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Can we prevent azole resistance in fungi?
COMMENTARY
Can
we
prevent azole resistance in fungi?
Although isolated instances of ketoconazole resistance in Candida were reported in the 1980s, the first reports of fluconazole resistance in the context of AIDS did not emerge until 1990.’ Resistance was initially noted in Canada and Europe, where fluconazole was first licensed, and subsequently in many other countries. Such resistance is in one sense a by-product of the drug’s success; worldwide sales in 1993 exceeded$600 million, or a quarter of the total world market for antifungal agents. With such exposure it is not surprising that resistance has emerged. Since fluconazole is projected to be the first billion-dollar antifungal agent by 2002,2 the incidence of resistance seems set to increase. Therapeutically, azole resistance is a substantial problem. Fluconazole is a safe and effective antifungal agent for Candida and Cryptococcus infections and, unlike amphotericin B, can be given orally. Cross-resistance to the other oral azoles, ketoconazole and itraconazole, is common and severely limits the options for oral therapy. Flucytosine and amphotericin B are used but resistance to flucytosine is also increased in Candida from AIDS patients; amphotericin is often ineffective clinically, especially for mucosal disease.4 Most instances of antimicrobial resistance have been linked to substantial drug pressure, although the timing has been unpredictable. Resistance to azoles is found in AIDS, intensive care, and leukaemia patients and manifests in two ways." The first is replacement of susceptible Candida isolates with intrinsically resistant Candida spp such as C glabrata and C krusei.5 One of the major difficulties is the small number of antifungal agents available, all of which are broad-spectrum, especially with respect to different Candida species. This limited choice substantially increases the pressure for development of resistance. The second manifestation is the in-situ development of resistance in a certain isolate. With fluconazole this has now been shown in C albicans6--8 and C glabrata, most commonly in mucosal candidosis in AIDS. The few typing studies that have been done have shown the persistence of individual genotypes of C albicans over time in most HIV-infected patients. Patients whose isolate of C albicans becomes resistant usually have very low CD4 counts,4,7 so there are probably important host factors contributing to the development of resistance. Episodes of oropharyngeal or oesophageal candidosis increase in frequency in most patients as the CD4 count declines, thus necessitating more antifungal treatment. As patients live longer with advanced AIDS, the likelihood of resistance will therefore increase. What do we know about the mechanisms of resistance? One C glabrata isolate that became resistant on therapy was shown to overexpress the target enzyme by two-fold," but recent transformation experiments in Saccharomyces
leading to overexpression of 14a-demethylase by more than twenty-fold only increased the minimal inhibitory concentration by five-fold." Perhaps modification of the target enzyme 14a-demethylase occurs but this has not been shown. Mutation in the sterol C5,6 desaturase step is another resistance mechanism that has been found in Saccharomyces;12 this mutation leads to the accumulation of the non-toxic 14a-methyl fecosterol instead of the toxic 14a-methyl-3,5-diol. In addition, resistant C albicans and
454
