Epirubicin + G-CSF as peripheral blood progenitor cells (PBPC) mobilising agents in breast cancer patients

BACKGROUND:: In an attempt to mobilise peripheral blood progenitor cells(PBPC) from patients with breast cancer, Epirubicin supportedwith G-CSF was tested. Another aim of the study was also tooptimize the procedure so that the number of leukapheresis procedurescould be reduced. These cells were subsequently reinfused ashematologic rescue after high-dose chemotherapy programs. PATIENTS AND METHODS:: Twenty-nine patients received Epirubicin 150 mg/sqm + G-CSFat the dose of 5 µg/kg/bw s.c. daily, starting 24 hoursafter chemotherapy. Twelve had metastatic, eight inflammatoryor locally advanced disease, and nine were treated in an adjuvantsetting. RESULTS:: The median numbers of CD34+ cells and CFU-GM collected were12.9 x 10Vkg/bw and 111.7 x 104/kg/bw, respectively. The meannumber of leukapheresis procedures per patient was 1.8 ±0.3(range 1–3), and the mean day of the first procedure wasthe tenth ± 1 (range 8–13) after Epirubicin. Theminimum required target for one high-dose procedure was collectedin a single leukapheresis in 13 patients. Moreover, in 9 casesone procedure was adequate for two high-dose courses (i.e. >10x 10Vkg/bw CD34+ cells). Response to Epirubicin was evaluablein 14/20 cases, with a response rate of 50%. CONCLUSIONS:: Epirubicin delivered at 150 mg/sqm is a very effective mobilisingagent for breast cancer patients; to ameliorate the responserate other active drug(s) should be added. breast cancer, epirubicin, high-dose, peripheral blood progenitor cells     

High-dose therapy with peripheral blood progenitor cell transplantation in multiple myeloma

Background: The objective of our study was to evaluate the efficacyand toxicity of a high-dose melphalan-based (HD-Mel) therapy with or withouttotal body irradiation (TBI) followed by peripheral blood progenitor (PBPC)transplantation in patients with multiple myeloma (MM).Patients and methods: Between June 1992 and May 1996, 100 patients(67 males/33 females) with a median age of 51 years (range 30–65) weretransplanted at our centre. PBPC were collected during G-CSF-enhancedleukocyte recovery following high-dose chemotherapy. Fifty patients weretreated with TBI + melphalan 140 mg/m², while 50 patientsreceived melphalan 200 mg/m².Results: Following PBPC autografting, the median time to reachplatelets 20 × 10⁹/l and neutrophils 0.5 ×10⁹/l was 11 and 14 days with no difference between thetreatment groups. In the TBI group significantly longer periods of totalparenteral nutrition were required due to severe mucositis. Two patients fromthe TBI group died due to transplantation-related complications. Followinghigh-dose treatment, remission state improved in 43 out of 98 patients. Nostatistically significant advantage in reaching CR or PR was observed with TBI+ HD-Mel compared to the treatment with HD-Mel alone.Conclusion: Dose-escalated treatments, with particular regard to theinclusion or omission of TBI, should be prospectively investigated to find thebest high-dose regimen.     

Non-cryopreserved,limited number (1 or 2) peripheral blood progenitor cell (PBPC) collections following GCSF administration provide adequate hematologic support for high dose chemotherapy

