Infusion Of Autologous Stem Cells Research Articles

Salvage Therapy with High-Dose Chemotherapy and Peripheral Blood Stem Cell Transplant in Patients with Primary Mediastinal Nonseminomatous Germ Cell Tumors

Salvage therapy with high-dose chemotherapy (HDCT) and bone marrow transplant (BMT) or peripheral blood stem cell transplant (PBSCT) has curative potential in patients with recurrent germ cell tumor. However, patients with primary mediastinal nonseminomatous germ cell tumors (PMNSGCTs) have had poor results with any form of salvage chemotherapy including HDCT. We switched from BMT to PBSCT in 1996. One hundred sixteen of 184 patients (63%) with recurrent or refractory germ cell tumors treated from 1996 to 2004 were alive and continuously disease-free. PMNSGCTs were excluded from that study because of poor results in the patient population with HDCT and BMTs. In 2006, we resumed treating patients with recurrent PMNSGCT with 2 consecutive courses of HDCT consisting of carboplatin 700 mg/m2 × 3 plus etoposide 750 mg/m2 × 3 and each followed by an infusion of autologous peripheral-blood hematopoietic stem cells with a second course 3 to 4 weeks later. Twelve patients were treated: 11 as initial salvage chemotherapy and 1 as fourth-line therapy. Eight of the 12 patients had major thoracic resections at the time of the relapse after initial chemotherapy. Three of the 12 patients achieved complete remission (CR; 10, 15, and 50 months' duration). One patient remains continuously with no evidence of disease (NED) at 50 months. An additional patient is currently NED at 52 months with HDCT and subsequent surgery. Median survival for the 12 patients was 11 months (range, 4-52 months). Results with tandem transplant for recurrent PMNSGCT remain poor compared to primary testis cancer, but durable CR and probable cure can be achieved in a small subset of patients with PMNSGCT. In our opinion, salvage surgical resection if anatomically feasible is the preferred option for patients with PMNSGT progressing after initial chemotherapy.

Are trials of intravascular infusions of autologous mesenchymal stem cells in patients with multiple system atrophy currently justified, and are they effective?

Are trials of intravascular infusions of autologous mesenchymal stem cells in patients with multiple system atrophy currently justified, and are they effective?

153Samarium-EDTMP administration followed by hematopoietic stem cell support for bone metastases in osteosarcoma patients

Bone metastatic patients with osteosarcoma have a very poor prognosis. Targeted radiation therapy has been pursued as a valid alternative. The primary end point of this study was progression-free survival (PFS) at 4 months. Twenty-two osteosarcoma patients were treated with Samarium-153 ethylenediaminetetramethylene phosphonic acid (153Sm-EDTMP) at various dosages. Administered activities ranged from 150 (3 mCi/kg) to 1140 MBq/kg (30 mCi/kg). Autologous hematopoietic stem cell infusion was carried out on day 14 after the (153)Sm-EDTMP infusion. The median PFS was 61 days (18-436 days) and the median overall survival (OS) was 189 days (31-1175 days). PFS and OS for the entire patient population were 32% [95% confidence interval (CI) 16-50] and 76% (95% CI 52-89) at 4 months, respectively. No statistical differences emerged according to 153Sm-EDTMP administered or 24-h retained activity. One-month pain palliation was only observed in a minority of subjects and in none at 4 months. Based on our series, the PFS is dramatically short even when higher activity of (153)Sm-EDTMP is administered. This would mean that, even at high level, 153Sm-EDTMP is itself ineffective against relapsed osteosarcoma or the residual activity is too low to be active on these particular subsets of patients.

Effect of time to infusion of autologous stem cells (24 vs. 48 h) after high‐dose melphalan in patients with multiple myeloma

High-dose melphalan (HD-Mel) is considered the current standard of care among the preparative regimens used in autologous peripheral blood stem cell transplantation (SCT) for multiple myeloma (MM), but optimal time and schedule of administration is not defined. We retrospectively analyzed outcomes and toxicities of HD-Mel administered on day -2 vs. day -1 before autologous stem cells infusion. A total of 138 consecutive MM patients treated at Penn State Hershey Cancer Institute between 2007 and 2010 were included in this study. No difference in time to hematopoietic recovery, common SCT-related toxicities, and clinical outcomes was seen between patients who received HD-Mel on day -2 (group A, n=47), and those who received it on day -1 (group B, n=91). Prompt and full hematopoietic recovery occurred even when stem cells were infused between 8 and 24h after completion of chemotherapy. In the absence of prospective and randomized data, we conclude that a single I.V. infusion of HD-Mel on day -1 is a safe and effective practice, and the so-called 'day of rest' before the transplant appears not to be necessary.

O6-benzylguanine (BG) and temozolomide (TMZ) therapy of glioblastoma multiforme (GBM) with infusion of autologous lentiviral transduced P140KMGMT+ hematopoietic progenitors to protect hematopoiesis: A phase I study.

