Yang Liu

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松开那只锚——造血干细胞如何离开骨髓,以及那些动员不出来的人 Loosening the Anchor — How Hematopoietic Stem Cells Leave the Marrow, and the People Who Don't Mobilize

2026-10-09 · hsc100, mobilization, CXCR4, CXCL12, G-CSF, plerixafor, motixafortide, apheresis, sickle cell disease

外周血里几乎找不到造血干细胞:健康志愿者每微升血液里,CD34⁺ 细胞只有几个。而一场自体移植,或一剂 ex vivo 基因治疗,需要的是按每公斤体重计、以百万为单位的细胞。这些细胞平时待在骨髓里,被一只看不见的锚拴着。要让它们出来,就得先弄清这只锚是什么、怎么松开,以及为什么对有些人,锚怎么也松不动。

骨髓里的锚

这只锚的主体是趋化因子 CXCL12(早年称 SDF-1)和它在造血干细胞表面的受体 CXCR4。1996 年,Nagasawa 等人在 Nature 上报告,敲除该趋化因子基因的小鼠在围产期死亡,骨髓里的髓系祖细胞明显减少,而胎肝里并不减少——这条轴从一开始就与”骨髓”这个地点绑在一起。2006 年,Sugiyama 等人在 Immunity 上进一步发现,在成年小鼠中诱导性删除 CXCR4,造血干细胞数量会严重下降。同一条轴也管着回家的路:1999 年,Peled 等人在 Science 上报告,用抗体处理人类细胞上的 CXCR4,它们就无法在 NOD/SCID 小鼠体内植入。

G-CSF:拆锚,而且是间接拆

最早成为临床标准的动员剂 G-CSF,并不直接去拉干细胞。2002 年,Petit 等人在 Nature Immunology 上报告,G-CSF 动员期间骨髓里的 SDF-1 逐步下降,主要因为被中性粒细胞弹性蛋白酶降解,下降幅度与动员程度相关;抑制弹性蛋白酶会同时削弱两者,而用抗体中和 CXCR4 或 SDF-1,则能抑制人和小鼠的动员。2003 年,Lévesque 等人在 J Clin Invest 上补充:在小鼠中,被动员的祖细胞上 CXCR4 的 N 端被切断,骨髓里 SDF-1 的浓度下降,同时积累着能切断它的丝氨酸蛋白酶,作者认为这可能是动员的关键一步。更反直觉的是,Liu 等人 2000 年在 Blood 上用嵌合小鼠证明,被动员的祖细胞自己并不需要表达 G-CSF 受体,G-CSF 的信号是”反式”起作用的。这些主要来自小鼠的结果合在一起,提示 G-CSF 是经由骨髓微环境里的蛋白酶等间接环节削弱 CXCL12–CXCR4 的滞留作用,而不是对干细胞下达直接指令;各环节的相对贡献,这些研究并没有给出定论。临床上通常每天 10 μg/kg,连打数天。

Plerixafor:直接堵受体

既然锚是 CXCL12–CXCR4,堵住受体便是更直接的办法。2005 年,Broxmeyer 等人在 J Exp Med 上报告,CXCR4 拮抗剂 AMD3100(即 plerixafor)能在小鼠和人中快速动员造血干祖细胞,与 G-CSF 有协同作用,动员到的人 CD34⁺ 细胞能在 NOD/SCID 小鼠中重建造血。2003 年 Liles 等人在 Blood 上给健康志愿者单次皮下注射:240 μg/kg 后,外周血 CD34⁺ 细胞从每微升 2.6 个升到 9 小时的 40.4 个——几个小时,而不是几天。

两项 III 期随机双盲试验把它推入临床,两组都在 G-CSF 10 μg/kg 的基础上加 plerixafor 240 μg/kg 或安慰剂。2009 年,DiPersio 等人报告了结果:在非霍奇金淋巴瘤(NCT00103610,J Clin Oncol)中,以 4 次以内的采集达到 5×10⁶ CD34⁺/kg 的比例为 59% 对 20%;在多发性骨髓瘤(NCT00103662,Blood)中,以 2 次以内的采集达到 6×10⁶/kg 的比例为 71.6% 对 34.4%。plerixafor 随后在 2008 年获 FDA 批准,美国说明书的适应症是联合 G-CSF,用于非霍奇金淋巴瘤或多发性骨髓瘤患者的自体移植。同一份说明书也提醒,与 G-CSF 合用时,肿瘤细胞可能随之从骨髓释放并进入采集物,白血病患者不应使用。

