Peripheral Blood Progenitor Cell Reinfusion Research Articles

Intensified alkylating chemotherapy for patients with oligometastatic breast cancer harboring homologous recombination deficiency: Primary outcomes from the randomized phase III OLIGO study

BackgroundOligometastatic breast cancer (OMBC) is a clinical entity with a prospect of long-term survival, but uncertainty remains on its optimal treatment. We studied whether intensified alkylating chemotherapy (IACT) improves long-term outcome compared to conventional-dose chemotherapy (CDCT) as part of a multimodality approach for patients with OMBC harboring homologous recombination deficiency (HRD). Patients and methodsEligible patients had HER2-negative OMBC, harboring HRD, with ≤ 3 distant metastases, pathologic proof of distant disease and a favorable response to three cycles CDCT. Participants were randomized 1:1 to continue with either CDCT or IACT. IACT consisted of one mobilization course followed by two cycles of mini-CTC (carboplatin, thiotepa and cyclophosphamide) supported by peripheral blood progenitor cell reinfusion. Primary outcome was event-free survival (EFS). Secondary endpoints included overall survival (OS), quality of life and safety. ResultsSeventy-five patients were randomized to either IACT (n = 36) or CDCT (n = 39). Twenty-three (31 %) patients had hormone receptor-positive disease and 52 (69 %) had triple-negative disease. Median EFS in the IACT-group was 28 months (95 % confidence interval [CI] 21-not reached [NR]) versus 25 months (95 %CI 14-NR) in the CDCT-group (hazard ratio [HR] for recurrence or death 0.78, 95 %CI 0.42–1.42). Median OS was 67 months (95 %CI 37-NR) in the IACT-group and 36 (95 %CI 26-NR) in the CDCT-group (HR 0.74, 95 %CI 0.37–1.48). ConclusionsThe entire study population experienced long-term survival, with median OS well over five years. IACT compared to CDCT did not improve outcome in patients with OMBC harboring study-defined HRD. The optimal therapy for patients with OMBC requires further study. Trial RegistrationClinicalTrials.gov: NCT01646034

Abstract OT1-01-08: Intensified alkylating chemotherapy in patients with oligo-metastatic breast cancer harboring homologous recombination deficiency: The OLIGO study

Abstract Background Approximately 5% of patients with metastatic breast cancer survive more than 10 years. Long-term survival is mostly seen in patients with limited metastatic disease, often referred to as 'oligo'-metastatic disease. Oligo-metastatic breast cancer is variably defined as a maximum of 3-5 metastases beyond the regional lymph nodes. Some believe that oligo-metastatic cancer can be treated with curative intent using a multidisciplinary approach that targets the detected metastases, circulating micro-metastases, and any locoregional disease if present. Optimal patient selection is of vital importance. Intensified alkylating chemotherapy in the treatment of breast cancer patients is controversial, as older studies have not shown a survival benefit in unselected groups of patients. More recent retrospective analyses, however, have suggested that patients with homologous recombination deficiency (HRD) derive significant benefit from intensified chemotherapy in comparison to conventional chemotherapy. Trial design In this phase 3 trial patients with oligo-metastatic breast cancer and HRD start with 3 cycles of induction chemotherapy. Chemotherapy schedule includes anthracyclines and taxanes in treatment naïve patients and is personalized according to previously received (neo-)adjuvant chemotherapy in others. Patients with at least stable disease after 3 cycles are 1:1 randomized to receive another 3 cycles of conventional chemotherapy or progenitor cell mobilization with cyclophosphamide followed by 2 cycles of intensified chemotherapy (carboplatin 400 mg/m2 (day 1&2), thiotepa 250 mg/m2 (day 2), and cyclophosphamide 3000 mg/m2 (day 1)) and peripheral blood progenitor cell reinfusion. Following systemic treatment, all patients receive maximal local therapy of locoregional and distant disease with surgery and/or radiotherapy. Eligibility criteria Eligible patients have histologically proven, HER2 negative, oligo-metastatic breast cancer (1-3 distant metastatic lesions), with or without locoregional disease, either as de novo disease or recurrence. All lesions must be amenable to surgery or radiotherapy with curative intent. The tumor has to be deficient in homologous recombination by array comparative genomic hybridization and no prior chemotherapy for metastatic disease is allowed. Specific aim To study the difference in event-free survival (EFS) between intensified alkylating chemotherapy compared to standard chemotherapy as part of a multimodality treatment approach in patients with oligo-metastatic breast cancer harboring HRD. Statistical methods and patient accrual Primary endpoint of the study is EFS at 3 years. Toxicity, time to recurrence, and overall survival will be evaluated as secondary endpoints. A total of 65 EFS events will provide 80% power to detect a hazard ratio of 2.0 between treatment arms at the 0.05 two-sided significance level. Assuming an accrual period of 48 months and a maximum follow-up time of 60 months, 86 patients are required. At the time of abstract submission, 33 patients were randomized. Contact information Principal investigator: Dr. GS Sonke, g.sonke@nki.nl. Study coordinator: TG Steenbruggen, t.steenbruggen@nki.nl. Clinicaltrials.gov: NCT01646034. Citation Format: Steenbruggen TG, Vrancken Peeters M-JTFD, Scholten AN, Schot M, Wesseling J, Linn SC, Sonke GS. Intensified alkylating chemotherapy in patients with oligo-metastatic breast cancer harboring homologous recombination deficiency: The OLIGO study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-01-08.

