Venetoclax in Relapsed/Refractory Acute Myeloid Leukemia: Are Supporting Evidences Enough?
Abstract
:Simple Summary
Abstract
1. Introduction
2. Mechanism of Action and Resistance in AML
3. Clinical evidence in R/R AML
3.1. Clinical Trials
3.2. Observational and Real-World Studies
4. The Regulatory Perspective: The Off-Label Use Regulation
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Author, Year | Study Design | Age (Range) | Number of Patients | Arms and Interventions | Efficacy | Safety |
---|---|---|---|---|---|---|
Konopleva et al., 2016 [46] | Phase II open-label, single-arm study | Median age 71 (19–84) | 32 (including 30 R/R AML) | VEN 800 mg/die with a stepwise ramp-up dosing | ORR = 19% (6/32); 6% (2) = CR; 13% (4) = CRi. Median duration of VEN therapy in responders = 144.5 days (83–256); Median duration of CR = 48 days. | VEN monotherapy was generally well tolerated. Most common AEs = nausea, diarrhea, hypokalemia, vomiting, and headache. Most common grade 3/4 AEs = febrile neutropenia, hypokalemia, pneumonia, hypotension, and urinary tract infection. |
DiNardo et al., 2020 [63] | Phase II study | Median age 62 (43–73) for R/R patients | 168 (including 55 R/R AML) | VEN 400 mg/die + 10-days decitabine 20 mg/m2 | ORR = 74% (n = 125, 95% CI: 67–80); CR/CRi = 61% (95% CI: 54–68); ORR in patients with R/R AML = 62% (n = 34/55, 95% CI: 49–74); CR = 24%, CRi = 18%, MLFS 18%. Median duration of response (CR or CRi) = 16.8 months (95% CI: 6.6–not reached) in R/R AML patients. | 261 TEAEs in 134 patients (193 grade 3 or 4). The most common = infections with prolonged grade 3 or 4 neutropenia, and febrile neutropenia, and 6 grade 5 AEs, related to neutropenic infections. |
DiNardo et al., 2021 [64] | Phase Ib/II study | Median age 46 (range, 20–73) | 68 (including 39 with R/R AML) | FLA-Ida + VEN | ORR = 75% in the phase Ib portion and 70% in the phase IIb. CR = 67% of R/R-AML patients (including 57% patients with prior alloHSCT). 100% CR rate and 83% 12-month OS = molecular subgroups (NPM1, IDH1, or IDH2) conferring sensitivity to VEN-based therapy in R/R-AML. | Grade 3 and 4 AEs = ≥10% of patients included febrile neutropenia (50%), bacteremia (35%), pneumonia (28%), and sepsis (12%). Deaths in R/R patients, including 4 non-responders (2 sepsis; 1 pneumonia; 1 pulmonary hemorrhage) and 2 responders (sepsis and hemophagocytic syndrome). |
DiNardo 2018 [65] | Retrospective study | Median 68 (25–83) | 43 R/R myeloid patients (including 39 with AML) | VEN-based salvage therapy at the median dose of 200 mg daily (range 100–800 mg), most commonly in combination with a HMA | ORR = 21% (n = 9); CR = 2 (5%); CRi = 3 (7%); MLFS = 4 (9%) | The most common AEs = grade ≥ 3 neutropenia and grade ≥ 3 infections, mainly pneumonia, bloodstream infections (gram − or gram + bacteria), cellulitis, invasive fungal infections and urinary tract infections. |
Aldoss et al. 2018 [66] | Retrospective study | Median 62 (19–81) | 33 R/R AML | VEN 400 mg daily + decitabine (20 mg/m2/day) or azacitidine (75 mg/m2/day for 7 days per cycle, 10-days or 5-days course) | ORR = 64% (n = 21); CR = 30% (n = 10); CRi = 21% (n = 7); MLFS = 12% (n = 4) | Serious neutropenic infections = 19 during the first cycle, including a prolonged cytopenia lasting more than 6 weeks, and 17 for the subsequent cycles, complicated by serious AEs (11 sepsis, 5 pneumonia, 3 colitis and diarrhea, 2 atrial fibrillation, and 2 acute renal failure). |
