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strategy toward further increase of cure rate Treatment of acute promyelocytic leukemia: strategy toward further increase of cure rate R Ohno1,2,3, N Asou1,2,3 and K Ohnishi1,2,3Received 3 September 2002; Accepted 28 March 2003. Top of pageAbstractAcute promyelocytic leukemia (APL) has become a curable disease by all trans retinoic acid (ATRA) based induction therapy followed by two or three courses of consolidation chemotherapy. Currently around 90% of newly diagnosed patients with APL achieve complete remission (CR) and over 70% of patients are curable. To further increase the CR and cure rates, detection and diagnosis of this disease at its early stage is very important, hopefully before the appearance of APL associated coagulopathy. In induction therapy, concomitant chemotherapy is indispensable, except for patients with low initial leukocyte counts. Prophylactic use of intrathecal methotrexate and cytarabine should be done, particularly for patients with hyperleukocytosis. If patients relapse hematologically or even molecularly, arsenic trioxide will be the treatment of choice under careful electrocardiogram monitoring. Am80, liposomal ATRA, gemtuzumab ozogamicin or ATRA in combination with cytotoxic drugs may be used at this stage or later. Allogeneic SCT will be the treatment of choice after patients of age Keywords: acute promyelocytic leukemia, all trans retinoic acid, molecular targeting therapy, arsenic trioxide, Am80 Top of pageIntroductionUntil a decade ago, the remission induction therapy of acute promyelocytic leukemia (APL) was the most difficult one among that of acute leukemia, and it required enormous efforts from both the patients and medical staff to get a complete remission (CR). This was especially true before sufficient platelet transfusions became routinely available through the use of blood cell separators. The management of excessive hemorrhaging due to disseminated intravascular coagulation and fibrinolysis was quite difficult at that time. Besides, hemorrhaging became exacerbated after the start of chemotherapy due to the destruction of leukemia cells, and many patients died of hemorrhaging before reaching CR. The introduction of all trans retinoic acid (ATRA) in the late 1980s has dramatically changed these situations and marked a major advance in the treatment of APL.1,2,3,4 With ATRA based induction therapy, around 90% of newly diagnosed patients with APL now achieve CR and over 70% of patients are curable with subsequent postremission chemotherapy, with or without ATRA.5,6,7,8,9,10,11,12,13,14,15 The treatment with ATRA was initially called a differentiation therapy, which is still true as an observed phenomenon. Subsequent analysis of the differentiation, however, has elucidated its mechanism, and now the ATRA treatment is regarded as a molecular targeted therapy aimed at the pathogenetic molecule of this leukemia, that is, PML/RAR. Thus, ATRA has turned to be the first successful molecular targeted drug in the history of cancer therapy. The treatment outcomes of other acute leukemias have probably reached their maximal limit during the past decade as far as currently available cytotoxic drugs are used. To make a major breakthrough for further increase of the cure rate of these diseases, targeting therapy on leukemogenic molecules is presently the most promising approach and should be developed further. In this review, we will discuss the treatment of APL with special emphasis on the strategy toward further increase of cure rate, and how to utilize the experience of ATRA therapy in molecular targeted therapy, not only for other types of leukemia but for other cancers in future as well. Top of pageRemission induction therapy of APLBeyond question, ATRA has become the first choice drug for newly diagnosed patients with APL from a medical, economical and patient quality of life point of view.16,17 ATRA, with or without cytotoxic drugs, is now able to induce over 90% CR in these patients. Some early studies mainly using ATRA alone failed to obtain such high CR rates in newly diagnosed APL patients. For example, the North American Intergroup study reported only a 72% CR rate in the ATRA arm compared to 69% CR in the chemotherapy arm.7 The low CR rates in the early to mid 1990s plausibly came from the inexperience of hematology oncologists in the hitherto unfamiliar differentiation therapy. Hematology oncologists at that time tended to discontinue ATRA when confronted with an increasing number of peripheral blood leukocytes during the administration of ATRA. They judged the treatment as a failure based on their experience of chemotherapy with cytotoxic drugs. If the same patients were treated by the same oncologists in 2003, CR rates would definitely be higher by around 20% because the oncologists have accumulated considerable experience and knowledge as to how to handle the initial ATRA induced leukocytosis and complications. To control the leukocytosis and consequent