Peripheral Blood Stem Cell Support Research Articles

Postremission therapy with repeated courses of high-dose cytarabine, idarubicin, and limited autologous stem cell support achieves a very good long-term outcome in European leukemia net favorable and intermediate-risk acute myeloid leukemia.

Consolidation treatment in acute myeloid leukemia (AML) patients achieving complete remission (CR) is warranted. High-dose cytarabine (HDAC) is considered first choice in favorable risk and an option in intermediate-risk AML. However, its optimal dose and schedule, as well as the benefit of additional chemotherapy agents remain controversial. Herein, we report on the long-term outcome of consecutive unselected AML patients treated with repeated courses of HDAC, with the addition of idarubicin, followed by autologous peripheral blood stem cell (PBSC) support, in order to limit toxicity, according to Northern Italy Leukemia Group (NILG) AML-01/00 study (EUDRACT number 00400673). Among 338 patients consecutively diagnosed from 2001 to 2017 at our center, 148 with high-risk AML (adverse cytogenetic, isolated FLT3-internal tandem duplication mutation, refractory to first induction) were addressed to allogeneic stem cell transplant. All other cases, 186 patients (55%), median age 53 (range 19-75), were considered standard-risk and received the NILG AML-01/00 program. After achieving CR, patients were mobilized with cytarabine 8 g/sqm to collect autologous CD34+-PBSC and received three consolidation cycles with HDAC (20 g/sqm) plus idarubicin (20 mg/sqm) per cycle, followed by reinfusion of limited doses of CD34+ PBSC (1-2x106/kg). The program was completed by 160 (86%) patients. Toxicity was acceptable. Neutrophils recovered a median of 10 days. Treatment-related mortality was 3/160 (1.8%). After a median follow-up of 66.4 months, overall survival (OS) and relapse-free survival (RFS) at 5-years were 61.4% and 52.4%, respectively. Twenty-eight selected patients aged >65 had similar outcomes. According to European leukemia net-2010 classification, the OS and RFS at 5-years were 76.4% and 65% in favorable risk, without differences between molecular subgroups, 52.3% and 47.2% in Intermediate-I, 45.2% and 36.5% in Intermediate-II risk patients, respectively. In conclusion, consolidation including repeated courses of high dose cytarabine and idarubicin, with limited PBSC support, proved feasible and very effective in nonhigh risk patients. The incorporation of novel agents in its backbone may be tested to further improve patient's prognosis.

A Prospective Observational Study of Clinico-Pathological Features, Prognostic Factors and Treatment Response to Primary Therapy in Multiple Myeloma at a Tertiary Care Centre

Title: "A prospective observational study of clinico-pathological features, prognostic factors and treatment response to primary therapy in Multiple Myeloma at a tertiary care centre" Background: Multiple myeloma (MM) is characterised by the neoplastic proliferation of plasma cells leading to excess monoclonal immunoglobulins. The incidence of multiple myeloma in India ranges from 1.2 to 1.8 per 100,000. There is paucity of cytogenetic data from this part of subcontinent. The aim of our study is to report various clinicopathological features, evaluate biological markers of prognostication including cytogenetic variables and assess treatment response after standard primary therapy. Methods and Materials: The study was carried out at a tertiary care center in Northern India. After final diagnosis of multiple myeloma was established, each patient was risk stratified via FISH cytogenetic analysis as per the revised ISS. Definitive management plan was individualised, including assessment for high dose therapy with peripheral blood stem cell support. Treatment response were recorded as per standard IMWG response criteria. Significant toxicities associated with treatment were also recorded. Results: Eighty consecutive patients with newly diagnosed multiple myeloma were enrolled prospectively from April 2017 to November 2018. The median age at diagnosis was 63 years, and number of males & females were equal. The most common presenting symptom was back pain (67.8 % patients) and most frequent clinical sign was pallor (86.4 %). All four CRAB features were documented only in 16.9% patients. M-Band was present in 96.6% patients and on SFLC assay 59.3% and 40.7% were kappa and lambda light chain restricted respectively. Most common heavy chain abnormality detected was IgG. Seventy percent patients had lytic lesions on imaging while only 3% suffered skeletal related events. Cytogenetic evaluation by interphase FISH was carried out in all patients upfront. No chromosomal abnormality was documented in 61.25 % while among those with chromosomal abnormalities, most commonly detected was del13q14.3 (23.75 %). Overall, 66.6% patients were stratified as standard risk, 28.1% as intermediate risk and only 3 (5.3%) patients were categorised as high risk. Most common induction regimen was VRD. Overall response rate was 94.9 % and VGPR or better responses were observed in 77.9% patients. Most common adverse effect of therapy was peripheral neuropathy of all grades. Of the 77 patients who completed primary therapy, 21.4% patients underwent high dose therapy with peripheral blood stem cell support while 67.7% patients were started on maintenance therapy. Four (5.1 %) non-responder was started on 2nd line treatment. On univariate analysis, higher deeper responses (VGPR or better) were observed in patients with IgA & IgG related myeloma and better overall response rates were seen in IgG related myeloma. Those with kappa light chain myeloma had 5.67 times higher likelihood of achieving response as compared to lambda light chain myeloma. Also, patients with kappa light chain myeloma achieved higher VGPRs as compared to lambda light chain myeloma. There was 17 times high risk of non-response in the presence of local bony tenderness. None of the findings were found to be significant on multivariate analysis. Conclusions: Use of interphase FISH to identify various cytogenetic markers help in stratification & staging of the disease which in turn act as a marker for prognostication. They should be a part of standard care in multiple myeloma. In majority we could administer treatment in accordance to standard practice guidelines and response rates were similar to those reported my seminal studies. Our study in a longer follow up will yield some useful information which will help in the better care of the patients. Disclosures No relevant conflicts of interest to declare.