Aldoss et al., 2019 [67] | Single-center retrospective analysis | 59 years (18–81) | 90 adults with R/R AML | VEN + HMA | ORR = 46% (n = 41); CR = 26%; CRi = 20%. In multivariate analysis, reduced CR/CRi only with ELN genetic risk (OR: 0.25; 95% CI: 0.09–0.67); better CR/CRi = whit the ASXL1 (OR: 4.88; 95% CI: 1.02–25.67, p = 0.029) or TET2 (OR 12.21; 95% CI: 1.19–636.50, p = 0.023) mutations. | - |
Aldoss et al., 2019 [68] | Retrospective study | Median age 68 years, (22–85) | 32 adult patients with TP53-mutated AML (16 R/R and 15 newly diagnosed) | VEN + HMA | RR = 52% (n = 16), with 38% CR/CRi rate in R/R. Lower response = 14% vs. 63%, p = 0.025 if prior HMA monotherapy. Higher CR/CRi rate = 78% vs. 41%, p = 0.062 if more than 1 TP53 mutation. | - |
Aldoss et al., 2020 [69] | Retrospective study | Median 66 (18–82) | 50 adverse-risk AML patients (33 R/R and 17 treatment-naïve) with FLT3 mutations | VEN-HMA | CR/CRi rate = 60% (n = 30) and 42% in R/R AML [37% for patients with prior exposure to FLT3-based TKIs and 50% in patients who were naïve for TKIs]. | 16 (32%) patients developed neutropenic fever, 3 (6%) blood stream bacterial infections, 2 (4%) invasive fungal infection, 2 (4%) grade ≥ 3 bleeding. |
Wang et al., 2020 [70] | Retrospective study | Median 63 years (20–88) | 40 R/R AML | VEN-based therapy | RR = 50%, with 9 (22.5%) CR/Cri. Higher CR/CRi rate = NPM1, RUNX1, or SRSF2 mutations; longer OS = RUNX1. Worse outcome = FLT3-ITD, TP53, or DNMT3A mutations. | The most common AE = prolonged cytopenia (67.5% febrile neutropenia). |
Piccini et al., 2021 [71,72] | Retrospective analysis | Median 56 (33–74) | 47 R/R AML patients | VEN-based regimens | Composite CR rate = 55%, with 16% MRD negative status. Favorable outcome = HSCT-naïve patients and aged >60 years; OS = 10.7 months; longer OS = NPM1 mutation (median not reached); shorter OS = NPM1-FLT3/ITD mutations (2.3 months). 13/24 (54%) patients were successfully bridged to HSCT. | The most common AE = myelosuppression. 100% = grade 4 neutropenia (47/47,) and 95% transfusion-dependent anemia and thrombocytopenia. 21 febrile neutropenia and 17 infectious events were reported (G2, n = 10; G3, n = 4; G4, n = 2). 10 patients experienced oral mucositis, in one case graded >2. |
Byrne 2020 [73] | Retrospective study | 64.5 years (range 34.5– 73.7 years). 64.5 years (range 34.5– 73.7 years). Median 64.5 (34.5–73.7). | 21 post-transplant relapsed AML patients | VEN-based regimens (mainly with HMAs) | RR = 42.1% (n = 8, 5 CR and 3 CRi). None of the 4 patients with complex karyotype and TP53 mutations responded to therapy. Median OS = 7.8 months (range 0.2–12.1 months); significantly longer OS = in patients achieving CR/CRi (p = 0.005). | 61.9% of patients = infections (7 bacterial pneumonia, 4 sepsis, 4 had fungal pneumonia, 2 oral infections). 9/11 deceased patients had active infections. No patients who achieved a CR/CRi died of infectious complications. |