863P - Multi-Cycle High-Dose Chemotherapy with TI-CE Regimen for Patients with Relapsed/Refractory Germ Cell Tumors – a Single Institution Experience

ABSTRACT Background A large international phase III randomized trial (TIGER study) has been recently planned to compare the TI-CE multi-cycle high-dose chemotherapy (HDCT) with standard chemotherapy as salvage treatment for patients with relapsed germ cell tumors (GCT), but to date there are no reported experiences with this regimen other than the phase 2 study from MSKCC (Feldman et al – JCO 2010). We present preliminary results of our experience with TI-CE in relapsed/refractory GCT patients. Methods From August 2009 to April 2012, patients with relapsed/refractory GCT received TI-CE comprising a mobilizing phase with paclitaxel and ifosfamide (TI) with leukapheresis of peripheral blood progenitor cells (PBPCs), followed by 3 HDCT courses with CE (carboplatin AUC 21 and etoposide 1200 mg/m2), with PBPC reinfusion. Biosimilar filgrastim (Zarzio®) was used in the HDCT phase for all patients after PBPC reinfusion. Results 26 patients (25 males, median age 34) started on TI, but 3 of them did not receive CE: two had rapidly progressive symptomatic brain metastases, the third one refused HDCT. Of 23 patients, 20 completed the TI-CE regimen and are evaluable, while 3 are still receiving treatment. There were no treatment-related deaths. The median number of days from the start of CE until recovery of neutrophils to 1,000/mm3 was 14. Twelve (60%) of the 20 evaluable patients achieved a complete remission (CR) (5 clinical CR, 5 pathological CR, 2 surgical CR), 5 had marker-negative partial remissions lasting 2, 2 + , 2 + , 6+ and 21+ months, and 3 progressed. After a median follow-up of 13 months (range, 2 to 33+), 15 (75%) evaluable patients are continuously progression-free. Of 4 mediastinal primary nonseminomatous GCT, 2 achieved a CR (1 sCR and 1 pCR) lasting 7 and 12+ months, respectively. Conclusions Our experience confirms that the TI-CE regimen is safe and active, with a response rate and a recovery time of neutrophils after CE similar to that reported in the MSKCC study. Updated results will be presented at the meeting. Disclosure All authors have declared no conflicts of interest.

Multiple cycles of PBPC-supported high-dose carboplatin and paclitaxel following mobilization with epirubicin and cisplatin are feasible but ineffective in treating patients with advanced non-small cell lung cancer

We verified the feasibility of a multi-cycle peripheral blood progenitor cell (PBPC)-supported high-dose chemotherapy (HDC) regimen in patients with non-small cell lung cancer (NSCLC). The HDC regimen consisted of a single course of high-dose epirubicin given in combination with cisplatin plus filgrastim, followed by three courses of high doses of carboplatin and paclitaxel with PBPC reinfusion and filgrastim. Of the 16 enrolled patients, 13 provided an adequate number of PBPCs by a single leukapheresis, while in the three needed two procedures, with a median number of CD34+, CD34+/CD33- and CD34+/CD38- cells collected per patient was 13.5 x 10(6), 10.9 x 10(6) and 0.9 x 10(6)/kg, respectively. No toxic death occurred, and the collected PBPCs supported a rapid hematopoietic reconstitution after HDC; however, seven patients early interrupted the treatment early due to early progressive disease (n=4) or prolonged grade 3 peripheral neurotoxicity (n=3). Despite an overall response rate of 42%, the median survival for stage IV patients has been 5 months (range: 1-25+). Of two patients with stage IIIB NSCLC, one is continuously disease-free at 71+ months, while of 14 with stage IV disease, one is currently alive with disease at 25+ months. In conclusion, the combination of high-dose epirubicin with cisplatin plus filgrastim is an effective regimen in releasing large amounts of PBPCs, which can then be safely employed to support multiple courses of HDC. Multiple cycles of PBPC-supported high-dose carboplatin and paclitaxel are ineffective in treating patients with advanced NSCLC.

Prolonged Survival of Lymphoma Patients Achieving Complete Remission Following High-Dose Sequential Chemotherapy and Autograft (HDS Program): A GITIL (Gruppo Italiano Terapie Innovative Nei Linfomi) Retrospective Study on 1,266 Patients.

