Michael J. Dugan

Safety and preliminary efficacy of plerixafor (mozobil) in combination with chemotherapy and G-CSF: An open-label, multicenter, exploratory trial in patients with multiple myeloma and non-Hodgkin's lymphoma undergoing stem cell mobilization

Plerixafor, a novel CXCR4 inhibitor, is effective in mobilizing PBSCs particularly when used in conjunction with G-CSF. In four cohorts, this pilot study explored the safety of plerixafor mobilization when incorporated into a conventional stem cell mobilization regimen of chemotherapy and G-CSF. Forty (26 multiple myeloma and 14 non-Hodgkins lymphoma) patients were treated with plerixafor. Plerixafor was well tolerated and its addition to a chemo-mobilization regimen resulted in an increase in the peripheral blood CD34+ cells. The mean rate of increase in the peripheral blood CD34+ cells was 2.8 cells/μl/h pre- and 13.3 cells/μl/h post-plerixafor administration. Engraftment parameters were acceptable after myeloblative chemotherapy, with the median day for neutrophil and plt engraftment being day 11 (range 8–20 days) and day 13 (range 7–77 days), respectively. The data obtained from the analysis of the cohorts suggest that plerixafor can safely be added to chemotherapy-based mobilization regimens and may accelerate the rate of increase in CD34+ cells on the second day of apheresis. Further studies are warranted to evaluate the effect of plerixafor in combination with chemomobilization on stem cell mobilization and collection on the first and subsequent days of apheresis, and its impact on resource utilization.

Transplantation of hematopoietic stem cells from the peripheral blood

Hematopoietic stem cells can be collected from the peripheral blood. These hematopoietic stem cells (HSC), or better progenitor cells, are mostly expressed as the percentage of cells than react with CD34 antibodies or that form colonies in semi‐solid medium (CFU‐GM). Under steady‐state conditions the number of HSC is much lower in peripheral blood than in bone marrow. Mobilization with chemotherapy and/or growth factors may lead to a concentration of HSC in the peripheral blood that equals or exceeds the concentration in bone marrow. Transplantation of HSC from the peripheral blood results in faster hematologic recovery than HSC from bone marrow. This decreases the risk of infection and the need for blood‐product support. For autologous stem‐cell transplantation (SCT), the use of peripheral blood cells has completely replaced the use of bone marrow. For allogeneic SCT, on the other hand, the situation is more complex. Since peripheral blood contains more T‐lymphocytes than bone marow, the use of HSC from the peripheral blood increases the risk of graft‐versus‐host disease after allogeneic SCT. For patients with goodrisk leukemia, bone marrow is still preferred, but for patients with high‐risk disease, peripheral blood SCT has become the therapy of choice.

Prediction of engraftment after autologous peripheral blood progenitor cell transplantation: CD34, colony‐forming unit–granulocyte‐macrophage, or both?

BACKGROUND: The rate of hematologic recovery after peripheral blood progenitor cell (PBPC) transplantation is influenced by the dose of progenitor cells. Enumeration of cells that express CD34+ on their surface is the most frequently used method to determine progenitor cell dose. In vitro growth of myeloid progenitor cells (colony‐forming unit–granulocyte‐macrophage [CFU‐GM]) requires more time and resources, but may add predictive information.

Transportation of peripheral blood progenitor cell products: effects of time, temperature and cell concentration

BACKGROUND AIMS Peripheral blood progenitor cell (PBPC) products are often transported at high cell concentrations (>200x10(9)/L) over long distances, requiring >36 h transport time. METHODS Fresh PBPC samples from 12 healthy donors were studied with various viability assays regarding the effects of temperature, cell concentration and duration of storage. RESULTS Trypan blue exclusion was far less sensitive to cell damage than two-color fluorescence for CD34 and 7-AAD, and colony-forming unit-granulocyte-macrophage (CFU-GM) assays; the latter assay proved the most sensitive. All products stored at 4 degrees C maintained their viability for up to 4 days. Thus, at 96 h, recovery of viable CD34(+) cells was still 82%, and of CFU-GM 57%, even at concentrations of 200x10(9)/L. Higher storage temperatures rapidly decreased the viability, with extensive variation between donors. At room temperature 80% of viable CD34(+) cells and >90% of CFU-GM were lost after 48 h of storage at 200x10(9)/L. Lower cell concentrations allowed storage at higher temperatures: at 17 degrees C a concentration of 50x10(9)/L resulted in only 5% loss of viable CD34(+) cells after 48 h, while the loss was >30% at 200x10(9)/L. CONCLUSIONS PBPC products should be transported at 4 degrees C. Dilution of the product may partly compensate for slightly higher temperatures. Trypan blue exclusion should be abandoned as a method for assessing viability after prolonged transportation. Proliferative assays should be used to validate transportation conditions.

