American Journal of Hematology ( IF 10.1 ) Pub Date : 2021-12-27 , DOI: 10.1002/ajh.26448 Abhishek A Mangaonkar 1 , Faiqa Farrukh 1 , Kaaren K Reichard 2 , Rhett P Ketterling 2 , Naseema Gangat 1 , Aref Al-Kali 1 , Kebede Begna 1 , Animesh Pardanani 1 , Mrinal M Patnaik 1 , Ayalew Tefferi 1
More than 10 years ago, we described the association between absolute lymphocyte count (ALC) and survival in myelodysplastic syndromes (MDS) with1 or without2 del(5q); the latter study included 503 patients with non-del(5q) MDS and reported median survival of 18.5 months for patients with ALC < 1.2 × 109/L versus 26.6 months for those with ALC ≥ 1.2 × 109/L (p < .001);2 the prognostic contribution of ALC in the study was shown to be independent of the International Prognostic Scoring System (IPSS).3 In a subsequent larger study of 889 patients with primary MDS,4 we confirmed the prognostic relevance of ALC < 1.2 × 109/L, in the context of the revised IPSS (IPSS-R),5 although significance was borderline (p = .06).4 These observations were more recently confirmed by another retrospective study of 1023 patients from the Düsseldorf MDS-registry, which included therapy-related and del(5q) cases;6 ALC < 1.2 × 109/L was associated with shorter survival that was not accounted for by age or cytogenetic risk groups; however, significance was lost (p = .09) after accounting for bone marrow (BM) blast percentage and degree of cytopenias. Of note, the Düsseldorf study6 included 140 patients with MDS with ring sideroblasts (MDS-RS), with single lineage (SLD) or multilineage (MLD) dysplasia, and the prognostic relevance of ALC < 1.2 × 109/L was most apparent in MDS-RS-SLD.6 The objectives for the current study were to examine the prognostic relevance of lymphocytopenia (ALC < 1.0 or 1.2 × 109/L; Mayo Clinic reference range 0.95–3.07 × 109/L) in both MDS-RS and myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T).
After approval from the institutional review board, we queried the Mayo Clinic database for myeloid neoplasms to identify 147 patients who met the 2016 World Health Organization (WHO) diagnostic criteria for either MDS-RS (n = 71) or MDS/MPN-RS-T (n = 76).7 The main diagnostic criterion was the presence of at least 15% BM RS for both MDS-RS and MDS/MPN-RS-T, which in the case of MDS-RS also included patients with ≥ 5% BM RS in association with SF3B1 mutation. Additional required diagnostic criteria for both entities included the presence of < 5% BM blasts, < 1% peripheral blood (PB) blasts, and, for MDS/MPN-RS-T, presence of platelet count ≥ 450 × 109/L Exclusionary criteria included the presence of Auer rods, diagnostic criteria for MDS with isolated del(5q), t(3;3)(q21.3;q26.2), inv (3)(q21.3q26.2), BCR:ABL1, or other rearrangements of PDGFRA, PDGFRB, FGFR1, PCM1-JAK2.7 Conventional methods were used for cytogenetic and next-generation sequencing studies. Statistical analyses considered parameters at the time of diagnosis and were performed using JMP Pro 14.0.0 software package, SAS Institute, Cary, NC.