TPS1616 Background: The administration of radiation therapy (RT) and concomitant and adjuvant temozolomide (TMZ) for the treatment of newly-diagnosed glioblastoma (GBM) is associated with modestly prolonged survival. However, the benefit of concurrent therapy is restricted to a subgroup of patients whose tumor exhibits methylation of the promoter for methylguanine-DNA-methyltransferase (MGMT). Promoter methylation silences the expression of DNA alkyltransferase (AGT), the product of the MGMT gene which functions to repair alkylated DNA. Unfortunately, the majority of GBMs have non-methylated MGMT promoters and do not appear to benefit from adding TMZ to radiotherapy. Two potential strategies for targeting MGMT-induced chemoprotection in gliomas include depletion of tumor MGMT, and dose escalation of TMZ accomplished by minimizing TMZ-induced bone marrow toxicity. In this study, we propose to combine the irreversible MGMT inhibitor O6-benzylguanine (BG) with infusion of autologous hematopoetic stem cells (HSCs) transduced with lentiviral P140K-MGMT, an MGMT mutant which is highly resistant to inactivation by BG, with the intent to reduce or prevent the myelosuppressive effects of TMZ. The primary objective is to assess the safety and feasibility of combining these two strategies in patients with newly-diagnosed GBM. Methods: This is a three cohort, Phase I study for patients with newly resected supratentorial GBM. There will be at least four evaluable patients per cohort. Cohort 1 will receive standard RT and concomitant TMZ prior to infusion of autologous lentiviral P140K-MGMT transduced HSCs, followed by adjuvant TMZ. Cohort 2 will receive an induction dose of TMZ+BG followed by infusion of autologous LV-P140K-MGMT HSCs prior to concomitant RT +TMZ and adjuvant TMZ. Cohort 3 will include intra-patient dose escalation of TMZ in patients who exhibit detectable levels of P140K-MGMT marked cells in vivo, using the design (i.e. cohort 1 or 2) proven to be safest and most effective. The study is open and has accrued the first patient.

Therapeutic Potential of Autologous Stem Cell Transplantation for Cerebral Palsy

Background. Cerebral palsy (CP) is a severe disabling disease with worldwide incidence being 2 to 3 per 1000 live births. CP was considered as a noncurable, nonreparative disorder, but stem cell therapy offers a potential treatment for CP. Objective. The present study evaluates the safety and efficacy of autologous bone-marrow-derived mononuclear cell (BMMNCs) transplantation in CP patient. Material and Methods. In the present study, five infusions of autologous stem cells were injected intrathecally. Changes in neurological deficits and improvements in function were assessed using Gross Motor Function Classification System (GMFCS-E&R) scale. Results. Significant motor, sensory, cognitive, and speech improvements were observed. Bowel and bladder control has been achieved. On the GMFCS-E&R level, the patient was promoted from grade III to I. Conclusion. In this study, we report that intrathecal infusion of autologous BMMNCs seems to be feasible, effective, and safe with encouraging functional outcome improvements in CP patient.

High White Blood Cell Concentration in the Peripheral Blood Stem Cell Product Can Induce Seizures during Infusion of Autologous Peripheral Blood Stem Cells

Seizures as a complication of the infusion of autologous peripheral blood stem cells (PBSC) are rare. Seizures during infusion of autologous PBSC in 3 of our patients prompted us to review our cell therapy and cytapheresis protocols and procedures. We retrospectively analyzed 159 adult patients collected between January 2006 and July 2009. Patients were collected on either the COBE Spectra (Caridian BCT, Lakewood, CO) cell separator (n = 85) or Fresenius AS (Fresenius Kabi AG, Bad Homburg, Germany) 104 cell separator (n = 74) and mobilized with granulocyte-colony stimulating factor (G-CSF) alone (n = 47), G-CSF and Plerixafor (n = 36), or G-CSF and chemotherapy (n = 76). Patient characteristics (including age, weight, number of collections, volume processed, disease type, and mobilization strategy) did not differ significantly between the COBE and Fresenius cohorts, and adverse effects from infusion were similar except for 3 of 159 patients who experienced seizures upon infusion of PBSC; all 3 were collected on the COBE and had PBSC product white blood cell (WBC) counts of 590 × 10(3)/μL or above. We prospectively correlated WBC counts midcollection, with final WBC counts to identify products with high WBC concentration during cytapheresis. Fifty-one patients had 66 cytapheresis procedures using the COBE, with WBC counts midway and at the end of collection of 287 × 10(3) ± 150/μL and 273 × 10(3) ± 144/μL, respectively. Mid-WBC therefore correlated with WBC at the end of the collection. Finally, we prospectively collected mid-WBC from 65 patients who underwent 80 PBSC collections between June 2009 and January 2010 to identify products with midcollection WBC concentration >450 × 10(3)/μL. In those cases, additional autologous plasma was collected at the time of collection to dilute the final product before cryopreservation. Patients who received diluted products experienced no delays in engraftment and no additional seizure episodes occurred.

