Table 2.
Clinical use of ATRA in patient with NPM1‐mutated AML: review of the literature
| Reference | Number of patients/clinical characteristics | Treatment schedule | Outcome | Comments |
|---|---|---|---|---|
| Hutter et al., 2008 13 | A total of 171 elderly patients with NPM1‐mutated AML enrolled in two consecutive AMLSG protocols and included in a retrospective analysis. |
Seventy‐eight patients (median age 67.8 years) from trial A, AML HD98B. Ninety‐three patients (median age 67.9 years) from trial B, AMLSG 06‐04, in which idarubicin was intensified in induction therapy and etoposide was omitted. 37% and 94% of patients received ATRA in trials A and B, respectively. |
CR 68% and 71% in trials A and B, respectively. No significant difference in OS between the two cohorts. Restricting the analysis to patients who received ATRA, better EFS and DFS for NPM1‐mutated/FLT3‐ITD negative patients in trial A compared to trial B. | Etoposide in combination with ATRA may exert a beneficial synergistic effect in elderly patients with AML having NPM1 mutation without concurrent FLT3‐ITD. |
| Schlenk et al., 2009 3 | A total of 377 patients with de novo or secondary AML, enrolled into the randomized AMLSG HD98B treatment trial. Median age 67 years (range 61–84). NPM1 mutations present in 60 of the 254 analyzed samples (24%). | Two induction cycles with idarubicin, standard‐dose cytarabine and etoposide with or without ATRA (45 mg/m2 on days 3–5 and then 15 mg/m2 on days 6–28), followed by one consolidation cycle of intermediate‐dose cytarabine and mitoxantrone with or without ATRA (15 mg/m2 on days 6–28). For second consolidation, patients were randomized to either intensive therapy with idarubicin and etoposide or oral maintenance therapy. | Patients randomized to ATRA had significantly better RFS and OS, with 4‐years RFS and OS rates 20.9% and 10.8%, respectively, as compared to 4.8% and 5%, respectively, in the standard treatment arm. | A significant interaction between NPM1‐mutated AML without FLT3‐ITD and treatment with ATRA was identified, in that the beneficial effect of ATRA on RFS and OS was restricted to this subgroup of patients. |
| Burnett et al., 2010 4 | A total of 1075 adult patients with AML, enrolled in MRC AML12 randomized protocol. Median age 48 years (range 14–68). FLT3‐ITD mutations were present in 137 (23%) and NPM1 mutations in 207 (35%) of the 592 patients with available molecular data. Patients with NPM1 and FLT3 mutations were equally distributed between treatment groups. | Randomization in induction to two courses of daunorubicin 50 mg/m2 on days 1,3,5, thioguanine 100 mg/m2 every 12 h on day 10 in course 1 and on day 8 in course 2, cytarabine at a dose of either 100 mg/m2 (standard DAT) or 200 mg/m2 (high DAT) every 12 h on days 1–10 in course 1 and days 1–8 in course 2, each with or without ATRA 45 mg/m2/day on days 1–60. Subsequently, patients received consolidation with course 3 (amsacrine, cytarabine, etoposide) and were randomized between one or two further courses, and to chemotherapy versus transplant. | Overall, there was no effect from the addition of ATRA (CR + CRi 83% with vs. 84% without ATRA; 8‐year OS 33% with vs. 30% without ATRA). | The effect of ATRA was not significantly different in any of the four subgroups defined by the combination of FLT3 and NPM1 status. In NPM1‐mutated AML without FLT3‐ITD patients eight‐year OS was 56% with ATRA and 40% without ATRA, but the difference was not statistically significant. There was a suggestion that ATRA reduced relapse in patients with lower MN1 levels, but no significant effect on OS was observed. This study did not identify any subgroup of patients likely to derive a significant survival benefit from the addition of ATRA. |