Sixty-two patients with a variety of malignant diseases including 44 with breast cancer, seven with sarcomas, five with germ cell tumours, four with Hodgkin's disease and two with multiple myeloma received short duration, high dose chemotherapy, with non-cryopreserved peripheral blood progenitor cell rescue as treatment for malignancy. Limited, (one or two) peripheral blood precursor cell collections were performed following either cyclophosphamide, cyclophosphamide + GCSF or GCSF priming. Total nucleated cell and CD34⁺ cell yields were significantly higher with either of the two GCSF priming regimens as compared to cyclophosphamide only priming. Cell viability at the time or reinfusion was also enhanced by GCSF priming. Chemotherapy regimens included either high dose cyclophosphamide, mitoxantrone and VP16 (HD-CNV); high dose melphelan plus VP16; high dose BCNU, cyclophosphamide and VP16 (BCV); or high carboplatin, cyclophosphamide and VP16 (PCV) all given over 8–12 h. Non-cryopreserved blood progenitor cells, stored at 4 °C, were reinfused 24 h after completion of chemotherapy. Sixty-one of 62 patients showed hematologic recovery. Median time to hematologic recovery was significantly shorter for patients receiving GCSF primed cell collections. There was also significantly less hospitalization and antibiotic usage for patients receiving GCSF primed precursor cell collections. The addition of post chemotherapy GCSF did not, however, appear to enhance the rate of hematologic recovery. This study shows that simplified schedules for high dose chemotherapy administration together with simple precursor cell collection procedures provide safe and effective methods for administering myeloablative chemotherapy treatment.     

Pharmaco-economic study of intensive chemotherapy with peripheral blood progenitor cell support for advanced breast cancer

Patients with high-risk breast cancer may benefit from dose-escalated chemotherapy. The rationale for high-dose chemotherapy with stem-cell rescue (HDC-SCR) in breast cancer is based on the principles of dose response and dose intensity. However, several results of properly randomized and prospective studies are necessary to determine the interest of HDC-SCR. The objective of this study, realised in the Anticancer Center of Montpellier, was to evaluate the cost of this type of transplantation. In this retrospective study, we analysed 30 patients treated for an advanced breast cancer between October 1995 and June 1998. We collected the data from the induction chemotherapy cycle (followed by cytapheresis) to the end of the hospitalisation for autograft. The mean total cost was US $25,845 per patient: US $6453 for drugs, US $4720 for transfusions, US $1865 for laboratory services and blood tests, US $5585 for staff pay, US $774 for material, US $1211 for administration cost, US $1111 for logistic cost, US $998 for structure cost and US$1578 for other. Antibiotics, granulocyte-colony stimulating factor, chemotherapy, transfusions and nutrition represent respectively 18% (US $1962), 14% (US $1590), 13% (US $1437), 42% (US $4720), 11% (US $1191) of the medication and blood products cost. The results of this study may help in identifying targets for cost reduction.     

Multiple cycles of high-dose doxorubicin and cyclophosphamide with G-CSF mobilized peripheral blood progenitor cell support in patients with metastatic breast cancer

Background: In a previous study we applied doxorubicin and cyclophosphamide in a dose-intensive regimen with GM-CSF to patients with metastatic breast cancer (MBC). That treatment failed to prolong the remission duration compared to conventional-dose chemotherapy. In the present study we escalated the dosages of the same agents to: 1) determine the maximum tolerated dosages (MTD) when given for three cycles with G-CSF mobilised peripheral blood progenitor cell (PBPC) reinfusion and 2) evaluate the antitumour effect of this regimen.Patients and methods: For mobilisation of PBPC, G-CSF 15 µg/kg/day was given subcutaneously (s.c.), and in subsequent cohorts leucapheresis was started on days 3, 4 or 6. The intention was to treat MBC patients with three cycles of doxorubicin and cyclophosphamide at a starting dose of doxorubicin 90 mg/m² and cyclophosphamide 1000 mg/m². Dosages were then escalated in subsequent cohorts of at least three patients. In case of dose-limiting mucositis, only the dose of cyclophosphamide was escalated in the next cohort.Results: Twenty-one patients entered this protocol, of which 18 patients received high-dose chemotherapy. The mobilisation of PBPC using G-CSF only was sufficient for three cycles of high-dose chemotherapy in 10 of 21 (47%) patients. Mucositis precluded dose escalation of doxorubicin beyond 110 mg/m². The MTD in this combination was 110 mg/m² for doxorubicin, and 4 g/m² for cyclophosphamide, with haemorrhagic cystitis being the dose-limiting toxicity. The overall response rate was 78% (95% confidence interval (95% CI): 57%–97%), with 22% (95% CI: 3%–41%) complete responses.Conclusion: The MTD of this three cycle high-dose regimen was doxorubicin 110 mg/m² and cyclophosphamide 4 g/m² with mucositis and cystitis being dose-limiting toxicities. Although the primary aim was not the evaluation of antitumour effect, this high-dose regimen does not appear to provide an improvement of treatment results in comparison with our previous study with the same drugs at moderately high-dosages without stem cell support.     