A broken heart: repair needed?

At the recent meeting of the American Heart Association (Orlando, Florida, USA, November 2011) two interesting studies on a broken heart were presented. The first study was conducted by Dr. Abhishek Deshmukh at the University of Arkansas, USA and addressed patients with Takotsubo cardiomyopathy, also known as the broken heart syndrome [1, 2]. It was shown that women are 7–9 times more likely to suffer from the broken heart syndrome than men. Takotsubo cardiomyopathy may happen when sudden or prolonged stress such as an emotional breakup or death causes overwhelming heart failure or heart attack-like symptoms. The syndrome was first recognised about 20 years ago by physicians in Japan and occurs when a great emotional shock, even a positive one, induces a burst of adrenaline and other stress hormones that cause the left ventricle to balloon suddenly with ensuing cardiac dysfunction. The Arkansas University study analysed records from a nationwide database in 2007. It was found that of 6230 patients with broken heart syndrome, 90% were women. In addition, in patients over 55 years, the chance of developing broken heart syndrome was 9.5 times higher in women than in men. Consequently, hormonal differences or coronary artery variations may act as causative mechanisms. Fortunately, almost all patients with Takotsubo cardiomyopathy recovered spontaneously without permanent cardiac damage in need of (aggressive) repair. The second study on a broken heart, the Stem Cell Infusion in Patients with Ischemic cardiomyopathy (SCIPIO) study, was presented by Dr. Roberto Bolli (Louisville, Kentucky, USA). The study was conducted in patients with ischaemic cardiomyopathy and addressed the question whether patients’ own stem cells may be used to reverse cardiac damage. The SCIPIO study is an ongoing clinical trial which addressed post-MI patients who received infusions with cardiac stem cells that had been harvested from their own hearts during coronary artery bypass surgery. Patients with post-MI left ventricular dysfunction (LVEF ≤40%) before bypass surgery were randomly assigned to treatment or the control group (2:3 ratio). One million autologous cardiac stem cells were administered by intracoronary infusion 4 months after bypass surgery, whereas the control group received no treatment. The primary endpoint was short-term safety of cardiac stem cells and the secondary endpoint was feasibility. Sixteen patients were assigned to the treatment group and seven to the control group. In 14 patients with ischaemic cardiomyopathy who underwent bypass surgery, LVEF improved from 30.3% to 38.5% (P = 0.001), whereas in seven control patients the LVEF did not change (30.1% vs. 30.2 ± 2.5%). In seven stem cell patients who underwent cardiac MRI, the investigators observed a significant 24% decrease in infarct size at 4 months. It was concluded that intracoronary infusion of autologous cardiac stem cells was effective in improving left ventricular function and reducing infarct size in patients with heart failure after myocardial infarction. The results of the SCIPIO trial were published in The Lancet by Early Online Publication, on 14 November 2011. The data of the SCIPIO trial are encouraging and suggest that, if the correct cell type is used, this approach may be effective in patients with reduced cardiac function. The SCIPIO trial is the first study of autologous cardiac stem cells in humans. However, data are based on an interim analysis from an ongoing study and additional patients and follow-up will be needed to confirm these impressive preliminary results [3–5]. Anyway, the afore-mentioned studies show that broken hearts are capable of repair, be it spontaneously (Takotsubo cardiomyopathy) or by using cardiac stem cells (ischaemic cardiomyopathy).

Seizures During Infusion of Autologous Peripheral Blood Stem Cells Are Related to High White Blood Cell Concentration in the Peripheral Blood Stem Cell Product and Can Be Prevented by Dilution of Product with Autologous Plasma