| Fredly et al., 2013 14 | Thirty‐six patients with either previously untreated (de novo or secondary) or relapsed AML, unfit for conventional intensive chemotherapy. Median age 77 years (range 48–90). NPM1 and FLT3‐ITD mutations documented in 35% (13) and 40% (14) of the cases, respectively. | On day 1, initial intravenous loading dose of VPA, then oral therapy 300 mg twice daily, continued indefinitely to maintain therapeutic concentrations. ATRA 21.5 mg/m2 twice daily on days 8–22 and repeated every 12th week. LDAC 10 mg/m2/day on days 15–24 and then repeated every 12th week. | Overall, 11 of 36 patients showed response to treatment (2 CR, 9 HI). The most common response was increased and stabilized platelet counts. Median survival 171 days and 33 days in responders and nonresponders, respectively. Detailed clinical outcome of NPM1‐mutated patients with AML is not reported. | Disease stabilization was seen in a subset of patients with AML. No significant differences with regard to age, gender, PB counts, de novo versus secondary AML, cytogenetic or molecular (FLT3, NPM1) abnormalities between responders and nonresponders. |
| Nazha et al., 2013 5 |
Seventy patients with NK‐AML who were enrolled in a previous phase II randomized clinical trial and had stored BM samples for NPM1 mutation analysis. Twenty (29%) patients had NPM1 mutation. Among them, seven patients received ATRA + chemotherapy. |
Patients were randomly assigned to receive, as remission induction treatment: (a) FAI regimen (fludarabine 30 mg/m2 on days 1–4, Ara‐C 2 g/m2 on days 1–4, idarubicin 12 mg/m2 on days 2–4); (b) FAI + G‐CSF; (c) FAI + ATRA (45 mg/m2/day); (d) FAI + ATRA + G‐CSF. If WBC count was <10 × 109/L, ATRA was begun 2 days before chemotherapy. If WBC count was ≥ 10 × 109/L, ATRA was begun on day 1. ATRA administration was continued for 3 days after completion of chemotherapy. |
CR rate in patients with NPM1 mutation was 71% and 69%, with or without ATRA, respectively. Median OS, EFS, RFS for the entire group were 11.5, 7, and 11.5 months, respectively. | The addition of ATRA to induction chemotherapy did not affect CR rate, OS, EFS, and RFS of patients with NK and NPM1 mutation. |
| Burnett et al., 2013 15 | A total of 616 older patients with either de novo or secondary AML or high‐risk MDS, enrolled in the NCRI AML16 trial. Median age 67 years (range 53–82). FLT3‐ITD and NPM1 data available for 422 and 404 patients, with mutation rates of 19% and 24%, respectively. | Randomization to DA versus ADE and ATRA versus no ATRA in a 2 × 2 factorial design. Daunorubicin 50 mg/m2 on days 1–3 and cytarabine 100 mg/m2 every 12 h on days 1–10 (course 1) or days 1–8 (course 2). Patients allocated to ATRA arms, received ATRA 45 mg/m2/day for 60 days. Etoposide in ADE arm was given at 100 mg/m2 on days 1–5 of courses 1 and 2. | ORR 69% and two‐year survival 35%. ORR not different between DA and ADE, although CR rates were nonsignificantly lower in patients given ATRA. At two‐years, neither OR nor RFS differed between arms (OS: ADE 33% vs. DA 36%; ATRA vs. not 35% vs. 35%). | In an analysis stratified by etoposide and by NPM1/FLT3 risk group, there was no significant heterogeneity of the effect of ATRA. No beneficial effect of ATRA in NPM1‐mutated AML without FLT3‐ITD appeared for patients receiving ADE. |
| Tassara et al., 2014 16 |
A total of 195 elderly (range 61–83 years) patients with either de novo or secondary AML. NPM1 mutations were found in 22 and 18 of the available samples from patients in standard group (26%) and VPA group (22.5%), respectively |
Randomization to receive induction either with (VPA group) or without (standard group) VPA. Induction therapy consisted of two cycles of idarubicin 12 mg/m2 on days 1–3, cytarabine 100 mg/m2 on days 1–5, ATRA 45 mg/m2 on days 3–5 and 15 mg/m2 day 6–28 (AIC) or by the same chemotherapy plus VPA 400 mg twice daily (V‐AIC). After interim analyses, idarubicin was reduced to days 1 and 3, and VPA was given only during the first cycle. A second amendment stopped randomization because of toxicity and inferior CR rates in V‐AIC arm. All patients in CR received two consolidation cycles with chemotherapy and ATRA. | CR rates after induction tended to be lower in VPA group (40%) compared with standard group (52%), as a result of the higher early death rate. After