Vigil et al., 2020 [74] | Real-world retrospective cohort | Median age 55.7 years (range 32–73) | 9 post allogenic HSCT relapsed AML patients | Low dose VEN (100 mg/day) + decitabine (20 mg/m2 day 1–5) (n = 8) or azacitidine (75 mg/m2 for 7 days) | ORR = 44% (n = 4); CRi after the first cycle = 3 | - |
Zucenka et al., 2021 [75] | Retrospective study | ACTIVE Median 59 (20–71) FLAG-Ida Median 48 (20–75) | 49 R/R patients after alloSCT treated | ACTIVE (n = 20) or FLAG-Ida (n = 29) | ORR 75% ACTIVE vs. 66%FLAG-Ida; p = 0.542; CR/CRi rate = 70% ACTIVE vs. 34% FLAG-Ida; p = 0.02; OS 13.1 ACTIVE vs. 5.1 months FLAG-Ida; p = 0.032. Treatment-related mortality = 0% ACTIVE and 34% FLAG-Ida group (p = 0.003). | Febrile neutropenia, catheter-related infections, bacteremia and sepsis = lower in ACTIVE vs. FLAG-Ida. Admission to the ICU during treatment 31% of FLAG-Ida and 5% ACTIVE patients was (p = 0.034). No treatment-related deaths in the ACTIVE group compared to 10 in the FLAG-Ida group (p = 0.003). |
Joshi et al., 2021 [76] | Retrospective analysis | Median 58 (20–72) | 29 patients with post allo-HCT AML relapse | VEN regimens as salvage therapy | RR = 38%; including CR/CRi in 8. Median duration of response = 7 months (1–11); median OS = 79 days (2–403), better in responders (403 vs. 55 days, p < 0.0001). | Most frequent Grade 3 or 4 toxicities = neutropenia, infections, thrombocytopenia, and anemia. Cycle length adjustments due to hematological toxicity = 19 patients. |
Zhao et al., 2021 [77] | Retrospective study | Mean 35.2 ± 11.4 | 26 patients with AML relapsed after alloHSCT | VEN + azacitidine and donor lymphocyte infusion | ORR = 61.5% (including 26.9% of CRi); median OS = 284.5 days (95% CI: 81–610). | Hematologic AEs occurred in all patients, in particular grade 3/4 agranulocytosis and thrombocytopenia. |
Goldberg et al., 2017 [78] | Retrospective single-center analysis | Median age of 66 (29–85) | 21 patients with a R/R myeloid malignancy (n = 20 AML and n = 1 MDS) | VEN + HMA (n = 8) or VEN + LDAC (n = 16) | ORR = 28.6% (95% CI: 11.3–52.2%) (n = 6) [23% for VEN-LDAC, 50% for VEN-azacitidine, and 0% for VEN-decitabine], with 5 CR. No CR in patients who received a prior allogenic HSCT or in those with FLT3 or RAS mutations. | - |
Feld et al., 2021 [79] | Retrospective study | Among patients with R/R AML, the median age was 61.5 years | 72 patients with AML (including 39 R/R) | VEN + HMA | ORR = 38.5% (n = 15/39); CR = 12.8%; CRi = 25.6%. Higher ORR = naïve to HMA (66.7% vs. 14.3% in patients previously exposed). Better response = those harboring TET2, IDH1 or IDH2 mutations, in contrast to FLT3 and RAS mutations. Median duration of response and median OS = 8.1 months. 8 (20.5%) R/R patients underwent post-treatment allogenic HSCT. | 59.1% = grade ≥ 3 infection, 46.5% neutropenic fever, and 71.8% persistent neutropenia |
Ganzel et al., 2020 [80] | Retrospective analysis | Median age 67 years, (21–82) | 40 adult R/R AML patients | Median daily dose of 400 mg (range 100–800), + HMAs (62.5%) or LDAC (22.5%) | CR/CRi = 37.5% (n = 15). Median OS = 5.5 months (6.5 months for patients who survived more than 2 months); shorter survival for patients who underwent prior allogenic HSCT (4.5 months vs. 6 months). 5 patients underwent allogenic HSCT after treatment with VEN. | Gastro-intestinal problems (n = 4), infections (n = 3), skin complications (n = 2), weakness (n = 2), and vertigo (n = 1). |