Abstract 4386Seizures are rare during infusion of autologous peripheral blood stem cells (PBSC). We retrospectively analyzed 159 adult patients (pts.) collected consecutively between January 2006 and July 2009. Pts. were collected on either COBE Spectra (COBE) (n=85) or Fresenius AS 104 (Fresenius) (n=74) cell separators and mobilized with granulocyte colony stimulating factor (G-CSF) alone (n=47), G-CSF and Plerixafor (n=26), or G-CSF and chemotherapy (n=66). Pts. characteristics did not differ between the COBE and Fresenius cohorts, but there were differences in PBSC product (Table). Pts. collected with COBE had higher white blood cell (WBC) and total nucleated count (TNC) but lower mononuclear cell (MNC) percentage and cell viability than pts. collected with the Fresenius. Absolute CD34+ cells in the PBSC product, CD34+ cells / kg and total CD34+ cells / kg infused at transplant were not significantly different. CD34+ yields (calculated as the ratio of CD34+ cells /μl of the PBSC product to the patient’s peripheral blood CD34+ cells / μl taken on the day of collection) were significantly higher on the COBE than Fresenius. No serious adverse events occurred during PBSC infusion except 3 of 159 pts. developed seizures during infusion of PBSC; all collected on the COBE and all three had product WBC > 590 × 103/μl (compared to a median of 163.3 × 103/ μl for all other products)(Figure). Evaluation of pts. did not identify abnormalities in imaging studies, cerebrospinal fluid analysis, electrolytes, or past history which might explain etiology of seizures. No significant difference in WBC or platelet engraftment was observed in pts. collected with COBE or Fresenius.We then prospectively correlated WBC counts midway and at the end of PBSC collections. Fourteen pts. had 15 apheresis using the Fresenius. Mid- and post-WBC concentrations were 64 +/− 23 × 103/μl and 69 +/− 20 × 103/μl, respectively. Fifty-one pts. had 66 apheresis using COBE, with WBC counts obtained midway and at the end of collection of 287 +/− 150 × 103/μl and 273 +/− 144 × 103/μl, respectively. Mid-WBC accurately correlated with WBC at the end of the collection in both the COBE and Fresenius cohorts (r2 = 0.940 and r2 = 0.904, respectively). Using this information, we prospectively evaluated 65 pts. who underwent 80 PBSC collections in anticipation of an autologous (n=44) or allogeneic (n=7) stem cell transplant between June 2009 and January 2010. Collections for these pts. were performed using the COBE (n=66) or the Fresenius (n=15). Mid-WBC were obtained and products with mid-collection WBC concentration > 450 × 103/uL (n=29) had additional autologous plasma collected at the time of collection for final product dilution to < 450 × 103/uL prior to cryopreservation. Pts weight, volume of PBSC product and CD34+ cells/kg infused did not differ between the pts who received diluted PBSC product and those who did not. There were also no differences in either ANC (12 ± 1.3 days vs. 11.5 ± 1.3 days, dilution vs. non-dilution, p = 0.760) or in platelet engraftment (18 ± 3.7 days vs. 16 ± 2.7 days, dilution vs. non-dilution, p = 0.561). No serious adverse infusion effects were observed in either group. In conclusion, high number of WBC in COBE collections is a possible cause of PBSC infusion related seizures. No seizures were observed after dilution of PBSC with high WBC concentration.TIENT AND PRODUCT CHARACTERISTICSCOBE (±SD)Fresenius (±SD)Number of Products165180Number of Patients8574Age at collection56 ± 1456 ± 15Weight at Collection (kg)82.7 ± 17.979.5 ± 15.9Collections / Patient2 ± 12 ± 1Blood Volume Processed at end of Collection (L)18.0 ± 2.418.1 ± 2.7(*)Product Volume (ml)241 ± 56.8402 ± 72.0Peripheral WBC (103/ μl)36.6 ± 18.933.3 ± 24.5(*)Product WBC(103/ μl)163.3 ± 136.055.8 ± 29.3(*)TNC (1010)3.51 ± 1.861.95 ± 1.19(*)MNC (1010)2.36 ± 1.191.60 ± 0.09(*)MNC (%)75.0 ± 23.385.0 ± 10.8Volume prior to freezing(ml)100 ± 54100 ± 32(*)Post Freeze Viability (%)70 ± 1475 ± 10Peripheral CD34+/ μl24.0 ± 43.825.3 ± 79.1(*)Product CD34+/μl726.7 ± 1325.9264.63 ± 781.0(*)Product / Peripheral CD34+24.87 ± 10.9010.91 ± 6.64Absolute Product CD34+ cells (108)1.77 ± 3.521.14 ± 3.35Product CD34+/kg (106)2.02 ± 4.671.39 ± 4.15Total CD34+ cells infused (106 / kg)3.85 ± 3.203.85 ± 2.24(*) = p values < 0.05 [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Outcomes of Salvage Autologous Stem Cell Transplant (ASCT) in Multiple Myeloma Patients Relapsed After An Initial ASCT and Refractory to Bortezomib and Immunomodulatory Agents

