Ineffective erythropoiesis in patients with nontransfusion-dependent β-thalassemia (NTDT) leads to chronic anemia that does not necessarily require lifelong transfusion therapy for survival.¹ Nonetheless, chronic anemia in these patients is associated with significant morbidity, especially in patients with a hemoglobin level lower than 10 g/dL.² Hemoglobin variations greater than 1 g/dL have also been shown to modify morbidity risk.³ Beyond the use of transfusions in specific clinical settings, there are currently no approved agents for the management of anemia in NTDT. Ineffective erythropoiesis can also lead to considerable iron overload due to hepcidin dysregulation and increased intestinal iron absorption.⁴ A serum ferritin level greater than 800 ng/mL is also associated with an increased risk of morbidity and is an indication for the use of iron chelation therapy.⁵ Such clinical complications in NTDT are often serious and involve various organ systems including hepatic, endocrine, and vascular disease.⁶ Despite the abundance of reports highlighting anemia and iron overload as the hallmarks of morbidity in NTDT, data on their association with long-term mortality outcomes remain limited.

For this work, we used data from an International Health Repository (IHR) formed by 13 international thalassemia reference centers from the US and seven countries in Europe, the Middle East, and Asia.⁷ The IHR was established and approved on May 25, 2017 by the Italian Ethical Committee (EudraCT and Sponsor's Protocol Code Numbers: 2017-004457-17 and 143AOR2017). All data were anonymized and added to the repository following informed consent by patients or their legal representatives in case of death. The IHR database includes all β-thalassemia patients who have attended participating centers from January 1, 1997 onward. We analyzed data from all patients with NTDT (defined as previously described⁸) who had not transitioned to regular transfusion programs and who had documented hemoglobin and serum ferritin levels. Patients were historically followed from birth up to December 31, 2019, death, or loss to follow-up. For each patient, we retrieved data on age and status at the last observation, sex, splenectomy status, iron chelation status, hemoglobin level, and serum ferritin level at the last observation. Hemoglobin and serum ferritin levels represented the average of all measurements done during the year of last observation.

A total of 415 patients (48.7% females) were included in the analysis (Table S1). The median age at last observation (follow-up time) was 30.1 years (interquartile range [IQR]: 23.6–44.2). The majority were splenectomized (n = 243, 58.6%) and received iron chelation therapy (n = 379, 91.3%). The median age at the start of iron chelation therapy was 7 years (IQR: 4.3–14). At last observation, the majority of patients were on deferoxamine (49%), followed by deferiprone (23.5%), deferasirox (22.5%), and deferoxamine + deferiprone combination (4.9%) therapy. The mean hemoglobin level was 9.2 ± 1.0 g/dL (range: 6–15) with 339 (81.7%) patients having a hemoglobin level ≤ 10 g/dL. The median serum ferritin level was 960 ng/mL (IQR: 500–2843) with 235 (56.6%) patients having a serum ferritin level > 800 ng/mL. A total of 185 patients (44.6%) had both a hemoglobin level ≤ 10 g/dL and a serum ferritin level > 800 ng/mL.

Thirty-two patients died during the observation period, giving a crude mortality rate of 7.7% (95% confidence interval [CI]: 5.3–10.7). Recorded causes of death included cardiovascular disease (n = 17), infection (n = 2), hepatic failure (n = 1), renal failure (n = 1), cancer (n = 1), and other disease complications (n = 10). The median age at death was 24.1 years (IQR: 28.3–61.9; 37.5% females). Survival was significantly worse in patients with a hemoglobin level ≤ 10 g/dL than those with > 10 g/dL (Log-rank test Chi-square: 4.259, p = .039, Figure 1A). Survival was also significantly worse in patients with a serum ferritin level > 800 ng/mL than those with ≤ 800 ng/mL (log-rank test Chi-square: 24.379, p < .001, Figure 1B). Finally, survival was significantly worse in patients with both a hemoglobin level ≤ 10 g/dL and a serum ferritin level > 800 ng/mL than those with either a hemoglobin level ≤ 10 g/dL or a serum ferritin level > 800 ng/mL and those with both a hemoglobin level > 10 g/dL and a serum ferritin level ≤ 800 ng/mL (Log-rank test Chi-square: 33.728, p < .001, Figure 1C).