The results of treatment with high-dose chemotherapy and peripheral blood stem cell support for gestational trophoblastic neoplasia

ObjectiveThe objective of the study was to evaluate the effect of high-dose chemotherapy (HDC) with peripheral blood stem cell support (PBSCS) on survival of patients with gestational trophoblastic neoplasia (GTN) with either refractory choriocarcinomas or a poor-prognosis placental site/epithelioid trophoblastic tumours (PSTT/ETTs). MethodsDatabases of two referral centres for gestational trophoblastic disease were searched, and 32 patients treated with HDC between 1994 and 2015 were identified. Tissue samples were retrieved for genetic evaluation. Cox regression analyses were performed to identify possible predictors of overall survival (OS). ResultsHDC induced a sustained complete response in 7 patients. Overall, 41% (13/32) of the patients remained disease free after HDC with or without additional treatment. Patients who survived had much lower human chorionic gonadotropin (hCG) values (all ≤12 IU/L) before and after HDC than those who died of disease. Univariable Cox regression analysis demonstrated that hCG >12 IU/L before or after HDC, International Federation of Gynaecology and Obstetrics (FIGO) stage II-IV and presence of metastases at the time of diagnosis were significantly associated with adverse OS. However, only hCG values before HDC remained significant in a multivariable model (p < 0.001). Five of 11 (45%) patients with PSTT/ETT presenting ≥48 months after antecedent pregnancy and 6 of 14 (43%) patients with refractory choriocarcinoma were in remission. Three treatment-related deaths occurred. ConclusionsDespite 3 treatment-induced deaths, HDC with PBSCS appears to be active in salvaging selected patients with poor-prognosis PSTT/ETTs and refractory choriocarcinomas. Low hCG values before HDC seems a beneficial predictor of OS and may suggest that HDC acts more like a consolidation therapy.

Pegfilgrastim: More Cost Effective and Equally Efficacious Option as Compared to Filgrastim in Autologous Stem Cell Transplant.

Use of growth factor after high-dose chemotherapy (HDC) and autologous peripheral blood stem cell (PBSC) support is current standard in reducing days of neutropenia. This retrospective study aims to compare the efficacy of two standard growth factors, pegfilgrastim (PEG) and filgrastim (FIL) after HDC. We collected data on 195 consecutive adult patients who received an autotransplant (myeloma, lymphoma and others) between January 2004 and December 2014 at two tertiary care centres. The primary end point was the duration of neutropenia in terms of days to reach an ANC > 0.5 × 109/L. Filgrastim was given to 110 patients and PEG was given to 85 patients. Time to engraftment, defined as the time to reach an ANC of 0.5 × 109/L on 2 consecutive days after the day of auto-SCT, was 12.6days with FIL compared with 12.1days with PEG group (p = 0.126). When comparing the total days of severe neutropenia (WBC < 0.1 × 109/L), there were 5.5days of severe neutropenia with FIL compared with 5.8days with PEG group (p = 0.7). The duration of febrile neutropenia was an average of 5.3days with FIL and 4.6days with PEG (p = 0.029). The total number of antibiotic days was shorter for the patients who received PEG, being 11.08days with PEG and 12.1days with FIL (p = 0.184).The average cost savings per person in terms of number of days of hospitalization and number of days of total parental nutrition was 582 Rs (p = 0.512) and 6003 Rs (p = 0.018) respectively in favour of PEG arm. PEG is similar to FIL in hematological reconstitution, however it is more cost effective alternative after HDC and PBSC.

Postremission Therapy with Repeated Courses of HD-Arac, Idarubicin and Limited Autologous Stem Cell Support Achieves a Very Good Long-Term Outcome in ELN Favourable and Intermediate-Risk AML Except in NPM-Mutated Patients Where Relapse May Occur Even after Five Years