Table 1 outlines presenting clinical and laboratory features, as well as postdiagnosis events, in 71 study patients with MDS-RS (median age 73 years, range 41–94; males 63%) and 76 with MDS/MPN-RS-T (median age 73 years, range 49–93; males 61%). IPSS-R risk distributions for MDS-RS were 34% very low, 59% low, 4% intermediate, 3% high, and 0% very high; the corresponding figures for MDS/MPN-RS-T were 29%, 62%, 3%, 3%, and 2%. SF3B1, JAK2, and ASXL1 mutation frequencies were 100%, 1%, and 11%, respectively, for MDS-RS and 92%, 30%, and 20%, respectively, for MDS/MPN-RS-T. Comparison of patients with MDS-RS versus MDS/MPN-RS-T revealed the former with lower absolute neutrophil count (ANC; median 3 vs. 4.6 × 109/L; p = .002) and the latter with higher absolute monocyte count (AMC; median 0.4 vs. 0.5 × 109/L; p = .05), but otherwise similar ALC (median 1.6 vs. 1.6 × 109/L; p = .4), degree of anemia (hemoglobin <10 g/dL in 65% vs. 67%; p = .8) and IPSS-R cytogenetic and overall risk distribution (p = .3 and .8, respectively). Median follow-up for living patients with MDS-RS was 2.1 years and for those with MDS/MPN-RS-T was 2.8 years. During follow-up, 46 (65%) deaths and 2 (2.8%) leukemic transformations were documented in MDS-RS and 36 (47%) deaths and 2 (2.6%) leukemic transformations in MDS/MPN-RS-T. Overall survival data were similar between MDS-RS (median 5.4 years) and MDS/MPN-RS-T (median 5.6 years; Figure 1A; p = .98).
| Variables at diagnosis | MDS-RS (N = 71) | MDS/MPN-RS-T (N = 76) | p value | MDS-RS with ALC <1 × 109/L (N = 17) | MDS-RS with ALC ≥1 × 109/L (N = 54) | p value |
|---|---|---|---|---|---|---|
| Age in years (median; range) | 73 (41–94) | 72 (49–93) | .74 | 74 (41–94) | 73 (45–88) | .7 |
| Males; N (%) | 45 (63) | 46 (60) | .72 | 11 (65) | 34 (63) | .9 |
| Leukocytes × 109/L; median (range) | 5.5 (1.5–13.1) | 7.5 (1.9–25.3) | <.001 | 3.6 (1.5–10.4) | 6.1 (2.6–13.1) | <.001 |
| ALCaa Absolute lymphocyte count (ALC) Mayo Clinic reference range 0.95–3.07 × 109/L. ; median (range) |
1.6 (0.25–3.57) | 1.56 (0.27–10.71) | .43 | 0.64 (0.25–0.92) | 1.72 (1–3.57) | N/A |
| ALC <1 × 109/L; N (%) | 17 (24) | 15 (20) | .54 | 17 (100) | 0 (0) | N/A |
| Absolute neutrophil count; median (range) | 3 (0.38–9.36) | 4.6 (0.17–19.6) | <.001 | 2.39 (0.38–9.36) | 3.45 (0.55–8.11) | .07 |
| Absolute neutrophil count <1 × 109/L; N (%) | 5 (7) | 2 (3) | .21 | 3 (18) | 2 (4) | .05 |
| Absolute monocyte count; median (range) | 0.41 (0.06–1.3) | 0.5 (0.03–2.78) | .05 | 0.25 (0.07–0.75) | 0.47 (0.06–1.3) | .008 |
