (PML) gene. The resultant PMURAR-a fusion protein appears t Tretinoin is not available as an oral formulation in Denmark, France or Germany; it is not approved for the treatment of acute promyelocytic leukaemia in Spain.

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Drugs & Therapy Perspectives Editor: C. Rhoda Lee ociate Editor: Rachel Webber-Foster Editorial Secretary: Carol Milligan Group Editorial Director: Rennie

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pubr hing Director, Periodicals: Paul

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R earch Edito .: Tracey Langsdale (Senior Editor); Pauline Curel: Tracey Hale: Gill I liggins: June Kau; Gillian Keating: Tamara. chwar/: There~a zelo; arlene Todd ditors, Iinical Pharma ology and Tb rapeuti ' : arnh &1m nds (Senior &lilOr); Alan . Beedle; laire L. Berkahn: lephen G. Coleman; Richard rampton: Katharine J. Palm r: Rosie lather Editors, Drug E aluatio : Donna McTavish (Sellior Editor): Julia A. Balti ur; Paul Benfield; Rex . Brogden; Harriel M. Bryson: Allan Coukcll; Rick Davi. : Christopher J. Dunn: Diana Faulds; Jane C. Oilh~: Karen L. Ooa: Malini Haraa: Wendy Jeal: Andrew P. Lea: Anthony Markham: . !Uart Noble: anjay . Patel: Car line M. Perry: Orcg L. PI ker; Caroline M. pencer; Antona WagMatT: Michelle I. Wilde; Lynda R. Wi eman

International Editorial Board . Abernethy, "~/slI",groll, D. A: • P. Iderman, Adelaide. A. Allstralia; C.D. Sa liff, Lolldofl. Ctmada. E.J. Segg, Chri.ltdrurdr. Nel>' Zealalld: T. B rgan, 0.1/0. OTway. G. Bianchi Porro. Milan. /w/y: . Drater, /fldia1lapolis. IN. USA; . 1. Breckenridge, Liverpool. UK; W.\ . Bu e, MadiwJII. WI. USA; .C. Carruthers, Halifax. Canada: G. arslens. HanOl'er, Germany: J. J.H. ritchie, HOllg Kong; R.O. Da ,Sydlley, N. ~v. AIlItralia; . Doreau, Paris. France: I.'. . Dukes. orborg. /)enmark: • Ebihara, Tochigiken. JapiJJl; L. Ereshel'k , SlIn An/onio. IX. USA: • Erill, Ban:elona. Spain; • Erush. Phi/adelphill, Ht USA; P. Fallet. Pari.l. Franu: J. Feely, Dllblin. /relafld; R.G. Finch, NOllinglram. UK; • Frio " Madrid, paill; W.H. Frishman, Bmnx. NY. USA: .T. Garner, NOfllllgham. UK; OJ. reenblatt. 80 tOil. MAo USA: R. ugler, Karlmtlre. Germany: F.D. Hart., wluloll. UK; D. . Henr., NewcQ.ltle. N AIHtralia: I. Hindmarch, Godalm;ng. UK; T. I hizaki, 1/lk),o, Japall; R . .Janknegt., ittarrl. The Netherlalld : C.L. Kearn. KClII.lm Citv. MO, USA; J. Kenyon Allck/a1ld. Nell Zeo/wlIl; .K. Lam, Hong KClIIg: M . Levy. Jerl/salelll. Israel: W.J. Loui Heidelberg. Vic. AII$lmlio: H.I. Maibach SCIII Francisco, CA. U. A: .
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VoL 8, No.1; July 8, 1996

Tretinoin alone does not totally eradicate the leukaemic clone - additional consolidation treatment with alternative antineoplastic agents is needed to eliminate remaining disease

Pharmacokinetics of tretinoin

Presid nl and Pubr her: Ora me . Avery

ee back cover ror ub cription detai

to playa pivotal role in the pathogenesis of APL, probably by blocking retinoic acid-mediated myeloid differentiationJl] Tretinoin progressively reduces the occurrence of the t(lS; 17) chromosomal translocation in cells from patients with APL; the small percentage of patients who have variant chromosomal abnormalities do not respond well to the drug.[1] Reverse transcriptase-polymerase chain reaction (RTPCR) analysis of the level of PMURAR-a fusion mRNA can be used to both predict and monitor patients' clinical responses to tretinoin, as well as to detect residual or recurrent disease.[l]

