作者
Amandeep Salhotra,Ni‐Chun Tsai,Jianying Zhang,Dat Ngo,Ahmed Aribi,Karamjeet S. Sandhu,Brian Ball,Monzr M. Al Malki,Haris Ali,Paul Koller,Andrew S. Artz,Stephen J. Forman,Ryotaro Nakamura,Anthony S. Stein,Guido Marcucci,Ibrahim Aldoss,Vinod Pullarkat
摘要
The combination of hypomethylating agent (HMA) azacytidine with venetoclax (HMA+Ven) was compared to azacytidine monotherapy in the recent multicentre phase III VIALE-A trial in patients with newly diagnosed acute myeloid leukaemia (AML) unfit for intensive chemotherapy either due to age (≥75 years) or comorbidities. The composite complete remission (CR) rate was 66·4% versus 28·3% in the study arm versus azacytidine alone (P < 0·001) with median overall survival (OS) of 14·7 versus 9·6 months (P < 0·001) in favour of the HMA+Ven arm. Based on these results, the combination of HMA+Ven is now United States Food and Drug Administration (FDA) approved for upfront treatment in the elderly AML population.1, 2 Given the inclusion criteria for enrolment on this study, patients were not eligible for allogeneic haematopoietic cell transplantation (allo-HCT), hence data regarding allo-HCT data after HMA+Ven induction is limited.3 We therefore analysed the clinical outcomes of 51 patients aged ≤74 years treated at our centre with HMA+Ven induction (2018–2020) to evaluate its performance in this age group and the clinical outcomes of patients, and evaluate the outcomes in patients who subsequently underwent HCT in remission. Response criteria from CR and CR without haematological recovery (CRi) were defined per standard International Working Group (IWG) AML response criteria.4 The primary end-point was defined as composite CR rate (cCR: defined as patients achieving CR +CRi). Minimal residual disease (MRD) assessment was done on post-induction bone marrow aspirate using multiparametric flow cytometric assessment with lower limit of sensitivity being 0·01%.5 The secondary end-point of OS, was defined as the time from the start of the therapy with either HMA+Ven to death and patients were censored if alive at the last follow-up. Leukaemia-free survival (LFS) among patients with CR/CRi was defined as the time interval from the date of response to relapse or death, whichever occurred first, and patients were censored at the last follow-up if still leukaemia free. Patients’ demographic, cytogenetic and molecular features are summarised in Table I. The majority of patients were European LeukemiaNET (ELN) adverse risk (69%; 35/51) and remaining (31%; 16/51) were good/intermediate risk. Physician rationale for choosing HMA+Ven were as follows: diagnosis of secondary AML (21 patients); age ≥70 years (nine); comorbid conditions at diagnosis (nine); poor performance status at diagnosis (six), concurrent second malignancy (five) and adverse risk cytogenetics (one). Among the nine patients with comorbidities at presentation, four had chronic kidney disease [including one with end-stage renal disease on dialysis], cardiac comorbidities (two), prior cerebrovascular accident (two) and one was intubated when induction chemotherapy with HMA+Ven was started. The cCR rate in patients treated with HMA+Ven was 68·6% (35/51), CR was seen in 21·5% (11/51) and CRi in 47% (24/51) of the patients (Table II). MRDneg remission was seen in 45% of the patients (23/51). With a median (range) duration of follow-up of 11·7 (0·6–40·6) months for all patients, the 1-year OS was 58% [95% confidence interval (CI) 43–70] and the median OS was 19·4 months (95% CI 6·8–26·2). The cCR rates were 55% in ELN adverse risk and 80% in ELN intermediate/good risk categories. In all, 16 patients presented with tumour protein p53 (TP53) mutation, of whom cCR was achieved in eight (50%). In patients with secondary AML (sAML), the cCR was 67% (21/31) with 48% (15/31) achieving MRDneg remission. In the de novo AML group (20 patients), the cCR was 65% (13/20) with MRD neg remission rate of 45% (nine of 20). A total of 25 patients (49%) eventually proceeded to allo-HCT after induction with HMA+Ven. This included 21 patients who achieved cCR with