| Hemoglobin in g/dL; median (range) | 9.5 (7–13.5) | 9.5 (6.6–14.5) | .8 | 9.2 (7–11.9) | 9.8 (7–13.5) | .1 |
| Hemoglobin <10 g/dL; N (%) | 46 (65) | 51 (67) | .77 | 15 (88) | 31 (57) | .02 |
| Platelets × 109/L; median (range) | 271 (62–599) | 585 (454–1741) | N/A | 193 (62–410) | 284 (75–599) | .002 |
| Platelets ≥450 × 109/L; N (%) | 10 (14) | 76 (100) | N/A | 0 (0) | 10 (18) | .06 |
| Platelets <100 × 109/L; N (%) | 2 (3) | 0 (0) | N/A | 1 (6) | 1 (2) | .38 |
| SF3B1 mutation; N (%) | 71 (100) | 45 (92) N evaluated = 49 |
.01 | 17 (100) | 54 (100) | N/A |
| JAK2 mutation; N (%) | 1(1) | 13 (30) N evaluated = 43 |
<.001 | 0 (0) | 1 (2) | .57 |
| ASXL1 mutation; N (%) | 8(11) | 10 (20) N evaluated = 49 | .17 | 1 (6) | 7 (13) | .42 |
| Karyotype | .22 | .29 | ||||
| NN; N (%) | 60 (84) | 55 (76) | 13 (76) | 47 (87) | ||
| Sole -Y; N (%) | 3(4) | 5 (7) | 0 (0) | 3 (6) | ||
| Abnormal; N (5) | 8 (11) | 12 (17) N evaluated = 72 |
4 (23) | 4 (7) | ||
| IPSS-R cytogenetics risk category | .27 | .1 | ||||
| Very good; N (%) | 2 (3) | 5 (7) | 0 | 2 (4) | ||
| Good; N (%) | 62 (87) | 58 (81) | 13 (76) | 49 (91) | ||
| Intermediate; N (%) | 6 (8) | 4 (6) | 3 (18) | 3 (6) | ||
| Poor; N (%) | 0 (0) | 3 (4) | 0 (0) | 0 (0) | ||
| Very poor; N (%) | 1 (1) | 2 (3) N evaluated = 72 |
1 (6) | 0 (0) | ||
| IPSS-R overall risk category | .82 | .04 | ||||
| Very low; N (%) | 24 (34) | 18 (29) | 3 (18) | 21 (39) | ||
| Low; N (%) | 42 (59) | 38 (62) | 11 (65) | 31 (57) | ||
| Intermediate; N (%) | 3 (4) | 2(3) | 1 (6) | 2 (4) | ||
| High; N (%) | 2 (3) | 2 (3) | 2 (12) | (0) | ||
| Very high; N (%) | 0 (0) | 1(2) N evaluated = 61 |
0 (0) | (0) | ||
| Bone marrow RS %; median (range) | 40 (15–80) | 47 (15–90) | .33 | 35 (15–80) | 42 (15–80) | .7 |
| Postdiagnosis events | ||||||
| Median follow-up for patients alive; median years (range) | 2.1 (0–17.4) | 2.75 (0–14.4) | .45 | 0.79 (0.17–2.1) | 3.7 (0–17.4) | .15 |
| Deaths; N (%) | 46 (65) | 36 (47) | .03 | 11 (65) | 35 (65) | .99 |
| Leukemic transformation; N (%) | 2 (3) | 2 (3) | .94 | 1 (6) | 1 (2) | .38 |
- Note: Bold values indicate statistically significant P values (P<0.05).
- Abbreviations: ALC, absolute lymphocyte count; IPSS, International Prognostic Scoring System; IPSS-R, revised IPSS; MDS, myelodysplastic syndromes; MDS-RS, MDS with ring sideroblasts; MDS/MPN-RS-T, myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis.
- a Absolute lymphocyte count (ALC) Mayo Clinic reference range 0.95–3.07 × 109/L.