Introduction: Postremission treatment in adult acute myeloid leukemia (AML) is mandatory to improve long-term remission duration. Allogeneic stem-cell transplantation (allo-SCT) is considered gold standard in younger patients (pts) with higher risk of relapse, whereas in pts categorized as standard-risk (SR) AML the optimal treatment remains an open issue. High-dose cytarabine (HD-ARAC) is considered the backbone of postremission treatment in SR AML. The optimal dose and schedule, and the clinical benefit of additional chemotherapeutic agents remain controversial (Schaich, 2011- Lowenberg, 2011- Lowenberg, 2013) as well as the relative efficacy of HD-ARAC in the different cytogenetic and molecular subgroups of SR AML. We analyzed the very long term outcome of consecutive unselected AML pts treated according to AML 00 NILG protocol (Bassan, Blood, 2003: 102; 11) with three repetitive HD-ARAC-based cycles, associated with idarubicin, followed by limited peripheral blood stem cell (PBSC) support, in order to reduce toxicities.Methods: We evaluated 263 consecutive AML pts, diagnosed at our Institution, from January 2001 to March 2016 (median age 52 years - range 15-65). The treatment plan included induction with ICE (Idarubicin-Cytarabine-Etoposide) followed by IC consolidation or HD-ARAC/HD-idarubicin (SPLIT therapy) in refractory cases. ARAC 1g/mq bd for 4 days (A8) was given to CR pts, to collect 3-6x10^6 CD34/kg in 3 aliquots. Patients with ELN favorable or intermediate risk AML, considered SR AML, received 3 cycles of HD-ARAC (2g/mq bd for 5 days) plus idarubicin (8mg/mq for 2 days) with PBSC reinfusion (1-2x10^6 CD34/Kg) (A20). The pts with insufficient CD34 cells yield, received 2 courses HD-ARAC (1g/mq bd for 5 days) plus idarubicin (10mg/mq day 1) (A10). The cumulative dose of ARAC and idarubicin given according to A20 protocol were 69,4 g/mq and 162 mg/mq, respectively.Results: Among 263 pts, 142 (54%) pts were considered SR and 116 (44.1%) HR. Only 5 pts were lacking molecular or cytogenetic information (1.9%) to allow ELN risk classification. Accordingly, 65 pts (25.2%) were favorable [35.4% core binding factor (CBF) positive, 9.2% CEPBA mutated and 55.4% NPM mutated], 87 (33.7%) Intermediate-I, 45 (17.4%) Intermediate II and 61 (23.7%) adverse risk. CR rate after ICE treatment was 77.6% (204/263), 95.8% in SR and 56% in HR pts and after ICE+SPLIT it was 88.2% (232/263); early or aplastic death was 6%. A8 course was administered in 218 pts, of whom 179 were successfully mobilized (82.1%). Among 136 SR pts, 127 were received HD-ARAC (A20 or A10), 4 allo-SCT for early relapse, 3 pts did not proceed to A20 because of prolonged cytopenia and 2 are ongoing. Hematological toxicity was acceptable. ANC recovered at a median of 10 days after CD34+ cells reinfusion. Two death in CR occurred within 100 days after A20 therapy (1.6%). After a median follow-up of 53.3 months (range 1-172), the median survival of SR AML patients was 118.9 months, the DFS and OS at 5 y were 51+/-4.8% and 56.5+/-4.7%, and at 10 y 43.3+/-5.9% and 49.6+/-5.7%, respectively. According to ELN risk, the OS at 5 y and 10 y was 78.3+/-6% and 68+/-8.7% in favorable (median OS not reached), 52.3+/-8% and 46+/-9.4% in Intermediate-I (median OS 118.8 months), and 42+10% and 33.6+/-10.9% in Intermediate-II (median OS 33.1 months) (p0.0034) (Figure1). According to molecular characteristics, the OS at 5-y was 100% in CEBPA-mutated, 77+/-9% (+/-SE) in CBF-mutated and 71+/-11% in NPM-mutated subgroups, respectively (Figure 2). In NPM-mutated pts it was 56+/-14% if FLT3 was mutated and 75+/-10% if not. At 8-y OS was not evaluable in CEBPA-mutated, it remained 77+/-9% in CBF mutated but dropped to 47+/-15% in NPM-mutated pts due to late relapses (28%), which occurred in pts without FLT3. The median time to relapse in NPM pts was 17 m, the latest relapse occurred after 97 months.Conclusion: A postremission program with repeated courses of HD-ARAC associated to idarubicin and limited autologous CD34+ cells support was feasible, well tolerated and very effective, also long-term, in pts with ELN favourable or intermediate risk AML. The late relapse tendency of NPM-mutated AML is puzzling and should be considered by innovative programs aimed at improving these results. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Dose-intensified bendamustine followed by autologous peripheral blood stem cell support in relapsed and refractory multiple myeloma with impaired bone marrow function.

Therapeutic options in heavily pretreated relapsed/refractory multiple myeloma patients are often very limited because of impaired bone marrow function. Bendamustine is effective in multiple myeloma and has a favourable toxicity profile. We hypothesized that dose-intensified bendamustine (180 mg/m2 , day 1 and 2) followed by autologous blood stem cell support (ASCS) would improve bone marrow function with low post-transplant toxicity in patients with severely impaired haematopoiesis. We analyzed 28 consecutive myeloma patients, with a median of three prior lines of therapy (range 2-7), who had relapsed from the last treatment with very limited bone marrow function and were therefore ineligible for conventional chemotherapy, novel agents or trial enrolment. Dose-intensified bendamustine with ASCS improved haematopoiesis as reflected by increased platelet counts (median 40/nl vs 94/nl, p = 0.0004) and white blood cell counts (3.0/nl vs 4.8/nl, p = 0.02) at day +100. The median time until engraftment of platelets (>50/nl) was 11 days (0-24 days) and of white cell counts (>1.0/nl) 0 days (0-24 days). At least, a minimal response was achieved in 36% of patients. The disease stabilization rate was 50% while the median progression-free survival rate was limited to 2.14 months. Most importantly, patients were once again eligible for alternative treatments including enrolment into clinical trials. We conclude that dose-intensified bendamustine followed by ASCS is safe and feasible for multiple myeloma patients with very limited bone marrow reserve. Copyright © 2015 John Wiley & Sons, Ltd.