a median follow‐up of 84 months, five‐year EFS (2.3% in standard and 7.6% in VPA) and OS (11.7% in standard and 11.4% in VPA) were not different between the two groups. However, five‐year RFS was significantly superior in VPA group (24.4%) compared with standard (6.4%). | The addition of VPA to intensive induction chemotherapy and ATRA did not result in an improvement of CR rates, EFS and OS, mainly as a result of increased VPA‐related hematologic toxicity and higher death rates during second induction cycle. Explorative subset analyses revealed that NPM1‐mutated AML may particularly benefit from VPA. |
| Guenounou et, 2014 17 | Three patients, aged 16, 21 and 51 years, respectively, affected with relapsed/refractory NPM1‐mutated with concurrent FLT3‐ITD positivity. | Sorafenib (400 mg twice a day) and ATRA (45 mg/m2/day on days 1–14). Each cycle was repeated every 28 days until progression or toxicity. Two patients received etoposide 150 mg/m2 for 2 days for debulking. | Patient 1 obtained fourth CR; sorafenib was stopped after 2 years for toxicity and relapse occurred. Patient 2 was still in CR after 18 months of treatment (ATRA was stopped after 11 months for liver toxicity). Patient 3 received therapy bridge to transplant, without obtaining remission. | Patients with FLT3‐ITD+ and NPM1‐mutated AML could obtain unexpected responses upon treatment with the combination of sorafenib and ATRA, which could not have been achieved with conventional therapies (patients 1 and 2 were previously allografted). |
| Schlenk et al., 2014 18 | A total of 1100 adult (age 18–60 years) with AML, entered in prospective randomized treatment trial AMLSG 07‐04. NPM1 mutation was documented in 29% of patients. | Induction therapy consisted of two cycles ICE (idarubicin 12 mg/m2 on days 1,3,5 or on days 1,3 in cycle 2; cytarabine 100 mg/m2 on days 1–7; etoposide 100 mg/m2 on days 1–3). For consolidation therapy, high‐risk patients received allo‐HSCT, while all other patients were assigned to high‐dose cytarabine (18 g/m2 per cycle). Patients were randomized to receive ATRA (during induction 45 mg/m2 on days 6–8, 15 mg/m2 on days 9–21; during consolidation 15 mg/m2 on days 6–28). |
A PP analysis revealed higher probability for NPM1‐mutated AML patients treated with ATRA to achieve a CR, with longer EFS. Explorative analysis in all patients on OS revealed a benefit for patients treated with ATRA compared to those who have not received ATRA (ITT, P = 0.09; PP, P = 0.01). |
The beneficial effect of ATRA on OS in the whole cohort of younger patients could be attributed to patients with ELN‐favorable risk including core‐binding factor AML, AML with CEBPAdm and NPM1‐mutated AML in the absence of FLT3‐ITD. |
| El Hajj et al., 2015 12 | Five elderly patients with previously untreated or relapsed NPM1‐mutated AML, unfit for chemotherapy. | Compassionate use of ATRA 45 mg/m2/day combined with ATO 0.1 mg/kg/day. | BM blasts significantly decreased in three patients and then re‐increased upon treatment discontinuation. One patient died from IA at day +21 with no evidence of response. Another patient rapidly died from bilateral pneumonia at day +10. | Although CRs were not observed, ATRA + ATO exerted a transient in vivo antileukemic effect, with leukemia regression in some patients. The combination is unlikely to be curative alone, but may be part of a broader therapeutic strategy. |
ATRA, all‐trans retinoic acid; AML, acute myeloid leukemia; CR, complete remission; BM, bone marrow; G‐CSF, granulocyte‐colony stimulating factor; WBC, white blood cell; EFS, event‐free survival; OS, overall survival; DFS, disease‐free survival; MDS; myelodysplastic syndrome; VPA, valproic acid; CRi, complete remission with incomplete blood count recovery; ORR, overall response rate; ORR, overall response rate; PB, peripheral blood; RFS, relapse‐free survival; NK, normal karyotype; HSCT, hematopoietic stem cell transplant; PP, per protocol; ITT, intention to treat; ELN, European LeukemiaNet; ATO, arsenic trioxide; IA, invasive aspergillosis.