Tretinoin is well absorbed after oral administration and plasma concentrations of tretinoin remain within the range required to differentiate leukaemic cells in vitro for approximately 4 hours after administration.[1] Orally administered tretinoin is rapidly and extensively distributed to tissues, but has not been detected in CSFJ2] This suggests that the drug is unlikely to be effective for the treatment ofleukaemic symptoms in the CNSJ I J

Pharmacokinetics linked to relapse/resistance The plasma drug concentrations and area under the curve (AUC) values of tretinoin tend to decrease dramatically with continuous daily use for as little as 1 weekJ2] This has been linked to the high rate of clinical relapse and rapid development of resistance to tretinoin when appropriate consolidation treatment is not givenJll Reasons for the decline in plasma concentrations have not yet been fully established, but it has been suggested that it is the result of an increase in the oxidative metabolism of tretinoin by the cytochrome p4S0 enzyme system. Other potential explanations include decreased oral bioavailability or increased levels of cellular retinoic acid binding.[l] Once plasma concentrations have declined, increasing the tretinoin dose does not appear to be particularly useful. However, some success in maintaining high plasma concentrations of tretinoin has been achieved by the concomitant use of interferon-a or a single dose of ketoconazole (a cyto-

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chrome p450 enzyme inhibitor), but there are insufficient data to justify routine use of these measures,D]

•

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Tretinoin Chemotherapy

*

Efficacy of tretinoin Although tretinoin induces complete remission in a high percentage of patients with APL, the duration of response is generally short-lived and most patients will relapse. In order to maximise response, induction of remission with tretinoin should be followed by intensive consolidation and maintenance therapy with other antineoplastics or bone marrow transplantation. It has been shown that this approach tends to prolong the period of remission compared with follow-up treatment consisting of, or containing, tretinoin. However, further evaluation to establish the best treatment combinations for induction, consolidation and maintenance therapy is needed. l1 ] In many of the clinical studies of remission induction with tretinoin described below, patients also received 2 to 4 courses of consolidation chemotherapy (e.g. an anthracycline and cytarabine) followed by maintenance therapy with thioguanine, mitoxantrone and/or methotrexate.l 1]

Induction therapy The extent of clinical testing of tretinoin has been limited by the small number of patients with APL.[1] In noncomparative trials that enrolled ~ 15 patients, the overall rates of complete remission after tretinoin treatment ranged from 64 to 100%. The duration of tretinoin therapy required to produce remission varied from 8 to 119 days. Remission rates were similar for newly diagnosed patients and those who had relapsed from, or were refractory to, standard antineoplastic therapy.[1]

Tretinoin appears to be associated with higher rates of complete remission and prolonged overall or event-free survival than conventional chemotherapy Prospective comparison with conventional therapy Remission induction therapy with tretinoin followed by intensive standard chemotherapy was associated with a reduced relapse rate and improved survival rate compared with standard chemotherapy alone in 1 randomised, multicentre study involving 101 patients with newly diagnosed APL (see figure 1))3,4] The patients in the tretinoin group received oral tretinoin 45 mg/m2/day until complete remission was achieved (maximum 90 days). Patients in both groups received 2 courses of daunorubicin (60 mg/m2/day on days 1 to 3) plus cytarabine (200 mg/m2/day on days 1

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Fig. 1. Efficacy of tretinoin vs conventional chemotherapy in newly diagnosed patients with acute promyelocytic leukaemia. [3,4] t Event was defined as failure to achieve complete remission, relapse or death in complete remission. Symbols: * p=O.Ol, ** p=0.0006, *** p= 0.0001 vs chemotherapy group.

to 7), and 1 or 2 additional courses of consolidation therapy with daunorubicin (or amsacrine) and cytarabine. In order to reduce the risk of retinoic acid syndrome (see Tolerability section) in tretinoin recipients, the first course of chemotherapy was initiated within the first few weeks of tretinoin therapy if the leucocyte count was high or increased beyond a predefined threshold; if the leucocyte count remained low, chemotherapy was initiated after the induction of complete remission.