C krusei have a reduced intracellular azole content, which accords with either reduced uptake or increased efflux from the cell." Thus resistance is probably due to several mechanisms but the relative importance of each, and for which azole, is unknown. Strategies for prevention of resistance have not been studied in any patient group. In AIDS the general feeling is that long-term intermittent or continuous fluconazole therapy (eg, 150 mg weekly) may engender resistance’ and should be avoided unless the patient has frequent (1-3 monthly) episodes of oesophageal candidosis or requires secondary prophylaxis for cryptococcal meningitis. Other possible ways of reducing exposure to azoles-eg, a shorter course of therapy-do not seem to be effective in reducing the incidence of resistance, since resistance emerges after multiple single-dose treatments.’ Some researchers argue that larger doses of fluconazole will reduce the frequency of resistance, but this approach is unproven and potentially costly. Others believe that alternative azoles such as ketoconazole and itraconazoles are less likely to lead to the emergence of resistance,’3 and certainly there seems to be less de novo resistance to these agents than to fluconazole. However, neither ketoconazole nor itraconazole capsules are well absorbed in advanced AIDS, and ketoconazole is inferior to fluconazole for the treatment of oesophageal candidosis. Two alternative agents-the azole D0870 (Zeneca) and itraconazole formulated in cyclodextrin (Janssen)-show promise for the treatment of fluconazole-resistant candidosis, but whether they will prevent or reduce the emergence of resistance in Candida is unknown. In intensive care units, prevention of resistance is difficult,’ but restraint in the use of antibiotics, is advised. There is an urgent need for new antifungal compounds with different chemical structures and intracellular targets. David W Denning University of Manchester and Department of Infectious Diseases & Tropical Medicine (Monsall Unit), North Manchester General Hospital, Manchester, UK Fulton P, Phillips P. Fluconazole resistance during suppressive therapy of AIDS-related thrush and esophagitis caused by Candida albicans. International Conference on AIDS, 1990; 6: 239 (abstr Th.B.468). 2 Cookson C. Hidden killer waits to strike. Financial Times, Aug 25, 1994: 10. 3 Law D, Moore CB, Wardle HM, Ganguli LA, Keaney MGL, Denning DW High prevalence of antifungal resistance in Candida spp from patients with AIDS. J Antimicrob Chemother 1994; 34: 659-68. 4 Vuffray S, Durussel C, Boerlin P, et al. Oropharyngeal candidiasis resistant to single-dose therapy with fluconazole in HIV-infected patients. AIDS 1994; 8: 708-09. 5 Wingard JR, Merz WG, Rinaldi MG, Johnson TR, Karp JE, Saral R. Increase in Candida krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole. N Engl J Med 1991; 325: 1274-77. 6 Sangeorzan JA, Bradley SF, He X, et al. Epidemiology of oral candidiasis in HIV-infected patients: colonization, infection, treatment and emergence of fluconazole resistance. Am J Med 1994; 97: 339-46. 7 Vaily GG, Perry FM, Denning DW, Mandal BK. Fluconazole-resistant candidosis in an HIV cohort. AIDS 1994; 8: 787-92. 8 Johnson EM, Warnock DW, Luker J, Porter SR, Scully C. Emergence of azole drug resistance in Candida species from HIV-infected patients receiving prolonged fluconazole therapy for oral candidosis. J Antimicrob Chemother 1995; 35: 103-14. 9 Goff DA, Koletar SL, Buesching WJ, Barnishan J, Fass RJ. Isolation of fluconazole-resistant Candida albicans from human immunodeficiency virus-negative patients never treated with azoles. Clin Infect Dis 1995; 20: 77-83. 10 Vanden Bossche H, Marichal P, Odds FC. Molecular mechanisms of drug resistance in fungi. Trends Microbiol 1994; 2: 393-400. 11 Kelly SL, Kelly DE. Molecular studies on azole sensitivity in fungi. In: 1
Maresca B, Kobayashi GS,Yamaguchi H, eds. Molecular biology and its application to medical mycology. NATO ASI Sciences, vol H 69, 12
Berlin: Springer-Verlag, 1993: 200-13. Kelly SL, Lamb DC, Corran A, Baldwin BC, Kelly DE. Mode of
action and resistance to azole antifungals associated with the formulation of 14&agr;-methylergosta-8,24(28)-dicn-3&bgr;,6&agr;-diol. Biochem Biophys Res Commun (in press). 13 Odds FC. Resistance of yeasts to azole-derivative antifungals. J Antimicrob Chemother 1993; 31: 463-71.