Abstract 4484 Background:Although the prognosis for patients with multiple myeloma (MM) has improved with the use of immunomodulatory drugs thalidomide and lenalidomide, as well as with the proteasome inhibitor bortezomib, eventually all patients relapse and become refractory to all available treatments. The prognosis for MM patients refractory to these two novel classes of therapies is dismal, with estimated progression free survival (PFS) and overall survival (OS) of only 5 and 9 months respectively (Kumar et al, ASH 2010). (Of note, only 60% of these patients had received prior stem cell transplants (SCT)). While clinical trials would be ideal for these patients, many have cytopenias (often due to heavy marrow replacement) that fail to meet standard inclusion criteria for clinical trials. Since autologous stem cells remain viable for many years, we have been performing intermediate or high dose chemotherapy with autologous stem cell transplant (ASCT) as a disease temporizing measure and also as a possible bridge to clinical trial participation. Although the safety and efficacy of salvage ASCT in relapsed MM has been reported (Olin et al, BMT 2009 and Qazilbash et al, Cancer 2006), no studies have focused on the novel agent refractory population. We review here the outcomes of salvage ASCTs in 63 patients with heavily pre-treated, relapsed, and novel agent refractory MM. Methods:Of the patients with MM who underwent ASCT between 1999 to 2010 at St Vincent's hospital, we first identified those patients who had a second autologous stem cell infusion at least 12 months after the first (i.e. non tandem SCTs). Of the 435 patients who met this criteria, 63 were found to have not only progressed on bortezomib containing regimens but also were refractory to IMids (thalidomide or lenalidomide). Results:The median age at time of salvage ASCT was 60 years [range 36–75] at a median of 5.6yrs [range 1.5 to 15.9] since the diagnosis of MM. Patients had a median of 5 lines of prior treatment [range 2–9] and a median of 58 months since the first auto SCT[range 12–164]. The median PFS in 59 evaluable patients after the initial ASCT was 21.6 months [range 4.5–76.8]. Of 58 evaluable patients, 56 patient were treated with a mephalan based conditioning regimen for the salvage ASCT including 11 at 200 mg/m2, 10 at 140 mg/m2, 24 at 100 mg/m2, and 11 who received 50–75 mg/m2. 27 of these patients received bortezomib with the melphalan conditioning and 3 patients received BCNU with melphalan. 2 other patients received VDT-PACE. 26 of these patients received their chemotherapy and stem cells in the outpatient setting. Of the available data, adverse effects included diarrhea in 3 patients, with grade 2 being the worst grade. Three patients had mucositis, one with grade 3.Of the 58 patients evaluable for response at day 100 post salvage SCT, 7 had a CR, 3 near CR, 5 VGPR, and 16 PR for an overall response rate of 53% by IMWG criteria. An additional 2 patients had SD. 25 patients had PD including 3 patients who died of PD within 30 days. The median PFS was 5.5 months [1.1–36 months] in 32 evaluable patients and median OS in 59 evaluable patients was 8.5 months [8 days-60 months]. 6 patients remain alive at a median of 16 months [7.7 – 53 months].Of 23 patients with baseline ANC < 1500 or plt < 50k making them ineligible for most clinical trials prior to salvage auto SCT, 20 (87%) exceeded those cut-offs at day 100 whereas 3 patients did not. Two of these patients died of PD at 3.1 and 6.4 months. The third had delayed platelet recovery and died of PD at 29 months. Results of univariate and multivariate analysis will be presented at the annual meeting. Conclusions:In a heavily pretreated population of patients with MM (median 5 lines of prior therapy) refractory to bortezomib and IMIDs, salvage auto SCT was associated with an overall response rate of 53%, a median OS of 8.5 months and PFS 5.5 months. Importantly, 87% of patients with cytopenias precluding clinical trial participation demonstrated hematologic recovery post salvage ASCT. This study demonstrates a continuing role for salvage ASCT in cytopenic, heavily pretreated, novel agent refractory patients with MM as a possible bridge to clinical trials. Disclosures:Chari:Millenium Takeda:; Celgene:. Jagannath:Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees.

Infusion of autologous peripheral blood stem cells in an unrelated donor who developed severe aplastic anemia following stem cell donation

Infusion of autologous peripheral blood stem cells in an unrelated donor who developed severe aplastic anemia following stem cell donation

Clinical effect of intracuronary infusion of autologous bone marrow-derived stem cells transplantation in patients with acute myocardial infarction: a recta-analysis

Full text of literatures on randomized clinical trials (RCTs) of intracoronary infusion of autologous bone marrow-derived stem cells (BMSCs) transplantation in patients with acute myocardial infarction (AMI) published at home and abroad were systematically retrieved and reviewed from PubMed database and the China Full Text Journal database to assess its efficacy and safety. Fifteen RCTs were included in a recta-analysis with RevMan version 5. 0 software after strict and standard screening. Results showed that global left ventricular ejection fraction (LVEF) in the patients with BMSCs transplantation improved significantly ( P < 0. 01 ), but no obvious change in their left ventricular end-diastolic volume (LVESV) was observed. Occurrence of end-stage cardiovascular events also decreases significantly ( OR =0. 51, 95% CI =0. 36-0. 72) in patients with AMI. Key words: Myocardial infarction; Stem cell transplantation

Tumor marker rise during second course high-dose chemotherapy in recurrent testicular cancer: Outcome analysis.