retinoic acid (RA) syndrome, concomitant use of cytotoxic drugs such as anthracyclines and cytarabine (Ara C) is indispensable. Since leukemia cells from patients with APL are particularly sensitive to anthracyclines (perhaps because of significantly lower P glycoprotein expression and other resistance markers in APL cells compared to other subtypes of acute myeloid leukemia (AML)18,19,20), anthracyclines may be more important than Ara C. In fact, shortly before the ATRA era, Gruppo Italiano per le Malattie Ematologiche dell Adulto (GIMEMA) compared idarubicin (IDR) alone to IDR+Ara C in the remission induction therapy of 257 patients with newly diagnosed APL in a prospective randomized study. Overall, 76% of the patients in the IDA arm alone and 67% of patients in the IDR+Ara C arm achieved CR, and event free survival (EFS) rates were 35 and 23%, respectively (P=0.0352).21 The results suggest that monotherapy with IDR favorably influences the EFS of patients with newly diagnosed APL. However, the dose of IDR in the monotherapy arm was 72 mg/m2 compared to 40 mg/m2 in the combination arm. Therefore, patients in the monotherapy arm received 1.8 times as much anthracycline as in the combination arm. Top of pageDo all patients need cytotoxic drugs to obtain CR?Whether all patients with APL require concomitant use of cytotoxic drugs is still controversial. Many patients with low initial leukocyte counts achieve CR with ATRA alone. For example, among 369 newly diagnosed patients with APL (median leukocyte counts, 2000/l) in the APL92 study of the Japan Adult Leukemia Study Group (JALSG), 223 patients (60%) received daily oral ATRA alone according to the study protocol which indicated to give ATRA 45 mg/m2 alone if patients initial leukocyte counts were l. According to this protocol, 126 patients (57%) continued ATRA alone and 119 (94%) of them obtained CR, and 97 patients (43%) received additional chemotherapy (daunorubicin+behenoyl cytarabine) at the time when their blasts and promyelocytes increased >1000/l and 85 (88%) of them achieved CR. Thus, 126 (34%) of 369 patients were able to achieve CR with ATRA alone, and these patients belonged to the good prognosis group for survival.9,15 Obviously potentially carcinogenic and organotoxic cytotoxic drugs should best be avoided whenever possible. If patients have >10 000/l leukocytes, concomitant use of more intensive chemotherapy is indispensable, because a level of >10 000/l leukocytes is shown to be an independent adverse prognostic factor in the JALSG APL929,15 and the British Medical Research Council (MRC) APL studies.10 GIMEMA5 and the Spanish PETHEMA group13 use ATRA and IDR (AIDA) for all patients regardless of leukocyte counts. The European APL Group compared two induction schedules in 208 newly diagnosed APL patients of age 65 years and with 5000 initial leukocytes in a prospective randomized study. The ATRA followed by chemotherapy group received daily ATRA and DNR+Ara C if the leukocytes increased to >6000, >10 000, or >15 000/l by days 5, 10 and 15 of ATRA treatment, respectively, and the ATRA+chemotherapy group received the same combination of ATRA and DNR+Ara C starting on day 3 of ATRA treatment. Relapse at 2 years was estimated at 6% in the ATRA+chemotherapy group vs 16% in the ATRA followed by chemotherapy group (P=0.04), and EFS at 2 years was estimated 84 vs 77%, respectively (P=0.1).11 The finding suggests that early addition of chemotherapy to ATRA can reduce the incidence of relapse in APL. They also recommend simultaneous administration of ATRA and chemotherapy Moncler Jackets Outlet Womens in patients with high initial leukocyte counts to reduce the risk of severe ATRA syndrome. MRC reported no benefit from ATRA among APL patients presenting with a high initial leukocyte count (>10 000/l). The predicted 5 year overall survival (OS) of patients receiving daily ATRA on the first day of chemotherapy until CR (extended ATRA) was 43% and the same for that of patients receiving a 5 day course of ATRA before commencing chemotherapy (short ATRA). In patients with a lower leukocyte count (l), however, extended ATRA gave better OS: 80 and 57%, respectively (P=0.0025).10 In addition, the European APL Group observed that even patients with initial leukocyte counts >10 000/l were benefiting from the combination of ATRA and chemotherapy compared with the chemotherapy alone group in the APL91 randomized trial. The predicted 4 year EFS was 50% in the ATRA group and 15% in the chemotherapy group (P=0.04) among patients presenting with initial leukocyte counts >10 000/l.12 JALSG also noted a beneficial effect of ATRA in combination with chemotherapy in patients with initial leukocyte counts >10 000/l compared with the same cohort of historical patients in their group before the ATRA era. Predicted 5 year OS of 93 patients with 10 000/l initial leukocyte counts receiving ATRA in the APL 92 study was 60%, while that of 37 patients receiving chemotherapy alone in the AML87 and AML89 studies was 37% (P=0.0445) (unpublished