动员失败者

即使有了这些药,仍有人采不出足够的细胞。2010 年,Wuchter 等人在 Biol Blood Marrow Transplant 上分析了一个中心 840 名拟行自体移植的骨髓瘤和淋巴瘤患者:129 人(15.3%)在 G-CSF 刺激峰值时 CD34⁺ 浓度低于每微升 20 个,被他们定义为”poor mobilization”;既往化疗的周期数和曾用 melphalan 与此显著相关。plerixafor 也被用在这类患者身上:2008 年 Calandra 等人在 Bone Marrow Transplant 上报告了 115 名在先前动员中失败的患者的同情用药数据,以采到 ≥2×10⁶ CD34⁺/kg 为目标,成功率在淋巴瘤中为 60.3%、骨髓瘤中 71.4%、霍奇金病 76.5%(这是非随机的同情用药数据)。

提升动员效率的另一条路是换更强、更久的拮抗剂。2023 年,Crees 等人在 Nature Medicine 上报告了 III 期 GENESIS 试验(NCT03246529):122 名多发性骨髓瘤患者按 2:1 随机接受 motixafortide 或安慰剂,均联合 G-CSF。motixafortide 是一种作用时间更长的环肽类 CXCR4 抑制剂;主要终点——两次采集内达到 ≥6×10⁶ CD34⁺/kg——在 motixafortide 组为 92.5%,对照组 26.2%;一次采集内达标则是 88.8% 对 9.5%。它于 2023 年获 FDA 批准,联合 filgrastim 用于多发性骨髓瘤患者的自体移植动员。

镰刀型贫血:最需要它的人

在镰刀型贫血里,这套标准流程被改写了。2009 年,Fitzhugh 等人在 Cytotherapy 上汇总:当时文献中共有 11 名 SCD 患者使用过 G-CSF,其中 7 人出现严重不良事件,包括血管闭塞发作、急性胸综合征、多器官衰竭和死亡;减量、分次、输血降低 HbS 等预防措施都没有带来一致的获益,作者建议除非别无选择,应避免常规使用。

于是 plerixafor 被单独拿来试。2018 年,同一期 Haematologica 上有两项研究:Boulad 等人的剂量递增研究(NCT02193191)中,15 名患者里仅 1 人长期输血、10 人在服 hydroxyurea,只有 8 人外周血 CD34⁺ 浓度超过每微升 30 个,且没有清楚的剂量反应,两人分别在 80 和 240 μg/kg 剂量下发作了血管闭塞危象,作者认为 hydroxyurea 可能是动员不足的原因之一;Lagresle-Peyrou 等人(NCT02212535)则先用红细胞置换把 HbS 压到 30% 以下再单次注射,未观察到不良事件,动员到的细胞富含造血干细胞,能高效植入免疫缺陷小鼠。

2021 年,Esrick 等人在 N Engl J Med 上报告 BCL11A shmiR 慢病毒基因治疗(NCT03282656),动员环节采用了停 hydroxyurea、输血、plerixafor 的做法:6 名 7–25 岁的患者在回输前至少 3 个月停用 hydroxyurea 并开始输血,以 240 μg/kg plerixafor 动员,一轮动员采集的 CD34⁺ 细胞产物中位数为每公斤 930 万个(范围 780 万至 1140 万);产量依然因人而异:Leonard 等人 2021 年在 Blood Advances 上报告 23 名 SCD 患者,两轮以内采到的 CD34⁺ 中位数为每公斤 400 万个,范围 150 万至 1200 万;产量与停用 hydroxyurea 的天数正相关(最长至 5 周),与前一年的住院次数、长期服用的止痛药种类数负相关——病得越重,越难采到,这是相关性,并非已证明的因果。

还在试的组合

motixafortide 也被带进了 SCD:一项 Phase 1 试验(NCT05618301)在接受红细胞置换的成年患者中,先单次给 motixafortide,再检验它与 natalizumab(阻断另一对黏附分子 VLA-4/VCAM-1)联用,作为基因治疗的动员方案;研究假设是同时阻断两条通路会比单用更有效。本文写作时没有查到该试验经同行评议的结果。