Introduction. The high-dose sequential (HDS) chemotherapy approach is characterized by early dose-intensification followed by autograft with peripheral blood progenitor cells (PBPC). The HDS program was introduced several years ago (Gianni & Bonadonna, 1989); subsequently, it has been increasingly used in the management of both non-Hodgkins (NHL) and Hodgkins Lymphoma (HL). The outcome of a large series of lymphoma patients treated with the HDS approach at 10 Centers associated to GITIL is reported.Patients and Methods. Data have been collected on 1,266 patients, who received either the original or slightly modified HDS regimens. There were 213 HL and 1,053 NHL patients (630 intermediate/high-grade, 423 low-grade); median age was 46 yrs, 57% were male. Overall, 671 (53%) patients received HDS as salvage treatment after one or more recurrence; 595 (47%) had HDS front-line, either for high-risk clinical presentation or unfavorable histology, i.e. mantle-cell l. Most patients were autografted with PBPC, few received BM cells (alone or with PBPC); 158 (12%) patients did not undergo autograft, due to several reasons, namely: toxicity, disease progression, poor harvests.Results. Overall, 1,013 (80%) patients reached Complete Remission (CR) following the HDS program. Up to now, 93 (7%) patients died for early/late toxicities, 328 (26%) died for lymphoma, 844 are known to be alive; at a median follow-up of 5 yrs, the 5-yr Overall Survival (OS) projection is 64% (s.e. 2%). As shown in Figure 1 A and B, a significantly higher survival was observed in patients receiving HDS at diagnosis vs. those at relapse and in those achieving CR vs. no CR patients. On multivariate Cox survival analysis, these two parameters maintained a significant impact on the 5-yr survival (relapse status at HDS: HR 1.39, c.i.: 1.12–1.72; CR achievement: HR 0.12, c.i.: 0.10–0.16). Also some histological features (low grade vs intermediate/high; B-cell vs. T-cell) had a significant impact on OS, whereas other parameters, including sex, bone marrow involvement, HL vs NHL, use of hd-Ara-C, had no relevance.Conclusions.the HDS program including PBPC collection and re-infusion is feasible in a multicenter setting and allows prolonged survival in a good proportion of lymphoma patients presenting with unfavorable prognosis;the long-term outcome is definitely good in patients achieving CR;given their poor outcome, early salvage treatment options, including allogeneic transplant, should be considered for those patients unable to reach CR following a HDS treatment approach. [Display omitted]

Total marrow irradiation and peripheral blood progenitor cell rescue following high-dose melphalan and peripheral blood progenitor cell rescue in patients with multiple myeloma

Tandem high-dose therapy (THDT) followed by peripheral blood progenitor cell reinfusion (PBPC) is associated with a projected 20% progression-free survival at 7 years after treatment for patients with multiple myeloma (MM). Combining standard fractionated total body irradiation (TBI) with high-dose melphalan precludes optimal dosing of melphalan, and results in equivalent efficacy but more toxicity in comparison to high-dose melphalan (mel) alone. Helical tomotherapy is a novel tool for delivering CT image guided intensity modulated radiation therapy and may allow for greater doses of total marrow irradiation (TMI) and less collateral damage to other organs. We set out to test the feasibility of THDT inclusive of TMI. Eligible patients (≤70 years old, with stages I-III MM, in response or with stable disease, with a creatinine clearance of ≥50 mL/min) underwent mobilization with cyclophosphamide 1.5 gm/m2 and G-CSF 10 microgram/kg and procurement of ≥ 4 × 106 CD34+ cells/kg. THDCT consisted of a set dose of mel 200 mg/m2 followed by PBPC. At a minimum of 6 weeks later, TMI 200 cGy daily × 5 days, (to be escalated up to 200 cGy twice daily in a standard phase one cohort by cohort fashion) an PBPC is administered. Upon recovery, thalidomide 50–200 mg daily and dexamethasone 40 mg/day × 4 days every 28 days is to be prescribed. At dose level 1 (TMI: 200 cGy daily × 5 days) two patients (a 53 year old female with stage I MM in complete response and a 48 year old male with stage III MM in partial response prior to THDT) have completed THDT and are currently receiving maintenance. Neutrophyl and platelet recovery following TMI was observed by days 9 and 11, and platelet independence (defined as the day after the last platelet transfusion) was observed by day 10. Grade 1 emesis and grade 2 nausea, but no evidence of oral mucositis, enteritis, or skin erythema were noted. The estimated reduction in organ exposure to radiation with TBI versus TMI ranged from 6.5–6.9-fold (lens) to 2.5–2.6-fold (bowel), and 1.4–1.7-fold (lungs) in the first two patients treated. TMI is feasible for patients undergoing THDT for MM. Accrual is ongoing and results in patients treated at higher doses of TMI will be presented.

Total Marrow Irradiation (TMI) with Helical Tomotherapy and PBPC Following High-Dose Melphalan and PBPC as Part of Tandem Therapy for Patients with Multiple Myeloma.