Adult leukaemia in 1995:
new
directions
In the past four decades, leukaemia has been transformed from a rapidly and universally fatal disease to one in which palliation for months or years is possible in most patients and cure is achievable in many. Although most cures have been reported in children with acute lymphoid leukaemia or in small subgroups of adults, the increasing numbers of long-term survivors have generated considerable optimism for adult leukaemia patients in general.Nevertheless, 80% of adults diagnosed in 1995 with leukaemia will still die of or with their disease.2,3 Where have we succeeded and what are the avenues for future progress? Cures in children with acute lymphoblastic leukaemia (ALL) have come about as a result of research into combination chemotherapy and into prophylaxis for central nervous system relapse.4 However, a similar approach in adults with leukaemia has yielded only 20-40% long-term survival in patients healthy enough to tolerate intensive therapy. 5,0 Adults differ from children in their tolerance of treatment and in the biology of their disease. For example, the frequency of the (9;22) chromosomal translocation in ALL increases in direct proportion to age: although t(9;22) is rarely seen in children, it accounts for 20-40% of ALL in adults. In general, patients with ALL exhibiting t(9;22) can be cured only by allogeneic bone marrow transplantation (BMT). Similar resistance is encountered in the 20% of adults whose leukaemia follows myelodysplasia or
chemotherapy. For those who are young enough and have an HLAmatched donor marrow, BMT offers a substantial chance of cure, but this option applies to only 10-15% of patients.’ Strategies to make BMT more widely available by use of unrelated and unmatched donors and more tolerable to older patients (the median age for AML is 65
years) are being explored-eg, new approaches to genetic and immunological engineering of donor cells to exert antileukaemia or antiviral effects, and ways of diminishing graft-versus-host disease.8 Researchers who champion the understanding of molecular biology take heart that most leukaemias are associated with specific genetic mutations, deletions, and translocations. There is
now one
successful
genetically
of trans-retinoic acid to treat targeted therapy-the acute promyelocytic leukaemia, a disease associated with the overexpression of a fusion protein containing the retinoic acid receptor.9,IO As it happens, this therapy was initially formulated without knowledge of the molecular mechanism." Meanwhile, the genetic defect and p210 protein causing chronic myeloid leukaemia (CML) have been extensively studied, yet no specific therapies have emerged. Although there may be dozens of genetic mechanisms for inducing leukaemia, the hope is that unifying themes of cellular dysregulation will emerge and use
to the development of a few agents that can induce remission in most leukaemias-eg, drugs that interfere with or replace faulty mechanisms of apoptosis, signal transduction, or cell cycling. Other recent successes include the use of cladribine in hairy-cell leukaemia, in which long-term remissions are achieved in more than 80% of patients with a single course of therapy. Equally encouraging is the use of alpha-interferon to achieve haematological improvement and cytogenetic remissions in many patients with CML. Interferon may also prolong survival in a subgroup of these patients.’2 Precise genetic and immunological characterisation of disease should lead to the tailoring of therapy according to disease subtype. Already, patients with t(15,17) may be directed to retinoic acid,9 and patients with t(8;21) and (inv 16), to high-dose cytarabine.’ New directions in diagnosing and treating minimal residual disease are needed since most patients will achieve clinical remission with conventional therapy but will relapse from residual leukaemia. By use of sensitive new markers-eg, t(15;17) in acute promyelocytic leukaemia-treatment can be pursued until all detectable disease is eliminated. Detection of t(9;22) by polymerase chain reaction can signal early relapse after BMT, at which point novel therapies such as T-cell infusions can be introduced.8 Sensitive markers can also lead to development of new therapies to eliminate residual disease. 1,11-15 At Memorial Sloan-Kettering Cancer Center, a patient with leukaemia is likely to receive engineered monoclonal antibody, retinoids, cytokines, peptide vaccines, or T-cell infusions, in addition to conventional cytotoxic agents. The ability to combine this new generation of more selective agents with established drugs bodes well for the future.