Experiences from Introducing Standardized High Dose 131I-mIBG Treatment of Children with Refractory Neuroblastoma: Differences in Effective Dose to Patients and Exposure to Caregivers

Aims: High dose 131I-meta iodobenzylguanidine (131I-mIBG) combined with radiosensitizing topotecan and peripheral blood stem cell support is a promising treatment regimen for children with neuroblastoma (NB). Here we present our first experiences, with particular focus on in vivo whole-body dosimetry and radiation exposure to family caregivers and hospital staff. Methods: Five children with relapsed or refractory NB were treated during 2012-2014. 131I-mIBG was administered in two fractions at two weeks apart, aiming for a total whole-body radiation-absorbed dose of 4 Gy. The 131I-mIBG activity for the 2nd administration was calculated on the basis of the measured whole-body dose following the 1st administration. Patients were isolated in a lead-shielded room, and all caregivers and staff received radiation safety training, and carried an electronic personal dosimeter. Results: The total administered activity ranged from 5.1 to 28.6 GBq (median: 22.9 GBq), resulting in effective whole-body doses ranging from 2.1 to 4.3 Gy (median: 3.8 Gy). Two out of five patients deviated from the anticipated dose exposure defined by the treatment protocol; one patient received 4.3 Gy after a single administration, and for one patient the total whole-body dose was lower than anticipated (2.1 Gy). Radiation dose to family caregivers ranged from 0.1 to 8.0 mSv. For staff members, the overall radiation dose was low, and provided no concern regarding personal dosimetry. Conclusion: High-dose 131I-mIBG treatment of children with NB has been successfully established at our institution. Radiation doses to caregivers and hospital staff are acceptable and in compliance with national and international guidelines. Two out of five patients deviated from the anticipated dose exposure, hence, accurate dosimetry-guidance during administration of high dose 131I-mIBG treatment is necessary.

Long-Term Treatment After Preoperative High-Dose Chemotherapy in a Lactating Breast Cancer Patient

Breast cancer during lactation is very rare, accounting for <3% of all breast cancers. Its diagnosis and treatment is often delayed during pregnancy. We report a case of female lactating breast carcinoma in a 29-year old patient. The disease was stage IIIB (T4N1M0). The patient received preoperative induction chemotherapy and high-dose chemotherapy with peripheral blood stem cell support, followed by adjuvant chemotherapy and endocrine therapy. The metastases were detected 17 months after operation, palliative treatment including different chemotherapy for 60 cycles, locoregional radiotherapy and endocrine therapy. The total number of cycles of chemotherapy was 67, and the survival time was 118 months. We discuss the diagnosis and treatment options for breast cancer during lactation, based on a literature review.

The Natural History of Myeloma Patients Who Relapse Early After High Dose Therapy.

AbstractAbstract 3125The median progression free survival (PFS) for younger, fitter patients with multiple myeloma is between 3 and 4 years, however some patients respond very poorly and relapse within a year of autologous transplantation. These patients then go on to receive relapse chemotherapy often with novel agents and, surprisingly, some have a longer remission with second line therapy. The prognostic factors which describe such patients are not well understood, and identifying and treating these patients remains a challenge. To characterise these patients further and describe prognostic markers, we have utilised 2 datasets (1081 patients) comprising 619 patients from the Myeloma IX trial and 462 patients from the Royal Marsden database (RMH). All patients were initially treated with high dose melphalan and peripheral blood stem cell support. Patients were then divided into two groups: early relapse (<12 months from transplant) or late relapse (>12 months after transplant or disease free at last follow up).The Myeloma IX trial consisted of 147 patients (23.7%) in the early relapse group compared to 472 patients (76.3%) in the late relapse group, with a median PFS1 of 7.6 vs. 27.8 months (P<0.001) and OS of 28 vs. 68.8 months (P<0.001), respectively. A similar pattern was seen in the RMH database, where the early relapse group consisted of 86 patients (18.6%) compared to 376 patients (81.4%) in the late relapse group, and with a median PFS of 6.3 vs. 38.6 months (P<0.001) and OS of 31.9 vs. 117.9 months (P<0.001), respectively.In order to describe prognostic factors for early relapse after autologous transplant, we utilized the Myeloma IX dataset, and show that a low Hb, a low platelet count, a low serum albumin, ß2M ≥5.5 mg/L, an ISS Stage III combined with adverse cytogenetics such as t(4;14) and 1q21+ at time of diagnosis predict for an early relapse (<12 months after transplant). In addition, we used Affymetrix gene expression profiling (GEP) to identify significant genes associated with early relapse. A distinct GEP signature containing 38 genes was identified as being associated with early relapse after transplantation, among which 10 genes were on chromosome X.We then used the Royal Marsden dataset to investigate the clinical outcome for patients who relapsed early following second line treatment. To do this, we divided the early relapse group (<12 months from transplant) into two groups: patients with a longer second remission than first remission (47 patients, group A) and patients with a shorter second remission than first remission (39 patients, group B). The median PFS after second line therapy between the two groups was 11.7 vs. 1.8 months (P<0.001) and the median OS was 51.5 vs. 23.0 months (P<0.001), respectively. Univariate analysis showed that a low Hb, a low platelet count, a high ß2M and an ISS stage III at time of second line therapy and no maintenance therapy after second line treatment predicted for a shorter second remission. Failure to achieve a response at the time of first transplant or post second line therapy was highly correlated with a shorter second remission and very aggressive disease outcomes. Multivariate analysis confirmed that failure to achieve a response after second line therapy was the only significant factor correlated with a shorter second remission, and poor survival.Taken together, our data demonstrates that approximately 20% of patients undergoing HDT will have a short remission. High ISS stage, adverse cytogenetics and failure to achieve a response to chemotherapy can be used to identify this group. In addition GEP signature can also identify such patients. About 45% of these early relapse patients will go on to have a very poor outcome, but 55% can be rescued with novel agents. Important aspects to consider in treating these patients are: careful assessment of the bone marrow reserve, the use of a non-cross reacting agent for second line treatment, an early assessment of response to therapy and incorporating novel agent maintenance therapy. Paying attention to these factors will hopefully prolong progression free survival, overall survival and in the end, quality of life in this poor prognosis group. Disclosures:Davies:Celgene, Johnson & Johnson, Onyx, Novartis: Honoraria, Speakers Bureau; Merck: Speakers Bureau.

