The discovery of the specific PML-RAR alpha gene rearrangement in acute promyelocytic leukemia (APL) and of the in vitro and in vivo differentiation of APL blasts by all transretinoic acid have ...allowed important advances in the pathophysiology and treatment APL. With a therapeutic strategy combining ATRA and anthracycline-AraC chemotherapy, about 70% of newly diagnosed APL cases can now be cured. ATRA syndrome--the major side effect of ATRA treatment--should, however, be prevented. Reverse transcription polymerase chain reaction of the PML-RAR alpha rearrangement is useful for the monitoring of minimal residual disease. Efforts are currently being made to treat patients that relapse and become resistant to ATRA.
Twenty-two patients with acute promyelocytic leukemia were treated with all-trans retinoic acid (RA, 45 mg/m2 per day) for 90 days. Of the 22, four patients were previously untreated, two were ...resistant after conventional chemotherapy, and 16 were in first (n = 11), second (n = 4), or third (n = 1) relapse. We observed 14 complete response, four transient responses, one failure, and three early deaths. Length of hospitalization and number of transfusions were notably reduced in complete responders. Correction of coagulation disorders and an increase of WBCs were the first signs of all-trans RA efficacy. Morphologic analysis performed at days 0, 15, 30, 45, 60, and 90 showed that complete remissions were obtained without bone marrow (BM) hypoplasia. Presence of Auer rods in the maturing cells confirmed the differentiation effect of the treatment. At remission, the t(15;17) initially present in 20 patients was not found. The in vitro studies showed a differentiation in the presence of all-trans RA in 16 of the 18 tested cases. The single nonresponder to all trans RA in vitro did not respond in vivo. Adverse effects of RA therapy—skin and mucosa dryness, hypertriglyceridemia, and increase of hepatic transaminases—were frequently noted. We also observed bone pain in 11 patients and hyperleukocytosis in four patients. Whether maintenance treatment consisted of low-dose chemotherapy or all-trans RA, early relapses were observed. Five patients are still in complete remission (CR) at 4 to 13 months. Our study confirms the major efficacy of all-trans RA in M3, even in relapsing patients. Remissions are obtained by a differentiation process.
Le syndrome myélodysplasique de haut risque (SMD-HR), caractérisé par une diminution de l’apoptose des précurseurs de la moelle osseuse, est à risque de transformation en leucémie aiguë myéloïde ...(LAM) et de mauvais pronostic en l’absence de chimiothérapie efficace. L’évaluation de nouveaux traitements dans les modèles animaux est entravée par l’absence de biomarqueur fiable permettant de suivre in vivo l’efficacité thérapeutique, la biopsie médullaire étant impossible chez la souris. La TEP-FLT permet de quantifier in vivo la prolifération cellulaire et a été suggérée comme outil de diagnostic et de suivi thérapeutique chez les patients atteints de LAM. Notre objectif était d’évaluer la TEP-FLT pour la quantification in vivo des blastes médullaires chez la souris.
Nous avons étudié 3 groupes de souris FVB/N : contrôles normales (n=4), souris porteuses du gène muté NRASD12 sous régulation du promoteur myéloïde MRP8 (n=6) et modèle transgénique MMTVtTA/TetoBCL-2/MRP8NRASD12 de SMD-HR (n=7). Toutes les souris ont une TEP/TDM à la FLT entre 10 et 19 semaines de vie. Des images statiques (10 mns) ont été acquises 1h après injection du radiotraceur. Le % de dose de FLT injectée par g de moelle osseuse (%ID FLT/g) a été quantifié sur les images au niveau des vertèbres dorsales et des épiphyses fémorales. Juste avant la TEP, des prélèvements sanguins ont été effectués pour la numération des plaquettes sanguines et la mesure de l’expression du transgène BCl-2. Après l’imagerie, la moelle osseuse des fémurs a été recueillie pour analyse cytologique.
Les chiffres de plaquettes sanguines était de 1496±688/mL et 966±226/mL (NS) chez, respectivement, les souris contrôles et les souris transgéniques ; l’expression de BCl-2 était de 1,2±1,1 % vs 24,3±15,1 % (p<0,01) ; les taux de blastes médullaires de 5±1 % vs 12±2 % (p<0,003) ; les %/ID/g moyen de FLT étaient de 1,3±0,9 % vs 2,7±1,2 % (p<0,02) dans les fémurs proximaux. Les taux de blastes médullaires n’étaient pas corrélés aux chiffres de plaquettes sanguines (r=0,43, NS), ni à l’expression de BCl-2 (r=0,35, NS). Par contre, ils étaient corrélés au %ID/g de FLT dans la moelle osseuse des vertèbres dorsales (r=0,85 ; p<0,0001), des fémurs proximaux (r=0,73 ; p<0,002) et des épiphyses fémorales distales (r=0,82 ; p=0,0001).