Tandem high-dose therapy (HDT) followed by peripheral blood progenitor cell reinfusion (PBPC) improves survival for patients with MM, but 80% of patients relapse within 7 years after HDCT. Attempts to treat all areas of skeletal involvement by combining total body irradiation (TBI) with high-dose melphalan (Mel) resulted in substantial organ toxicities and precluded optimal dosing of Mel. Helical tomotherapy allows for 3D CT image guided intensity modulated radiation therapy to large target regions. Radiation beams can be shaped and directed at disease sites from multiple directions. This technology may allow delivery of total marrow irradiation (TMI) at high doses in order to treat MM, while avoiding collateral toxicities. We had performed pre-clinical simulation studies for an adult female patient generating dose volume histograms (DVH) which demonstrated a 2–7 fold reduction in median dose to critical organs and which predicted for the ability to deliver up to 2.0 Gy to the marrow compartment with comparable or reduced risks of mucositis, espohagitis, enteritis, pneumonitis, nephropathy, and cardiomyopathy as it would be expected with TBI of 1.2 Gy. We then designed a phase I/II study for patients with responding or stable stage I-III MM who undergo PBPC mobilization with cyclophosphamide 1.5 gm/kg and G-CSF 10 microgram/kg, and than receive tandem HDT first with melphalan 200 mg/m2 and PBPC, and a minimum of 6 weeks later they are treated with escalating doses of TMI (starting dose: 200 cGy daily x 5, to be escalated up to 200 cGy twice daily x 5 days), and PBPC. Subsequent maintenance therapy consists of dexamethasone 40 mg/day x 4 days every 28 days and thalidomide 50-200 mg/day. The first patient treated with 1 Gy of TMI was a 53 year old woman with stage I IgGκ MM in complete remission after thalidomide and dexamethasone induction. Neutrophil (ANC) and platelet nadirs were observed on days 5 and 9 after melphalan and PBPC; ANC recovery to > 500/uL occured by day 13 and the patient became platelet transfusion independent by day 9. TMI and PBPC were administered 12 weeks later. ANC and platelet nadirs occurred on days 3 and 5; ANC recovered in 10 days and platelet transfusion independence was accomplished by day 11. The patient experienced partial alopecia, grade 2 nausea and grade 1 emesis on the second day of TMI, but she was completely devoid of erythema, mucositis, or diarrhea. The actual DVHs were comparable to those seen in the preclinical studies/simulations and reflected an estimated 2.5 fold median decrease in the amount of radiation delivered to non-target organs in comparison to the target: bone marrow. [Display omitted] Accrual to the first dose level is completed. Details of toxicities and DVH curves from additional patients/cohorts who will have completed their TMI cycles will be presented.

CD34 Positive Cells Mobilized with Chemotherapy Plus Recombinant Human Growth Hormone (rhGH) and Recombinant Human Granulocyte Colony-Stimulating Factor (rhG-CSF) Allows Sustained Engraftment in Previously Non-Mobilizer Patients.

The availability of adequate amounts of peripheral blood progenitor cells (PBPC) is a prerequisite for the feasibility of high-dose therapy program in patients with neoplastic diseases. Due to prior chemio-radiotherapy or disease related factors, 20–30% of patients fails to mobilize sufficient amounts of PBPC. Therefore, non-mobilizer patients cannot complete their therapeutic program. The aims of the present study were: 1) to evaluate the combination rhGH+rhG-CSF after chemiotherapy as a mobilization regimen in previously non-mobilizers patients; 2) to assess safety and tolerability of rhGH+rhG-CSF treatment; 3) to evaluate hematopoietic recovery after reinfusion of rhGH+rhG-CSF mobilized PBPC. After informed consent, three patients (2 male, 1 female), that failed a previous mobilization cycle, were remobilized with chemotherapy plus rhGH (100μg/Kg/d, sc) and rhG-CSG (5μg/Kg/d, sc).CaseDiseaseTNC (x 108/Kg)CD34+ (x 106/Kg)CFC (x 106/Kg)LTC-IC (x 104/Kg)1LNH8.57.65.6815.92LNH186.23.575.03MM151.31.2612.0No specific side effects were noticed due to rhGH treatment. Reinfusionof PBPC after myeloablative therapy resulted in hematopoietic recovery with 16, 9, 11 days respectively to reach an absolute neutrophil count ≥ 500/μl and 24, 15, 15 days respectively to reach a platelet count ≥ 50000/μl. Hematopoietic engraftment is complete and sustained with a follow-up of 18, 11 and 9 months, respectively.In conclusion our data confirm that the addition of rhGH to rhG-CSF allows mobilization and collection of PBPC in previously non-mobilizer patients, and therefore the programmed high-dose therapy program can be satisfactorily completed, with sustained hematopoietic recovery.

Efficacy of high-dose alkylating chemotherapy in the adjuvant treatment of HER2/neu-negative primary breast cancer: update of the Dutch randomized trial

The role of high-dose chemotherapy in the adjuvant treatment of high-dose breast cancer has not been established. Results have been reported from six randomized studies with a symmetrical study design (Table ​(Table1).1). All show a lower relapse rate in the high-dose arm, but in only one study was this result statistically significant. Table 1 Randomized studies evaluating the role of high-dose chemotherapy in high-risk breast cancer Methods Patients below 56 years of age who had undergone surgery for stage II or III breast cancer were eligible if they had at least four tumor-positive axillary lymph nodes. Patients in the conventional dose (CD) arm received five courses of FEC (fluorouracil 500 mg/m2, epirubicin 90 mg/m2 and cyclophosphamide 500 mg/m2; every 3 weeks) followed by radiation therapy and tamoxifen. The high-dose (HD) arm was identical, except that high-dose chemotherapy (CTC [cyclophosphamide 6 g/m2, thiotepa 480 mg/m2 and carboplatin 1600 mg/m2]) with peripheral blood progenitor cell reinfusion was given instead of the fifth FEC course.

