Barlogie B, Jagannath S, Dixon D O, Cheson B, Smallwood L, Hendrickson A, Purvis J D, Bonnem E, Alexanian R
Division of Hematology-Oncology, University of Arkansas for Medical Sciences, Little Rock.
Blood. 1990 Aug 15;76(4):677-80.
High-dose melphalan has induced remissions in about 40% of patients with refractory myeloma, but the mortality has been high, at about 20%, due to complications of prolonged granulocytopenia. In an attempt to stimulate earlier granulocyte recovery, recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) was administered subcutaneously to 23 patients with refractory myeloma who had been treated with melphalan at a high dose of 100 mg/m2. Thirty-nine percent of patients achieved marked tumor cytoreduction by at least 75%, 2 died within 2 months from infectious complications during severe neutropenia; and median durations of relapse-free and overall survival were 7 and 10+ months, respectively. The nine patients presenting with both advanced age over 50 years and a long history of prior therapy of over 1 year required significantly longer median times of 31 days for granulocytes and of 63 days for platelets to reach safe levels of at least 500/microL and 50,000/microL, respectively, than the 14 remaining patients who had none or only one of these adverse features (21 and 26 days, respectively). In a historic control of 43 patients treated previously with high-dose melphalan but without GM-CSF, hematologic recovery to the aforementioned levels of granulocytes and platelets proceeded over almost 5 weeks, regardless of age and prior treatment exposure. Thus GM-CSF seems to hasten marrow recovery, especially in patients with adequate normal marrow stem-cell reserve as defined by younger age or less prior therapy. While not shortening the duration of neutropenia, GM-CSF dose increments (from 0.25 to 0.5 to 0.75 mg/m2) increased the incidence of severe toxicity from 0% to almost 40%, especially among older patients. These results support the usefulness of low-dose GM-CSF (0.25 mg/m2) in stimulating marrow recovery in selected patients with adequate marrow reserve treated with high-dose melphalan for refractory multiple myeloma.
大剂量美法仑可使约40%的难治性骨髓瘤患者获得缓解，但由于长期粒细胞减少的并发症，死亡率一直较高，约为20%。为了促进粒细胞更早恢复，对23例接受100mg/m²高剂量美法仑治疗的难治性骨髓瘤患者皮下注射重组人粒细胞-巨噬细胞集落刺激因子（GM-CSF）。39%的患者实现了至少75%的显著肿瘤细胞减少，2例在严重中性粒细胞减少期间因感染并发症在2个月内死亡；无复发生存期和总生存期的中位数分别为7个月和10多个月。9例年龄超过50岁且既往治疗史超过1年的患者，粒细胞达到至少500/μL的安全水平所需的中位时间显著更长，为31天，血小板达到至少50,000/μL的安全水平所需的中位时间为63天，而其余14例没有或仅有其中一项不良特征的患者，粒细胞和血小板达到上述水平所需的时间分别为21天和26天。在一项对43例先前接受高剂量美法仑但未使用GM-CSF治疗的患者的历史对照研究中，无论年龄和既往治疗情况如何，血液学恢复到上述粒细胞和血小板水平需要近5周时间。因此，GM-CSF似乎能加速骨髓恢复，尤其是在年龄较轻或既往治疗较少、具有足够正常骨髓干细胞储备的患者中。虽然GM-CSF没有缩短中性粒细胞减少的持续时间，但GM-CSF剂量增加（从0.25mg/m²增加到0.5mg/m²再增加到0.75mg/m²）使严重毒性的发生率从0%增加到近40%，尤其是在老年患者中。这些结果支持低剂量GM-CSF（0.25mg/m²）在刺激经高剂量美法仑治疗的难治性多发性骨髓瘤且具有足够骨髓储备的特定患者的骨髓恢复方面的有效性。