La TEP-FLT est corrélée au taux blastes médullaires dans notre modèle murin de SMD-HR. Par contre, le taux de plaquettes sanguines et l’expression de BCl-2 n’apparaissent pas corrélés à l’infiltration blastique de la moelle osseuse. La TEP-FLT pourrait permettre le diagnostic de transformation des SMD-HR et éviter les biopsies de moelle osseuse répétées au cours du suivi thérapeutique.
We designed a multicenter randomized trial comparing chemotherapy with daunorubicin-Ara C (chemotherapy group) and all transretinoic acid (ATRA) combined to the same chemotherapy (ATRA group) in ...newly diagnosed APL patients aged 65 years or less. The major endpoint of the study was event-free survival (EFS) (“events” being defined as failure to achieve complete remission CR, occurrence of relapse, or death in CR). Early termination of the trial was decided after the first interim analysis, as EFS was significantly higher in the ATRA group. At the time, 101 patients had been randomized (54 in the ATRA group and 47 in the chemotherapy group). In the ATRA group, 49 (91%) patients achieved CR, 5 (9%) had early death, and 0 had resistant leukemia, compared with 38 (81%), 4 (8%), and 5 (10%) patients, respectively, in the chemotherapy group. The difference in CR rate between the two groups was not significant. The duration of coagulopathy was significantly reduced in the ATRA group, compared with the chemotherapy group. In the ATRA group, six patients relapsed after 7 to 15.5 months. In the chemotherapy group, 12 patients relapsed after 1 to 16 months, and 2 died in CR. Kaplan-Meier EFS was estimated at 79% ± 7% and 50% ± 9% at 12 months, respectively, in the ATRA and the chemotherapy group (P = .001). Kaplan-Meier estimate of relapse was 19% ± 8% and 40% ± 12% at 12 months (P = .005). In conclusion, ATRA followed by chemotherapy increases EFS in newly diagnosed APL. These results strongly suggest that ATRA should be incorporated in the front line therapy of newly diagnosed APL.
The purpose of this study was to assess the safety and efficacy of stem cell transplantation (SCT) mainly autologous SCT as consolidation therapy in APL patients who relapsed and achieved a second ...complete remission (CR2). Fifty adult patients with a first relapsed APL, of whom 39 had been previously treated with ATRA, entered a multicenter trial of oral ATRA until complete remission (CR) achievement followed by timed sequential chemotherapy (EMA combining etoposide 200 mg/m2/day for 3 days, mitoxantrone 12 mg/m2/day for 3 days, and cytarabine 500 mg/m2/day for two sequences of 3 days). EMA was started either after CR achievement, or on day 1 of ATRA because of initial white blood cell (WBC) counts >5 x 10(9)/l, or rapidly added to ATRA in order to prevent ATRA syndrome because WBC count increased under ATRA. Forty-five patients (90%, 95% CI 78%-97%) were in CR after induction therapy. Five patients died from infection during aplasia following EMA chemotherapy. Eleven patients who achieved CR had a familial HLA-identical donor and were allografted. The median disease-free survival (DFS) of allografted patients was 8.2 months. The 34 other CR patients were scheduled for autologous peripheral blood (PB) SCT (intent-to-treat group). Actually, autologous transplantation was only carried out in 22 patients (65%) (17 PBSCT and five autologous bone marrow transplantation (BMT)). Reasons for not autografting were early relapse (three patients), severe toxicity of EMA chemotherapy (six patients), and refusal or failure of stem cell harvest (three patients). The 3-year DFS rate of patients actually autografted was 77%. Among the 17 autografted patients still in CR2, nine patients have already reached a longer CR2 than first CR (CR1). Results of detection of PML/RARalpha by RT-PCR after autologous transplantation show negative findings in eight of the nine patients tested. We conclude that (1) ATRA combined to EMA chemotherapy is effective in the treatment of relapsed APL; (2) allogeneic BMT may be too toxic after salvage treatment including EMA intensive chemotherapy; (3) clinical outcome of autografted patients and preliminary molecular results regarding detection of PML/RARalpha after autologous PBSCT are encouraging.
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