4612 Background: Metastatic germ cell tumors that cannot be successfully treated by platinum based initial chemotherapy regimen are potentially curable with salvage chemotherapy. Relapsed or refractory testicular cancer has been treated at Indiana University with two courses of high-dose carboplatin and etoposide chemotherapy (HDCE), each course followed by peripheral stem cell rescue. Einhorn et al published the result of 184 consecutive recurrent metastatic patients treated 1996-2004 with two cycles of HDCE. 63% of these 184 patients were continuously NED with median follow-up 48 months (NEJM 357,340 2007). Several patients were noted to have rising tumor markers—hCG and/AFP—during their second course of high-dose chemotherapy. Similar phenomenon has been noted in some patients treated subsequently. We present retrospective analysis of the frequency and outcome of a rising tumor marker at start of second course of HDCE or within 1 week after initiation of second course. Methods: 391 patients have been treated with HDCE and stem cell rescue from Feb 1996 to December 2010. Each patient received two consecutive courses of 700 mg of carboplatin per square meter of body-surface-area (BSA) and 750mg of etoposide per square meter of BSA, each for 3 consecutive days, and each followed by autologous stem cell infusion. The second HDCE was administered 3-4 weeks after the first course. Weekly tumor markers were obtained. Results: 25 of 391 (6.4%) patients were noted to have rising hCG, AFP or both at initiation or within one week of second course of HDCE. 14 patients had rising hCG (median 61.9 mIU/mL; range 3.2-8,863). 11 patient developed rising AFP (median 18.3 ng/mL; range 4.2-1,018.8). Six patients had increase in both hCG and AFP. 24 of 25 patients had a subsequent decline in tumor marker with second course HDCE. 7 of 25 (28%) patients are continuously disease free at median follow-up of 69 months (range 28-124 months). Conclusions: Tumor marker rise during second course of HDCE is uncommon. Although it represents an adverse prognostic variable, cure is still possible with institution of second course of HDCE.

Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke

Transplantation of human mesenchymal stem cells has been shown to reduce infarct size and improve functional outcome in animal models of stroke. Here, we report a study designed to assess feasibility and safety of transplantation of autologous human mesenchymal stem cells expanded in autologous human serum in stroke patients. We report an unblinded study on 12 patients with ischaemic grey matter, white matter and mixed lesions, in contrast to a prior study on autologous mesenchymal stem cells expanded in foetal calf serum that focused on grey matter lesions. Cells cultured in human serum expanded more rapidly than in foetal calf serum, reducing cell preparation time and risk of transmissible disorders such as bovine spongiform encephalomyelitis. Autologous mesenchymal stem cells were delivered intravenously 36-133 days post-stroke. All patients had magnetic resonance angiography to identify vascular lesions, and magnetic resonance imaging prior to cell infusion and at intervals up to 1 year after. Magnetic resonance perfusion-imaging and 3D-tractography were carried out in some patients. Neurological status was scored using the National Institutes of Health Stroke Scale and modified Rankin scores. We did not observe any central nervous system tumours, abnormal cell growths or neurological deterioration, and there was no evidence for venous thromboembolism, systemic malignancy or systemic infection in any of the patients following stem cell infusion. The median daily rate of National Institutes of Health Stroke Scale change was 0.36 during the first week post-infusion, compared with a median daily rate of change of 0.04 from the first day of testing to immediately before infusion. Daily rates of change in National Institutes of Health Stroke Scale scores during longer post-infusion intervals that more closely matched the interval between initial scoring and cell infusion also showed an increase following cell infusion. Mean lesion volume as assessed by magnetic resonance imaging was reduced by >20% at 1 week post-cell infusion. While we would emphasize that the current study was unblinded, did not assess overall function or relative functional importance of different types of deficits, and does not exclude placebo effects or a contribution of recovery as a result of the natural history of stroke, our observations provide evidence supporting the feasibility and safety of delivery of a relatively large dose of autologous mesenchymal human stem cells, cultured in autologous human serum, into human subjects with stroke and support the need for additional blinded, placebo-controlled studies on autologous mesenchymal human stem cell infusion in stroke.