Marked telomere shortening in mobilized peripheral blood progenitor cells (PBPC) following two tightly spaced high-dose chemotherapy courses with G-CSF.

The purpose of the study was to compare telomere length (TL) in peripheral blood progenitor cells (PBPC) collected after two tightly spaced high-dose (hd) chemotherapy courses. We assessed 37 previously untreated lymphoma patients undergoing a hd-chemotherapy program with autografting. They sequentially received hd-cyclophosphamide (CY) and hd-Ara-C, both followed by PBPC harvesting. Both post-CY and post-Ara-C harvests were assessed for TL by Southern blot analysis. In 12 patients, the assay was also performed on purified CD34+ cells. All patients displayed high PBPC mobilization following both hd-CY and hd-Ara-C. In all but one patient, TL was shorter in PBPC collected after Ara-C compared to CY: 7226bp (range: 4135-9852) vs 8282 bp (range 4895-14860) (P < 0.0001). This result was confirmed on CD34+ cells. Platelet recovery in patients receiving post-Ara-C PBPC was significantly slower compared to those receiving post-CY PBPC. In conclusion, (i) administration of tightly spaced hd-chemotherapy courses induces marked telomere shortening on harvested PBPC; (ii) engraftment kinetics seem slower, with delayed platelet recovery, in patients autografted with PBPC suffering marked TL erosion; (iii) long-term follow-up is required to verify whether PBPC with shortened telomeres display defective engraftment stability and/or risk of secondary leukemia; (iv) TL evaluation is advisable whenever new mobilization procedures are developed.     

The peripheral blood Valpha24+ NKT cell numbers decrease in patients with haematopoietic malignancy

Valpha24TCR+ CD161+ NKT (Valpha24+ NKT) cells are activated by alpha-galactosylceramide and can exert anti-tumor activity against a variety of tumor cells. In this study, we assessed the Valpha24+ NKT cell numbers in peripheral blood (PB) from 30 healthy donors and 70 patients with haematopoietic malignancy including chronic myelogenous leukemia (CML), malignant lymphoma (ML), acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). Here, we demonstrated that PB Valpha24+ NKT cell numbers were significantly decreased in all the patients with haematopoietic malignancy in comparison with that in healthy donors (P < 0.005). In particular CD4- CD8- Valpha24+ NKT cell numbers were more significantly decreased in the patients with haematopoietic malignancy (P < 0.0001).     

High-dose mitoxantrone + melphalan (MITO/L-PAM) as conditioning regimen supported by peripheral blood progenitor cell (PBPC) autograft in 113 lymphoma patients: high tolerability with reversible cardiotoxicity.