回到开头那只锚。对多数患者,拆锚是一件几天或几小时就能完成的事;对另一部分人,是骨髓本身的状态——既往治疗、疾病、用药——决定了锚能被松开多少。而 ex vivo 基因治疗恰恰把这一步变成了必经之路:没有被松开的细胞,后面的编辑和制造便无从谈起。

参考文献

  1. Nagasawa T, Hirota S, Tachibana K, et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature. 1996;382(6592):635-638. DOI
  2. Sugiyama T, Kohara H, Noda M, Nagasawa T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity. 2006;25(6):977-988. DOI
  3. Peled A, Petit I, Kollet O, et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science. 1999;283(5403):845-848. DOI
  4. Petit I, Szyper-Kravitz M, Nagler A, et al. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol. 2002;3(7):687-694. DOI
  5. Lévesque JP, Hendy J, Takamatsu Y, Simmons PJ, Bendall LJ. Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. J Clin Invest. 2003;111(2):187-196. DOI
  6. Liu F, Poursine-Laurent J, Link DC. Expression of the G-CSF receptor on hematopoietic progenitor cells is not required for their mobilization by G-CSF. Blood. 2000;95(10):3025-3031. DOI
  7. Broxmeyer HE, Orschell CM, Clapp DW, et al. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med. 2005;201(8):1307-1318. DOI
  8. Liles WC, Broxmeyer HE, Rodger E, et al. Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist. Blood. 2003;102(8):2728-2730. DOI
  9. DiPersio JF, Micallef IN, Stiff PJ, et al. Phase III prospective randomized double-blind placebo-controlled trial of plerixafor plus granulocyte colony-stimulating factor compared with placebo plus granulocyte colony-stimulating factor for autologous stem-cell mobilization and transplantation for patients with non-Hodgkin’s lymphoma. J Clin Oncol. 2009;27(28):4767-4773. DOI
  10. DiPersio JF, Stadtmauer EA, Nademanee A, et al. Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood. 2009;113(23):5720-5726. DOI
  11. Mozobil (plerixafor) injection, US Prescribing Information. Genzyme; 2020. FDA label
  12. Wuchter P, Ran D, Bruckner T, et al. Poor mobilization of hematopoietic stem cells-definitions, incidence, risk factors, and impact on outcome of autologous transplantation. Biol Blood Marrow Transplant. 2010;16(4):490-499. DOI
  13. Calandra G, McCarty J, McGuirk J, et al. AMD3100 plus G-CSF can successfully mobilize CD34+ cells from non-Hodgkin’s lymphoma, Hodgkin’s disease and multiple myeloma patients previously failing mobilization with chemotherapy and/or cytokine treatment: compassionate use data. Bone Marrow Transplant. 2008;41(4):331-338. DOI
  14. Crees ZD, Rettig MP, Jayasinghe RG, et al. Motixafortide and G-CSF to mobilize hematopoietic stem cells for autologous transplantation in multiple myeloma: a randomized phase 3 trial. Nat Med. 2023;29(4):869-879. DOI
  15. APHEXDA (motixafortide) for injection, US Prescribing Information. BioLineRx; revised 9/2023. FDA label
  16. Fitzhugh CD, Hsieh MM, Bolan CD, Saenz C, Tisdale JF. Granulocyte colony-stimulating factor (G-CSF) administration in individuals with sickle cell disease: time for a moratorium? Cytotherapy. 2009;11(4):464-471. DOI
  17. Boulad F, Shore T, van Besien K, et al. Safety and efficacy of plerixafor dose escalation for the mobilization of CD34+ hematopoietic progenitor cells in patients with sickle cell disease: interim results. Haematologica. 2018;103(5):770-777. DOI
  18. Lagresle-Peyrou C, Lefrère F, Magrin E, et al. Plerixafor enables safe, rapid, efficient mobilization of hematopoietic stem cells in sickle cell disease patients after exchange transfusion. Haematologica. 2018;103(5):778-786. DOI
  19. Esrick EB, Lehmann LE, Biffi A, et al. Post-transcriptional genetic silencing of BCL11A to treat sickle cell disease. N Engl J Med. 2021;384(3):205-215. DOI
  20. Leonard A, Sharma A, Uchida N, et al. Disease severity impacts plerixafor-mobilized stem cell collection in patients with sickle cell disease. Blood Adv. 2021;5(9):2403-2411. DOI
  21. ClinicalTrials.gov NCT05618301: A pilot safety and feasibility study to evaluate motixafortide (CXCR4/SDF-1 inhibition) and natalizumab (VLA-4/VCAM-1 inhibition) as a novel regimen to mobilize CD34+ hematopoietic stem cells for gene therapy in sickle cell disease. 链接