Gaut et al., 2020 [81] | Retrospective analysis | Median age of 58 years | 14 patients with R/R AML (mainly characterized by adverse cytogenetics) | VEN + 8 with azacytidine, 5 with decitabine, and 1 with LDAC | ORR = 35.7% (n = 5); CRi = 21.4%; partial remission = 14.3% | 100% = grade ≥ 3 neutropenia and thrombocytopenia; 92.9% = grade ≥ 3 anemia. 64.3% febrile neutropenia; 50.0% grade ≥ 3 infection. |
Lou et al., 2020 [82] | Retrospective analysis | Median age 61 years (19–73) | 48 adult patients with R/R AML | VEN + azacitidine | ORR = 47.9%; CR = 29.2%; CRi = 18.8%. ORR = 75% if IDH1/2 mutations or RUNX1 mutation. Median OS = 9.6 months; OS significantly longer = ifCR/CRi (p < 0.001) and if IDH1/2 mutations (not reached vs. 3.2 months in wild-type, p < 0.001; HR = 0.069, 95% CI: 0.006–0.726, p = 0.026); OS significantly shorter = TP53 mutation (4.7 months vs. not reached in wild-type, p < 0.001; HR = 22.855, 95% CI: 2.549–204.949, p = 0.005). | Most common grade 3/4 AEs = neutropenia (91.7%, n = 44) and thrombocytopenia (89.6%, n = 43). Febrile neutropenia occurred in 40 patients (83.3%). |
Morsia et al., 2020 [83] | Retrospective study | Median age of 64.5 years (18–79) | 42 R/R AML with the exclusion of post-transplant relapses. | VEN + HMA (mainly decitabine) as salvage therapy | CR/CRi rate = 33.3% (n = 14); CR = 19%; CRi = 14.3%. Median OS = 5 months (95% CI: 3–9 months); longer OS if CR/CRi (15 vs. 3 months in non-responders, p < 0.001); shorter OS = if TP53 mutations (p = 0.04). | Infections = 85.7%; invasive fungal infections = 9.5% despite azole prophylaxis; heart failure = 19%; renal impairment = 4.8%. |
Zappasodi et al. [84] | Retrospective study | From 23 to 67 years | 10 heavily pretreated patients with refractory AML | VEN with azacitidine as bridge to allogeneic SCT | ORR = 60%, including 4 CR, 1 CRi, and 1 MLFS. HSCT performed in all 6 responders and in 1 non-responder. Median OS = 8.9 months (range 2–19) and 11.7 months among transplanted patients. | Most frequent AEs = hematological (deep and prolonged grade 3/4 neutropenia, anemia, and thrombocytopenia). 4 infections (3 bacterial infections and 1 invasive aspergillosis), all successfully managed. |
Ram et al. 2019 [85] | Retrospective cohort | Median 76 (41–92) | 23 patients AML refractory to HMAs–including also patients relapsed after allogenic HSCT | VEN + LDAC (n = 4), azacitidine (n = 13), azacitidine and donor lymphocyte infusions (n = 5), and donor lymphocyte infusions alone (n = 1) | CR/CRi = 43%. 6- and 12-month OS rate = 74% and 25%, respectively. Median OS = 5.6 months (95% CI: 4.9–6.2), Median OS in responders = 10.8 months, 95% CI: 6.2–15.4 Median OS in non-responders = 2.8 months, 95% CI: 0.9–4.8, (p < 0.001). CR/CRi = 67% in those relapsed after allogeneic HSCT (n = 6) with a median OS of 12.4 months. | Febrile neutropenia = 78% of patients. |