Toxicity of the high-dose chemotherapy CTC regimen (cyclophosphamide, thiotepa, carboplatin): the Netherlands Cancer Institute experience

High-dose chemotherapy (HD-CT) has a role in the potentially curative treatment of several tumours. The relative efficacies of the different regimens have not been studied in comparative trials, but it is clear that toxicities differ significantly between them. We analysed the immediate and long-term toxicity in the first 100 consecutive patients treated with the CTC regimen (cyclophosphamide 6000 mg m−2, carboplatin 1600 mg m−2 (or 20 mg ml−1 min under the curve (AUC)) both as daily 1 h infusion, thiotepa 480 mg m−2 as twice daily 30 min infusion, all divided over 4 consecutive days) followed by peripheral blood progenitor cell reinfusion (PBPC-Tx). Most patients had high-risk (n=86) or metastatic (n=4) breast cancer, or a germ cell tumour (n=8). Two patients (with a medulloblastoma and an aesthesioneuroblastoma, respectively) received CTC as off-protocol salvage regimen. The main toxicity was bone marrow suppression. Most patients had PBPC-Tx with granulocyte colony-stimulating factor (G-CSF), and the median time to neutrophil count 500 × 106 l−1 and platelet count >20 × 109 l−1 without transfusion independence was 10 (range 8–25) and 13 (8–60) days, respectively. The toxic death rate was 1%. Other frequent toxicities were neutropenic fever requiring antibiotics (n=65), central catheter-related infection (n=12) or a bleeding episode (n=48), mostly epistaxis (n=26). Reversible cardiac toxicity was seen in six patients and pulmonary events occurred in seven patients (infection (n=6), embolism (n=1)). Grade 3–4 gastrointestinal toxicity was frequent: nausea and vomiting 55%, diarrhoea 28% and mild liver toxicity (transaminase elevations) 9%. One patient pretreated with cisplatin had a kidney transplantation 8 years after HD-CT. Late complications included reversible radiation pneumonitis (n=12) and chronic heart failure (n=2). We found five second solid malignancies and two myelodysplasias. In conclusion, the CTC regimen is associated with a moderate, mainly reversible, toxicity. Future studies need to compare the efficacy and toxicity of the different HD-CT regimens.

Intensified chemotherapy supported by DMSO-free peripheral blood progenitor cells in breast cancer patients

The majority of high-dose chemotherapy (HDC)-related complications results from bone marrow aplasia, but the graft infusion per se may cause adverse reactions due to the injection of both dimethyl sulfoxide (DMSO) and cell lysis products. We evaluated the feasibility of a two-step chemotherapy regimen with peripheral blood progenitor cell (PBPC) support in association with a novel procedure to remove DMSO and products of cell lysis from the cryopreserved cells. Stage III and IV breast cancer patients received induction chemotherapy with three cycles of CEF (cyclophosphamide 600 mg/m2, epirubicin 100 mg/m2, 5-fluorouracil 600 mg/m2) followed by three cycles of HDC consisting of escalating doses of cyclophosphamide (dose range 1200 3000 mg/m2) and carboplatin (dose range 600-1000 mg/m2), supported by DMSO-free PBPC reinfusion. DMSO was removed by a washing/enzymatic digestion procedure. Twenty patients received induction chemotherapy and eighteen completed the entire chemotherapy program; a total of fifty-four cycles of HDC were administered. Dose limiting toxicity of HDC was long-lasting grade 4 neutropenia associated with documented infection. The maximum tolerated dose (MTD) was cyclophosphamide 3000 mg/m2 and carboplatin 600 mg/m2. No side effects related to PBPC reinfusion were observed. The proposed two-step chemotherapy regimen, associated with a novel washing/enzymatic digestion procedure, is feasible in advanced breast cancer patients in the absence of complications related to the specific toxicity of PBPC reinfusion.

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.

Evaluation of acute toxicities associated with autologous peripheral blood progenitor cell reinfusion in patients undergoing high-dose chemotherapy.

Peripheral blood progenitor cell reinfusion (PBPC) in patients undergoing high-dose chemotherapy (HDC) for poor prognosis malignancies, has been described as causing possible acute gastrointestinal (nausea, vomiting), allergic (oedema, bronchospasm, anaphyl- axis), renal (proteinuria, haematuria) and/or cardiovascular (hypotension, arrhythmia, conduction disturbances, transient ischaemic phenomena) toxicities. To establish the clinical relevance of these observations and the possible relationship with different HDC regimens used, we performed a clinical and instrumental evaluation on 33 patients with advanced breast cancer, non-Hodgkin's lymphoma, Hodgkin's disease, relapsed ovarian cancer, Ewing's sarcoma, extragonadal germinal tumour and small cell lung cancer. They underwent at least one reinfusion each for a total of 51 studied procedures. No patient had a previous history of cardiovascular disease or significant intercurrent illness such as diabetes or liver, renal or neurologic impairment. All patients had totally implanted central venous catheters, through which the transplants had been collected and reinfused without technical consequences. To evaluate cardiovascular function, we continuously monitored 12-lead ECGs, with arterial pressure (AP) measurements every 5 min from the beginning of the procedure to 15 min after the reinfusion ended. We did not observe any significant differences between basal and subsequent steps in AP, heart rate, PQ and QTc time, P wave and QRS complex duration or P wave and QRS electrical axes. No patient showed any ST-T tract pathological abnormality, but one patient developed a transient ectopic atrial rhythm, without any haemodynamic disfunction and with spontaneous reversion to sinus rhythm. No patient complained of symptoms of haemodynamic failure. Gastrointestinal side-effects appeared to be strictly related to speed of reinfusion and to the number of packs reinfused, probably reflecting on the amount of dimethylsulphoxide infused. In one patient a tonic-clonic seizure occurred during a vomiting episode, but no patient developed allergic or renal toxicities. We conclude that PBPC reinfusion, if managed according to the procedure we propose in patients without organic impairment, is a safe procedure not associated either with increased risk of acute arrhythmias or ischaemic or significant systemic acute toxicities. Bone Marrow Transplantation (2000) 25, 173-177.