Matched-pair analysis of hematopoietic progenitor cell mobilization using G-CSF vs. cyclophosphamide, etoposide, and G-CSF: Enhanced CD34+ cell collections are not necessarily cost-effective

Using matched-pair analysis, we compared two popular methods of stem cell mobilization in 24 advanced-stage breast cancer patients who underwent two consecutive mobilizing procedures as part of a tandem transplant protocol. For the first cycle, 10 microg/kg/day granulocyte colony-stimulating factor (G-CSF) was given and apheresis commenced on day 4 and continued for < or =5 days (median 3 days). One week after the first cycle of apheresis, 4000 mg/m2 cyclophosphamide, 400 mg/m2 etoposide, and 10 microg/kg G-CSF were administered for < or =16 days (cycle 2). Apheresis was initiated when the white blood cell (WBC) count exceeded 5000 cells/microL and continued for < or =5 days (median 3 days). Mean values of peripheral blood WBC (31,700+/-3200 vs. 30,700+/-3300/microL) were not significantly different between cycles 1 and 2. Mean number of mononuclear cells (MNC) collected per day was slightly greater with G-CSF mobilization than with the combination of chemotherapy and G-CSF (2.5+/-0.21x10(8) vs. 1.8+/-0.19x10(8) cells/kg). Mean daily CD34+ cell yield, however, was nearly six times higher (12.9+/-4.4 vs. 2.2+/-0.5x10(6)/kg; p = 0.01) with chemotherapy plus G-CSF. With G-CSF alone, 13% of aphereses reached the target dose of 5x10(6) CD34+ cells/kg in one collection vs. 57% with chemotherapy plus G-CSF. Transfusions of red blood cells or platelets were necessary in 18 of 24 patients in cycle 2. Three patients were hospitalized with fever for a median of 3 days after cycle 2. No patients received transfusions or required hospitalization during mobilization with G-CSF alone. Resource utilization (cost of drugs, aphereses, cryopreservation, transfusions, hospitalization) was calculated comparing the median number of collections to obtain a target CD34+ cell dose of 5x10(6) cells/kg: four using G-CSF vs. one using the combination in this data set. Resources for G-CSF mobilization cost

Hematopoietic growth factor after autologous peripheral blood transplantation: comparison of G-CSF and GM-CSF

7326 vs.

Barriers to Physician Adherence to Evidence-Based Monitoring Guidelines in Chronic Myelogenous Leukemia

8693 for the combination, even though more apheresis procedures were performed using G-CSF mobilization. The cost of chemotherapy administration, more doses of G-CSF, transfusions, and hospitalizations caused cyclophosphamide, etoposide, and G-CSF to be more expensive than G-CSF alone. A less toxic and less expensive treatment than cyclophosphamide, etoposide, and G-CSF is needed to be more cost-effective than G-CSF alone for peripheral blood progenitor cell mobilization.