70 The HeartMate II Risk Score: Predicting Survival in Candidates for Left Ventricular Assist Device Support

Purpose: Nearly one-third of children diagnosed with dilated cardiomyopathy (DCM) receive a transplant or die within the first year after diagnosis. Limited long-term outcome of heart transplantation and scarcity of young donors justify every effort to improve medical therapy and to find alternative therapeutic approaches. There is increasing evidence that cardiac stem cell transplantation induce sustained improvement in cardiac function in patients with heart failure. We describe the compassionate use of intracoronary autologous peripheral stem cell therapy in two young infants diagnosed with DCM and severe heart failure. Methods and Materials: Descriptive study that analyzes the evolution of two pediatric patients diagnosed with DCM and severe heart failure, and who were treated with intracoronary infusion of autologous stem cells. Patient 1 is a 3-month male infant weighing 4 Kg. Patient 2 is a 4-month male infant weighing 5 Kg. Results: At the time of admission, both patients were in poor clinical status (NYHA IV), had high levels of NT-ProBNP and severe LV dilation and systolic dysfunction (EF 30%). Both were mechanically ventilated and needed IV inotropes. Endomyocardial biopsy ruled out myocarditis. In each case, after treatment with G-CSF for 4 days, autologous stem cells were recovered from peripheral blood, implanting them via the coronary arteries afterwards. As soon as one week after the procedure, echocardiography showed a remarkable improvement in LV dilation. One month later a significant gain in their EF ( 40%) was also detected and this was maintained over time. The long-term outcome was favorable. Although first patient has shown LV dilation 17 weeks after the procedure, he is still in functional class I and has adequate weight gain. Conclusions: Although currently heart transplantation is the only established treatment for DCM, stem cell therapy could be an option to improve clinical status, and serve as a bridge to decision, to transplantation or, more importantly, to recovery for these very sick children.

69 Intracoronary Autologous Peripheral Stem Cell Therapy: A Promising Treatment for Heart Failure in Pediatric Dilated Cardiomyopathy

<h3>Purpose</h3> Nearly one-third of children diagnosed with dilated cardiomyopathy (DCM) receive a transplant or die within the first year after diagnosis. Limited long-term outcome of heart transplantation and scarcity of young donors justify every effort to improve medical therapy and to find alternative therapeutic approaches. There is increasing evidence that cardiac stem cell transplantation induce sustained improvement in cardiac function in patients with heart failure. We describe the compassionate use of intracoronary autologous peripheral stem cell therapy in two young infants diagnosed with DCM and severe heart failure. <h3>Methods and Materials</h3> Descriptive study that analyzes the evolution of two pediatric patients diagnosed with DCM and severe heart failure, and who were treated with intracoronary infusion of autologous stem cells. Patient 1 is a 3-month male infant weighing 4 Kg. Patient 2 is a 4-month male infant weighing 5 Kg. <h3>Results</h3> At the time of admission, both patients were in poor clinical status (NYHA IV), had high levels of NT-ProBNP and severe LV dilation and systolic dysfunction (EF<30%). Both were mechanically ventilated and needed IV inotropes. Endomyocardial biopsy ruled out myocarditis. In each case, after treatment with G-CSF for 4 days, autologous stem cells were recovered from peripheral blood, implanting them via the coronary arteries afterwards. As soon as one week after the procedure, echocardiography showed a remarkable improvement in LV dilation. One month later a significant gain in their EF (>40%) was also detected and this was maintained over time. The long-term outcome was favorable. Although first patient has shown LV dilation 17 weeks after the procedure, he is still in functional class I and has adequate weight gain. <h3>Conclusions</h3> Although currently heart transplantation is the only established treatment for DCM, stem cell therapy could be an option to improve clinical status, and serve as a bridge to decision, to transplantation or, more importantly, to recovery for these very sick children.

Novel mobilization strategies to enhance autologous immune effector cells in multiple myeloma

The immune system plays a critical role determining the outcomes in transplanted multiple myeloma patients, since enhanced lymphocyte recovery results in improved survival. Since mobilization regimens influence the cellular subsets collected and infused for transplant, these regimens may determine immune recovery following transplant. We hypothesized that a mobilized stem cell product harboring an increased number of lymphocytes would enhance immune recovery following autologous stem cell infusion, increase lymphocyte recovery, and improve clinical outcomes. We designed a phase I immune mobilization trial using IL-2 and growth factors to increase the number of lymphocytes within the stem cell product. This regimen efficiently mobilized CD34+ progenitor cells (median: 3.6 x 10(6) cells/kg; range 1.9-6.6 x 10(6) cells/kg) and improved the immune properties of the mobilized stem cells, including an increase in CD8+ T cells expressing an NK activating receptor called NKG2D (P less than 0.004), cells that are extremely potent at killing myeloma cells using non-MHC-I restricted and TCR-independent mechanisms. Novel mobilization techniques can improve the mobilized graft and may improve clinical outcomes in myeloma patients.