Hematological and extrahematological toxicity of high-dose (hd) mitoxantrone (MITO) and melphalan (L-PAM) as conditioning regimen prior to peripheral blood progenitor cell (PBPC) autograft was evaluated in 113 lymphoma patients (87 at disease onset). Autograft was the final part of a hd-sequential (HDS) chemotherapy program, including a debulkying phase (1-2 APO +/- 2 DHAP courses) and then sequential administration of hd-cyclophosphamide, methotrexate (or Ara-C) and etoposide, at 10 to 30 day intervals. Autograft phase included: (1) hd-MITO, given at 60 mg/m2 on day -5; (2) hd-L-PAM, given at 180 mg/m2 on day -2; (3) PBPC autograft, with a median of 11 x 10(6) CD34+/kg, or 70 x 10(4) CFU-GM/kg, on day 0. A rapid hematological recovery was observed in most patients, with ANC >500/microL and Plt >20,000/microl values reached at a median of 11 and 10 days since autograft, respectively. The good hemopoietic reconstitution allowed the delivery of consolidation radiotherapy (RT) to bulky sites in 53 out of 57 candidate patients, within 1 to 3 months following autograft; five of these patients required back-up PBPC re-infusion due to severe post-RT pancytopenia. Few severe infectious complications were recorded. There was one single fatal event due to severe pancytopenia following whole abdomen RT. Cardiac toxicity was evaluated as left ventricular ejection fraction (LVEF), monitored by cardiac radionuclide scan. LVEF prior to and after autograft was significantly reduced (median values: 55% vs 46%) in 58 evaluated patients; however, a significant increase to a median value of 50% was observed in 45 patients evaluated at 1 to 3 years since autograft. At a median follow-up of 3.6 years, 92 patients are alive, with a 7-year overall survival projection and 6.7-year failure-free survival projection of 77% and 69%, respectively. We conclude that a conditioning regimen with hd-MITOIL-PAM fits well within the HDS program. It implies good tolerability and reversible cardiotoxicity and it may have contributed to the good long-term outcome observed in this series of patients.     

高剂量化疗并自体外周血干细胞移植治疗实体瘤九例分析

目的 探讨高剂量化疗并自体外周血干细胞移植治疗高危实体瘤的可行性及疗效,了解外周血干细胞动员及采集时机、造血功能重建等问题.方法 9例经病理组织学确诊的高危乳腺癌2例,非霍奇金淋巴瘤(NHL)3例及4例小细胞肺癌经过诱导化疗后,进行了高剂量化疗并自体外周血干细胞的移植.结果 随访7(1.6～13.8)个月,9例全部生存,7例无瘤生存.回输的单个核细胞(MNC)＞1.5×108/kg时,中性粒细胞(ANC)恢复≥0.5×109/L和血小板20×109/L所需的天数分别为9天和9.4天,无1例骨髓功能重建不全.结论 高剂量化疗并自体外周血干细胞移植对化疗敏感的乳腺癌、NHL及小细胞肺癌具有较好疗效且较安全,回输足够数量的造血干细胞,可使造血功能快速重建.     

Adenosine deaminase activity in peripheral blood cells of patients with haematological malignancies.

Adenosine deaminase (EC 3.5.4.4, ADA) has been assayed in lymphocytes, granulocytes and erythrocytes from 45 patients with haematological malignancies. Activities were uniformly low in lymphocytes from patients with chronic lymphocytic leukaemia. Variable, but abnormal activities were frequently found in multiple myeloma, untreated lymphoma and leukaemic reticuloendotheliosis. High values were observed in lymphocytes from patients with lymphoma during intensive combination chemotherapy. ADA levels in lymphocytes were not correlated with levels in granulocytes or erythrocytes. ADA was elevated in blasts of patients with acute lymphocytic and myelogenous leukaemias but the ranges of activities per cell were so similar that ADA assay is unlikely to be of major help in distinguishing the two diseases.     

大剂量化疗并自体外周血干细胞移植治疗9例实体瘤分析

目的：探讨高剂量化疗并自体外周血干细胞移植治疗高危实体瘤的可行性及疗效并了解干,细胞动员、采集时机、骨髓恢复时间等问题。方法：９例经病理确诊的高危乳腺癌、淋巴癌及小细胞肺癌在经不同程度的化疗后,进行了大剂量化疗并自体外周血干细胞的移植。结果：经追踪７个月,９例全部生存,７例无病生存。当回输的单个核细胞（ＭＮＣ）大于１．５×１０＾８/kg,中性恢复至大于或等于０．５×１０＾９/Ｌ和血小板大于或等于２０×     