Hematopoietic stem cells are almost impossible to find in peripheral blood: in healthy volunteers, CD34⁺ cells number only a few per microliter. Yet an autologous transplant, or a dose of ex vivo gene therapy, calls for cells counted per kilogram of body weight, in the millions. These cells normally stay in the marrow, tethered by an invisible anchor. To get them out, one first has to understand what the anchor is, how it is loosened, and why for some people it will not budge.

The anchor in the marrow

The core of the anchor is the chemokine CXCL12 (formerly SDF-1) and its receptor on the stem cell surface, CXCR4. In 1996, Nagasawa and colleagues reported in Nature that mice lacking this chemokine gene died perinatally and had markedly fewer myeloid progenitors in the bone marrow, but not in the fetal liver — so from the start this axis was tied to the place called the marrow. In 2006, Sugiyama and colleagues reported in Immunity that inducible deletion of CXCR4 in adult mice severely reduced hematopoietic stem cell numbers. The same axis also governs the way home: in 1999, Peled and colleagues reported in Science that treating human cells with an antibody against CXCR4 prevented them from engrafting in NOD/SCID mice.

G-CSF: loosening the anchor, indirectly

G-CSF, the first mobilizing agent to become clinical standard, does not pull on stem cells directly. In 2002, Petit and colleagues reported in Nature Immunology that during G-CSF mobilization, SDF-1 in the marrow progressively declined, mainly through degradation by neutrophil elastase, and the extent of the decline correlated with the extent of mobilization; inhibiting elastase weakened both together, while neutralizing CXCR4 or SDF-1 with antibodies suppressed mobilization in humans and mice. In 2003, Lévesque and colleagues added in J Clin Invest that in mice, the CXCR4 on mobilized progenitors had its N-terminus cleaved, the concentration of SDF-1 in the marrow fell, and serine proteases capable of cutting it accumulated; the authors suggested this may be a key step in mobilization. More counterintuitively, Liu and colleagues showed in 2000 in Blood, using chimeric mice, that mobilized progenitors do not themselves need to express the G-CSF receptor: the G-CSF signal acts in trans. Taken together, these results — mostly from mice — suggest that G-CSF weakens CXCL12–CXCR4 retention through indirect steps in the marrow microenvironment, such as proteases, rather than by issuing a direct command to the stem cell; the studies did not settle the relative contribution of each step. Clinically it is usually given at 10 μg/kg per day for several days.

Plerixafor: blocking the receptor directly

If the anchor is CXCL12–CXCR4, blocking the receptor is the more direct approach. In 2005, Broxmeyer and colleagues reported in J Exp Med that the CXCR4 antagonist AMD3100 (plerixafor) rapidly mobilized hematopoietic stem and progenitor cells in mice and humans, acted synergistically with G-CSF, and that the mobilized human CD34⁺ cells could reconstitute hematopoiesis in NOD/SCID mice. In 2003, Liles and colleagues gave healthy volunteers a single subcutaneous injection in Blood: after 240 μg/kg, peripheral blood CD34⁺ cells rose from 2.6 per microliter to 40.4 at 9 hours — a matter of hours, not days.

