Klassen J

Superior autologous blood stem cell mobilization from dose-intensive cyclophosphamide, etoposide, cisplatin plus G-CSF than from less intensive chemotherapy regimens

The study purpose was to determine if G-CSF plus dose-intensive cyclophosphamide 5.25 g/m2, etoposide 1.05 g/m2 and cisplatin 105 mg/m2 (DICEP) results in superior autologous blood stem cell mobilization (BSCM) than less intensive chemotherapy. From January 1993 until May 1997, 152 consecutive patients with non-Hodgkin’s lymphoma (n = 55), breast cancer (n = 47), Hodgkin’s disease (n = 14), multiple myeloma (n = 9), AML (n = 9), or other cancers (n = 18) initially underwent BSCM by one of three methods: Group 1: G-CSF alone × 4 days (n = 30). Group 2: disease-oriented chemotherapy, dosed to avoid blood transfusions, followed by G-CSF starting day 7 or 8, and apheresis day 13 or 14 (n = 82). Group 3: DICEP days 1–3, G-CSF starting day 14, and apheresis planned day 19, 20 or 21 (n = 40). A multivariate analysis was performed to determine which factors independently predicted BSCM. The median peripheral blood CD34+ (PB CD34+) cell count the morning of apheresis linearly correlated with the number of CD34+ cells removed per litre of apheresis that day. The median PB CD34+ cell count and median CD34+ cells × 106 removed per litre of apheresis were highest for Group 3, intermediate for Group 2, and lowest for Group 1. By multivariate analysis, mobilization group (3 > 2 > 1), disease other than AML, no prior melphalan or mitomycin-C, and less than two prior chemotherapy regimens predicted better BSCM. Out of 15 Group 3 patients who had infiltrated marrows, 11 had no detectable cancer in marrow and apheresis products after DICEP. These data suggest that DICEP results in superior BSCM than less intensive chemotherapy regimens.

Factors predicting engraftment of autologous blood stem cells : CD34+ subsets inferior to the total CD34+ cell dose

Data were analyzed on 178 consecutive patients (median age 43 years) who underwent autologous blood stem cell transplantation (ABSCT) at a single institution to determine if CD34+subsets (CD34+38−, CD34+33−, CD34+33+, CD34+41+) or various clinical factors affect hematopoietic engraftment independent of the total CD34+ cell dose/kg. Using Cox proportional hazards models, the factors independently associated with rapid neutrophil engraftment were higher CD34+ dose/kg, use of G-CSF post-ABSCT, and conditioning regimen (single-agent melphalan ± TBI slower). Factors independently associated with rapid platelet engraftment were higher CD34+ cell dose/kg, higher ratio of CD34+33−/total CD34+ cells infused, conditioning regimen (mitoxantrone, vinblastine, cyclophosphamide faster), and no CD34+ cell selection of the autograft. The CD34+ cell selection process seemed to deplete CD34+41+ cells to a greater extent than total CD34+cells which may explain our observation that it resulted in slower platelet engraftment. In conclusion, the total CD34+ dose/kg was a better predictor of hematopoietic engraftment following ABSCT than the dose of any CD34+ subset. Platelet engraftment, however, was also influenced by the ratio of CD34+33−/total CD34+cells for unmanipulated autografts, and possibly by the CD34+41+dose for autografts manipulated by CD34+ selection. The use of CD34+ subsets requires further investigation in predicting engraftment of autografts which undergo ex vivo manipulation.

Mobilized blood cells vs bone marrow harvest: experience compared in 171 donors with particular reference to pain and fatigue

Summary:This prospective study compared the donor experience of blood cell (BC) mobilization and leukapheresis (n=116) with that of bone marrow (BM) harvest (n=55). Internal jugular catheters were inserted electively in 89% of BC donors. Most (80%) BM donors had a harvest with general anesthesia; 20% had epidural or spinal anesthesia. Pain and fatigue were frequent with both procedures and were compared in responses to questionnaires. A total of 85% of BM donors reported moderate or severe pain compared with 68% of BC donors (P=0.02). The median duration of pain was 14 days for BM donors compared with 3 days after BC mobilization (P<0.0001). More BM donors had pain for more than 7 days (75% vs 0%, P<0.0001). Severe fatigue was experienced by more BM donors (49 vs 16%, P<0.0001). Fatigue lasted significantly longer in BM donors (median 11 vs 4 days, P<0.0001) and more BM donors were fatigued for more than 1 week (69 vs 0%, P<0.0001). A total of 11 donors had both BM and BC collection; seven preferred the latter. Simply considered with respect to pain and fatigue, BC donation appears better tolerated by donors. However, there are other sequelae of both influencing the acceptability for individual donors.