The prevalence of ALC < 1.0 × 109/L and ALC <1.2 × 109/L was 24% (n = 17) and 31% (n = 22), respectively, in MDS-RS and 20% (n = 15) and 29% (n = 22), respectively, in MDS/MPN-RS-T. In univariate analysis, the detrimental impact of ALC < 1.0/1.2 × 109/L on survival was evident in MDS-RS (p < .001/.001; Figure 1B) but not in MDS/MPN-RS-T (p = .3/.4; Figure 1C). Considering the higher strength of survival segregation at ALC cutoff of 1.0 (hazard ratio [HR] 4.3; 95% confidence interval [CI] 2.1–8.8) versus 1.2 (HR 2.9; 95% CI 1.5–5.6), further survival analysis in MDS-RS was performed using the ALC cutoff of 1.0 × 109/L; we should also note that the ROC analysis determined optimal ALC cutoff level was 1.1 × 109/L, but we chose the 1.0 × 109/L as the clinically more consistent cutoff level for “lymphocytopenia,” considering the institutional ALC reference range of 0.95–3.07 × 109/L. As outlined in Table 1, MDS-RS patients with ALC < 1 × 109/L, compared to their counterparts with higher ALC, were more likely to display neutropenia, severe anemia, thrombocytopenia, and lower absolute monocyte count, whereas the distribution of age, sex, and cytogenetic risk categories were similar between the two groups. On multivariable analysis, the prognostic impact of ALC <1.0 × 109/L (p < .001) eclipsed that of IPSS-R (p = .16). On the other hand, age as a continuous variable (p = .04), hemoglobin < 10 g/dL (p = .04; HR 1.9, 95% CI 1.02–3.6), IPSS-R cytogenetic risk profile (p = .04; intermediate vs. very good/good HR 4.9; 95% CI 1.6–14.6) retained significance in a multivariable model that included ALC < 1,0 × 109/L (p < .001; HR 4.3, 95% CI 2.0–9.1). No other variable, including those that clustered with ALC < 1.0 × 109/L (Table 1), showed additional significance. The number of leukemic events was too low to allow assessment of leukemia-free survival.
The current study confirms the special relevance of MDS-RS on previously reported associations between ALC and survival in primary MDS, as was astutely pointed out by Silzle et al.,6 in the latter study, the authors analyzed 721 patients with primary MDS and were able to demonstrate a significant association between ALC < 1.2 × 109/L and reduced survival among 42 patients with MDS-RS-SLD (p < .001; median survival 62 vs. 155 months), but not among other low-risk WHO-defined subcategories, including MDS-RS-MLD (p = .3), MDS-SLD (p = .3), MDS-MLD (p = .4), and MDS del(5q) (p = .2). Whether or not these observed significance levels would have changed had they used an ALC cutoff of 1 × 109/L remains to be followed up by the authors; of note, in the current study, a significant association was also apparent for ALC < 1.2 × 109/L in MDS-RS (p = .001). The current study did not distinguish between MDS-RS-SLD and MDS-RS-MLD because of sample size restriction; however, the significant association between ALC < 1.0 × 109/L (p < .001) and reduced survival in MDS-RS remained intact during multivariable analysis that accounted for thrombocytopenia (platelet count < 100 × 109/L; p = .15), neutropenia (ANC < 1.8 × 109/L; p = .5), and anemia (hemoglobin < 10 g/dL; p = .04). Importantly, we show that the survival impact of lymphocytopenia might not hold true in the context of MDS/MPN-RS-T, which otherwise shares morphologic (RS ≥ 15%) and molecular (SF3B1 mutation) similarities to MDS-RS; in this regard, the exclusion of patients with platelet count > 450 × 109/L in MDS-RS or those with JAK2V617F in MDS/MPN-RS-T did not alter the influence of ALC < 1.0 × 109/L on survival (p values <.001 and .7, respectively). Whether or not lymphocytopenia in MDS-RS constitutes a component of a clone-intrinsic defect in the effective hematopoiesis or additionally contributes to myeloid-lineage cytopenias remains to be clarified. The latter possibility suggests a potentially salutary effect for immune modulation as a treatment option, as in the case of lenalidomide treatment-associated modulation of the BM immune microenvironment in MDS.8 Regardless, the observation from the current study argues for the inclusion of ALC in future prognostic models for MDS-RS.
