We analyzed the outcome of patients aged more than 60 included in a multicenter trial in newly diagnosed acute promyelocytic leukemia (APL93 trial), which tested the role of early addition of chemotherapy to all trans retinoic acid (ATRA) and of maintenance with ATRA and/or low-dose chemotherapy. In total, 129/533 (24.2%) patients included in this trial were older than 60. The CR rate was 86% in patients older than 60 as compared to 94.5% in younger patients (P=0.0014), due to a higher incidence of early deaths in elderly patients. The 4-year incidence of relapse was 15.6% in adults older than 60 and 23.2% in younger adults although most elderly patients received less intensive consolidation chemotherapy. However, 18.6% of the patients older than 60 years who achieved CR died in CR, mainly from sepsis during consolidation course or maintenance treatment, as compared to 5.7% of younger adults (P<0.001). Thus, overall 4-year survival of elderly patients was 57.8% as compared to 78% in younger adults (P<0.0001). APL in elderly patients appears as sensitive to ATRA-Chemotherapy based regimen as in younger adults. Less favorable outcome is mainly due to an increase of early deaths and to toxicity of consolidation treatment, strongly suggesting a beneficial role for less intensive consolidation chemotherapy and possibly introduction of arsenic derivates in the treatment of APL in the elderly.
All trans retinoic acid (ATRA) combined to or followed by anthracycline-based chemotherapy is currently the reference treatment of newly diagnosed acute promyelocytic leukemia (APL), which yields overall complete remission (CR) rates ranging from 85 to 95% and 5-year overall survival of 65–70%.1, 2, 3, 4, 5, 6 APL predominates in middle aged adults (median age in most series being 40–45 years) and is relatively rare in children and elderly patients.1, 2, 3, 4, 5, 6 In children, we recently showed that, with ATRA and combination chemotherapy, the outcome of APL was similar to that of adult APL.7
The incidence of patients aged more than 60 and 70 years ranged from 15–20 and 1–6%, respectively, in published APL series.2, 3, 4, 5, 6 To our knowledge, two studies have specifically analyzed the impact of ATRA on the outcome of elderly APL patients.5, 8
In this study, we report our experience of newly diagnosed APL in patients older than 60 years treated with ATRA and intensive chemotherapy. Our data show that APL in elderly patients is as sensitive to ATRA-Chemotherapy regimens as APL in younger patients, but we observed a less favorable outcome, mainly due to a higher incidence of early deaths and to myelotoxicity of consolidation chemotherapy.
Patients and methods
Between April 1993 and October 1998, 576 patients including 533 adults aged 18 years or more from 97 Europeans centers with newly diagnosed APL were included in APL 93 trial, whose preliminary results have been published.2 This trial had been approved by ethical committees in all participating countries.
Inclusion criteria were: (i) Diagnosis of APL based on FAB morphological criteria;9 (ii) age of 75 years or less and (iii) written informed consent. Diagnosis had to be subsequently confirmed by the presence of t(15;17) or PML-RAR gene rearrangement. In the absence of t(15;17) and if no analysis of the rearrangement could be performed, review of initial marrow sides by an independent morphologist was mandatory.
APL 93 Protocol design2
Induction treatment was stratified by age and initial white blood cell count (WBC). Patients aged ⩽65 years with WBC <5 × 109/l were assigned to receive ATRA 45 mg/m2/day followed by chemotherapy (ATRA → CT group) or ATRA plus chemotherapy (ATRA+CT). In the ATRA → CT group, patients received ATRA orally until CR, for a maximum of 90 days. After CR achievement, they received a course of daunorubicin (DNR) 60 mg/m2/day for 3 days and AraC 200 mg/m2/day for 7 days (course I). Course I was, however, added to ATRA if the WBCs increased above 6 × 109, 10 × 109 or 15 × 109/l by days 5, 10 and 15 of ATRA treatment, respectively, as, from our experience, patients were at risk of ATRA syndrome above those thresholds. Patients randomized to the ATRA+CT group received the same combination of ATRA and chemotherapy, with course I of chemotherapy starting on day 3 of ATRA treatment.