Recombinant Human Thrombopoietin in Combination With Granulocyte Colony-Stimulating Factor Enhances Mobilization of Peripheral Blood Progenitor Cells, Increases Peripheral Blood Platelet Concentration, and Accelerates Hematopoietic Recovery Following High-Dose Chemotherapy

AbstractLineage-specific growth factors mobilize peripheral blood progenitor cells (PBPC) and accelerate hematopoietic recovery after high-dose chemotherapy. Recombinant human thrombopoietin (rhTPO) may further increase the progenitor-cell content and regenerating potential of PBPC products. We evaluated the safety and activity of rhTPO as a PBPC mobilizer in combination with granulocyte colony-stimulating factor (G-CSF) in 29 breast cancer patients treated with high-dose chemotherapy followed by PBPC reinfusion. Initially, patients received escalating single doses of rhTPO intravenously (IV) at 0.6, 1.2, or 2.4 μg/kg, on day 1. Subsequent patients received rhTPO 0.6 or 0.3 μg/kg on days −3, −1, and 1, or 0.6 μg/kg on days −1 and 1. G-CSF, 5 μg/kg IV or subcutaneously (SC) twice daily, was started on day 3 and continued through aphereses. Twenty comparable, concurrently and identically treated patients (who were eligible and would have been treated on protocol but for the lack of study opening) mobilized with G-CSF alone served as comparisons. CD34+ cell yields were substantially higher with the first apheresis following rhTPO and G-CSF versus G-CSF alone: 4.1 × 106/kg (range, 1.3 to 17.6) versus 0.8 × 106/ kg (range, 0.3 to 4.2), P = .0003. The targeted minimum yield of 3 × 106CD34+ cells/kg was procured following a single apheresis procedure in 61% of the rhTPO and G-CSF–mobilized group versus 10% of G-CSF–mobilized patients (P = .001). In rhTPO and G-CSF mobilized patients, granulocyte (day 8 v 9, P= .0001) and platelet recovery (day 9 v 10, P= .07) were accelerated, and fewer erythrocyte (3 v 4,P = .02) and platelet (4 v 5, P = .02) transfusions were needed compared with G-CSF–mobilized patients. Peripheral blood platelet counts, following rhTPO and G-CSF, were increased by greater than 100% and the platelet content of PBPC products by 60% to 110% on the first and second days of aphereses (P < .0001) with the greatest effect seen with repeated dosing of rhTPO at 0.6 μg/kg. rhTPO is safe and well tolerated as a mobilizing agent before PBPC collection. Mobilization with rhTPO and G-CSF, in comparison to a comparable, nonrandomized G-CSF–mobilized group of patients, decreases the number of apheresis procedures required, may accelerate hematopoietic recovery, and may reduce the number of transfusions required following high-dose chemotherapy for breast cancer.

Recombinant Human Thrombopoietin in Combination With Granulocyte Colony-Stimulating Factor Enhances Mobilization of Peripheral Blood Progenitor Cells, Increases Peripheral Blood Platelet Concentration, and Accelerates Hematopoietic Recovery Following High-Dose Chemotherapy

Lineage-specific growth factors mobilize peripheral blood progenitor cells (PBPC) and accelerate hematopoietic recovery after high-dose chemotherapy. Recombinant human thrombopoietin (rhTPO) may further increase the progenitor-cell content and regenerating potential of PBPC products. We evaluated the safety and activity of rhTPO as a PBPC mobilizer in combination with granulocyte colony-stimulating factor (G-CSF) in 29 breast cancer patients treated with high-dose chemotherapy followed by PBPC reinfusion. Initially, patients received escalating single doses of rhTPO intravenously (IV) at 0.6, 1.2, or 2.4 micrograms/kg, on day 1. Subsequent patients received rhTPO 0.6 or 0.3 micrograms/kg on days -3, -1, and 1, or 0.6 micrograms/kg on days -1 and 1. G-CSF, 5 micrograms/kg IV or subcutaneously (SC) twice daily, was started on day 3 and continued through aphereses. Twenty comparable, concurrently and identically treated patients (who were eligible and would have been treated on protocol but for the lack of study opening) mobilized with G-CSF alone served as comparisons. CD34(+) cell yields were substantially higher with the first apheresis following rhTPO and G-CSF versus G-CSF alone: 4.1 x 10(6)/kg (range, 1.3 to 17.6) versus 0.8 x 10(6)/ kg (range, 0.3 to 4.2), P =.0003. The targeted minimum yield of 3 x 10(6) CD34(+) cells/kg was procured following a single apheresis procedure in 61% of the rhTPO and G-CSF-mobilized group versus 10% of G-CSF-mobilized patients (P =.001). In rhTPO and G-CSF mobilized patients, granulocyte (day 8 v 9, P =.0001) and platelet recovery (day 9 v 10, P =.07) were accelerated, and fewer erythrocyte (3 v 4, P =.02) and platelet (4 v 5, P =.02) transfusions were needed compared with G-CSF-mobilized patients. Peripheral blood platelet counts, following rhTPO and G-CSF, were increased by greater than 100% and the platelet content of PBPC products by 60% to 110% on the first and second days of aphereses (P <.0001) with the greatest effect seen with repeated dosing of rhTPO at 0.6 microgram/kg. rhTPO is safe and well tolerated as a mobilizing agent before PBPC collection. Mobilization with rhTPO and G-CSF, in comparison to a comparable, nonrandomized G-CSF-mobilized group of patients, decreases the number of apheresis procedures required, may accelerate hematopoietic recovery, and may reduce the number of transfusions required following high-dose chemotherapy for breast cancer.