中文翻译：
淋巴细胞减少可预测骨髓增生异常综合征伴环状铁粒幼细胞 (MDS-RS) 的生存期缩短，但在 MDS/MPN-RS-T 中则不然
10 多年前，我们描述了绝对淋巴细胞计数 (ALC) 与骨髓增生异常综合征 (MDS) 生存率之间的关联，其中有1 个或没有2 个del(5q)；后一项研究包括 503 名非 del(5q) MDS 患者，报告 ALC < 1.2 × 10 9 /L 患者的中位生存期为 18.5 个月，而 ALC ≥ 1.2 × 10 9 /L 的患者中位生存期为 26.6 个月（p < . 001); 2 ALC 在研究中的预后贡献被证明独立于国际预后评分系统 (IPSS)。3在随后对 889 名原发性 MDS 患者进行的更大规模研究中，4我们证实了 ALC < 1.2 × 10 9的预后相关性/L，在修订后的 IPSS (IPSS-R) 的背景下，为5 ，尽管显着性处于临界值 ( p = .06)。4最近，另一项回顾性研究证实了这些观察结果，该研究对杜塞尔多夫 MDS 登记处的 1023 名患者进行了调查，其中包括治疗相关病例和 del(5q) 病例；6 ALC < 1.2 × 10 9 /L 与更短的生存期相关，这与年龄或细胞遗传学风险组无关； 然而，在考虑了骨髓 (BM) 原始细胞百分比和血细胞减少程度后，显着性消失了 ( p = .09)。值得注意的是，杜塞尔多夫研究6包括 140 名伴有环状铁粒幼细胞 (MDS-RS)、单系 (SLD) 或多系 (MLD) 发育不良的 MDS 患者，ALC < 1.2 × 10 9 /L 的预后相关性在 MDS-RS-SLD 中最为明显。6本研究的目的是检查MDS-RS 和骨髓增生异常/骨髓增生性肿瘤中淋巴细胞减少（ALC < 1.0 或 1.2 × 10 9 /L；Mayo Clinic 参考范围 0.95–3.07 × 10 9 /L）的预后相关性伴有 RS 和血小板增多症 (MDS/MPN-RS-T)。
在获得机构审查委员会的批准后，我们查询了 Mayo Clinic 骨髓肿瘤数据库，以确定 147 名符合 2016 年世界卫生组织 (WHO) MDS-RS ( n = 71) 或 MDS/MPN-RS-诊断标准的患者。 T ( n = 76)。7主要诊断标准是 MDS-RS 和 MDS/MPN-RS-T 至少存在 15% 的 BM RS，在 MDS-RS 的情况下，还包括与SF3B1相关的 ≥ 5% BM RS 的患者突变。两个实体的其他必需诊断标准包括存在 < 5% 的 BM 原始细胞，< 1% 的外周血 (PB) 原始细胞，对于 MDS/MPN-RS-T，存在血小板计数 ≥ 450 × 10 9/L 排除标准包括 Auer 棒的存在、MDS 的诊断标准与孤立的 del(5q)、t(3;3)(q21.3;q26.2)、inv (3)(q21.3q26.2)、BCR:ABL1或PDGFRA、PDGFRB、FGFR1、PCM1-JAK2的其他重排。7常规方法用于细胞遗传学和二代测序研究。统计分析考虑了诊断时的参数，并使用 JMP Pro 14.0.0 软件包，SAS Institute，Cary，NC 进行。
表 1 概述了 71 名 MDS-RS 研究患者（中位年龄 73 岁，范围 41-94；男性 63%）和 76 名 MDS/MPN-RS-T 患者（中位73 岁，范围 49-93；男性 61%）。MDS-RS 的 IPSS-R 风险分布为 34% 非常低、59% 低、4% 中等、3% 高和 0% 非常高；MDS/MPN-RS-T 的相应数字分别为 29%、62%、3%、3% 和 2%。SF3B1、JAK2和ASXL1突变频率对于 MDS-RS 分别为 100%、1% 和 11%，对于 MDS/MPN-RS-T 分别为 92%、30% 和 20%。