Predictive factors for long-term engraftment of autologous blood stem cells

Data from 170 consecutive patients aged 19–66 years (median age 46 years) who underwent unmanipulated autologous blood stem cell transplant (ASCT) were analyzed to determine if total CD34+ cells/kg infused, CD34+ subsets (CD34+41+, CD34+90+, CD34+33−, CD34+38−, CD34+38−DR−), peripheral blood CD34+ cell (PBCD34+) count on first apheresis day, or various clinical factors were associated with low blood counts 6 months post ASCT. Thirty-four patients were excluded from analysis either because of death (n = 17) or re-induction chemotherapy prior to 6 months post ASCT (n = 13), or because of lack of follow-up data (n = 4). Of the remaining 136 patients, 46% had low WBC (<4 × 109/l), 41% low platelets (<150 × 109/l), and 34% low hemoglobin (<120 g/l) at a median of 6 months following ASCT. By Spearmans rank correlation, both the total CD34+ cell dose/kg and the PBCD34+ count correlated with 6 month blood counts better than any subset of CD34+ cells or any clinical factor. The PBCD34+ count was overall a stronger predictor of 6 month blood counts than was the total CD34+ cells/kg infused. Both factors retained their significance in multivariate analysis, controlling for clinical factors. In conclusion, subsets of CD34+ cells and clinical factors are inferior to the total CD34+ cell dose/kg and PBCD34+ count in predicting 6 month blood counts following ASCT. Bone Marrow Transplantation (2000) 26, 1299–1304.

Double high-dose therapy for Hodgkin's disease with dose-intensive cyclophosphamide, etoposide, and cisplatin (DICEP) prior to high-dose melphalan and autologous stem cell transplantation.

We previously reported a 50% (95% CI = 33–76%) 5 year event-free survival (EFS) rate for 23 patients with Hodgkins disease (HD) who received salvage therapy with single agent high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT). Predictors of poor outcome included bulky disease and initial remission <1 year. since 1995, similar poor prognosis patients have been treated with double high-dose therapy consisting of dose-intensive cyclophosphamide 5.25 g/m2, etoposide 1.05 g/m2, cisplatin 105 mg/m2(DICEP) for tumor cytoreduction and stem cell mobilization followed by HDM/ASCT. The purpose of the present study is to determine if the use of DICEP is associated with improved event-free (EFS) and overall survival (OAS) for patients treated with HDM/ASCT. From February 1981 to June 1999, 46 consecutive patients received HDM/ASCT for relapsed (n = 35) or refractory (n = 11) hd. dicep re-induction and blood stem cell mobilization was used for 21 patients. factors considered for univariate and multivariate analyses included age at transplant, number of failed chemotherapy regimens, prior radiotherapy, length of initial remission, relapsed or refractory disease status, extranodal relapse, b symptoms at relapse, bulk, post-asct radiotherapy, and dicep re-induction therapy. cox proportional hazards models were constructed for both event and death. dicep and hdm were well tolerated with no early treatment-related mortality or toxicity requiring life-sustaining measures. for all 46 patients, the projected 5 year efs was 52% (95% ci = 38–72%) and oas was 57% (95% ci = 40–82). factors independently associated with relapse in multivariate analysis included bulk >5 cm (RR = 6.38, P = 0.002), prior radiotherapy (RR = 3.59, P = 0.027), and not using DICEP (RR = 5.29, P = 0.005). factors independently associated with death included bulk >5 cm (RR = 5.13, P = 0.009), ⩾3 prior chemotherapy regimens (RR = 4.72, P = 0.019), and not using DICEP (RR = 7.49, P = 0.015). This study demonstrates that DICEP re-induction prior to HDM/ASCT is feasible. The preliminary data are sufficiently encouraging to warrant a multicenter phase II or a phase III trial evaluating DICEP followed by HDM/ASCT as salvage therapy for HD. Bone Marrow Transplantation (2000) 26, 383–388.

The CD34+90+ cell dose does not predict early engraftment of autologous blood stem cells as well as the total CD34+ cell dose.