Two phase 3 randomized, double-blind trials moved it into the clinic; in both, patients received G-CSF 10 μg/kg plus either plerixafor 240 μg/kg or placebo. DiPersio and colleagues reported the results in 2009: in non-Hodgkin lymphoma (NCT00103610, J Clin Oncol), the proportion reaching 5×10⁶ CD34⁺/kg within 4 or fewer collections was 59% versus 20%; in multiple myeloma (NCT00103662, Blood), the proportion reaching 6×10⁶/kg within 2 or fewer collections was 71.6% versus 34.4%. Plerixafor was subsequently approved by the FDA in 2008, and the US label indication is in combination with G-CSF to mobilize cells for autologous transplantation in patients with non-Hodgkin lymphoma or multiple myeloma. The same label also warns that, when combined with G-CSF, tumor cells may be released from the marrow and enter the apheresis product, and that it should not be used in patients with leukemia.

When mobilization fails

Even with these drugs, some people cannot yield enough cells. In 2010, Wuchter and colleagues analyzed in Biol Blood Marrow Transplant 840 myeloma and lymphoma patients at one center who were candidates for autologous transplantation: 129 (15.3%) had a CD34⁺ concentration below 20 per microliter at the peak of G-CSF stimulation, which they defined as “poor mobilization”; the number of prior chemotherapy cycles and prior melphalan exposure were significantly associated with it. Plerixafor has also been used in such patients: in 2008, Calandra and colleagues reported in Bone Marrow Transplant compassionate-use data on 115 patients who had failed earlier mobilization, aiming to collect ≥2×10⁶ CD34⁺/kg, with success rates of 60.3% in lymphoma, 71.4% in myeloma and 76.5% in Hodgkin disease (these are non-randomized compassionate-use data).

Another route to better mobilization is a stronger, longer-acting antagonist. In 2023, Crees and colleagues reported in Nature Medicine the phase 3 GENESIS trial (NCT03246529): 122 patients with multiple myeloma were randomized 2:1 to motixafortide or placebo, both with G-CSF. Motixafortide is a longer-acting cyclic-peptide CXCR4 inhibitor; the primary endpoint — reaching ≥6×10⁶ CD34⁺/kg within two collections — was met by 92.5% in the motixafortide arm and 26.2% in the control arm; reaching the target in a single collection was 88.8% versus 9.5%. It was approved by the FDA in 2023, in combination with filgrastim, to mobilize cells for autologous transplantation in patients with multiple myeloma.

Sickle cell disease: the people who need it most

In sickle cell disease, this standard procedure is rewritten. In 2009, Fitzhugh and colleagues summarized in Cytotherapy: in the literature at that time, 11 SCD patients had received G-CSF, of whom 7 had serious adverse events, including vaso-occlusive episodes, acute chest syndrome, multi-organ failure and death; precautions such as dose reduction, split dosing, and lowering HbS by transfusion did not bring consistent benefit, and the authors advised avoiding routine use unless there was no alternative.

So plerixafor was tried on its own. In 2018, two studies appeared in the same issue of Haematologica. In the dose-escalation study by Boulad and colleagues (NCT02193191), of 15 patients only 1 was on chronic transfusion and 10 were taking hydroxyurea; only 8 had a peripheral blood CD34⁺ concentration above 30 per microliter, with no clear dose-response, and two patients had vaso-occlusive crises at doses of 80 and 240 μg/kg; the authors suggested hydroxyurea may be one reason for poor mobilization. Lagresle-Peyrou and colleagues (NCT02212535) first used red cell exchange to bring HbS below 30% and then gave a single injection; no adverse events were observed, and the mobilized cells were rich in hematopoietic stem cells and engrafted efficiently in immunodeficient mice.

In 2021, Esrick and colleagues reported in N Engl J Med the BCL11A shmiR lentiviral gene therapy (NCT03282656), whose mobilization step used stopping hydroxyurea, transfusion, and plerixafor: six patients aged 7–25 years stopped hydroxyurea and began transfusions at least 3 months before the infusion, were mobilized with plerixafor 240 μg/kg, and a single mobilization and collection yielded a median CD34⁺ cell product of 9.3 million cells per kilogram (range 7.8 million to 11.4 million). Yield nonetheless varies from person to person: Leonard and colleagues reported in 2021 in Blood Advances on 23 SCD patients, in whom the median CD34⁺ collected within two rounds was 4 million per kilogram, with a range of 1.5 million to 12 million; yield correlated positively with the number of days off hydroxyurea (up to 5 weeks) and negatively with the number of hospitalizations in the prior year and the number of chronically used pain medication classes — the sicker the patient, the harder the collection, though this is a correlation and not a demonstrated causal relationship.