Radiation therapy after high-dose chemotherapy with peripheral blood stem cell support for high-risk breast cancer

Multidisciplinary treatment in high-risk breast cancer improves survival and local control. The feasibility and patterns of failure after several induction and high-dose consolidation regimens of chemotherapy were evaluated in this study. Between November 1990 and January 1997, 65 patients with histologically proven breast cancer American Joint Committee on Cancer stages II-III with four or more axillary lymph nodes positive or locally advanced breast cancer underwent high-dose chemotherapy (HDC) with peripheral stem cell support after surgery and induction chemotherapy. All patients were subsequently treated with radiotherapy (up to total doses of 50-60 Gy), which included the ipsilateral axilla and supraclavicular fossa and the chest wall or breast. A minimum follow-up period of 2 years from the completion of radiotherapy was required for analysis. Local control (LC), disease-free survival (DFS), overall survival (OS), and toxicity were evaluated. With a median follow-up of 62 months (range: 32-107 months), LC was 89%, and 5-year OS and DFS were 78% and 63%, respectively. Symptomatic pneumonitis developed in six patients (9%); only one patient had her radiotherapy interrupted because of hematologic toxicity. No treatment-related mortality was observed. Radiation therapy after HDC provides excellent local control rates without excessive toxicity. Delaying the start of irradiation until recovery from HDC does not seem to increase local failure rates.     

High-dose carboplatin, etoposide and melphalan (CEM) with peripheral blood progenitor cell support as late intensification for high-risk cancer: non-haematological, haematological toxicities and role of growth factor administration.

The present report describes the non-haematological toxicity and the influence of growth factor administration on haematological toxicity and haematopoietic recovery observed after high-dose carboplatin (1200 mg m(-2)), etoposide (900 mg m(-2)) and melphalan (100 mg m(-2)) (CEM) followed by peripheral blood progenitor cell transplantation (PBPCT) in 40 patients with high-risk cancer during their first-line treatment. PBPCs were collected during the previous outpatient induction chemotherapy programme by leukaphereses. CEM administration with PBPCT was associated with low non-haematological toxicity and the only significant toxicity consisted of a reversible grade III/IV increase in liver enzymes in 32% of the patients. Haematopoietic recovery was very fast in all patients and the administration of granulocyte colony-stimulating factor (G-CSF) plus erythropoietin (EPO) or granulocyte-macrophage colony-stimulating factor (GM-CSF) plus EPO after PBPCT significantly reduced haematological toxicity, abrogated antibiotic administration during neutropenia and significantly reduced hospital stay and patient''s hospital charge compared with patients treated with PBPCT only. None of the patients died early of CEM plus PBPCT-related complications. Low non-haematological toxicity and accelerated haematopoietic recovery renders CEM with PBPC/growth factor support an acceptable therapeutic approach in an adjuvant or neoadjuvant setting.     

Immune reconstitution following allogeneic peripheral blood progenitor cell transplantation

Delayed immune reconstitution following allogeneic stem cell transplantation remains a major clinical problem, resulting in significant transplant-related mortality from infectious complications. The recovery of immunity after bone marrow transplantation (BMT) is a complex process dependent on a large number of pre- and post-transplant factors. It has been suggested that the use of peripheral blood instead of bone marrow as stem cell source may accelerate immune reconstitution after allogeneic transplantation. Some authors have recently reported a more rapid recovery of the number and function of T and B cells after allogeneic peripheral blood progenitor cell transplant (allo-PBPCT) in comparison with conventional BMT, results which would reflect the high number of lymphocytes infused to the patients. Such a rapid immune recovery could indeed contribute to the apparent therapeutic advantage of PBPCT when compared with BMT. However, there is limited knowledge on this issue and randomized trials are required to prove whether allo-PBPCT is indeed superior to BMT in terms of immune reconstitution post-transplant. A review of some quantitative and functional aspects of immune recovery after allo-PBPCT is presented in this article.     