MDS-RS 与 MDS/MPN-RS-T 患者的比较显示前者具有较低的绝对中性粒细胞计数（ANC；中位数 3 对 4.6 × 10 9 /L；p = .002），后者具有更高的绝对单核细胞计数（AMC；中位数 0.4 对 0.5 × 10 9 /L；p = .05），但其他方面的 ALC 相似（中位数 1.6 对 1.6 × 10 9 /L；p = .4)、贫血程度（65% vs. 67% 的血红蛋白 <10 g/dL；p = .8）和 IPSS-R 细胞遗传学和总体风险分布（p = .3 和 .8，分别）。MDS-RS 存活患者的中位随访时间为 2.1 年，MDS/MPN-RS-T 患者的中位随访时间为 2.8 年。在随访期间，MDS-RS 记录了 46 例（65%）死亡和 2 例（2.8%）白血病转化，MDS/MPN-RS-T 记录了 36 例（47%）死亡和 2 例（2.6%）白血病转化。MDS-RS（中位 5.4 年）和 MDS/MPN-RS-T（中位 5.6 年；图 1A； p = .98）的总生存期数据相似。
| 诊断时的变量 | MDS-RS ( N = 71) | MDS/MPN-RS-T ( N = 76) | p值 | ALC <1 × 10 9 /L ( N = 17)的 MDS-RS | ALC ≥1 × 10 9 /L ( N = 54)的 MDS-RS | p值 |
|---|---|---|---|---|---|---|
| 年龄（中位数；范围） | 73 (41–94) | 72 (49–93) | .74 | 74 (41–94) | 73 (45–88) | .7 |
| 男性；氮(%) | 45 (63) | 46 (60) | .72 | 11 (65) | 34 (63) | .9 |
| 白细胞×10 9 /L；中位数（范围） | 5.5 (1.5–13.1) | 7.5 (1.9–25.3) | <.001 | 3.6 (1.5–10.4) | 6.1 (2.6–13.1) | <.001 |
| 阿尔茨海默氏症a 绝对淋巴细胞计数 (ALC) Mayo Clinic 参考范围 0.95–3.07 × 10 9 /L。 ; 中位数（范围） |
1.6 (0.25–3.57) | 1.56 (0.27–10.71) | .43 | 0.64 (0.25–0.92) | 1.72 (1–3.57) | 不适用 |
| ALC <1×10 9 /L；氮(%) | 十七 (24) | 15 (20) | .54 | 17 (100) | 0 (0) | 不适用 |
| 中性粒细胞绝对计数；中位数（范围） | 3 (0.38–9.36) | 4.6 (0.17–19.6) | <.001 | 2.39 (0.38–9.36) | 3.45 (0.55–8.11) | .07 |
| 中性粒细胞绝对计数<1×10 9 /L；氮(%) | 5 (7) | 2 (3) | .21 | 3 (18) | 2 (4) | .05 |
| 绝对单核细胞计数；中位数（范围） | 0.41 (0.06–1.3) | 0.5 (0.03–2.78) | .05 | 0.25 (0.07–0.75) | 0.47 (0.06–1.3) | .008 |
| 以 g/dL 为单位的血红蛋白；中位数（范围） | 9.5 (7–13.5) | 9.5 (6.6–14.5) | .8 | 9.2 (7–11.9) | 9.8 (7–13.5) | .1 |
| 血红蛋白 <10 g/dL；氮(%) | 46 (65) | 51 (67) | .77 | 15 (88) | 31 (57) | .02 |
| 血小板×10 9 /L；中位数（范围） | 271 (62–599) | 585 (454–1741) | 不适用 | 193 (62–410) | 284 (75–599) | .002 |
| 血小板≥450×10 9 /L；氮(%) | 10 (14) | 76 (100) | 不适用 | 0 (0) | 10 (18) | .06 |
| 血小板<100×10 9 /L；氮(%) | 2 (3) | 0 (0) | 不适用 | 1 (6) 个 | 1 (2) 个 | .38 |
| SF3B1突变；氮(%) | 71 (100) | 45 (92) N 评估 = 49 |