Treatment of relapse or resistance The success of tretinoin in reinducing remission in patients who relapse after achieving a remission with the drug appears to be highly variable)l] Resistance to tretinoin is acquired rapidly and almost universally during prolonged daily treatment. However, resistance appears to be transient, as some patients will achieve a second remission with tretinoin if there has been a sufficient period since the drug was last taken.[1] Complete remission has been achieved in a small number of tretinoin-resistant patients by the concomitant administration of granulocyte colony-stimulating factor.l 1]

Tolerability Remission induction therapy with tretinoin is generally well tolerated and does not appear to add further to

Vol. 8, No.1; July 8, 1996

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Aclis Evaluation Key points in the overall evaluation of tretinoin in acute promyelocytic leukaemia CLINICAL BENEFITS

• •

Produces high rates of clinical remission Improves survival rates compared with conventional chemotherapy, when it is used with appropriate consolidation therapy

•

Does not exacerbate coagulopathy or cause bone marrow suppression

POTENTIAL LIMITATIONS

•

High rate of clinical relapse if no consolidation therapy is administered

• • • •

Resistance is rapidly and almost universally acquired No role as consolidation or maintenance therapy Associated with development of retinoic acid syndrome Only effective in patients with t(15;17) chromosomal translocation

the toxicity of standard chemotherapy regimens when a combination approach is takenJI] Importantly, tretinoin does not exacerbate coagulopathy, in contrast to conventional chemotherapy regimens which may contribute to the estimated 10-30% of patients who die as a result of severe bleeding. Furthermore, tretinoin does not cause bone marrow depression.[1]

Most adverse events are of mild to moderate severity and are reversible or easily managed with symptomatic treatment Dryness of the skin or mucous membranes, fever, headache, and bone pain are among the most commonly reported adverse effects.[S] Treatment with tretinoin during pregnancy carries a high risk of teratogenicity.£S] Thus, tretinoin is strictly contraindicated during pregnancy, and it should not be used in women of child-bearing potential unless adequate contraception is used for at least 1 month before, during, and 1 month after discontinuing therapy. Breastfeeding is not recommended during tretinoin therapy.[6] Children seem to be less tolerant of tretinoin than adults, and they are particularly vulnerable to dose-related neurotoxicity. The dosage of tretinoin should be reduced, or the drug discontinued, if a child develops severe neurological symptomsJI]

Retinoic acid syndrome a serious problem One of the most serious potential sequelae of tretinoin treatment is the retinoic acid syndrome. This is character-

Vol. 8, No.1; July 8, 1996

ised by fever, respiratory distress, interstitial pulmonary infiltrates, pleural effusions and weight gain, and it can lead to multiorgan failure and death. Symptoms usually develop after 2 to 21 days of treatment, and may affect up to 25% of patients.l 1] The onset of symptomatic retinoic acid syndrome is usually, but not always, preceded by an increase in white blood cell (leucocyte) count.£4] Retinoic acid syndrome is difficult to treat once established; early recognition and treatment is vital. The use of high-dose corticosteroids has been reported to be useful in treating symptoms and can be given empirically if retinoic acid syndrome is suspected. The risk for development of retinoic acid syndrome appears to be reduced if patients with high or rapidly increasing leucocyte counts receive a full-dose course of standard chemotherapy during early tretinoin treatment (see recommendations below).

Dosage and administration The recommended oral dosage of tretinoin for all patients (including children and the elderly) is 45 mg/m2/day in 2 equally divided doses.lS] No significant improvement in therapeutic efficacy was seen with higher doses in clinical trials investigating daily doses of up to 100 mg/m 2)1] Tretinoin treatment should be continued for 30 to 90 days, until a complete remission is achieved. Consolidation chemotherapy with agents other then tretinoin should then be initiated immediatelyJ5] However, this latter recommendation may change as more data become available on the optimal regimens for consolidation and maintenance. In order to reduce the risk for the development of retinoic acid syndrome, the guidelines outlined in table 1 should be followed. If retinoic acid syndrome is suspected, high-dose corticosteroids should be administered for at least 3 days.[l]

Prescribing and formulary considerations The demonstrated efficacy of tretinoin suggests that this drug can be used for the induction of remission in patients with newly diagnosed APL or who have relapsed from, are refractory to, or are unable to tolerate anthracycline-based antineoplastic therapy. However, tretinoin is not approved for use in newly diagnosed patients in some countries. Tretinoin should not be used for consolidation or maintenance therapy.