Impaired PBPC collection in patients with myeloma after high-dose melphalan

Autologous peripheral blood stem cell (PBSC) transplantation results in rapid hematologic recovery when sufficient numbers of CD34+ cells/kg are infused. Recent studies suggest that filgrastim (G-CSF) administration following transplantation leads to more rapid neutrophil recovery and lower total transplant costs. This study compares the use of G-CSF (5 μg/kg/day) with sargramostim (GM-CSF) 500 μg/day from day 0 until neutrophil recovery (ANC >1500/mm3) in patients with breast cancer or myeloma who had PBSC mobilized with the combination of cyclophosphamide, etoposide, and G-CSF. Twenty patients (13 breast cancer and seven myeloma) received GM-CSF and 26 patients (14 breast cancer and 12 myeloma) received G-CSF. The patients were comparable for age and stage of disease, and received stem cell grafts that were not significantly different (CD34+×106/kg was 12.5 ± 11.1 (mean ± s.d.) for GM-CSF and 19.8 ± 18.5 for G-CSF; P = 0.10). The use of red cells (2.8 vs 2.3 units), and platelet transfusions (2.5 vs 3.1) was similar for the two groups, as was the use of intravenous antibiotics (4.3 vs 4.6 days) and the number of days with temperature >38.3°C (2.3 vs 1.8). Platelet recovery was also similar in both groups (platelets >50 000/mm3 reached after 11.8 vs 14.9 days). The recovery of neutrophils, however, was faster using G-CSF. ANC >500/mm3 and >1000/mm3 were reached in the GM-CSF group at 10.5 ± 1.5 and 11.0 ± 1.7 days, respectively, whereas with G-CSF only 8.8 ± 1.2 and 8.9 ± 2.2 days were required (P < 0.001). as a result, patients given g-csf received fewer injections than the gm-csf patients (10.9 vs 12.3). Resource utilization immediately attributable to the use of growth factors and the duration of pancytopenia, excluding hospitalization, were similar for the two groups. This study suggests that neutrophil recovery occurs more quickly following autologous PBSC transplant using G-CSF in comparison to GM-CSF, but the difference is not extensive enough to result in lower total cost.

Slow platelet recovery after PBPC transplantation from unrelated donors

PURPOSE Although monitoring of cytogenetic/molecular responses to therapy in chronic myelogenous leukemia (CML) facilitates superior outcomes, less than one half of CML patients are monitored using published evidence-based guidelines. Barriers to physician adherence with guidelines are unknown. METHODS An anonymous survey was mailed to 515 hematologist-oncologists in New Jersey and Indiana exploring attitudes toward monitoring guidelines. RESULTS Ninety-six physicians (19%) responded-89% in community practice, 83% with more than 10 years of experience, and 92% caring for CML patients. Eighty-four percent self-reported using CML monitoring guidelines, 14% were familiar with but did not adopt guidelines and 2% were unfamiliar. Eighty-four percent performed molecular monitoring quarterly as recommended; 6% did not perform molecular monitoring at all during the first year. Guidelines were considered evidence based by 98%, but only 54% strongly considered them easy to find; only 51% strongly felt they addressed all aspects of disease management. Patient resource barriers were a significant deterrent toward implementation with 30% citing high costs. Physician resources, including lack of time to search guidelines, limited use in one fifth. Despite 90% believing an online database helpful, between one third and one half did not feel that additional training, professional society endorsements, or availability of expert consultations would encourage use. CONCLUSIONS Significant barriers to adherence with evidence-based CML guidelines exist. Resource barriers, lack of familiarity and lack of agreement restrict adoption, but efforts to facilitate use are not desired. Multifaceted educational strategies, including automated computerized reminders at point of care, are needed to improve quality outcomes in CML.

Delayed ABLC prophylaxis after allogeneic stem-cell transplantation

BACKGROUND Tandem stem cell transplantation is an important treatment option for patients with myeloma and some additional tumors. In an attempt to reduce the contamination of the stem cell graft with tumor cells, patients with myeloma who entered complete remission after the first transplant underwent a second episode of mobilization to obtain progenitor cells for the second transplant. METHODS Twenty-two patients with myeloma participated in the study. The first mobilization utilized CY, etoposide and filgrastim. The second mobilization used the same regimen, but seven patients received only filgrastim. The interval between the two collection periods was 6 months (median; range 4-9 months). The preparative regimen for the first transplant consisted of melphalan 200 mg/m(2). RESULTS The number of total white cells collected during the two collection episodes was similar: 10.8+/-1.6 x 10(8)/kg white cells vs. 11.8+/-1.7 x 10(8)/kg white cells (P=0.63). The collected CD34(+) cell dose was much larger during the first collection: 45.2+/-8.4 x 10(6)/kg vs. 6.9+/-2.7 x 10(6)/kg (P<0.001). Similarly, the collected colony-forming unit (CFU)-GM dose was much larger during the first collection: 295.4+/-59.3 x 10(4)/kg vs. 67.3+/-21.6x10(4)/kg (P<0.001). While the CD34(+) cells collected during the two collection episodes correlated significantly (r=0.55, P<0.01); the first dose was a median of 14.9-fold larger. DISCUSSION No laboratory parameter was able reliably to predict the results of the second collection. A second mobilization/collection episode as part of a tandem transplant approach carries a considerable risk of failing to obtain sufficient progenitor cells.