Tiong et al., 2021 [86] | Retrospective study | 5 patients age 59–79; 7 patients age 25–81. | 12 patients with R/R AML carrying the NPM1 mutation (5 with molecular persistence and 7 with progression or relapsed) | VEN + LDAC or azacitidine | CR with MRD negativity = 92% after 1–2 cycles. Median relapse-free survival = not reached in the 5 responders with previous molecular persistence (median follow-up = 20 months). | Most common AEs = grade 4 neutropenia (n = 8, 67%), grade 4 thrombocytopenia (n = 5, 42%), and febrile neutropenia (n = 2, 17%) associated with 1 invasive fungal infection and 1 grade 4 lung infection. |
Stahl et al., 2021 [87] | Retrospective study | Median 67 (29–86) | Large cohort of real-world patients (n = 86) with R/R AML | VEN + HMA or LDAC | ORR = 31%; CR/CRi rate = 24%. RR = 49% in patients treated with VEN + azacitidine or decitabine vs. 15% in those treated with VEN + LDAC; OR = 5.43, 95% CI: 1.55–19, p = 0.008; 25% vs. 15%; OR = 1.92, 95% CI: 0.44–8.31, p = 0.38. Median duration of response = 7.8 months; median OS = 6.1 months (95% CI: 4.9–10 months); median OS = 25 months in those treated with VEN + azacitidine (), compared to VEN + decitabine (5.4 months) (p = 0.13) and VEN + LDAC (3.9 months) groups (p = 0.003). Higher response = if NPM1 mutations; lower response = if adverse cytogenetics and mutations in TP53, KRAS/NRAS and SF3B1. | - |
Tenold et al., 2021 [13] | Retrospective study | Median 57 (range 25–86) | A small cohort (n = 25) of real-world patients with R/R AML | VEN + decitabine or azacitidine | ORR = 52%, with 4 achieving CR (16%), 4 CRi (16%), and 5 MLFS (20%). Median OS = 5.5 months (95% CI: 2.9–21.6), significantly longer for patients achieving CR/CRi (21.6 months, 95% CI: 15.2-not reached; p < 0.0026). 1-year OS rate = 100% for patients reaching CR/CRi, higher than for patients with MLFS (0%) or no responders (14%). | Most common AEs = febrile neutropenia (n = 10, 40%) and prolonged pancytopenia (n = 9, 36%). |
Tong et al., 2021 [88] | Retrospective study | Median 47.5 (12–84) | 22 heavily pre-treated R/R-AML (8 relapsed AML including 2 after HSCT and 14 primary refractory AML including) | VEN + decitabine | ORR = 45.5%; 4 patients relapsed with a median time of 5 months. 1-year OS rate = 31.8%, including 59.1% in those achieving CR/CRi and 10.4% in non-responders (p = 0.001). | All patients had grade 4 neutropenia and thrombocytopenia. |
Maiti et al., 2021 [89] | Retrospective study | DEC10-VEN median 64 (18–85); IC cohort 58 (19–80). | 65 R/R patients compared to 130 patients receiving IC | 10-day decitabine + VEN | ORR = 60% DEC10-VEN vs. 36% IC cohort; OR 3.28; p < 0.001; CRi = 19% DEC10-VEN vs. 6% IC cohort; OR, 3.56; p = 0.012; MRD negativity = 28% DEC10-VEN vs. 13% IC cohort; OR, 2.48; p = 0.017; median event-free survival = 5.7 months DEC10-VEN vs. 1.5 IC cohort; hazard ratio [HR], 0.46; 95% CI, 0.30–0.70; p < 0.001; median OS = 6.8 months DEC10-VEN vs. 4.7IC cohort; HR, 0.56; 95% CI, 0.37–0.86; p = 0.008. | Nonhematologic grade 3/4 TEAEs = 21 patients with IC and 45 receiving DEC10-VEN (p = 0.628). Grade 3/4 infections = 25 patients in the DEC10-VEN group and 5 patients in the IC group (p = 0.057). Febrile neutropenia = 30% in the DEC10-VEN cohort and in the IC cohort (p = 0.101). |