High-dose therapy with peripheral blood stem cell (PBSC) support using an innovative mobilization regimen in patients with high-risk primary or chemoresponsive metastatic breast cancers

High-dose therapy followed by peripheral blood stem cell (PBSC) support was performed in 29 patients with primary high-risk (Group I) or chemoresponsive metastatic (Group II) breast cancer patients. Group I patients had received PBSC mobilization within 4 weeks of modified radical mastectomy. Group II patients had to achieve minimal residual disease (MRD) by induction chemotherapy before being considered eligible for PBSC mobilization and high-dose therapy. An innovative FE₁₂₀C regimen (5-FU 600 mg/m², i.v., day 1; epirubicin 120 mg/m², i.v., day 1; cyclophosphamide 600 mg/m², i.v., day 1) plus G-CSF (300 g/day, subcutaneous injection for 9 days, from day 4 post-FE₁₂₀ C) was used to mobilize PBSCs. After high-dose CTCb (cyclophosphamide 6,000 mg/m², thiothepa 500 mg/m², carboplatin 800 mg/m², in 4 days), patients received PBSC infusion and daily C-CSF 300 g sub cutaneous injection.There were 19 and 16 patients enrolled into Group I and Group II, respectively. Ten of the Group II patients had achieved minimal residual disease (MRD) after induction chemotherapy. The median numbers of mobilized total CD34 + cells for Group I and Group II patients were 27.3 (9.2 to 114.1) × 10⁶/kg and 17.1 (5.9 to 69.1) × 10⁶/kg respectively. The median time to neutrophil recovery (ANC 500/L) was 8 and 9 days in Group I and II, respectively. The median time to platelet recovery ( 50,000/L) was 10 and 15 days in Group I and II, respectively. No major treatment-related toxicities were noted. In Group I, 13 out of 19 patients (68.4%; 43–87%, 95% C.I.) remained recurrence-free with a median follow-up of 31 months (6 + to 55 + months). In Group II, 3 out of 10 patients (30%; 7–65%, 95% C.I.) remained progression-free at 33 +, 35 +, 39 + months from induction therapy.We suggest that the FE₁₂₀C plus G-CSF is an effective and innovative regimen for PBSC mobilization in breast cancer patients, and high-dose CTCb therapy with PBSC support is a safe and well-tolerated treatment modality.     

Single-agent paclitaxel in patients with metastatic breast cancer receiving high-dose chemotherapy with peripheral blood stem cell support

The purpose of this trial was to determine the effects of paclitaxel in patients with newly diagnosed metastatic breast cancer scheduled to receive high-dose chemotherapy with peripheral blood stem cell support. Eighty-four patients received anthracycline-based induction and two doses of paclitaxel at 170 mg/m2 (n = 52) or 250 mg/m2 (n = 32). Eighty-two (98%) received cyclophosphamide and etoposide (n = 50) or paclitaxel and cyclophosphamide (n = 32) with granulocyte colony-stimulating factor for mobilization of peripheral blood stem cells, and 79 (94%) received cyclophosphamide, thiotepa, and carboplatin with peripheral blood stem cell support. One patient (1%) died of infection and 56 (67%) died of progressive disease. For patients with measurable disease, the complete response rate was 21% after induction and 29% after paclitaxel (p = 0.54). Results were compared with those of 125 patients who received the same sequence of therapy without paclitaxel. The complete response rate after high-dose chemotherapy was 54% for patients receiving paclitaxel and 62% for those not receiving paclitaxel (p = 0.60). The probabilities of overall survival and event-free survival at 3 years for patients receiving paclitaxel were 46% and 24%, respectively, compared with 54% and 22%, respectively, for patients not receiving paclitaxel (p = 0.62). Further trials evaluating this dose and schedule of paclitaxel in patients with metastatic breast cancer receiving high-dose chemotherapy are not warranted.