Cost saving? The use of tretinoin may reduce hospitalisation costs, primarily through reduced expenditure on antibacterial

II 72·0360/96/00013-0041$0 1_00 <)Adis International Limited. All rights reserved

J:'Drugs

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treatment and platelet and erythrocyte transfusions. For example, in 76 patients with newly diagnosed APL who received standard chemotherapy, tretinoin alone, or tretinoin combined with low-dose chemotherapy, the average total treatment costs during the first 2 months of hospitalisation were ¥4.2, 2.6 and 3.3 million ($US46 300, $28 900 and $36 700), respectivelyV]

References 1. Gillis lC, Goa KL. Tretinoin. A review of its phannacodynamic and phannacokinetic properties and use in the management of acute promyelocytic leukaemia. Drugs 1995; 50 (5): 897-923 2. Muindi lRF, Frankel SR, Huselton C, et al. Clinical phannacology of oral all-trans-retinoic acid in patients with acute promyelocytic leukaemia. Can Res 1992 Apr 15; 52: 2138-42 3. Fenaux P, Le Deley MC, Castaigne S, et al. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukaemia. Results of a multicentre randomized trial. Blood 1993 Dec I; 82 (11): 3241-9 4. Degos L, Dombret H, Chomienne C, et al. All-trans retinoic acid as a differentiating agent in the treatment of acute promyelocytic leukaemia. Blood 1995 May 15; 85 (10): 2643-53 5. FDA news and product notes. Vesanoid. Formulary 1996 Feb; 31: 87-8 6. New Ethicals Compendium. 5th ed. Auckland: Adis International, 1994: 1144-6

I~'CI

Table 1. Guidelines for the prevention of retinoic acid syndrome during tretinoin treatment(1)

wec count' WBC count remains <5000 cellslmm

Recommendation 3

Tretinoin therapy can be administered without concomitant chemotherapy

Initial WBC count of <5000 cells/mm 3 increases to: 3 • >6000 cells/mm by day 5 or 3 • > 10 000 cellslmm by day 10 or 3 • >15 000 cellslmm by day 15

Initiate concomitant chemotherapy8 on day, 5,10 or 15, respectively, of tretinoin treatment

Initial WBC count >5000 cellslmm 3

Initiate chemotherepy8 when starting tretinoin therapy

t

To convert cells/mm 3 to cells x 10 9/L multiply by 0.001 For example, one full-dose course of daunorubicin + cytarabine. Abbreviation: wee = white blood cell (leucocyte)

a

7. Takeshita A, Sakamaki H, Miyawaki S, et al. Significant reduction of medical costs by differentiation therapy with all-trans retinoic acid during remission induction of newly diagnosed patients with acute promyelocytic leukaemia. Cancer 1995; 76: 602-8

Nonspecific immunosuppressive therapies still the mainstay for SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that has a highly variable clinical presentation and can be fatal.[I] Severe SLE remains difficult to treat. This is largely because the aetiology and pathogenetic mechanisms of this disease are not well understood.

The most logical approach for immune intervention has not yet been defined Therapy is largely limited to symptomatic treatment and nonspecific immunosuppressive agents,lI,2] No treatment is curative. However, several new approaches are being investigated with the hope of finding treatments that are more effective with fewer adverse effects.[1,3]

Overall picture of SLE SLE is the result of hormonal, exogenous and endogenous polygenic factors that lead to the production of autoantibodies and/or lymphoid cells. Inflammatory processes are triggered and lead to a wide variety of clinical manifestations,ll] Suggested criteria for diagnosis are outlined in table 1.

1172-0360/96/00013-005/$01.00 e Adis International LimiJed. All rights reserved

SLE is estimated to affect 3/10 000 people in the UK[4] and::; 5/10 000 people in the US[2]. It occurs approximately 9 times more frequently in women than in men, and usually presents between the ages of 15 and 40 years. It is more prevalent among Afro-Caribbean, Asian and Chinese ethnic groups than among Caucasians.[4] The severity of the disease differs between patients, and also fluctuates over time as remissions and exacerbations occur.[1] Current methods of treatment have greatly improved the prognosis of patients with SLE, and now approximately 90% of patients in Western countries can expect to survive for at least 10 years after diagnosis,l2,3)

Management of SLE There is often multisystem involvement in SLE. Management requires identification and monitoring of the organs affected, with therapy directed towards organspecific manifestations. Remembering that the pattern of involvement may change over time, treatment must be individualised and may often require adjustment. The selection of treatment is largely dependent on the severity of the patient's disease at each point in time (see Patient care guidelines).

VoL 8, No. I; July 8,1996

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