Masarova et al., 2021 [90] | Retrospective study | Median 69 (46–80) | 14 naïve and 17 R/R post–MPN-AML patients AML post myeloproliferative neoplasms | VEN regimens | No responses. Median OS = 3 months. | Most frequent AEs = prolonged cytopenias and infections. |
Amit et al., 2021 [91] | Retrospective study | Median 65 (41–75) | 22 | VEN + donor lymphocyte infusion | RR = 50% (9 CR/CRi, 2 MLFS). Median time to response = 28 days (18–67); duration of response = 135 days (31–564). Median OS = 6.1 months (95% CI 0.73–11.4). | 50% = gastrointestinal toxicity (grade 1–2 diarrhea); 73% = hematological toxicity that resulted in complete discontinuation of azacitidine or dose reduction of VEN. |
Moukalled et al., 2019 [92] | Case report/case series | 48-years 27-year 34-year 45-year | 4 cases of heavily pretreated R/R AML patients | VEN-based regimens | Stable disease for around 4 months in patient 1 (a female with NPM1 mutation and de novo FLT3 ITD relapsed after haploidentical-SCT and treatment with azacitidine + sorafenib and 2 doses of donor lymphocyte infusion); complete molecular remission in patient 2 (a male with inv (16) relapsed after matched-related-allogenic SCT and azacitidine treatment and refractory to donor lymphocyte infusion); No response in the other 2 patients—a male with FLT3-TKD mutation and a male with AML-myelomonocytic features, both relapsed after SCT. | 1 patient developed a suspected skin GVHD; 1 a grade 3 cytopenia (mainly neutropenia) requiring intermittent interruptions of VEN; 2 developed fatal infections with multiorgan failure. |
Andreani et al., 2019 [93] | Case report/case series | 60-years | Patient with NPM1-, IDH1-, and FLT3cod835-mutation, relapsed after alloSCT and refractory to a new re-induction chemotherapy | VEN plus decitabine | Responded to combined treatment of with persistent molecular remission. | Cytopenia, infection of central venous catheter, sepsis. |
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Brancati, S.; Gozzo, L.; Romano, G.L.; Vetro, C.; Dulcamare, I.; Maugeri, C.; Parisi, M.; Longo, L.; Vitale, D.C.; Di Raimondo, F.; et al. Venetoclax in Relapsed/Refractory Acute Myeloid Leukemia: Are Supporting Evidences Enough? Cancers 2022, 14, 22. https://doi.org/10.3390/cancers14010022
Brancati S, Gozzo L, Romano GL, Vetro C, Dulcamare I, Maugeri C, Parisi M, Longo L, Vitale DC, Di Raimondo F, et al. Venetoclax in Relapsed/Refractory Acute Myeloid Leukemia: Are Supporting Evidences Enough? Cancers. 2022; 14(1):22. https://doi.org/10.3390/cancers14010022
Chicago/Turabian StyleBrancati, Serena, Lucia Gozzo, Giovanni Luca Romano, Calogero Vetro, Ilaria Dulcamare, Cinzia Maugeri, Marina Parisi, Laura Longo, Daniela Cristina Vitale, Francesco Di Raimondo, and et al. 2022. "Venetoclax in Relapsed/Refractory Acute Myeloid Leukemia: Are Supporting Evidences Enough?" Cancers 14, no. 1: 22. https://doi.org/10.3390/cancers14010022
APA StyleBrancati, S., Gozzo, L., Romano, G. L., Vetro, C., Dulcamare, I., Maugeri, C., Parisi, M., Longo, L., Vitale, D. C., Di Raimondo, F., & Drago, F. (2022). Venetoclax in Relapsed/Refractory Acute Myeloid Leukemia: Are Supporting Evidences Enough? Cancers, 14(1), 22. https://doi.org/10.3390/cancers14010022