thereby lead
David A
Scheinberg
Leukemia Service, Memorial New York, NY, USA
Sloan-Kettering Cancer Center,
Adult leukemias. CA 1994, 44: 323-77. Hernández JA, Land KJ, McKenna RW. Leukemias, myeloma, and other lymphoreticular neoplasms. Cancer 1995; 75: 381-94. 3 The Toronto Leukemia Study Group. Results of chemotherapy for unselected patients with acute myeloblastic leukaemia: effect of exclusions on interpretation of results. Lancet 1986; i: 786-88. 4 Rivera GK, Pinkel D, Simone JV, Hancock ML, Crist WM. Treatment of acute lymphoblastic leukemia: 30 years’ experience at St Jude Children’s Research Hospital. N Engl J Med 1993; 329: 1289-95. 5 Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 1994; 331: 896-903. 6 Clarkson B, Berman E, Little C, et al. Update on clinical trials of chemotherapy and bone marrow transplantation in acute myelogenous leukemia in adults at Memorial Sloan-Kettering Cancer Center (MSKCC) 1966-1989. In: Gale RP, ed. Acute myelogenous leukemia: progress and controversies. New York: Wiley-Liss, 1990: 239-72. 7 Berman E, Little C, Gee T, O’Reilly R, Clarkson BD. Accrual of adult patients with acute myelogenous leukemia in first remission to allogeneic bone marrow transplantation. N Engl J Med 1992; 326: 156-59. 8 Antin JH. Graft versus leukemia: no longer an epiphenomena. Blood 1993; 82: 2273-77. 9 Frankel SR, Eardley A, Heller G, et al. All-trans retinoic acid for acute promyelocytic leukemia: results of the NewYork Study. Ann Intern Med 1994; 120: 278-86. 10 Castaigne S, Chomienne C, Daniel MT, et al. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia: I, clinical results. Blood 1990; 76: 1704-09. 1 1 Huang ME,YeYC, Chen SR, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988; 72: 567-72. 12 Kantarjian HM, Smith TL, O’Brien S, et al. Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-&agr; therapy. Ann Intern Med 1995; 122: 254-61. 13 Jurcic JG, Caron PC, Miller WH Jr, et al. Sequential targeted therapy 1
2
455
Can
we
prevent azole resistance in fungi?
Although isolated instances of ketoconazole resistance in Candida were reported in the 1980s, the first reports of fluconazole resistance in the context of AIDS did not emerge until 1990.’ Resistance was initially noted in Canada and Europe, where fluconazole was first licensed, and subsequently in many other countries. Such resistance is in one sense a by-product of the drug’s success; worldwide sales in 1993 exceeded$600 million, or a quarter of the total world market for antifungal agents. With such exposure it is not surprising that resistance has emerged. Since fluconazole is projected to be the first billion-dollar antifungal agent by 2002,2 the incidence of resistance seems set to increase. Therapeutically, azole resistance is a substantial problem. Fluconazole is a safe and effective antifungal agent for Candida and Cryptococcus infections and, unlike amphotericin B, can be given orally. Cross-resistance to the other oral azoles, ketoconazole and itraconazole, is common and severely limits the options for oral therapy. Flucytosine and amphotericin B are used but resistance to flucytosine is also increased in Candida from AIDS patients; amphotericin is often ineffective clinically, especially for mucosal disease.4 Most instances of antimicrobial resistance have been linked to substantial drug pressure, although the timing has been unpredictable. Resistance to azoles is found in AIDS, intensive care, and leukaemia patients and manifests in two ways." The first is replacement of susceptible Candida isolates with intrinsically resistant Candida spp such as C glabrata and C krusei.5 One of the major difficulties is the small number of antifungal agents available, all of which are broad-spectrum, especially with respect to different Candida species. This limited choice substantially increases the pressure for development of resistance. The second manifestation is the in-situ development of resistance in a certain isolate. With fluconazole this has now been shown in C albicans6--8 and C glabrata, most commonly in mucosal candidosis in AIDS. The few typing