.01 | 17 (100) | 54 (100) | 不适用 |
| JAK2突变；氮(%) | 1(1) | 十三 (30) N 评估 = 43 |
<.001 | 0 (0) | 1 (2) 个 | .57 |
| ASXL1突变；氮(%) | 8(11) | 10 (20) N 评估 = 49 | .17 | 1 (6) 个 | 七 (13) | .42 |
| 核型 | .22 | .29 | ||||
| 神经网络；氮(%) | 60 (84) | 55 (76) | 13 (76) | 47 (87) | ||
| 鞋底-Y；氮(%) | 3(4) | 5 (7) | 0 (0) | 3 (6) | ||
| 异常的; N (5) | 8 (11) | 十二 (17) N 评估 = 72 |
4 (23) | 4 (7) | ||
| IPSS-R 细胞遗传学风险类别 | .27 | .1 | ||||
| 很好; 氮(%) | 2 (3) | 5 (7) | 0 | 2 (4) | ||
| 好的; 氮(%) | 62 (87) | 58 (81) | 13 (76) | 49 (91) | ||
| 中间的; 氮(%) | 6 (8) | 4 (6) | 3 (18) | 3 (6) | ||
| 较差的; 氮(%) | 0 (0) | 3 (4) | 0 (0) | 0 (0) | ||
| 很穷; 氮(%) | 1 (1) | 2 (3) N 评估 = 72 |
1 (6) 个 | 0 (0) | ||
| IPSS-R 总体风险类别 | .82 | .04 | ||||
| 非常低; 氮(%) | 24 (34) | 十八 (29) | 3 (18) | 21 (39) | ||
| 低的; 氮(%) | 42 (59) | 38 (62) | 11 (65) | 31 (57) | ||
| 中间的; 氮(%) | 3 (4) | 2(3) | 1 (6) 个 | 2 (4) | ||
| 高的; 氮(%) | 2 (3) | 2 (3) | 2 (12) | (0) | ||
| 很高; 氮(%) | 0 (0) | 1(2) N 评估 = 61 |
0 (0) | (0) | ||
| 骨髓 RS %；中位数（范围） | 40 (15–80) | 47 (15–90) | .33 | 35 (15–80) | 42 (15–80) | .7 |
| 诊断后事件 | ||||||
| 存活患者的中位随访；年中位数（范围） | 2.1 (0–17.4) | 2.75 (0–14.4) | .45 | 0.79 (0.17–2.1) | 3.7 (0–17.4) | .15 |
| 死亡人数; 氮(%) | 46 (65) | 36 (47) | .03 | 11 (65) | 35 (65) | .99 |
| 白血病转化；氮(%) | 2 (3) | 2 (3) | .94 | 1 (6) 个 | 1 (2) 个 | .38 |
- 注：粗体值表示具有统计学意义的 P 值（P<0.05）。
- 缩写：ALC，绝对淋巴细胞计数；IPSS，国际预后评分系统；IPSS-R，修订后的 IPSS；MDS，骨髓增生异常综合征；MDS-RS，带环形铁粒幼细胞的 MDS；MDS/MPN-RS-T，骨髓增生异常/骨髓增生性肿瘤伴 RS 和血小板增多。
- a 绝对淋巴细胞计数 (ALC) Mayo Clinic 参考范围 0.95–3.07 × 10 9 /L。
