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Late first relapses in APL treated with all-trans-retinoic acid- and anthracycline- based chemotherapy: the European APL group experience (APL 91 and APL 93 trials)

The routine use of frontline all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy has greatly improved the outcome of APL, particularly by reducing the incidence of relapses, notably early relapses. Overall, the combination of ATRA and anthracycline-based chemotherapy yields complete remission rates greater than 90% in newly diagnosed APL.1, 2 With maintenance combining continuous 6-mercaptopurine (6MP) and methotrexate (MTX) to intermittent ATRA and possibly with early introduction of chemotherapy during induction treatment, the relapse risk in APL has now been reduced to 10–15%.1, 2, 3, 4

Before the ATRA era, the large majority of first relapses in APL occurred within 3 years of CR achievement, and only 2–3% of the patients relapsed after 4 years.5, 6 Theoretically, the possibility exists that the addition of ATRA to chemotherapy in newly diagnosed APL may only delay some of the relapses that were seen earlier with chemotherapy alone. The incidence and characteristics of late relapses occurring after ATRA- and anthracycline-based chemotherapy, however, are not known.

Between 1991 and 1997 (APL 91 and 93 trials) 630 newly diagnosed APL patients received ATRA combined to or followed by daunorubicin–cytarabine chemotherapy (for a total of three courses), with or without (randomization) maintenance treatment by 6MP and methotrexate and/or intermittent ATRA.1, 7 A total of 582 (92.5%) patients achieved hematological CR and 154 (26.4%) relapsed, after 5–120 months. Nineteen of those first relapses occurred more than 4 years after CR achievement (‘late relapses’), representing 12.3% of the relapses and 3.2% of the patients who achieved CR. Median age of the 19 patients was 45 years (range 20–68), and male/female ratio was 7/12. Median time to relapse was 72 months (range 50–120), and all relapses involved the bone marrow only. t(15;17) translocation and/or PML-RARa rearrangement was seen in all cases at relapse, confirming that those relapses were APL and not therapy-related AML.8 Salvage treatment consisted of ATRA+anthracycline-based chemotherapy in 14 patients, ATRA alone in two patients, anthracycline-based chemotherapy without ATRA in one patient, arsenic trioxide (As2O3) in one patient and a combination of ATRA and As2O3 in one patient. Seventeen of the 19 patients (89.4%) achieved a second hematological complete remission (CR2) and two patients experienced early death. Post-remission treatment consisted of allogeneic stem cell transplantation in three patients, autologous stem cell transplantation in five patients, consolidation and maintenance chemotherapy with or without ATRA in seven patients and maintenance with ATRA alone in two patients. Fourteen of the 17 (82%) patients remained in CR2 after 5+ to 78+ months. Two patients had a second relapse after nine and 22 months and died, and one patient developed secondary MDS and died. Second haematological complete remission was longer than CR1 in five cases and shorter in two cases (comparison between CR2 duration was not possible in the other patients, still in CR2 but with short follow-up). Three-years survival from relapse was 77%.

By comparison to patients who did not relapse and patients who relapsed after less than 4 years (Table 1), patients with late relapse did not differ for age and initial platelets. They were more often female patients (M/F=0.54 vs 2; P=0.01) and had lower initial WBC counts than patients who relapsed earlier than 4 years (mean WBC 7800/mm3 vs 18 000/mm3, P<0.05) but these features did not significantly differ from patients who did not relapse (M/F=0.86 and mean WBC=8700/mm3). Percentages of patients with late relapse who had not received maintenance treatment (known in APL 93 trial to have reduced the incidence of relapse) were intermediate between those with early relapses and those who did not relapse: 15, 26 and 32% for no relapse, late relapse and early relapse, respectively, although differences were not statistically significant (Table 1).

Table 1 Occurrence of relapse in APL 93 trial

We finally tried to determine if early addition of chemotherapy to ATRA, which reduced the incidence of early relapses in APL 93 trial,1 also had an impact on the incidence of late relapses. This analysis was restricted to the groups randomized between ATRA followed (after CR achievement) by chemotherapy, and ATRA combined to upfront chemotherapy (i.e. 306 patients of APL 93 trial). Five late relapses were seen after ATRA combined to chemotherapy (2.7% of the 184 patients and 23% of all relapsing patients included in that treatment arm), vs four after ATRA followed by chemotherapy (3.2% of the 122 patients and 15% of all relapsing patients included in that treatment arm), showing the absence of obvious impact of early addition of chemotherapy on the occurrence of late relapses.

Thus, first late relapse (>4 years) was seen in about 3% of this large cohort of APL patients treated with ATRA and intensive chemotherapy. This incidence is similar to that previously reported after treatment of APL with chemotherapy alone.5, 6 This finding further confirms that the addition of ATRA to chemotherapy not only delays relapses but also reduces their incidence. Initial characteristics of the patients who had late relapses were rather those of ‘low-risk’ APL (especially with WBC<10 000/mm3 and female predominance). On the other hand, the proportion of patients with late relapse who had received maintenance was slightly lower than that of patients who did not relapse, suggesting that systematic use of maintenance treatment in APL may further reduce the incidence of late relapses. Whether those late relapses were due to re-emergence of the initial leukemic clone or due to occurrence of a secondary APL clone remains unknown.

In our experience, the prognosis of late relapses was overall favorable, in spite of the fact that they generally occurred before As2O3 – now considered as the treatment of choice for relapsing APL patients – was available.

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Acknowledgements

This work was supported by the Programme Hospitalier de Recherche Clinique (CHU Lille), the Association de Recherche Contre le Cancer and the Ligue Nationale Contre le Cancer (Comité du Nord).

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Correspondence to P Fenaux.

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Kelaidi, C., Ades, L., Chevret, S. et al. Late first relapses in APL treated with all-trans-retinoic acid- and anthracycline- based chemotherapy: the European APL group experience (APL 91 and APL 93 trials). Leukemia 20, 905–907 (2006). https://doi.org/10.1038/sj.leu.2404158

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