Patients with WBC >5 × 109/l at presentation (irrespective of their age) and patients aged 66–75 years with WBC ⩽5 × 109/l were not randomized, but received ATRA plus CT course I from day 1 (high WBC group) and the same schedule as in the ATRA → CT group, respectively.
Treatment of coagulopathy during the induction phase was based on platelet support to maintain the platelet count above 50 × 109/l until disappearance of coagulopathy. The use of heparin, tranexamic acid, fresh-frozen plasma and fibrinogen transfusions was optional.
CR patients received two chemotherapy consolidation courses, including course II (identical to course I) and course III, consisting of DNR 45 mg/m2/day for 3 days and AraC 1 g/m2 every 12 h for 4 days. Patients aged >65 years received only course II.
At 3 to 4 weeks after haematological recovery from this consolidation CT, patients who were still in CR were randomized either to receive or not intermittent ATRA (45 mg/m2/day, 15 days every 3 months) and to receive or not continuous CT with 6 mercaptopurine (90 mg/m2/day, orally) and methotrexate (15 mg/m2/week, orally), according to a two-by-two factorial design stratified on the initial induction treatment group. Maintenance treatment was scheduled for 2 years.
Hematological complete remission was defined by normal bone marrow cellularity without abnormal promyelocytes, neutrophils >1.5 × 109/l, and platelet>100 × 109/l and no transfusion requirement. In this trial started in 1993, when RT–PCR was not widely available, molecular CR was not considered.
Early death was defined by death occurring during ATRA, before CR had been reached, or during or after chemotherapy, especially during the phase of aplasia, without evidence of leukemic resistance. Analysis was made at the reference data of 1 January 2003.Times to outcome in the absence of competing risks (event-free survival and overall survival) were estimated by the Kaplan–Meier method and compared by the log-rank test. Otherwise, that is, when death prior to relapse could occur and avoid its occurrence, cumulative incidence curves were computed, then compared by the Gray test. Adjustment for WBC count was performed using the Fine and Gray model. Statistical analyses were performed on the SAS 8.2 (SAS Inc., Cary, NC, USA) software package. All tests were two-sided and used 0.05 as the significance level.
Results and discussion
Initial patient characteristics
Of the 533 adult patients included in APL93 trial, 129 (24.2%) were older than 60, including 71 patients (13%) older than 65 and 34 patients (6%) older than 70 (Figure 1). Main clinical and hematological characteristics of this population are summarized in Table 1. Mean WBC count was 2.8 109 and 1.6 109/l in adult patients younger than 60 and older than 60, respectively (P=0.02). Distribution of other pretreatment parameters, including gender, platelet count, incidence of M3v, cytogenetic abnormalities in addition to t(15;17) and distribution of PML-RAR breakpoints did not significantly differ in adult patients older and younger than 60. The mean lower WBC count we observed in elderly patients had not been found in the Italian GIMEMA experience, where other pretreatment parameters were also similar in elderly patients and younger adults.8 The use of heparin, tranexamic acid and fresh frozen plasma transfusion did not differ statistically according to the age group (data not shown).