Successful mobilisation of peripheral blood stem cells in children using plerixafor: a case report and review of the literature.

High-dose chemotherapy followed by autologous peripheral blood stem cell (PBSC) support is a salvage therapy for patients with relapsed or refractory malignant disease. Previous chemotherapy treatments, such as alkylating agents, purine analogues and radiotherapy, are known to affect subsequent mobilisation of PBSC1. On the basis of a history of a previously failed mobilisation attempt or the presence of one or more factors predicting an unsuccessful harvest (advanced disease, prior extensive radiotherapy, prolonged treatment with stem cell poisons, advanced age, or extensive bone marrow involvement) these patients have been identified as “predicted poor mobilisers”2. In fact, in about 10 to 30% of patients it is not possible to collect an adequate number of PBSC to support haematopoietic stem-cell transplantation when growth factor alone or in combination with chemotherapy is used for the mobilisation3. Plerixafor is a new agent that inhibits stromal cell-derived factor-1a/CXCR4 binding, resulting in rapid mobilisation of CD34+ cells into peripheral blood and is well recognised as a solution to save adults in whom conventional mobilisation regimens have failed4,5. In this context, in combination with growth factor, plerixafor leads to successful mobilisation in 70% of adult patients with non-Hodgkin’s lymphoma, Hodgkin’s lymphoma and multiple myeloma6. Give the low rate of poor mobilisation in children, few experiences have been reported regarding the use of plerixafor in this context7–11. Since Plerixafor is not yet authorised as a standard mobilising regimen in paediatric patients its administration should be considered as off-label therapy, thus requiring parental informed consent. A European Bone Marrow Transplantation (EBMT) study is currently investigating the off-label use of plerixafor (“Non-interventional study on the off-label transplant use of plerixafor”). Here we describe our experience using plerixafor on demand to mobilise PBSC in a young patient with Hodgkin’s lymphoma.

Ifosfamide, carboplatin, and etoposide for neuroblastoma

The authors report a retrospective analysis of high-dose ifosfamide, carboplatin, and etoposide (HD-ICE) for patients with refractory or relapsed neuroblastoma (NB). A major reason for using this regimen was the long time since patients received previous treatment with a platinum compound. The authors also summarized the published experience on ICE in patients with NB. Treatment comprised ifosfamide (2000 mg/m(2) daily for 5 days), carboplatin (500 mg/m(2) daily for 2 days), and etoposide (100 mg/m(2) daily for 5 days). Patients who had poor hematologic reserve (platelet count <100,000/μL) from previous therapy received peripheral blood stem cells (PBSCs) after HD-ICE. Disease status before and after HD-ICE was defined according to International Neuroblastoma Response Criteria (expanded to include (123) I-metaiodobenzylguanidine findings). Publications that were informative about ICE for NB were reviewed. Seventy-four patients received 92 cycles of ICE, including 37 patients who received PBSC rescue. Grade 3 toxicities were rare: 1-3 patients had encephalopathy, mucositis, or gastroenteritis. Bacteremia was documented in 24 of 92 cycles (26%). The absolute neutrophil count reached 500/μL on day 17-30 (median, day 22) in patients who had satisfactory hematologic reserve. Disease regressions (major and minor responses) were achieved by 14 of 17 patients (82%) with a new relapse, 13 of 26 patients (50%) with refractory NB, and 12 of 34 patients (35%) who were treated for progressive disease during chemotherapy (P = .005). In the literature, patients received ICE at lower dosages and achieved major response rates >36% in phase 1 and 2 studies (in which less comprehensive staging evaluations were used) that involved resistant NB and >70% in induction for newly diagnosed NB. HD-ICE is appealing as salvage treatment or consolidative therapy because of its anti-NB activity and the low risk of major nonhematologic toxicity. PBSC support is unnecessary for patients who had intact hematologic reserve.

High-Dose Chemotherapy As Adjuvant Therapy in Breast Cancer: Could There Be a Survival Benefit?

TO THE EDITOR: Results of the recent meta-analysis by Berry et al provide evidence that high-dose chemotherapy (HDC) with hematopoietic stem-cell support prolongs relapse-free survival but does not improve overall survival in patients with high-risk primary breast cancer. In my opinion, a clinical point that needs to be stressed further is the striking 6% rate of death resulting from toxicity in the HDC group (procedure related, in most cases). The high mortality rate is attributable, at least in part, to the use of bone marrow as a source of stem cells in some patients and the highly toxic high-dose regimens (ie, carmustine containing) used in early studies. When patients whose deaths were attributed to toxicity were excluded, an HDC advantage in terms of overall survival was also observed. These data are clinically relevant, because HDC with peripheral-blood stem-cell support is today a safe procedure with a mortality rate and quality-adjusted survival parameters similar to those of conventional therapies. Furthermore, as pointed out by Berry et al, the control arms of some studies (eg, those by the Scandinavian Breast Group and Southwest Oncology Group) have involved nonconventional treatment with increased dose intensity. It would be interesting to know the survival data of only those studies—the vast majority—in which real, conventional control arms have been used. Mauro Moroni San Carlo Borromeo Hospital, Milan, Italy

A phase II trial of high dose carboplatin and paclitaxel with G-CSF and peripheral blood stem cell support followed by surgery and/or chest radiation in patients with stage III non-small cell lung cancer: CALGB 9531