High CD34+ Cell Counts Decrease Hematologic Toxicity of Autologous Peripheral Blood Progenitor Cell Transplantation

Optimal numbers of CD34+ cells to be reinfused in patients undergoing peripheral blood progenitor cell (PBPC) transplantation after high-dose chemotherapy are still unknown. Hematologic reconstitution of 168 transplantations performed in patients with lymphoproliferative diseases was analyzed according to the number of CD34+ cells reinfused. The number of days from PBPC reinfusion until neutrophil recovery (&gt;1.0 × 109/L) and unsustained platelet recovery (&gt;50 × 109/L) were analyzed in three groups defined by the number of CD34+ cells reinfused: a low group with less than or equal to 2.5 × 106 CD34+ cells/kg, a high group with greater than 15 × 106 CD34+cells/kg, and an intermediate group to which the former two groups were compared. The 22 low-group patients had a significantly delayed neutrophil (P &lt; .0001) and platelet recovery (P &lt; .0001). The 41 high-group patients experienced significantly shorter engraftment compared with the intermediate group with a median of 11 (range, 8 to 16) versus 12 (range, 7 to 17) days for neutrophil recovery (P = .003), and a median of 11 (range, 7 to 24) versus 14 (range, 8 to 180+) days for platelet recovery (P&lt; .0001). These patients required significantly less platelet transfusions (P = .002). In a multivariate analysis, the amount of CD34+ cells reinfused was the only variable showing significance for neutrophil and platelet recovery. High-group patients had a shorter hospital stay (P = .01) and tended to need fewer days of antibotic administration (P = .12). In conclusion, these results suggest that reinfusion of greater than 15 × 106 CD34+ cells/kg after high-dose chemotherapy for lymphoproliferative diseases further shortens hematopoietic reconstitution, reduces platelet requirements, and may improve patients' quality of life.

High CD34+Cell Counts Decrease Hematologic Toxicity of Autologous Peripheral Blood Progenitor Cell Transplantation

AbstractOptimal numbers of CD34+cells to be reinfused in patients undergoing peripheral blood progenitor cell (PBPC) transplantation after high-dose chemotherapy are still unknown. Hematologic reconstitution of 168 transplantations performed in patients with lymphoproliferative diseases was analyzed according to the number of CD34+cells reinfused. The number of days from PBPC reinfusion until neutrophil recovery (>1.0 × 109/L) and unsustained platelet recovery (>50 × 109/L) were analyzed in three groups defined by the number of CD34+cells reinfused: a low group with less than or equal to 2.5 × 106CD34+cells/kg, a high group with greater than 15 × 106CD34+cells/kg, and an intermediate group to which the former two groups were compared. The 22 low-group patients had a significantly delayed neutrophil (P< .0001) and platelet recovery (P< .0001). The 41 high-group patients experienced significantly shorter engraftment compared with the intermediate group with a median of 11 (range, 8 to 16) versus 12 (range, 7 to 17) days for neutrophil recovery (P =.003), and a median of 11 (range, 7 to 24) versus 14 (range, 8 to 180+) days for platelet recovery (P< .0001). These patients required significantly less platelet transfusions (P =.002). In a multivariate analysis, the amount of CD34+cells reinfused was the only variable showing significance for neutrophil and platelet recovery. High-group patients had a shorter hospital stay (P =.01) and tended to need fewer days of antibotic administration (P= .12). In conclusion, these results suggest that reinfusion of greater than 15 × 106CD34+cells/kg after high-dose chemotherapy for lymphoproliferative diseases further shortens hematopoietic reconstitution, reduces platelet requirements, and may improve patients' quality of life.

Sequential high-dose therapy and autologous stem cell transplantation for treatment of mantle cell lymphoma

Mantle cell lymphoma (MC) is not curable with conventional chemotherapy. To improve the prognosis of patients with this disease, we prospectively studied an intensive sequential therapy consisting of the Dexa-BEAM regimen (dexamethasone, BCNU, etoposide, ara-C, melphalan) followed by myeloablative therapy with autologous stem cell reinfusion. Nine consecutive patients with stage III/IV MC were included. Two had untreated disease, four were in first remission, whereas three had more advanced disease. All patients underwent one to two cycles of Dexa-BEAM chemotherapy to reduce the tumor load and to mobilize peripheral blood progenitor cells (PBPC). Subsequently, patients were treated with high-dose radiochemotherapy followed by PBPC reinfusion and were prospectively analyzed for residual disease by clinical methods as well as by PCR amplification clonal CDRIII rearrangements. With an overall response rate of 100%, the initial Dexa-BEAM cycles effectively reduced the tumor load. All patients proceeded to high-dose therapy and subsequent stem cell rescue. Engraftment was prompt, and procedure-related deaths did not occur. With a median follow-up of 12 (3-33) months post transplant, all patients are alive in continuing clinical and molecular remission. Sequential intensive therapy consisting of Dexa-BEAM and high-dose radiochemotherapy appears to be a highly effective treatment for patients with MC. However, the data are still preliminary, and larger patient numbers and a longer follow-up are required.