We constructed a multivariate Cox regression analysis including hemoglobin level (≤ 10 vs. > 10 g/dL), serum ferritin level (> 800 vs. ≤ 800 ng/mL), sex, splenectomy, and iron chelation status. A hemoglobin level ≤ 10 g/dL was independently associated with a 7.6-fold increase in the risk of mortality (hazard ratio [HR]: 7.632, 95% CI: 1.036–56.219, p = .046). A serum ferritin level > 800 ng/mL was also independently associated with a 9.8-fold increase in the risk of mortality (HR: 9.755, 95% CI: 3.368–28.257, p < .001).

Our study furthers our understanding of the detrimental effects of anemia and iron overload in NTDT and highlights an increased risk of mortality in patients with clinically relevant thresholds. Our work is limited by our ability to only analyze a subset of patients with documented hemoglobin and serum ferritin levels, which could have introduced a selection bias for patients with severe disease requiring regular follow-up, as is also evident from a higher and earlier mortality in this subset of patients compared to our overall cohort.⁸ Prospective studies are merited in such context, as they could also assess the effects of longitudinal variations over time and not only spot measurements which may not be ideally representative. The risks of mortality from low hemoglobin and high serum ferritin levels seem to be additive, which suggests a need to address both factors with prompt and comprehensive conventional management. We have previously highlighted a role for regular transfusion and iron chelation therapy in this patient population,⁸ but data from novel agents targeting anemia and iron overload are eagerly awaited.⁹

非输血依赖性 β-地中海贫血 (NTDT) 患者的无效红细胞生成导致慢性贫血，不一定需要终生输血治疗才能生存。¹尽管如此，这些患者的慢性贫血与显着的发病率相关，尤其是在血红蛋白水平低于 10 g/dL 的患者中。²大于 1 g/dL 的血红蛋白变异也被证明可以改变发病风险。³除了在特定临床环境中使用输血外，目前还没有批准的药物用于治疗 NTDT 中的贫血。由于铁调素失调和肠道铁吸收增加，无效的红细胞生成也会导致相当大的铁过载。⁴血清铁蛋白水平大于 800 ng/mL 也与发病风险增加相关，并且是使用铁螯合疗法的指征。⁵ NTDT 的此类临床并发症通常很严重，涉及各种器官系统，包括肝脏、内分泌和血管疾病。⁶尽管有大量报告强调贫血和铁超负荷是 NTDT 发病的标志，但关于它们与长期死亡率结果相关性的数据仍然有限。

在这项工作中，我们使用了由来自美国和欧洲、中东和亚洲的 7 个国家的 13 个国际地中海贫血参考中心组成的国际健康信息库 (IHR) 的数据。⁷ IHR 于 2017 年 5 月 25 日由意大利伦理委员会制定和批准（EudraCT 和发起人的协议代码编号：2017-004457-17 和 143AOR2017）。在患者或其法定代表人死亡的情况下知情同意后，所有数据都被匿名化并添加到存储库中。IHR 数据库包括从 1997 年 1 月 1 日起就诊于参与中心的所有 β-地中海贫血患者。我们分析了所有 NTDT 患者的数据（定义如前所述⁸) 尚未过渡到常规输血计划且已记录血红蛋白和血清铁蛋白水平的人。历史上对患者从出生到 2019 年 12 月 31 日、死亡或失访进行随访。对于每位患者，我们检索了最后一次观察时的年龄和状态、性别、脾切除状态、铁螯合状态、血红蛋白水平和最后一次观察时血清铁蛋白水平的数据。血红蛋白和血清铁蛋白水平代表了最后一次观察年份中所有测量值的平均值。