studies that have been done have shown the persistence of individual genotypes of C albicans over time in most HIV-infected patients. Patients whose isolate of C albicans becomes resistant usually have very low CD4 counts,4,7 so there are probably important host factors contributing to the development of resistance. Episodes of oropharyngeal or oesophageal candidosis increase in frequency in most patients as the CD4 count declines, thus necessitating more antifungal treatment. As patients live longer with advanced AIDS, the likelihood of resistance will therefore increase. What do we know about the mechanisms of resistance? One C glabrata isolate that became resistant on therapy was shown to overexpress the target enzyme by two-fold," but recent transformation experiments in Saccharomyces
leading to overexpression of 14a-demethylase by more than twenty-fold only increased the minimal inhibitory concentration by five-fold." Perhaps modification of the target enzyme 14a-demethylase occurs but this has not been shown. Mutation in the sterol C5,6 desaturase step is another resistance mechanism that has been found in Saccharomyces;12 this mutation leads to the accumulation of the non-toxic 14a-methyl fecosterol instead of the toxic 14a-methyl-3,5-diol. In addition, resistant C albicans and
454
C krusei have a reduced intracellular azole content, which accords with either reduced uptake or increased efflux from the cell." Thus resistance is probably due to several mechanisms but the relative importance of each, and for which azole, is unknown. Strategies for prevention of resistance have not been studied in any patient group. In AIDS the general feeling is that long-term intermittent or continuous fluconazole therapy (eg, 150 mg weekly) may engender resistance’ and should be avoided unless the patient has frequent (1-3 monthly) episodes of oesophageal candidosis or requires secondary prophylaxis for cryptococcal meningitis. Other possible ways of reducing exposure to azoles-eg, a shorter course of therapy-do not seem to be effective in reducing the incidence of resistance, since resistance emerges after multiple single-dose treatments.’ Some researchers argue that larger doses of fluconazole will reduce the frequency of resistance, but this approach is unproven and potentially costly. Others believe that alternative azoles such as ketoconazole and itraconazoles are less likely to lead to the emergence of resistance,’3 and certainly there seems to be less de novo resistance to these agents than to fluconazole. However, neither ketoconazole nor itraconazole capsules are well absorbed in advanced AIDS, and ketoconazole is inferior to fluconazole for the treatment of oesophageal candidosis. Two alternative agents-the azole D0870 (Zeneca) and itraconazole formulated in cyclodextrin (Janssen)-show promise for the treatment of fluconazole-resistant candidosis, but whether they will prevent or reduce the emergence of resistance in Candida is unknown. In intensive care units, prevention of resistance is difficult,’ but restraint in the use of antibiotics, is advised. There is an urgent need for new antifungal compounds with different chemical structures and intracellular targets. David W Denning University of Manchester and Department of Infectious Diseases & Tropical Medicine (Monsall Unit), North Manchester General Hospital, Manchester, UK Fulton P, Phillips P. Fluconazole resistance during suppressive therapy of AIDS-related thrush and esophagitis caused by Candida albicans. International Conference on AIDS, 1990; 6: 239 (abstr Th.B.468). 2 Cookson C. Hidden killer waits to strike. Financial Times, Aug 25, 1994: 10. 3 Law D, Moore CB, Wardle HM, Ganguli LA, Keaney MGL, Denning DW High prevalence of antifungal resistance in Candida spp from patients with AIDS. J Antimicrob Chemother 1994; 34: 659-68. 4 Vuffray S, Durussel C, Boerlin P, et al. Oropharyngeal candidiasis resistant to single-dose therapy with fluconazole in HIV-infected patients. AIDS 1994; 8: 708-09. 5 Wingard JR, Merz WG, Rinaldi MG, Johnson TR, Karp JE, Saral R. Increase in Candida krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole. N Engl J Med 1991; 325: 1274-77. 