Growth factor plus preemptive ('just-in-time') plerixafor successfully mobilizes hematopoietic stem cells in multiple myeloma patients despite prior lenalidomide exposure.

Lenalidomide is associated with suboptimal autologous hematopoietic stem cell (AHSC) mobilization. We hypothesized that growth factor plus preemptive plerixafor is an effective strategy for AHSC mobilization in multiple myeloma (MM) despite prior exposure to lenalidomide. We retrospectively reviewed patient characteristics and mobilization outcomes of 89 consecutive MM patients undergoing first mobilization with filgrastim or pegfilgrastim +/- preemptive plerixafor using a previously validated algorithm based on day 4 peripheral blood CD34+ cell count (PB-CD34+) and mobilization target. Outcomes were analyzed according to the extent of prior exposure to lenalidomide: no prior exposure (group A, n=40), 1- 4 cycles (group B, n=30) and >4 cycles (group C, n=19). Multivariate analysis yielded only age and number of cycles of lenalidomide as negatively associated, and mobilization with pegfilgrastim as positively associated with higher PB-CD34+. Only 45% of patients in group A required plerixafor vs 63% in groups B and 84% in C, P=0.01. A higher proportion of patients in group A (100%) met the mobilization target than in groups B (90%) or C (79%), P=0.008. All patients yielded at least 2 × 10(6) CD34+/kg. Growth factor mobilization with preemptive plerixafor is an adequate upfront mobilization strategy for MM patients regardless of prior exposure to lenalidomide.

Development and validation of a decision-making algorithm to guide the use of plerixafor for autologous hematopoietic stem cell mobilization.

Plerixafor is an inhibitor of CXCR-4 (CXC chemokine receptor-4)/SDF (stromal cell-derived factor)-1 binding used in combination with granulocyte colony-stimulating factor (G-CSF) for mobilization of autologous peripheral blood hematopoietic stem cells (HSCs). We developed a data-generated, cost-saving decision-making algorithm that uses the CD34+ count in the peripheral blood on the fourth day of G-CSF administration (PB-CD34+), and the collection target (T-CD34+) to decide between continuing G-CSF only (G approach) or adding plerixafor to the mobilization regimen (G+P approach) aiming at the lowest cost. The G+P approach was more cost-effective with lower PB-CD34+. It was possible to determine, for each T-CD34+, the maximum PB-CD34+ for which the G+P approach is cost-effective, generating an algorithm for the use of plerixafor. We validated this algorithm in a cohort of 34 patients undergoing HSC mobilization. In all, 11 patients completed collection on the G approach and 23 patients on the G+P approach, with 91% of the patients completing collection within the predicted number of apheresis sessions. All patients who underwent transplantation engrafted with minimal differences in engraftment time between G and G+P approaches. This validated algorithm provides a potential cost-saving decision tool for the use of plerixafor in autologous HSC mobilization.

Growth factor and patient-adapted use of plerixafor is superior to CY and growth factor for autologous hematopoietic stem cells mobilization.

The ideal method to mobilize autologous hematopoietic stem cells (AHSCs) in patients with lymphoma or multiple myeloma remains to be determined. The use of plerixafor, added to growth factor, may overcome the limitations to the use of growth factor mobilization without chemotherapy. We developed and validated a cost-based decision-making algorithm that uses the CD34+ cell count in the peripheral blood on the fourth day of G-CSF administration and the target CD34+ cell count for the specific patient to decide on the use of plerixafor (MUSC algorithm). We compared this approach (MA cohort) with a historical cohort of patients undergoing mobilization with CY 2000 mg/m(2) followed by G-CSF and GM-CSF (CY cohort). Fifty individuals are included in the MA cohort and 81 in the CY cohort. The mobilization failure rate was 2% in the MA cohort vs 22% in the CY cohort (P=0.01). Fewer patients in the MA cohort than in the CY cohort had infectious complications during mobilization requiring hospitalization (2 vs 30% P<0.01). There was significant shortening in the median number of days between starting mobilization and undergoing transplantation in the MA cohort (14 vs 43 days, P<0.01). In conclusion, growth factor and patient-adapted use of plerixafor provides safer hematopoietic stem cell mobilization and faster access to AHSC transplantation.

The influence of serum tumor necrosis factor-alpha and interleukin-6 concentrations on nonhematologic toxicity and hematologic recovery in patients with acute myelogenous leukemia.

To confirm the reported correlation of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) serum concentrations with nonhematologic toxicity after cytotoxic chemotherapy and to examine their possible effects on hematopoiesis, we evaluated serum TNF-alpha and IL-6 concentrations every 3 days during 21 chemotherapy cycles in 11 patients with acute myelogenous leukemia (AML) and one patient with chronic myelogenous leukemia in blast crisis (CML-BC). All patients developed grade IV hematologic toxicity. In 13 patient cycles, grade III-IV nonhematologic toxicity developed: hepatic (nine), pulmonary (six), and stomatitis (five). In these patient cycles, IL-6 concentrations increased from 10.1 pg/mL (4.6-15.6, 95% CI) before nonhematologic toxicity to 64.8 (5.3-124.2, 95% CI) at the onset of toxicity (p = 0.02). TNF-alpha concentrations were not detectable before nonhematologic toxicity but increased to 20.4 pg/mL (not detectable [ND]-45.5, 95% CI) at the onset of grade III-IV toxicity. In six patient cycles, grade II nonhematologic toxicity developed: hepatic (five), pulmonary (one), and stomatitis (two). In these six, IL-6 concentrations increased from 12.1 pg/mL (6.8-17.4, 95% CI) before toxicity to 21.4 (11-31.8, 95% CI) at the onset of toxicity (p = 0.03). TNF-alpha concentrations were detectable in one patient cycle before toxicity and detectable in only two patient cycles at the onset of toxicity. The peak IL-6 and TNF-alpha concentrations did not correlate with the onset of nonhematologic toxicity in 87% of patient cycles. In patient cycles with a cumulative IL-6 area-under-the-serum concentration vs. time curve (AUC) > 1000 pg/mL.d, platelet recovery (> 30 x 10(9)/L and platelet transfusion-independent) occurred earlier at 21.9 days (18.7-25.1, 95% CI) compared to the 30.6 days (23.6-37.5, 95% CI, p = 0.02) in patient cycles with an IL-6 AUC < 1000 pg/mL.d. Patient cycles with a cumulative TNF-alpha AUC > 150 pg/mL.d required a mean of 17.5 units of red blood cells (RBCs) (9.3-25.7, 95% CI) compared to patient cycles with an AUC < 150 pg/mL.d, which required only 8.9 units of RBCs (6.2-11.7, 95% CI, p = 0.03). The peak concentration and AUC for IL-6 and TNF-alpha were not significantly different between those receiving growth factors (G-CSF, six; GM-CSF, one) and those not receiving growth factors (14). Endogenous IL-6 and TNF-alpha serum concentrations increase in patients who experience nonhematologic toxicity and correlate with hematologic recovery after chemotherapy.