Purpose We designed a phase II trial to evaluate the efficacy and tolerability of high dose induction chemotherapy with carboplatin and paclitaxel with G-CSF and stem cell support followed by surgical resection and/or chest radiotherapy in patients with stage III non-small cell lung cancer (NSCLC). Patients and methods Patients had pathologically confirmed stage IIIA–IIIB NSCLC, adequate end-organ function, no prior chemotherapy or radiation, and performance status 0–1. Peripheral stem cells were mobilized with G-CSF stimulation on days 1–5 and collected prior to chemotherapy. Chemotherapy consisted of 2 cycles of paclitaxel 250 mg/m 2 over 3 h and carboplatin at an AUC 18 on days 11 and 32, each followed by stem cell reinfusion. Stable and responding patients went on to surgical resection (in patients deemed resectable) followed by post-operative radiation, or to conventional chest radiotherapy to 66 Gy in unresectable patients. Results Twelve patients (11 eligible) were accrued from 1996 to 1999. The 11 patients were predominately male (64%), white (82%), of performance status 0 (64%), and with weight loss less than 5% (55%). The median age was 51 (range 31–63). Ten (10) patients (91%) experienced grade 4 toxicity. There were no lethal toxicities. Grade 3–4 toxicities most commonly reported included: platelets (100%), lymphocytopenia (91%), leukopenia (91%), neutropenia (73%), anemia (55%), pain (45%), and nausea (27%). Three patients (27%) had a partial response to induction chemotherapy. Of the 11 patients, 7 underwent surgical exploration, and 10 received radiation. Two patients were completely resected, 3 patients had incomplete resections, and 2 patients had no resection. There were 4 complete responses and 3 partial responses following surgery and/or radiation. The median overall survival time was 17.8 months. The median failure-free survival time was 8.3 months. One-year and 2-year overall survival are estimated at 64% and 27%, respectively. Conclusions High dose induction chemotherapy with carboplatin and paclitaxel and stem cell support in patients with stage IIIA–IIIB NSCLC produced response rates and survival similar to standard therapy. Excessive toxicity (and cost) suggests that this approach does not merit further investigation.

The Risk of Secondary Myelodysplastic Syndrome/Acute Leukemia Following High-Dose Yttrium-90 Ibritumomab Tiuxetan Is Analogous to That Observed Following High-Dose Chemotherapy: a Matched-Pair Analysis In Non-Hodgkin Lymphoma Patients.

AbstractAbstract 1289 Introduction:Myeloablative doses of Yttrium-90 (90Y)-Ibritumomab Tiuxetan combined with tandem autologous peripheral blood stem cell (PBSC) support can be safely administered to patients aged up to 76 years (Devizzi L et al, J Clin Oncol 2008). Whether marrow exposure to myeloablative doses of radiolabelled antibodies (hd-radio-immunotherapy) could increase the risk of secondary myelodysplastic syndrome and acute leukemia (sMDS/AL) remains a matter of concern. Therefore, we prospectively investigated by means of a longitudinal study the incidence of sMDS/AL in a cohort of high-risk non-Hodgkin lymphoma (NHL) patients receiving hd-radio-immunotherapy. The cumulative incidence of sMDS/AL in the study group was compared with that observed in a historical group of patients autografted following chemotherapy-based myeloablative conditioning. Additionally, to further investigate marrow damage induced by hd-radio-immunotherapy, hematopoietic and stromal progenitors, as well as telomere length (TL) were assessed. Patients and Methods:From July 2004 through December 2007, 53 relapsed/refractory (n= 36) or de novo high-risk (n= 17) NHL patients (median age, 64 years; range, 26 – 76 years) received a high-dose sequential (HDS) chemotherapy program, including a myeloablative phase with 90Y-Ibritumomab Tiuxetan (1.2 mCi/kg body weight). Patients were monitored for frequency of colony-forming cells (CFCs), cytogenetic and TL analysis. Bone marrow (BM) samples were collected prior to hd-radio-immunotherapy, every six months for two years and annually thereafter. The study was approved by the Institutional Ethical Committee and written informed consent was obtained from each patient. The study group included 29 patients with aggressive lymphoma (diffuse large B-cell lymphoma, n = 19; mantle cell lymphoma, n = 8; Richter syndrome, n = 2) and 24 with indolent NHL subtypes (follicular lymphoma, n = 20; marginal zone lymphoma, n = 3; lymphocytic lymphoma, n = 1). Thirty patients were relapsed after one (n=15) or more (n=15) previous chemotherapy regimens, 6 patients were refractory and 17 patients were previously untreated with high-risk prognostic index. Pre-exposure to alkylating agent involved 68% of the patients. A historical group of 55 NHL patients who received an analogous HDS program with final chemotherapy-based autografting was used as control group. Study and control groups were pair-matched for age, gender, histological subtype, disease status at transplant and type of grafted PBSC. Results:At a median follow-up of 49 months (range, 32 – 74), 4 out of 53 patients of the study group developed sMDS/AL at 6, 12, 27 and 36 months from transplant. According to WHO criteria, refractory anemia with excess of blasts 1 (RAEB-1) was diagnosed in one patient, whereas refractory cytopenia with unilineage dysplasia (RCUD) was diagnosed in the other three cases, with acute leukemia transformation being observed in two patients at 12 and 18 months after initial detection of abnormal cytogenetics, respectively. The cumulative incidence of sMDS/AL resulted of 8.29% at 5-years. An analogous 5-year cumulative incidence of 8.05% was observed in the historical control group autografted following a chemotherapy-based conditioning. Radioimmunotherapy-treated patients showed a significant but transient decrease in granulocyte-macrophage colony forming unit (CFU-GM) at 6 months after transplant, with recovery to baseline values at 12 months. Multilineage colony-forming units (CFU-Mix), erythroid burst-forming units (BFU-E) and fibroblast CFU (CFU-F) were not show significantly affected over time. In contrast, a progressive and significant decrease in BM TL was evident from 12 months after transplant. Conclusion:In our series of elderly NHL patients receiving hd-radio-immunotherapy, the incidence of sMDS/AL was found increased compared to recently reported series of younger lymphoma patients receiving chemotherapy-based conditioning. However, the increased risk of sMDS/AL was not associated with the type of myeloablative conditioning, i.e. chemotherapy vs radio-immunotherapy. Other factors may have favored the development of sMDS/AL, including advanced age at transplant, extensive pre-transplant therapy and type of reinfused PBSC. The observed progressive TL loss gives support to the concept that TL loss might be involved in sMDS/AL development. Disclosures:No relevant conflicts of interest to declare.

