Purpose

We previously demonstrated poor outcomes of patients with acute myeloid leukemia (AML) with antecedent myeloproliferative neoplasms (MPN) undergoing allogeneic hematopoietic stem cell transplantation (HCT) (Gupta et al, BBMT, 2019; abstract 140). In particular, we did not find any difference in outcomes of patients who received transplant “in remission” defined as blood and bone marrow blasts < 5% compared to those with “active leukemia” defined as blood and or bone marrow blasts ≥ 5%. We hypothesized that genetic mutations may help in predicting the efficacy of HCT in molecularly defined sub-groups of post MPN AML. In addition, we hypothesized that patients considered “in remission” at the time of HCT may have a molecular profile similar to those who have “active leukemia” at the time of HCT.

Patients and Methods

Of the 177 patients with post MPN AML identified in the Center for International Blood and Marrow Transplant Research (CIBMTR) database, 95 (54%) had sufficient DNA to perform molecular analysis that consisted of targeted Next-Generation sequencing on 49 genes clinically relevant in hematologic malignancies.

Results

Of the 95 patients analyzed, 54 were “in remission”, and 41 had “active leukemia”. Adverse risk cytogenetics was seen in 39 patients. The most frequently mutated genes (≥10% patients) in study cohort were: JAK2 (55%); TP53 (23%); ASXL1 (22%); TET2 (19%), SRSF2 (16%); DNMT3A (14%), RUNX1 (14%); CALR (13%); SF3B1 (10%). Cumulative incidence of non-relapse mortality (NRM), relapse, progression-free survival (PFS), and survival in the study cohort at 5-years were 23% (95% CI 15-32), 66% (95% CI 56-75), 11% (95% CI 6-19) and 16% (95% CI 9-25). In a multivariate model, TP53 mutation status was the only factor associated with outcomes of HCT; patients with mutated TP53 mutations had inferior overall survival [RR 1.99 (95% CI 1.14-3.49)] and increased relapse [RR 2.59 (95% CI 1.41-4.74)], and inferior PFS (RR 2.18 (95% CI 1.25-3.82)]. Disease status at HCT was not associated with outcomes. Moreover, there were no differences in the mutational landscape, number of mutations and variant allele frequency (VAF) between patients who underwent HCT “in remission” (n=54) versus those with “active leukemia” (n=41).

Conclusions

We conclude that there is minimal benefit of HCT in patients with post MPN AML with mutated TP53, and novel strategies are required for these patients. We did not observe any difference in clinical outcomes or mutational profile of patients undergoing transplant “in remission” compared to those with “active leukemia” questioning the clinical benefit of blast reduction strategies in post MPN AML.

中文翻译：

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遗传突变对急性髓细胞性白血病先天性粒细胞白血病患者同种异体造血细胞移植结果的影响。

目的

我们先前证明患有异体造血干细胞移植（HCT）的急性骨髓性白血病（AML）伴有先前的骨髓增生性肿瘤（MPN）的患者预后不良（Gupta等人，BBMT，2019;摘要140）。特别是，我们发现在“缓解期”接受移植的患者定义为血液和骨髓母细胞<5％，而在“活动性白血病”中定义移植的血液或骨髓母细胞≥5％的患者的预后没有发现任何差异。我们假设遗传突变可能有助于预测HCT在MPN AML后分子定义的亚组中的疗效。另外，我们假设在HCT时被认为“缓解”的患者可能具有与在HCT时患有“活动性白血病”的患者相似的分子特征。

患者和方法

在国际血液和骨髓移植研究中心（CIBMTR）数据库中鉴定出的177名MPN AML后患者中，有95名（54％）具有足够的DNA来进行分子分析，该分子分析包括针对与临床相关的49个基因的靶向下一代测序血液系统恶性肿瘤。

结果

在分析的95例患者中，有54例“缓解”，41例“活动性白血病”。在39例患者中发现了不良风险的细胞遗传学。在研究队列中最频繁突变的基因（≥10％的患者）是：JAK2（55％）；TP53（23％）; ASXL1（22％）；TET2（19％），SRSF2（16％）；DNMT3A（14％），RUNX1（14％）；CALR（13％）；SF3B1（10％）。5年研究队列中非复发死亡率（NRM），复发，无进展生存（PFS）和生存的累积发生率分别为23％（95％CI 15-32），66％（95％CI 56） -75），11％（95％CI 6-19）和16％（95％CI 9-25）。在多变量模型中，TP53突变状态是与HCT结果相关的唯一因素。TP53突变的患者总体生存期较差[RR 1.99（95％CI 1.14-3.49）]和复发增加[RR 2.59（95％CI 1.41-4.74）]，PFS较差（RR 2.18（95％CI 1.25-3.82） ）]。HCT的疾病状况与结局无关，而且，“缓解”（n = 54）接受HCT的患者与那些患者相比，突变情况，突变数和变异等位基因频率（VAF）没有差异患有“活动性白血病”（n = 41）。

结论

我们得出结论，在MPN AML发生后TP53突变的患者中，HCT的获益最小，这些患者需要采取新的策略。与“活动性白血病”患者相比，我们对在“缓解期”接受移植的患者的临床结局或突变情况没有发现任何差异，这些患者对在MPN AML后使用爆炸抑制策略的临床益处提出了质疑。