Response to induction treatment
The incidence of ATRA syndrome was not significantly different in younger adults (15%) and elderly patients (12.4%). In total, 111 (86%) of the patients older than 60 years achieved CR and 18 (14%) died during induction (Table 2). This CR rate, although high, was significantly lower than the CR rate observed in adults <60 years (94.6%, P=0.0014). However, even in patients older than 70, the CR rate remained high (85%) in the present study. On the other hand, since the WBC count was lower in the older patients, the effect of age on CR might have been greater than estimated here. In the 18 patients older than 60 years who suffered early death, the cause of death was sepsis in eight cases, bleeding in four cases, cardiac failure in three cases, ATRA syndrome in one case, acute renal failure in one case and unknown in one case. Among the 58 patients who, because they were age 60–65, were randomized, there was no statistical difference in early death between randomized groups (ATRA → CT and ATRA+CT). Similar findings were made by the Italian GIMEMA study, where 86% of the patients older than 60 years with newly diagnosed APL treated with ATRA and idarubicin achieved complete remission and 12% died during induction, mainly from hemorrhage, ATRA syndrome, sepsis or heart failure.8 A lower CR rate in elderly patients was also found by the Spanish PETHEMA and the Japanese groups with ATRA combined to or followed by chemotherapy, but data in those two studies were only available for patients older than 703, 4, 5 (Table 2). As in the present study, the difference with younger adults was due to a higher incidence of early deaths, generally secondary to bleeding or sepsis. However, although elderly patients have a lower CR rate than younger patients, they appear to have particularly benefited from the introduction of ATRA. Indeed, in historical series of APL treated with chemotherapy alone, CR rates in elderly patients were in the range of 50%.10, 11 Moreover, in a British MRC study where APL patients received either 5 days of ATRA followed by chemotherapy (‘short ATRA’) or chemotherapy combined to ATRA until recovery from aplasia (‘extended ATRA’), the latter gave higher CR rates in patients <60 years than ‘short ATRA’ (89 vs 72% CR) but the difference between extended and short ATRA was greater in patients >60 years (73 vs 50%).12
Relapse and overall survival
In total, 22 of the 129 patients aged over 60 relapsed as compared to 103 of the younger adults (Figure 1). The 4-year cumulative incidence of relapse (Figure 1) was 15.6% in adults older than 60 and 23.2% in younger adults (P=0.05 by the Gray test), although most elderly patients (those aged >65 years) received less intensive consolidation chemotherapy (one Anthracycline-AraC courses vs two in younger patients). This lower incidence of relapse in elderly patients has no clear explanation. It was not due to mean lower pretreatment WBC counts in elderly patients, as the difference persisted after adjustment for baseline WBC count (P=0.023). The GIMEMA group found a similar incidence of relapse in younger and older adults whereas data were not available in other studies (Table 3). Furthermore, in the GIMEMA study, the relapse rate in elderly APL patients was similar whether postremission therapy included one, two of three consolidation cycles. This finding in APL is different from that observed other types of AML where older age is usually correlated with a higher incidence of relapse (due to poor prognostic features such as unfavorable cytogenetic abnormalities).13
Of the 129 older patients, only 26 were randomly allocated between the four arms of maintenance therapy. There was no difference in outcomes according to the maintenance group.
The 4-year event-free survival was 53% in patients older than 60 years as compared to 66% in younger adults (P=0.002 by the log-rank test). In total, 24 (18.6%) patients older than 60 years died in CR, as compared to 23 (5.7%) of the younger adults (P<0.001 by the Gray test). Causes of death in CR are shown in Table 4. Deaths due to infection during an episode of neutropenia following consolidation courses or, less often, maintenance treatment predominated. In the GIMEMA study the incidence of death in CR in patients aged >60 was 12% and the cause of death in CR was also mainly sepsis during consolidation courses.
Finally, we found a log linearity effect of older age on the hazard of death and EFS, as estimated using a Cox model in which age was introduced as a continuous covariate (data not shown).
Thus, overall survival of elderly patients in our experience was significantly poorer than that of younger patients, not because of an increased relapse rate but due to early deaths and deaths in CR.
Our study confirms that ATRA combined to chemotherapy has improved the outcome of elderly patients with APL. Our results and the literature suggest that the intensity of postremission chemotherapy could be reduced in elderly APL patients, without increasing relapse rates, in order to reduce the mortality related to intensive chemotherapy we observed. For example in the GIMEMA study, a 13% incidence of deaths in CR were seen in patients who received three consolidation chemotherapy courses vs 5% in patient who received one consolidation course.8 Reduction in mortality can also be obtained by avoiding the use of Ara C in the chemotherapy regimen, as shown by the Spanish PETHEMA group4, 5 and also by other studies.14 Early introduction of arsenical compounds like As3O315 or As4S4,16 which have no myelosuppressive effect, during induction or consolidation treatment, could also allow reduction of the total amount of chemotherapy administered in elderly APL patients.
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Ades, L., Chevret, S., De Botton, S. et al. Outcome of acute promyelocytic leukemia treated with all trans retinoic acid and chemotherapy in elderly patients: the European group experience. Leukemia 19, 230–233 (2005). https://doi.org/10.1038/sj.leu.2403597
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