High‐dose carboplatin–irinotecan–temozolomide: Treatment option for neuroblastoma resistant to topotecan

We report a retrospective study of a novel regimen for neuroblastoma (NB) resistant to standard induction or salvage chemotherapy which now routinely includes topotecan. Forty-five patients received carboplatin (500 mg/m(2)/day, 2×)-irinotecan (50 mg/m(2)/day, 5×)-temozolomide (250 mg/m(2)/day, 5×) (HD-CIT). Only one course was planned. Patients with thrombocytopenia indicative of poor bone marrow (BM) reserve resulting from extensive prior therapy received peripheral blood stem cells (PBSCs) post-HD-CIT. Modest acute toxicity allowed outpatient treatment. Low-grade diarrhea was common; there was no mucositis, nephrotoxicity, or cardiotoxicity. Myelosuppression was prolonged but uncomplicated. The absolute neutrophil count reached 500/µl on days 20-30 (median, 25) in 25 patients with satisfactory BM reserve, and on days 9-14 (median, 11) post-PBSC infusion. Anti-NB activity was common against refractory (non-progressing) disease or new relapse occurring off therapy (68% objective response rate), but not against disease progressing on therapy. Seven of 26 patients treated for refractory NB are progression-free and in complete remission following subsequent therapy, including anti-G(D2) immunotherapy, at ≥ 29+ months post-HD-CIT. HD-CIT is appealing as salvage or consolidative therapy because of anti-NB activity and modest non-hematologic toxicity. PBSC support is unnecessary when BM reserve is intact. The wide antineoplastic activity of its three components and their potential for activity against disease in the central nervous system support applicability to other cancers.

Pegfilgrastim versus filgrastim after high-dose chemotherapy and autologous peripheral blood stem cell support

BackgroundAmerican Society of Clinical Oncology guidelines recommend the use of growth factor after high-dose chemotherapy (HDC) and peripheral blood stem cell (PBSC) support. This randomized trial aims to demonstrate the noninferiority of pegfilgrastim (PEG) compared with filgrastim (FIL) after HDC. Patients and methodsEighty patients were assigned to FIL at a daily dose of 5 μg/kg or a single fixed dose of PEG (6 mg) 1 day after PBSC. The primary end point was the duration of neutropenia both in terms of absolute neutrophil count (ANC) <0.5 × 109/l and of days to reach an ANC >0.5 × 109/l. ResultsThe mean duration of neutropenia was 6 and 6.2 days and the mean time to reach an ANC >0.5 × 109/l was 11.5 and 10.8 in the FIL and PEG group, respectively. No differences were observed in the mean time to reach an ANC >1.0 × 109/l (12.2 versus 12.0 days) in the incidence of fever (62% versus 56%) and of documented infections (31% versus 25%). The mean duration of antibiotic therapy was 5.7 and 4.0 days in FIL and PEG group, respectively. ConclusionPEG is not inferior to FIL in hematological reconstitution and represents an effective alternative after HDC and PBSC.

42 A therapeutic sphingosine 1-phosphate antibody inhibits intratumoural hypoxia and sensitizes to chemotherapy in prostate cancer animal model

High-dose chemotherapy regimens can cure a number of otherwise incurable diseases, such as Hodgkin's disease, non-Hodgkin's lymphoma, neuroblastoma, acute leukemia (in remission), and breast cancer. Trials of high-dose chemotherapy have generally used autologous bone marrow transplant or peripheral blood stem cell support to ensure hematologic recovery after intensive chemotherapy and/or radiation. This report describes an approach in which high-dose carboplatin chemotherapy was followed initially by granulocyte-macrophage colony-stimulating factor (GM-CSF; Escherichia coli. Sandoz-Schering, East Hanover and Kenilworth, NJ) and in subsequent patients, by both GM-CSF and repeated cycles of peripheral blood progenitor cell (PBPC) collection and administration. The addition of PBPC to this regimen led to significant reductions in the duration of neutropenia and thrombocytopenia, the requirement for erythrocyte and platelet transfusions, the length of hospital stay, and the use of intravenous antibiotics in this group relative to those patients who received GM-CSF alone. In addition, laboratory studies are presented that show a direct correlation between the number of progenitor cells reinfused and the duration of neutropenia and thrombocytopenia. The report also reviews data indicating that circulating progenitor cells are depleted by this approach. This suggests that the number of progenitor cells available for mobilization is finite. Finally, the magnitude of these effects, and their implications for future trials with repetitive cycles of dose-intensive therapy, are discussed.