MDS-RS中 ALC < 1.0 × 10 9 /L 和 ALC <1.2 × 10 9 /L 的患病率分别为 24%（n = 17）和 31%（n = 22）和 20%（n = 15 ） ) 和 29% ( n = 22)，分别在 MDS/MPN-RS-T 中。在单变量分析中，ALC < 1.0/1.2 × 10 9 /L 对生存的不利影响在 MDS-RS 中很明显（p < .001/.001；图 1B），但在 MDS/MPN-RS-T（p = .3/.4；图 1C)。考虑到 ALC 截止值为 1.0（风险比 [HR] 4.3；95% 置信区间 [CI] 2.1-8.8）与 1.2（HR 2.9；95% CI 1.5-5.6）相比，生存分离强度更高，在 MDS 中进行进一步的生存分析-RS 使用 1.0 × 10 9 /L 的 ALC 截止值进行；我们还应该注意到，ROC 分析确定最佳 ALC 截止水平为 1.1 × 10 9 / L，但考虑到机构 ALC 参考范围0.95～3.07×10 9 /L。如表 1 所述，ALC < 1 × 10 9的 MDS-RS 患者/L 与具有较高 ALC 的对应物相比，更容易出现中性粒细胞减少、严重贫血、血小板减少和较低的绝对单核细胞计数，而两组之间的年龄、性别和细胞遗传学风险类别的分布相似。在多变量分析中，ALC <1.0 × 10 9 /L ( p < .001)的预后影响 超过了 IPSS-R ( p = .16)。另一方面，年龄作为连续变量 ( p = .04)，血红蛋白 < 10 g/dL ( p = .04；HR 1.9, 95% CI 1.02–3.6)，IPSS-R 细胞遗传学风险概况 ( p = . 04；中等 vs. 非常好/好 HR 4.9；95% CI 1.6–14.6) 在包括 ALC < 1,0 × 10 9的多变量模型中保持显着性/L ( p < .001; HR 4.3, 95% CI 2.0–9.1)。没有其他变量，包括那些与 ALC < 1.0 × 10 9 /L 聚类的变量（表 1），显示出额外的意义。白血病事件的数量太少，无法评估无白血病存活率。
目前的研究证实了 MDS-RS 与先前报道的 ALC 与原发性 MDS 生存之间的关联的特殊相关性，正如 Silzle 等人6敏锐地指出的那样，在后一项研究中，作者分析了 721 名原发性 MDS 患者，并在能够证明 ALC < 1.2 × 10 9 /L 与 42 名 MDS-RS-SLD 患者的生存期降低之间存在显着相关性（p < .001；中位生存期 62 个月与 155 个月），但在其他低风险 WHO 中没有- 定义的子类别，包括 MDS-RS-MLD ( p = .3)、MDS-SLD ( p = .3)、MDS-MLD ( p = .4) 和 MDS del(5q) ( p = .2)。如果使用 1 × 10 9 /L的 ALC 截止值，这些观察到的显着性水平是否会发生变化仍有待作者跟进；值得注意的是，在目前的研究中，ALC < 1.2 × 10 9 /L 在 MDS-RS中也有明显的相关性（ p = .001）。由于样本量的限制，目前的研究没有区分 MDS-RS-SLD 和 MDS-RS-MLD；然而，在多变量分析中，ALC < 1.0 × 10 9 /L ( p < .001) 与 MDS-RS 存活率降低之间的显着关联仍然完好无损（血小板计数 < 100 × 10 9 /L；p = . 15)、中性粒细胞减少症 (ANC < 1.8 × 10 9/L; p = .5）和贫血（血红蛋白 < 10 g/dL；p = .04）。重要的是，我们表明在 MDS/MPN-RS-T 的背景下，淋巴细胞减少对生存的影响可能并不成立，否则它与 MDS-RS 具有形态学（RS ≥ 15%）和分子（SF3B1突变）相似性；在这方面，排除 MDS-RS 中血小板计数 > 450 × 10 9 /L 或MDS/MPN-RS-T 中JAK2 V617F 的患者并没有改变 ALC < 1.0 × 10 9 /L生存（p值分别 <.001 和 .7）。MDS-RS 中的淋巴细胞减少是否构成有效造血过程中的克隆固有缺陷的一个组成部分，或者是否另外导致髓系血细胞减少仍有待澄清。后一种可能性表明免疫调节作为一种治疗选择具有潜在的有益效果，例如来那度胺治疗相关的 MDS 中 BM 免疫微环境的调节。8不管怎样，当前研究的观察结果支持将 ALC 纳入未来 MDS-RS 的预后模型中。
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