6 Sangeorzan JA, Bradley SF, He X, et al. Epidemiology of oral candidiasis in HIV-infected patients: colonization, infection, treatment and emergence of fluconazole resistance. Am J Med 1994; 97: 339-46. 7 Vaily GG, Perry FM, Denning DW, Mandal BK. Fluconazole-resistant candidosis in an HIV cohort. AIDS 1994; 8: 787-92. 8 Johnson EM, Warnock DW, Luker J, Porter SR, Scully C. Emergence of azole drug resistance in Candida species from HIV-infected patients receiving prolonged fluconazole therapy for oral candidosis. J Antimicrob Chemother 1995; 35: 103-14. 9 Goff DA, Koletar SL, Buesching WJ, Barnishan J, Fass RJ. Isolation of fluconazole-resistant Candida albicans from human immunodeficiency virus-negative patients never treated with azoles. Clin Infect Dis 1995; 20: 77-83. 10 Vanden Bossche H, Marichal P, Odds FC. Molecular mechanisms of drug resistance in fungi. Trends Microbiol 1994; 2: 393-400. 11 Kelly SL, Kelly DE. Molecular studies on azole sensitivity in fungi. In: 1
Maresca B, Kobayashi GS,Yamaguchi H, eds. Molecular biology and its application to medical mycology. NATO ASI Sciences, vol H 69, 12
Berlin: Springer-Verlag, 1993: 200-13. Kelly SL, Lamb DC, Corran A, Baldwin BC, Kelly DE. Mode of
action and resistance to azole antifungals associated with the formulation of 14&agr;-methylergosta-8,24(28)-dicn-3&bgr;,6&agr;-diol. Biochem Biophys Res Commun (in press). 13 Odds FC. Resistance of yeasts to azole-derivative antifungals. J Antimicrob Chemother 1993; 31: 463-71.
Adult leukaemia in 1995:
new
directions
In the past four decades, leukaemia has been transformed from a rapidly and universally fatal disease to one in which palliation for months or years is possible in most patients and cure is achievable in many. Although most cures have been reported in children with acute lymphoid leukaemia or in small subgroups of adults, the increasing numbers of long-term survivors have generated considerable optimism for adult leukaemia patients in general.Nevertheless, 80% of adults diagnosed in 1995 with leukaemia will still die of or with their disease.2,3 Where have we succeeded and what are the avenues for future progress? Cures in children with acute lymphoblastic leukaemia (ALL) have come about as a result of research into combination chemotherapy and into prophylaxis for central nervous system relapse.4 However, a similar approach in adults with leukaemia has yielded only 20-40% long-term survival in patients healthy enough to tolerate intensive therapy. 5,0 Adults differ from children in their tolerance of treatment and in the biology of their disease. For example, the frequency of the (9;22) chromosomal translocation in ALL increases in direct proportion to age: although t(9;22) is rarely seen in children, it accounts for 20-40% of ALL in adults. In general, patients with ALL exhibiting t(9;22) can be cured only by allogeneic bone marrow transplantation (BMT). Similar resistance is encountered in the 20% of adults whose leukaemia follows myelodysplasia or
chemotherapy. For those who are young enough and have an HLAmatched donor marrow, BMT offers a substantial chance of cure, but this option applies to only 10-15% of patients.’ Strategies to make BMT more widely available by use of unrelated and unmatched donors and more tolerable to older patients (the median age for AML is 65
years) are being explored-eg, new approaches to genetic and immunological engineering of donor cells to exert antileukaemia or antiviral effects, and ways of diminishing graft-versus-host disease.8 Researchers who champion the understanding of molecular biology take heart that most leukaemias are associated with specific genetic mutations, deletions, and translocations. There is
now one
successful
genetically