CD90 or Thy-1 is an antigen co-expressed with CD34+ on putative immature hematopoietic stem cells. Peak mobilization of CD34+90+ cells into the blood occurs a few days earlier than peak mobilization of total CD34+ cells. Because it is not known which cell type best correlates with engraftment, the optimal timing of apheresis remains unclear. The purpose of the study was to determine if the CD34+90+ cell dose predicts engraftment of autologous blood stem cells independent of the total CD34+ cell dose/kg, the dose of other CD34+ cell subsets (CD34+33−, CD34+38−, CD34+41+), or various clinical factors. Data were analyzed on 125 consecutive patients ranging in age from 19 to 66 years (median 46) who underwent autologous blood stem cell transplantation (ABSCT) for breast cancer (54), lymphoma (59), or other malignancies (12). By univariate analysis, neutrophil (⩾0.5 × 109/l) and platelet (⩾20 × 109/l or ⩾100 × 109/l) engraftment correlated better with the total CD34+ cell dose than with the CD34+90+ cell subset. Using Cox proportional hazards models, factors independently associated with both neutrophil engraftment (⩾0.5 × 109/l) and platelet engraftment (⩾20 × 109/l and ⩾100 × 109/l) were higher total CD34+ dose/kg and high-dose regimen (melphalan-containing slower than other regimens). In conclusion, the total CD34+ dose/kg was a better predictor of hematopoietic engraftment following ABSCT than the dose of any CD34+ subset, including CD34+90+ cells. Apheresis should continue to be timed according to peak CD34+ levels. Bone Marrow Transplantation (2000) 25, 435–440.

Micrometastases in apheresis products predict shorter progression-free and overall survival in patients with breast cancer undergoing high-dose chemotherapy (HDCT) and autologous blood stem cell transplantation (ABSCT)

Summary:The presence of cancer cells in autografts of breast cancer patients has been described to have prognostic value or directly lead to relapse. Previously, we demonstrated that apheresis products (APs) collected after induction chemotherapy have a significantly lower likelihood of tumor cell contamination. Here, we examine the prognostic value of micrometastases in autografts. Data from 83 patients with breast cancer treated with autologous blood stem cell transplantation were analyzed. Pan-cytokeratin-FITC conjugated antibodies were used to detect contaminating breast cancer cells in the APs. Progression and survival data analyzed on the basis of three or fewer cancer cells showed no significant differences in outcomes. Of the 83 patients, 11 had more than three cancer cells detectable in their APs. In total, 72 patients were shown to have less than three cells detectable. When patients with more than three cells were compared to patients with 0–3, we found statistically significant differences in progression-free survival. We also found a significant difference in overall survival (OS) between the two groups. No difference was observed in OS since the time of diagnosis. We conclude that patients with more than three contaminating cells in their APs have micrometastases and represent a poor prognosis group.

Single-agent high-dose melphalan salvage therapy for Hodgkin's disease: Cost, safety, and long-term efficacy

BACKGROUND Few data are available on the cost, safety, and long-term efficacy of single-agent high-dose melphalan (HDM) followed by autologous bone marrow (ABMT) or blood stem cell (ABSCT) transplantation in the salvage therapy of Hodgkins disease (HD). PATIENTS AND METHODS From February 1981 to September 1996, 23 patients with relapsed (n = 15) or refractory (n = 8) HD received salvage therapy with HDM 140-200 mg/m2 followed by non-cryopreserved ABMT (n = 18) or cryopreserved ABSCT (n = 5). The cost of HDM/ABSCT in 1996, from initial consultation until transfer back to referring physician, was determined and compared to the estimate costs of two multi-agent regimens commonly used for HD. RESULTS HDM was well tolerated with no early transplant-related mortality. The five-year overall and progression-free survival rates were 52% and 50%, respectively. The average total cost in Canadian funds of HDM/ABSCT in 1996 was

Partially mismatched blood cell transplants for high-risk hematologic malignancy

34,400/patient. This cost was estimated to be

A Low CD34+ Cell Dose Predicts Relapse and Death Early following Autologous Blood Stem Cell Transplantation.

4,700-6,800 cheaper per patient than the multi-agent high-dose regimens. CONCLUSION These data suggest that HDM is safe, feasible, active, and reasonably inexpensive salvage therapy for patients with relapsed/refractory HD.