Lymphomes B primitifs du médiastin : aspect clinique

Primary mediastinal B-cell lymphoma (PMBL) is a clinicopathological entity among the world health organization classification of lymphoid neoplasms. PMBL often concerns young adults, and the disease remains a localized disease in the majority of cases. The outcome of patients with PMBL is variable and unlike diffuse large cell lymphomas, the international prognostic index seems to be less applicable to such disease. The combination of rituximab and chemotherapy is the gold standard treatment of patients with good prognosis features and allows high cure rates. However, high-dose chemotherapy supported by peripheral blood stem cell support is often warranted in poor-prognosis patients. The use of positrons emission tomography examination is more and more used in such situations to select the best therapeutic strategy.

Peripheral blood stem cell support for multiple cycles of dose intensive induction therapy is feasible with little risk of tumor contamination in advanced stage neuroblastoma: A report from the Childrens Oncology Group

Poor outcome in Stage 4 neuroblastoma may be improved with increased dose intensity of therapy. We investigated the feasibility of sequential collection and infusion of peripheral blood stem cells (PBSCs) as hematopoietic support for non-myeloablative dose intensive induction chemotherapy given every 21-28 days. Twenty-two children with Stage 4 neuroblastoma (>or=1 year of age) received two cycles of high-dose cyclophosphamide (4 g/m(2)), doxorubicin (75 mg/m(2)), and vincristine (2 mg/m(2)) followed by three cycles of interpatient dose escalating carboplatin (Dose Level 0 = 800 mg/m(2); Dose Level 1 = 1,000 mg/m(2)), high-dose cyclophosphamide (4 g/m(2)), and etoposide (600 mg/m(2)). PBSC were harvested following cycle 2, 3, and 4 in Cohort 1 and infused after each subsequent cycle. In Cohort 2, PBSC were harvested after cycle 2 and split into three aliquots for infusion. Dose limiting toxicity (DLT) and ability to administer cycles within 28 days was assessed. Sufficient PBSC (>or=2 x 10(6) CD34 cells/kg per infusion) were collected from 17/21 eligible patients with minimal toxicity and no detectable neuroblastoma cells by immunocytology. Carboplatin at 1000 mg/m(2) resulted in DLT of delayed platelet recovery >28 days in 4/8 patients. Despite de-escalation to 800 mg/m(2), platelet DLT occurred in 4/7 Cohort 1 and 3/7 Cohort 2 patients. As defined in this protocol, doses of carboplatin were not tolerable with the PBSC dose administered. However, it was feasible to collect sufficient PBSC from small neuroblastoma patients to use as hematopoietic support with minimal risk of tumor contamination and toxicity.

Chemotherapy-resistant intravascular lymphoma accompanied by ADAMTS13 inhibitor successfully treated with rituximab

Intravascular large B-cell lymphoma (IVL) is a subtype of diffuse large B-cell lymphoma (DLBCL), in which lymphoma cells infiltrate blood vessels without mass formation, and its prognosis is generally poor due to diagnostic difficulties. The authors previously described a patient with IVL accompanied by features of thrombotic thrombocytopenic purpura (TTP), expression of ADAMTS13 inhibitor, and a severe deficiency in ADAMTS13 activity [1]. Although standard CHOP chemotherapy was initially effective, the disease gradually became resistant despite intensive high-dose chemotherapy with autologous peripheral blood stem cell support. However, the chimeric anti-CD20 monoclonal antibody, rituximab, induced complete remission (CR) for a prolonged period. We describe the clinical course of this patient and the unique effects of treatment with rituximab alone. A 54-year-old man was admitted to our hospital with the onset of a psychological disorder and convulsions. Laboratory data revealed obvious thrombocytopenia (3.6 9 10/ lL) accompanied by elevated levels of serum lactic dehydrogenase (LDH) and soluble interleukin-2 receptor. Multiple cerebral venous embolisms, bilateral adrenal gland swelling, and hepatosplenomegaly were present without nodal disease. Despite normal chest X-rays and thoracic CT scans, the patient developed rapidly progressive respiratory failure. A definitive diagnosis of IVL was made from transbronchial lung biopsy (TBLB) specimens. Bone marrow smears revealed no obvious lymphoma cell invasion and megakaryocyte hyperplasia without hemophagocytic syndrome (HPS), although the peripheral blood platelet count was markedly decreased. We concluded that the thrombocytopenia was caused by the same pathogenesis as TTP, since plasma ADAMTS13 activity had decreased to below 3%, and active ADAMTS13 inhibitor (IgG-type autoantibody) was confirmed. After standard CHOP chemotherapy cycles, the platelet counts immediately recovered to within normal limits and all symptoms improved. The ADAMTS13 activity improved to 49% and inhibitor levels, which had never been negative, decreased. Whole brain irradiation after chemotherapy resulted in relapse of systemic disease. Although we performed highdose conditioning chemotherapy followed by autologous peripheral stem cell transplantation, respiratory failure and high-grade fever appeared with severe thrombocytopenia and massive serum LDH elevation at day 50 after transplantation. Salvage combination chemotherapies had extremely limited effects against the disease, and we started to administer 375 mg/m of rituximab after its use for CD20-positive DLBCL was permitted according to the regulations established by the Japanese National Health Insurance system. The patient did not develop any major M. Kanno (&) Tumor Center, Nara Medical University Hospital, 840 Shijo-cho, Kashihara 634-8522, Japan e-mail: mkanno@naramed-u.ac.jp