data). Thus, ATRA also appears beneficial in APL patients with a high leukocyte count. Concomitant use of more intensive chemotherapy will probably improve the prognosis of patients with higher leukocyte counts even with currently available drugs. For example, the German AML Cooperative Group (GACC) employs intensified double induction therapy including high dose Ara C and mitoxantrone in combination with ATRA, although patients are of age 60 years and the follow up period is too short to permit definitive conclusions. The early results show a CR rate of 92% and a 2 year relapse free survival of 96%.14 Thus, ATRA+intensified chemotherapy seems to give better results regardless of leukocyte counts in younger patients who can tolerate intensive chemotherapy. Top of pageCan we induce a 100% CR rate in newly diagnosed APL?So, with accumulating experience, the next question is whether CR can be obtained in almost all newly diagnosed patients with APL. The answer will probably be no. In multicenter studies, there are about 5 early deaths within 1 month after the start of ATRA treatment with or without chemotherapy.5,6,7,8,9,10,11,12,13,14,15,17 The cause of death is mainly intracranial bleeding. Even in individuals without APL, intracranial bleeding occurs more frequently in elderly people. Thus, elderly APL patients would be more prone to intracranial bleeding. Among 369 consecutively registered, newly diagnosed APL patients in the JALSG APL92 study, only one out of 72 patients of age 70 years failed to do so chiefly due to early death by hemorrhaging in the cranium or other sites such as the lungs.15 Younger patients can generally overcome the APL associated coagulopathy, but not elderly patients. Whether there is an intrinsic ATRA resistance in APL was extensively reviewed in the latest issue of this journal.22 We believe that hematology oncologists in major centers will be able to induce CR by ATRA based regimens in almost 100% of APL patients, if patients do not have high leukocyte counts nor pre existing coagulopathy. We assume that this is also true even in reportedly ATRA resistant subtypes such as APL with t(11;17) or PLZF/RAR, if experienced hematology oncologists use cytotoxic drugs and/or granulocyte colony stimulating factors in addition to ATRA,23,24,25 although such subtypes are too rare to make firm conclusions. If some studies report more than 95% of CR and claim that their regimens are superior, the regimens themselves are probably not the reason for the high CR rate. As discussed above, if only patients with good prognostic factors, such as those of a younger age and without pre existing coagulopathy, are registered or Moncler Kids Jackets Blouson Ski Blanc Bebe Hooded White analyzed, current regimens employed in most multicenter study groups would probably produce nearly 100% CR. The problem is whether patients are diagnosed early before the APL associated coagulopathy develops. Thus, if community doctors are well educated on APL and diagnose this leukemia at its early stage, the CR rate will plausibly increase. In APL, the number of leukocytes at diagnosis is rather low in the majority of patients. The median numbers of leukocytes are around 2500/l at diagnosis in most multicenter studies. The reason why leukopenia rather than leukocytosis is common in APL is not well understood. One reason is that APL is diagnosed earlier than other types of AML, because APL patients often manifest hemorrhagic diatheses due to the coagulopathy and thus patients visit doctors rather early. This explanation would be supported by the fact that, even in other types of AML, leukopenia is a common laboratory finding preceding relapse. Therefore, if patients notice purpura or any abnormal bleeding tendency and have prompt access to community doctors, they can be diagnosed as having APL at its early stage by competent doctors and then immediately referred to hematology oncologists. Thus, the CR rate and consequently cure rate of this leukemia will increase. Otherwise, the remission rate could probably not surpass 95% in multicenter studies. Top of pageCoagulopathy during remission induction phaseGIMEMA assessed the clinical effectiveness of ATRA on the incidence of early hemorrhagic deaths and on APL associated coagulopathy in a total of 622 consecutive patients with APL treated within the group during 1989 Of those, 499 were treated with IDR plus ATRA (Study A) and 123 with IDR alone (Study B). Deaths occurring within 10 days of starting treatment were 4% in Study A and 7% in Study B (P=0.09), with 3 and 4% due to hemorrhaging. Overall induction mortality Moncler Outlet Chicago was 8 and 16%, respectively (P20 000/l or with fibrinogen 1 g/l were reduced by about 30%, the hemorrhagic score by 50% and the consumption of blood products by about 40%, and fewer patients were treated with antihemorrhagic drugs (39 vs 61%; P30 000/l at diagnosis (P26 This analysis indicated that even ATRA could not prevent early fatal hemorrhages within 10 days in the