Departments of 1 Medicine and 2 Pathology, Queen Mary Hospital, Hong Kong; Departments of 3 Medicine and 4 Pathology, Queen Elizabeth Hospital, Hong Kong; 5 Department of Medicine, Tuen Mun Hospital, Hong Kong; 6 Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong, Peoples Republic of China
Received 26 August 2002; revised 19 November 2002; accepted 3 December 2002
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Abstract |
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The best overall treatment strategy for patients with acute promyelocytic leukaemia (APL) in relapse with chemotherapy, bone marrow transplantation (BMT) or arsenic trioxide (As2O3) based therapy remains undefined.
Patients and methods:
We reviewed the clinical course and treatment outcome of 143 APL cases seen in four major hospitals in Hong Kong over a 10-year period.
Results:
Complete remission (CR) was attained in 113 cases (79%) with all-trans retinoic acid (ATRA) and chemotherapy. Relapse occurred at a median of 16 months in 54 cases, with a 3-year disease free survival of 56%. Post-relapse treatment was successful in 41 cases (76%), giving an actuarial 3-year overall survival (OS) of 81% from CR1. Three different protocols were used: chemotherapy alone (n = 19), allogeneic BMT (n = 14) and an As2O3-based regimen (n = 21). Chemotherapy was associated with the highest treatment-related mortality (TRM) at 53%, giving a CR2 rate of 47%. TRM was 36% for BMT. The CR2 rate for the As2O3-based regimen was 100%, with no TRM. However, 38% of As2O3 treated patients had subsequent relapses, which were further salvaged in 75% by combined As2O3 plus ATRA. The actuarial OS for the three protocols leveled off by 2 years at 82% for As2O3, 43% for BMT and 23% for chemotherapy (P = 0.0004).
Conclusions:
Our results suggest that As2O3 may be superior to chemotherapy and BMT for the treatment of APL in relapse.
Key words: acute promyelocytic leukaemia, allogeneic bone marrow transplantation, arsenic trioxide, relapse
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Introduction |
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In relapsed APL, the best treatment strategy remains contentious. Some patients are still responsive to ATRA and chemotherapy. Allogeneic bone marrow transplantation (BMT) may give lasting remissions, but the patient selection and timing for BMT are unresolved issues. Clinical and laboratory evidence indicates that As2O3 is a highly effective treatment for relapsed APL. However, the role of As2O3, in comparison with further chemotherapy or allogeneic BMT, has not hitherto been formally evaluated.
In this report, we studied the treatment results of newly diagnosed and relapsed cases of APL over a 10-year period, with a specific focus on evaluating the relative merits of chemotherapy, allogeneic BMT and As2O3 in the treatment of relapses.
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Materials and methods |
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Treatment of newly diagnosed APL
The standard induction protocol was ATRA (45 mg/m2/day x6 weeks), together with daunorubicin (50 mg/m2/day x3 days) and cytosine arabinoside (100 mg/m2/day x7 days). Consolidation therapy consisted of two to four courses of an anthracycline (daunorubicin or mitoxantrone) containing regimen. Maintenance therapy (ATRA 45 mg/m2/day x15 every 3 months, methotrexate 15 mg/m2/week, 6-mercaptopurine 50 mg/m2/day for 18 months) was used in three centres. Prospective monitoring of minimal residual leukaemia was not performed routinely.
Treatment of relapsed APL
All relapses were diagnosed by marrow biopsy and confirmed cytogenetically or molecularly (Table 1). From 1991 to 1997, chemotherapy and ATRA were used for induction of second complete remission (CR2) (n = 33). Patients reaching CR2 and with a suitable marrow donor (n = 14) proceeded to allogeneic BMT, while the others (n = 19) received consolidation with conventional chemotherapy. After 1997, As2O3 (10 mg daily until remission) and idarurbicin (72 mg/m2 in nine divided doses over 3 months) were used in all relapsed cases (n = 21), as previously reported [7]. Patients who relapsed again after As2O3/idarubicin treatment (n = 8) were further treated with As2O3 (10 mg/m2/day) and ATRA (45 mg/m2/day) until CR3, followed by further consolidation with As2O3 plus ATRA, each given for 14 days every 46 weeks for six courses, as reported previously [8].