Intensive therapy with peripheral blood progenitor cell transplantation in 60 patients with poor-prognosis follicular lymphoma

Intensive therapy, mainly with purged autologous bone marrow transplantation (ABMT), has been proposed in recent years as consolidation treatment in young patients with follicular lymphoma. Reported experience with transplantation of peripheral blood progenitor cells (PBPC) is, so far, limited. The feasibility and the therapeutic efficacy of intensive therapy followed by unpurged autologous PBPC reinfusion were evaluated in 60 patients with poor-prognosis follicular lymphoma. Twelve patients were in first partial remission (PR), 34 were in second partial or complete remission (CR), and 14 were in subsequent progression. At the time of the procedure, 39 patients (65%) had persistent bone marrow involvement, 49 patients (82%) were in PR, and 16 patients had presented with a histologic transformation (HT). PBPC were collected after chemotherapy followed by granulocyte (G) colony-stimulating factor (CSF) or granulocyte-macrophage (GM)-CSF in 50 patients. Conditioning regimens included high-dose chemotherapy alone (14 patients); mainly the BCNU, etoposide, aracytine, melphalan [BEAM] regimen), or cyclophosphamide with or without etoposide plus total body irradiation (46 patients). The median time to reach a neutrophil count greater than 0.5 x 10(9)/L was 13 days. There were five treatment-related deaths, with four being associated with a delayed engraftment and all occurring in patients in third or subsequent progression. At a median follow-up of 21 months, 48 patients were still alive, 18 relapsed, and seven died of lymphomas progression. Estimated 2-year overall survival (OS) and failure-free survival (FFS) rates were 86% and 53%, respectively, without or plateau. Patients treated in PR1 or PR2/CR2 had a significantly longer rate of OS and FFS than those treated in subsequent progression (P = .002 and P = .001, respectively), whereas age, response to salvage treatment, presence or absence of residual bone marrow involvement, or conditioning regimen had no influence on outcome. Patients with HT tended to have a worse FFS rate (P = .04) without an OS difference. Along with an unusual rate of engraftment failure, the poor FFS observed in heavily pretreated patients suggests that intensive therapy should be performed early in the course of the disease. Given the high percentage of patients intensified in PR with residual bone marrow involvement, our results are comparable with those achieved with ABMT published to date. Prospective trials are warranted to compare this strategy with standard therapy in patients with relapsing or PR follicular lymphoma.

Intensive Therapy With Peripheral Blood Progenitor Cell Transplantation in 60 Patients With Poor-Prognosis Follicular Lymphoma

Intensive therapy, mainly with purged autologous bone marrow transplantation (ABMT), has been proposed in recent years as consolidation treatment in young patients with follicular lymphoma. Reported experience with transplantation of peripheral blood progenitor cells (PBPC) is, so far, limited. The feasibility and the therapeutic efficacy of intensive therapy followed by unpurged autologous PBPC reinfusion were evaluated in 60 patients with poor-prognosis follicular lymphoma. Twelve patients were in first partial remission (PR), 34 were in second partial or complete remission (CR), and 14 were in subsequent progression. At the time of the procedure, 39 patients (65%) had persistent bone marrow involvement, 49 patients (82%) were in PR, and 16 patients had presented with a histologic transformation (HT). PBPC were collected after chemotherapy followed by granulocyte (G) colony-stimulating factor (CSF) or granulocyte-macrophage (GM)-CSF in 50 patients. Conditioning regimens included high-dose chemotherapy alone (14 patients); mainly the BCNU, etoposide, aracytine, melphalan [BEAM] regimen), or cyclophosphamide with or without etoposide plus total body irradiation (46 patients). The median time to reach a neutrophil count greater than 0.5 x 10(9)/L was 13 days. There were five treatment-related deaths, with four being associated with a delayed engraftment and all occurring in patients in third or subsequent progression. At a median follow-up of 21 months, 48 patients were still alive, 18 relapsed, and seven died of lymphomas progression. Estimated 2-year overall survival (OS) and failure-free survival (FFS) rates were 86% and 53%, respectively, without or plateau. Patients treated in PR1 or PR2/CR2 had a significantly longer rate of OS and FFS than those treated in subsequent progression (P = .002 and P = .001, respectively), whereas age, response to salvage treatment, presence or absence of residual bone marrow involvement, or conditioning regimen had no influence on outcome. Patients with HT tended to have a worse FFS rate (P = .04) without an OS difference. Along with an unusual rate of engraftment failure, the poor FFS observed in heavily pretreated patients suggests that intensive therapy should be performed early in the course of the disease. Given the high percentage of patients intensified in PR with residual bone marrow involvement, our results are comparable with those achieved with ABMT published to date. Prospective trials are warranted to compare this strategy with standard therapy in patients with relapsing or PR follicular lymphoma.