advanced APL, although a substantial clinical improvement was evident in terms of reduction of the severity of bleeding symptoms, blood product consumption and overall induction mortality when ATRA was combined with IDR. The coagulopathy in APL is mainly related to the tumor burden in patients bodies. Thus, in patients with fewer numbers of leukocytes at the start of ATRA therapy, coagulopathy seldom occurs. The bulk of evidence clearly shows that ATRA has a profound impact on the hemostatic system including thrombomodulin27 and annexin II,28 thus leading to rapid resolution of the APL associated coagulopathy.29 ATRA has an effect on the leukemia cell functions in hemostasis, which are considered major pathogenetic determinants for the coagulopathy. These anticoagulant effects on tumor cells occur together with the drug s anticoagulation effects on normal endothelial and monocytic cells.29 In some patients with a high number of leukocytes, however, the coagulopathy already exists before they reach oncology centers, and in these patients even ATRA therapy cannot rescue life threatening hemorrhaging. Additionally, no or minor purpura at diagnosis is a significant independent favorable prognostic factor for achieving CR in the JALSG APL92 study.9 Therefore, it is very important for APL to be diagnosed at its early stage and have ATRA started as soon as possible. Top of pageRA syndrome during remission induction phaseAnother problem during the remission induction phase is the RA syndrome.30,31,32 The incidence of this syndrome ranges from 6 to 31%, and was apparently higher when ATRA alone was used in remission induction therapy at the early ATRA era.17 Since the RA syndrome was not reported when ATRA was used in postremission therapy in APL as well as in other diseases, it is evidently associated with the increase of neutrophils due to their differentiation by ATRA. Physiologically, around 10 times more neutrophils are said to be present extravascularly and thus, even if some patients show no increased numbers of peripheral leukocytes at the presentation of RA syndrome, this does not exclude the association between the increase of neutrophils and this syndrome, because leukocytosis eventually appears even in cases without leukocytosis at presentation. The median peak leukocyte counts in patients who developed the syndrome were 36 400/l (range, 6300 300/l) in one report30 and 31 000/l (range, 6800 000/l) in another.32 Of note, RA syndrome is also observed during the remission induction therapy with arsenic trioxide (As2O3) due to a similar mechanism.33 The European APL Group analyzed cases of RA syndrome in newly diagnosed APL. Out of 413 patients, 64 (15%) experienced ATRA syndrome during induction therapy. Clinical signs developed after a median of 7 days (range, 0 days). In two patients, they were already present before the start of ATRA. A total of 60 patients received chemotherapy in addition to ATRA, 58 also received high dose dexamethasone, and ATRA was stopped when clinical signs developed in 30 patients. In total, 86% of patients who experienced RA syndrome achieved CR, as compared to 94% of patients who had no RA syndrome (P=0.07) and 1.2% died of RA syndrome. None of the patients who received ATRA for maintenance had RA syndrome recurrence. No significant predictive factors of ATRA syndrome, including pretreatment leukocyte counts, could be found. Kaplan estimates of relapse, EFS and survival at 2 years were 32, 63 and 68% in patients who had RA syndrome as compared with 15, 77 and 80% in patients who had no ATRA syndrome (P=0.05, 0.003, and 0.03), respectively. In a stepwise Cox model, RA syndrome remained predictive for EFS and survival.31 The USA Intergroup also examined the incidence, clinical course and outcome of patients with newly diagnosed APL who developed RA syndrome. In total, 44 (26%) of 167 patients developed the syndrome at a median of 11 days of ATRA (range, 2 days). The median leukocyte count was 1450/l at diagnosis and was 31 000/l at the time the syndrome developed. ATRA was discontinued in 36 (82%) of the 44 patients, and continued in eight patients, with subsequent resolution of the syndrome in seven of the eight. ATRA was resumed in 19 (53%) of the 36 patients in whom ATRA was stopped and discontinued in 17 (47%). The syndrome recurred in three of those 19 patients, with one death attributable to a resumption of the drug. Two deaths were definitely attributable to the syndrome. None of their patients receiving ATRA as maintenance developed the syndrome.32 Currently, hematology oncologists are well aware of RA syndrome and know how to handle this practically the sole, serious, adverse event of ATRA therapy.34 Prevention of rapid development of leukocytosis by concomitant use of cytotoxic drugs is most important. Prophylactic use of corticosteroids is recommended by Australian investigators for patients whose leukocyte counts rose above 10 000/l,35 but is controversial because the number of patients studied was too small and no