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Results |
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Statistical analysis
The 2-year actuarial OS from R1 leveled off at 23% for the chemotherapy group, 43% for the BMT group and 82% for the As2O3 group (Figure 3). As a result of efficient salvage of advanced relapses, the 5-year actuarial OS from CR1, at 68%, was much better than the DFS.
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Discussion |
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In relapsed APL, allogeneic BMT, chemotherapy and As2O3 are all useful treatment modalities, but the best choice and timing of treatment is as yet undefined [13]. Reported data on the use of ATRA plus chemotherapy for relapsed APL showed that only 2935% of patients could be induced into durable remission [14, 15]. Allogeneic BMT for relapsed patients who achieved a second remission after ATRA plus chemotherapy also gave poor results. In one study, the leukaemia-free survival (LFS) was 22%, relapse rate (RR) was 54%, and the treatment-related mortality (TRM) was 40% [16]. In another study, only two of 11 APL patients in second remission survived the transplantation [17]. Data published by the European Blood and Marrow Transplantation (EBMT) Group showed that in 127 relapsed APL patients who received allogeneic BMT, the LFS was 5361%, the RR was 1022% and the TRM was 3234% [18]. The data from the EBMT appeared to be slightly better than the former two studies, which could be related to different patient selection. However, these studies all showed that allogeneic BMT in APL patients in second remission was associated with a high TRM and an overall unsatisfactory outcome. As for As2O3, although a high remission rate can be achieved, the long-term follow-up results are less well defined. In two series comprising 87 relapsed cases, the 18- and 24-month LFS was 56% and 42%, respectively [19, 20].
In comparison with the studies of relapsed APL described above, our data offer a few advantages. This study involved a consecutive series, so that bias related to patient selection for various treatment options was diminished. This was particularly important for BMT, where patient selection could often affect the treatment outcome. Furthermore, the treatment and supportive care were similar. Our results might therefore give a better perspective on the relative merits of the different treatment options in relapsed APL.
We showed that with a follow-up of 3 years, treatment results for BMT were comparable to chemotherapy, but inferior to arsenic-based treatment for relapsed APL. The lower relapse rate with BMT was offset by the high early TRM, a phenomenon also observed in other studies [1618]. Although few late relapses occurred after BMT, the survival curve remained unstable owing to late deaths from GvHD and organ toxicity. Furthermore, survivors after BMT might still suffer from the permanent side effects of immunosuppression, exposure to alkylating agents, infertility, premature menopause and increased risks of secondary malignancies. In contrast, As2O3-based therapy was associated with minimal toxicity or mortality. Although As2O3-induced second remissions were apparently associated with more subsequent relapses, long-term remission after combination therapy with As2O3 and ATRA might still be achieved in these patients [8]. Furthermore, the lack of organ damage meant that further relapses might still be salvaged by allogeneic BMT, although this was not required in any of our cases. Our results therefore suggest that As2O3-based therapy may be the treatment of choice for APL in first or more advanced relapses. For this reason, we have not performed BMT in any APL patients after 1997.
In conclusion, the availability of effective first-line and salvage therapy means that APL patients in any stage of their illness should be treated with curative intent, even when they have late advanced diseases [13]. As2O3 appears to be the best option for relapsed cases. The high efficacy of As2O3 in inducing second remissions means that optimal consolidation and maintenance of remission are key factors that will improve the cure rate. For allogeneic BMT to be offered as a consolidation, TRM must be improved. On the other hand, APL in advanced and repeated relapse appears to continue to respond to As2O3 treatment, which is associated with minimal side effects. Among these options, our data with short-term follow-up seemed to favour the use of repeated courses of As2O3. However, prospective clinical trials are needed to fully resolve the issue of As2O3 as compared with allogeneic BMT as the optimal treatment for relapsed APL.