of trans-retinoic acid to treat targeted therapy-the acute promyelocytic leukaemia, a disease associated with the overexpression of a fusion protein containing the retinoic acid receptor.9,IO As it happens, this therapy was initially formulated without knowledge of the molecular mechanism." Meanwhile, the genetic defect and p210 protein causing chronic myeloid leukaemia (CML) have been extensively studied, yet no specific therapies have emerged. Although there may be dozens of genetic mechanisms for inducing leukaemia, the hope is that unifying themes of cellular dysregulation will emerge and use
to the development of a few agents that can induce remission in most leukaemias-eg, drugs that interfere with or replace faulty mechanisms of apoptosis, signal transduction, or cell cycling. Other recent successes include the use of cladribine in hairy-cell leukaemia, in which long-term remissions are achieved in more than 80% of patients with a single course of therapy. Equally encouraging is the use of alpha-interferon to achieve haematological improvement and cytogenetic remissions in many patients with CML. Interferon may also prolong survival in a subgroup of these patients.’2 Precise genetic and immunological characterisation of disease should lead to the tailoring of therapy according to disease subtype. Already, patients with t(15,17) may be directed to retinoic acid,9 and patients with t(8;21) and (inv 16), to high-dose cytarabine.’ New directions in diagnosing and treating minimal residual disease are needed since most patients will achieve clinical remission with conventional therapy but will relapse from residual leukaemia. By use of sensitive new markers-eg, t(15;17) in acute promyelocytic leukaemia-treatment can be pursued until all detectable disease is eliminated. Detection of t(9;22) by polymerase chain reaction can signal early relapse after BMT, at which point novel therapies such as T-cell infusions can be introduced.8 Sensitive markers can also lead to development of new therapies to eliminate residual disease. 1,11-15 At Memorial Sloan-Kettering Cancer Center, a patient with leukaemia is likely to receive engineered monoclonal antibody, retinoids, cytokines, peptide vaccines, or T-cell infusions, in addition to conventional cytotoxic agents. The ability to combine this new generation of more selective agents with established drugs bodes well for the future.
thereby lead
David A
Scheinberg
Leukemia Service, Memorial New York, NY, USA
Sloan-Kettering Cancer Center,
Adult leukemias. CA 1994, 44: 323-77. Hernández JA, Land KJ, McKenna RW. Leukemias, myeloma, and other lymphoreticular neoplasms. Cancer 1995; 75: 381-94. 3 The Toronto Leukemia Study Group. Results of chemotherapy for unselected patients with acute myeloblastic leukaemia: effect of exclusions on interpretation of results. Lancet 1986; i: 786-88. 4 Rivera GK, Pinkel D, Simone JV, Hancock ML, Crist WM. Treatment of acute lymphoblastic leukemia: 30 years’ experience at St Jude Children’s Research Hospital. N Engl J Med 1993; 329: 1289-95. 5 Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 1994; 331: 896-903. 6 Clarkson B, Berman E, Little C, et al. Update on clinical trials of chemotherapy and bone marrow transplantation in acute myelogenous leukemia in adults at Memorial Sloan-Kettering Cancer Center (MSKCC) 1966-1989. In: Gale RP, ed. Acute myelogenous leukemia: progress and controversies. New York: Wiley-Liss, 1990: 239-72. 7 Berman E, Little C, Gee T, O’Reilly R, Clarkson BD. Accrual of adult patients with acute myelogenous leukemia in first remission to allogeneic bone marrow transplantation. N Engl J Med 1992; 326: 156-59. 8 Antin JH. Graft versus leukemia: no longer an epiphenomena. Blood 1993; 82: 2273-77. 9 Frankel SR, Eardley A, Heller G, et al. All-trans retinoic acid for acute promyelocytic leukemia: results of the NewYork Study. Ann Intern Med 1994; 120: 278-86. 10 Castaigne S, Chomienne C, Daniel MT, et al. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia: I, clinical results. Blood 1990; 76: 1704-09. 1 1 Huang ME,YeYC, Chen SR, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988; 72: 567-72. 12 Kantarjian HM, Smith TL, O’Brien S, et al. Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-&agr; therapy. Ann Intern Med 1995; 122: 254-61. 13 Jurcic JG, Caron PC, Miller WH Jr, et al. Sequential targeted therapy 1
2
455