Combinations still being tested

Motixafortide has also been taken into SCD: a phase 1 trial (NCT05618301) in adult patients undergoing red cell exchange first gives motixafortide alone, then tests it together with natalizumab (which blocks another adhesion pair, VLA-4/VCAM-1) as a mobilization regimen for gene therapy; the working hypothesis is that blocking both pathways at once will be more effective than either alone. At the time of writing, no peer-reviewed results for this trial could be found.

Back to the anchor at the start. For most patients, loosening it is something that takes days or hours; for others, the state of the marrow itself — prior therapy, the disease, the medications — determines how much the anchor can be loosened. And ex vivo gene therapy turns this step into a mandatory passage: without cells that have been freed, there is nothing to edit or manufacture afterward.

References

  1. Nagasawa T, Hirota S, Tachibana K, et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature. 1996;382(6592):635-638. DOI
  2. Sugiyama T, Kohara H, Noda M, Nagasawa T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity. 2006;25(6):977-988. DOI
  3. Peled A, Petit I, Kollet O, et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science. 1999;283(5403):845-848. DOI
  4. Petit I, Szyper-Kravitz M, Nagler A, et al. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol. 2002;3(7):687-694. DOI
  5. Lévesque JP, Hendy J, Takamatsu Y, Simmons PJ, Bendall LJ. Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. J Clin Invest. 2003;111(2):187-196. DOI
  6. Liu F, Poursine-Laurent J, Link DC. Expression of the G-CSF receptor on hematopoietic progenitor cells is not required for their mobilization by G-CSF. Blood. 2000;95(10):3025-3031. DOI
  7. Broxmeyer HE, Orschell CM, Clapp DW, et al. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med. 2005;201(8):1307-1318. DOI
  8. Liles WC, Broxmeyer HE, Rodger E, et al. Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist. Blood. 2003;102(8):2728-2730. DOI
  9. DiPersio JF, Micallef IN, Stiff PJ, et al. Phase III prospective randomized double-blind placebo-controlled trial of plerixafor plus granulocyte colony-stimulating factor compared with placebo plus granulocyte colony-stimulating factor for autologous stem-cell mobilization and transplantation for patients with non-Hodgkin’s lymphoma. J Clin Oncol. 2009;27(28):4767-4773. DOI
  10. DiPersio JF, Stadtmauer EA, Nademanee A, et al. Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood. 2009;113(23):5720-5726. DOI
  11. Mozobil (plerixafor) injection, US Prescribing Information. Genzyme; 2020. FDA label
  12. Wuchter P, Ran D, Bruckner T, et al. Poor mobilization of hematopoietic stem cells-definitions, incidence, risk factors, and impact on outcome of autologous transplantation. Biol Blood Marrow Transplant. 2010;16(4):490-499. DOI
  13. Calandra G, McCarty J, McGuirk J, et al. AMD3100 plus G-CSF can successfully mobilize CD34+ cells from non-Hodgkin’s lymphoma, Hodgkin’s disease and multiple myeloma patients previously failing mobilization with chemotherapy and/or cytokine treatment: compassionate use data. Bone Marrow Transplant. 2008;41(4):331-338. DOI
  14. Crees ZD, Rettig MP, Jayasinghe RG, et al. Motixafortide and G-CSF to mobilize hematopoietic stem cells for autologous transplantation in multiple myeloma: a randomized phase 3 trial. Nat Med. 2023;29(4):869-879. DOI
  15. APHEXDA (motixafortide) for injection, US Prescribing Information. BioLineRx; revised 9/2023. FDA label
  16. Fitzhugh CD, Hsieh MM, Bolan CD, Saenz C, Tisdale JF. Granulocyte colony-stimulating factor (G-CSF) administration in individuals with sickle cell disease: time for a moratorium? Cytotherapy. 2009;11(4):464-471. DOI
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  21. ClinicalTrials.gov NCT05618301: A pilot safety and feasibility study to evaluate motixafortide (CXCR4/SDF-1 inhibition) and natalizumab (VLA-4/VCAM-1 inhibition) as a novel regimen to mobilize CD34+ hematopoietic stem cells for gene therapy in sickle cell disease. link