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Acknowledgements |
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Footnotes |
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References |
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2. Chen GQ, Shi XG, Tang W et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effect on APL cells in vitro and in vivo. Blood 1997; 89: 33453353.
3. Head D, Kopecky KJ, Weick J et al. Effect of aggressive daunomycin therapy on survival in acute promyelocytic leukemia. Blood 1995; 86: 17171728.
4. Cunningham I, Gee TS, Reich LM et al. Acute promyelocytic leukemia: treatment results during a decade at Memorial Hospital. Blood 1989; 73: 11161122.[Abstract]
5. Fenaux P, Chomienne C, Degos L. All-trans retinoic acid and chemotherapy in the treatment of acute promyelocytic leukemia. Semin Hematol 2001; 38: 1325.[ISI][Medline]
6. Kwong YL, Wong KF, Chan TK. Trisomy 8 in acute promyelocytic leukaemia: an interphase study by fluorescence in situ hybridization. Br J Haematol 1995; 90: 697700.[ISI][Medline]
7. Kwong YL, Au WY, Chim CS et al. Arsenic trioxide- and idarubicin-induced remissions in relapsed acute promyelocytic leukaemia: clinicopathological and molecular features of a pilot study. Am J Hematol 2001; 66: 274279.[CrossRef][ISI][Medline]
8. Au WY, Chim CS, Lie AKW et al. Combined arsenic trioxide and all trans retinoic acid treatment for acute promyelocytic leukemia recurring from previous relapses successfully treated by arsenic trioxide. Br J Haematol 2002; 117: 130132.[CrossRef][ISI][Medline]
9. Fenaux P, Chomienne C, Degos L. All-trans retinoic acid and chemotherapy in the treatment of acute promyelocytic leukemia. Semin Hematol 2001; 38: 1325.[ISI][Medline]
10. Sanz MA, Lo Coco F, Martin G et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood 2000; 96: 12471253.
11. Fenaux P, Chastang C, Chevret S et al. A randomized comparison of all trans retinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 1999; 94: 11921200.
12. Chiu EK, Chan LC, Liang R et al. Poor outcome of intensive chemotherapy for adult acute lymphoblastic leukemia: a possible dose effect. Leukemia 1994; 8: 14691473.[ISI][Medline]
13. Tallman MS, Nabhan C, Feusner JH, Rowe JM. Acute promyelocytic leukemia: evolving therapeutic strategies. Blood 2002; 99: 759767.
14. Cortes JE, Kantarjian H, OBrien S et al. All-trans retinoic acid followed by chemotherapy for salvage of refractory or relapsed acute promyelocytic leukemia. Cancer 1994; 73: 29462952.[ISI][Medline]
15. Thomas X, Anglaret B, Thiebaut A et al. Improvement of prognosis in refractory and relapsed acute promyelocytic leukemia over recent years: the role of all-trans retinoic acid therapy. Ann Hematol 1997; 75: 195200.[CrossRef][ISI][Medline]
16. Meloni G, Diverio D, Vignetti M et al. Autologous bone marrow transplantation for acute promyelocytic leukemia in second remission: prognostic relevance of pretransplant minimal residual disease assessment by reverse-transcription polymerase chain reaction of the PML/RAR alpha fusion gene. Blood 1997; 90: 13211325.
17. Thomas X, Dombret H, Cordonnier C et al. Treatment of relapsing acute promyelocytic leukemia by all-trans retinoic acid therapy followed by timed sequential chemotherapy and stem cell transplantation. APL Study Group. Acute promyelocytic leukemia. Leukemia 2000; 14: 10061013.[CrossRef][ISI][Medline]
18. Zanz MA, Arcese W, de la Rubia J et al. Stem cell transplantation (SCT) for acute promyelocytic leukemia (APL) in the ATRA era: a survey of the European Blood and Marrow Transplantation Group (EBMT). Blood 2000; 96: (Abstr 2247).
19. Niu C, Yan H, Yu T et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood 1999; 94: 33153324.
20. Soignet SL, Frankel SR, Douer D et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 2001; 19: 38523860.