共有 415 名患者（48.7% 女性）被纳入分析（表 S1）。最后一次观察的中位年龄（随访时间）为 30.1 岁（四分位距 [IQR]：23.6-44.2）。大多数被切除脾脏（n  = 243, 58.6%）并接受铁螯合疗法（n = 379, 91.3%)。铁螯合治疗开始时的中位年龄为 7 岁（IQR：4.3-14）。在最后一次观察中，大多数患者使用去铁胺 (49%)，其次是去铁酮 (23.5%)、地拉罗司 (22.5%) 和去铁胺 + 去铁酮联合 (4.9%) 治疗。平均血红蛋白水平为 9.2 ± 1.0 g/dL（范围：6-15），其中 339 名（81.7%）患者的血红蛋白水平 ≤ 10 g/dL。中位血清铁蛋白水平为 960 ng/mL (IQR: 500–2843)，其中 235 (56.6%) 名患者的血清铁蛋白水平 > 800 ng/mL。共有 185 名患者 (44.6%) 的血红蛋白水平 ≤ 10 g/dL 和血清铁蛋白水平 > 800 ng/mL。

32 名患者在观察期间死亡，粗死亡率为 7.7%（95% 置信区间 [CI]：5.3-10.7）。记录的死因包括心血管疾病（n  = 17）、感染（n  = 2）、肝功能衰竭（n  = 1）、肾功能衰竭（n  = 1）、癌症（n  = 1）和其他疾病并发症（n  = 10）。死亡时的中位年龄为 24.1 岁（IQR：28.3-61.9；37.5% 为女性）。血红蛋白水平 ≤ 10 g/dL 的患者的生存率明显低于血红蛋白水平 > 10 g/dL 的患者（对数秩检验卡方：4.259，p = .039，图 1A）。血清铁蛋白水平 > 800 ng/mL 的患者的存活率也明显低于 ≤ 800 ng/mL 的患者（对数秩检验卡方：24.379，p  < .001，图 1B）。最后，血红蛋白水平 ≤ 10 g/dL 和血清铁蛋白水平 > 800 ng/mL 的患者的生存率明显低于血红蛋白水平 ≤ 10 g/dL 或血清铁蛋白水平 > 800 ng/mL 的患者。以及血红蛋白水平 > 10 g/dL 和血清铁蛋白水平 ≤ 800 ng/mL 的患者（对数秩检验卡方：33.728，p  < .001，图 1C）。

我们构建了一个多变量 Cox 回归分析，包括血红蛋白水平（≤ 10 vs. > 10 g/dL）、血清铁蛋白水平（> 800 vs. ≤ 800 ng/mL）、性别、脾切除术和铁螯合状态。血红蛋白水平 ≤ 10 g/dL 与死亡风险增加 7.6 倍独立相关（风险比 [HR]：7.632，95% CI：1.036–56.219，p  = .046）。血清铁蛋白水平 > 800 ng/mL 也与死亡风险增加 9.8 倍独立相关（HR：9.755，95% CI：3.368–28.257，p  < .001）。

我们的研究进一步加深了我们对 NTDT 中贫血和铁过载的不利影响的理解，并强调了具有临床相关阈值的患者的死亡风险增加。我们的工作受限于我们仅分析有记录的血红蛋白和血清铁蛋白水平的一部分患者的能力，这可能会给需要定期随访的严重疾病患者带来选择偏倚，这从更高和更早的死亡率也可以看出与我们的整体队列相比，在这部分患者中。⁸在这种情况下，前瞻性研究是值得的，因为它们还可以评估纵向变化随时间的影响，而不仅仅是可能不具有理想代表性的现场测量。低血红蛋白和高血清铁蛋白水平导致的死亡风险似乎是累加的，这表明需要通过及时和全面的常规管理来解决这两个因素。我们之前曾强调过定期输血和铁螯合疗法在该患者群体中的作用，⁸但迫切需要来自针对贫血和铁过载的新型药物的数据。⁹