G-CSF Starting Day +1 after Autologous Transplant Is Safer Than Day +5 or Day +7 in Patients with Multiple Myeloma

Introduction: For fit multiple myeloma (MM) patients, autologous hematopoietic stem cell transplant (HSCT) is standard of care as part of first line therapy, demonstrating longer progression-free survival when compared to upfront bortezomib, lenalidomide, and dexamethasone (IFM/DFCI 2009, ASH 2015). The use of granulocyte colony stimulating factor (G-CSF) after HSCT accelerates time to neutrophil recovery by 1 - 6 days when compared with control (Klumpp TR et al, JCO, 1995 & Schmitz N et al, BMT 2004). The American Society of Clinical Oncology guidelines recommend that G-CSF should be initiated 1-5 days after administration of high-dose chemotherapy and should be continued until the absolute neutrophil count (ANC) is 2000-3000/mm³ (Smith TJ, JCO, 2015). We have evaluated the role of G-CSF starting day +1, day +5, and day +7 post-transplant in three sequential cohorts of MM patients focusing on the duration of severe neutropenia (rather than the time to neutrophil engraftment), infections, and mucositis.

Methods: As part of changes in the standard of care institutional protocols for autologous HSCT of myeloma patients at Ohio State University, three sequential cohorts of myeloma patients were identified that received G-CSF daily post-transplant until ANC>1500/mm³ or WBC>5/mm³. Two hundred twenty-six (226) patients received G-CSF on day +1 (n=43), day +5 (n=78), and day +7 (n=105) from May 2012 to August 2015. The majority of the patients received levofloxacin, acyclovir and fluconazole as prophylaxis. We evaluated the duration of severe neutropenia (ANC<500), the onset of bacteremia, WHO grade 2-4 mucositis, and the time to biochemical progression as part of an IRB approved protocol (NCT01653106).

Results:The cohort of patients receiving G-CSF on day +5 had a shorter median follow up (455 days versus 979 days in the day +1 and 1355 days in the day +7 cohorts), since the patients were enrolled at a later timepoint. No statistically significant difference was noted in terms of age, gender, cytogenetic or ISS stage distribution, number of infused cells per kg, and melphalan dose among the three cohorts of patients. The duration of severe neutropenia was significantly increased for patients receiving G-CSF on day +7 (mean 153.4 hrs, SD 36.9) compared to those receiving G-CSF on day +1 (mean: 104.8 hrs, SD 19.4; p-value <0.0001) or day +5 (mean: 120.5 hrs, SD 27.4; p-value <0.0001). There was also a statistically significant difference between the duration of severe neutropenia for G-CSF day +1 or day +5 (p-value 0.013). The duration of neutropenia was not influenced by gender, International Staging System or R-ISS at diagnosis. Moreover, no statistically significant difference was noted in terms of duration of severe neutropenia when patients were subdivided based on the number of stem cell infused (< or > of 5 x 10⁶ cells). Patients who received G-CSF on day +1 or day +5 had a significantly decreased incidence of grade 2 or higher mucositis (4.65% vs 10.3%) for day +1 and day +5 versus 21.9% for day +7 (fisher-test, p = 0.014 and 0.0255). Similarly, the incidence of bacteremia was decreased in those patients treated with G-CSF on days +1 and +5 versus day +7 (21.8%, 23.2%, and 33.3% for those treated on days +1, +5, and +7, respectively; p = 0.09). The group of patients who received G-CSF on day +5 had a longer length of stay, with two patients with prolonged hospitalization (mean 17.7 days, SD 5.6 days, range 12-49) when compared to the other groups (day +1 group mean 13.88 days, SD 2.8 days, range 10-21 versus day +7 group mean 15.2 days, SD 2.7 days, range 11-21 days; Two-tailed t-test p = 0.012). Lastly, our data indicates a trend, though not statistically significant, toward a longer time to biochemical progression in patients who received G-CSF on day +1 when compared to the other two groups.

Conclusion: We conclude that starting G-CSF injections the day after stem cell infusion (day +1) decreases the duration of severe neutropenia, infections, and mucositis in comparison to day +5 and day +7 in patients receiving autologous transplant for MM. A prospective trial would definitively test this, but a multi-institution meta-analysis via CIBMTR would be more cost-effective, acknowledging that differing anti-infective prophylaxis regimens would prevent effective between institution comparisons of infection.