HMA+Ven and four who were refractory to HMA+Ven and received alternative salvage therapy and allo-HCT in remission (three) and one was transplanted with active disease on study. These four patients were excluded from final analysis. Of the 21 allo-HCT recipients 12 had sAML (38%; 12/31) and nine presented with de novo AML (45%; nine of 20). Pre-HCT MRDneg status was achieved in 71·4% of the patients (15/21). All patients received reduced-intensity conditioning with fludarabine and melphalan and received peripheral blood stem cells grafts from human leucocyte antigen matched unrelated donors. The median LFS for HCT patients was not achieved, compared to 7·8 months (95% CI 2·0–13·9) for non-HCT patients in cCR. The 1-year LFS in patients who underwent HCT (21 patients) was 67% (95% CI 41–84%) versus 33% (95% CI 10–57%) in non-HCT patients in cCR (14 patients). The 1-year OS for HCT patients (21 patients) was 85% (95% CI 61–95%) compared to 41% (95% CI 16–65%) in non-HCT patients in cCR (14 patients). The non-relapse mortality (NRM) at day 100 and 1 year was 12% (95% CI 4–35%). The reasons for not proceeding to allo-HCT in remission were advanced age (five patients, mean age 72·8 years), concurrent non-haematological cancer (four) and comorbidities (five). Poor outcomes were seen in patients who did not achieve remission with HMA+Ven or allo-HCT, the median follow-up was 3·5 months and the 1-year was OS 8% in this very high-risk group. Early mortality due to sepsis/infectious complications was seen in three patients, resulting in 28-day induction mortality rate of 5·8%. All three patients with induction mortality were included in the final analysis for the intent-to-treat analysis. On longer follow-up, 21 more patients died due to relapsed AML (nine patients), sepsis (five), fungal pneumonia (five), congestive heart failure (one) and unknown cause (one). In this retrospective analysis, we report the real-world outcomes in patients with AML who received treatment with HMA+VEN in the frontline setting followed by allo-HCT. In our study population, which was enriched for patients with adverse cytogenetic and molecular features, we saw a very promising cCR rate of 68% with median LFS not reached for CR1 patients, an OS of 19·4 months and low rate of induction mortality of 5·8%. MRDneg remissions of 45% in all patients and 71% in allo-HCT recipients consistent with the known mechanism of action of B-cell leukaemia/lymphoma 2 (BCL-2) inhibitors in targeting the leukaemia stem cell.6 In 41% patients who underwent allo-HCT, the NRM at day 100 was 12% and the 1-year LFS/OS was 67%/85% (Fig 1). In conclusion, our report shows that in patients with newly diagnosed AML, upfront treatment with HMA+Ven is associated with high cCR and low induction mortality and excellent post allo-HCT outcomes. This suggests that HMA+Ven may be an effective regimen prior to transplant in patients with AML. Amandeep Salhotra and Vinod Pullarkat designed the research study and wrote the manuscript. Ni-Chun Tsai and Jianying Zhang performed statistical analysis. Remaining authors (Dat Ngo, Ahmed Aribi, Karamjeet Sandhu, Brian Ball, Monzr Al-Malki, Haris Ali, Paul Koller, Andrew Artz, Stephen Forman, Ryotaro Nakamura, Anthony Stein, Guido Marcucci and Ibrahim Aldoss) critically reviewed the manuscript. All authors approve of the submitted final version. Amandeep Salhotra has research funding from Bristol Myers Sqibb and Advisor for Kadmon. Anthony Stein serves on the speaker bureau for Stemline, Amgen and Celgene, and on advisory boards for Stemline and Amgen. Guido Marcucci is a member of the speakers’ bureau for AbbVie and Novartis and serves on advisory board with Janssen Pharm. Vinod Pullarkat has served on the advisory boards for AbbVie and Jazz Pharmaceuticals and is member of speakers’ bureau for Jazz, Amgen, Novartis and AbbVie. Ibrahim Aldoss has served on advisory boards with AbbVie, Amgen, KiTE pharmaceuticals, Agios, consultant for Autolus and Amgen, speaker for Jazz Pharmaceuticals. The remaining authors have no relevant conflict of interest to declare.