Conditioning regimen using busulfan plus melphalan in hematopoietic stem cell transplantation

Conditioning regimen using busulfan plus melphalan in hematopoietic stem cell transplantation

A Pilot Study of Melphalan, Lenalidomide and Dexamethasone In AL Amyloidosis: Interim Results

AbstractAbstract 1946 BackgroundAL amyloidosis is a clonal disorder of light-chain secreting plasma cells. The light chains deposit as beta-pleated sheets, resulting in significant hematologic and organ toxicity. A recent randomized trial failed to demonstrate superiority of myeloablative melphalan followed by autologous stem cell infusion over the less toxic oral melphalan and high-dose dexamethasone regimen (Jaccard, New Engl J Med 2007). Furthermore, chemotherapeutic options now often include lenalidomide; however, this agent has had limited evaluation in combination with melphalan and dexamethasone and has been hampered by high rates of toxicity at doses of 25mg/day. To assess whether combination therapy at reduced doses would be tolerable and effective, we conducted a single center prospective clinical trial of an oral three drug regimen consisting of melphalan, lenalidomide and dexamethasone (MLD) in AL amyloidosis. MethodsThe primary endpoint is evaluation of the safety and tolerability of MLD in patients with AL amyloidosis. The secondary endpoint is evaluation of the hematologic response rate, the relevant organ responses and the time to progression. Enrolled patients had a biopsy-proven diagnosis of AL amyloidosis with the presence of measurable disease. Exclusion criteria included absolute neutrophil count < 1000 cells/mm3, platelets < 75,000/mm3, creatinine clearance < 15 ml/min, an ECOG performance status > 3, and potential future candidacy for autologous stem cell transplant. There were no exclusions based on patients' cardiac function. Treatment consisted of a 28 day cycle of lenalidomide 10 mg days 1–21, melphalan 0.18 mg/kg days 1–4, and dexamethasone 40 mg weekly. Stepwise dose reductions were allowed for toxicity. Evaluation of hematologic response rate was via serum free kappa and lambda light chains and/or serum or urine immunofixation. Relevant organ responses were measured with 24-hour urine protein/serum creatinine for patients with renal amyloidosis, transthoracic echocardiogram, troponin-I and NT-BNP for patients with cardiac amyloidosis, and alkaline phosphatase for patients with hepatic amyloidosis. The trial has been expanded from the originally planned 15 patients to 25 patients given rapid enrollment; this report reflects an interim analysis of the first 12 patients. ResultsTwelve patients have been enrolled. One patient died prior to initiation of therapy, and thus was excluded from further evaluation. The median age of the remaining 11 patients was 65 years (range of 62–84). The median number of organs involved was 2 (range of 1–4). Ten patients had cardiac involvement, 3 patients had renal involvement, and 2 patients had hepatic involvement. Nine of the 11 patients (82%) were newly diagnosed. The mean number of cycles was 3 (range of 1–9 with a total of 36 cycles). A complete hematologic response (CHR) was seen in 3 patients, a partial hematologic response (PHR) was seen in 4 patients, and 3 patients exhibited stable disease, according to consensus criteria (Gertz, Am J of Hem 2005). One patient died during the first cycle and thus response to treatment was not evaluable. Toxicities included: grade 4 neutropenia in 1 patient and grade 3 anemia, thrombocytopenia, and infection in 3 patients. Seven of the 11 patients have died, all of whom had cardiac amyloidosis, of progressive heart failure or arrhythmias. Of these 7 patients, 2 exhibited a CHR and 3 had a PHR. Of the 9 evaluable patients with cardiac amyloidosis, 2 patients exhibited stable cardiac disease, while the other 7 patients had disease progression, primarily via a rising NT-BNP and Troponin-I. Of the 3 patients with renal involvement, 2 had organ disease progression and 1 patient had stable disease, and of the 2 patients with hepatic involvement, 1 had organ disease progression and 1 had stable disease, according to consensus criteria (Gertz, Am J of Hem 2005). ConclusionIn a patient cohort consisting primarily of newly diagnosed patients with advanced AL amyloidosis, MLD has promising complete and partial hematologic response rates. Hematologic and infectious toxicities remain significant even at reduced doses. Despite promising hematologic response rates, organ responses occur less frequently. Patients with cardiac amyloidosis, particularly those presenting with heart failure, continue to have poor overall prognosis. A larger trial is warranted to further assess drug toxicity and organ response rates. Disclosures:Witteles:Celgene: Research Funding. Witteles:Celgene: Research Funding. Liedtke:Celgene: Lecture fee, Research Funding. Schrier:Celgene: Research Funding. Off Label Use: Melphalan and Lenalidomide as therapy for AL amyloidosis.

High Dose Intravenous Busulfan (BU) and Melphalan (MEL) Followed by Bortezomib (BTZ) as Conditioning with Autologous Peripheral Blood Stem Cell Transplantation (ASCT) for Patients with Multiple Myeloma (MM)

AbstractAbstract 1355 Background:Overall survival for patients with MM has improved significantly over the past 10 years primarily as a result of novel therapeutics. High dose therapy with ASCT continues to be an effective modality but the progression-free survival following ASCT has improved minimally over the same period of time due to a continued reliance on single agent melphalan. Many chemotherapy/chemoradiotherapy regimens have been used in preparation for stem cell transplantation. However, no regimen has proven superior to high dose melphalan 200 mg/ m2 (MEL 200) which is considered the standard conditioning for patients with MM with relatively predictable results. In order to improve progression free survival (PFS) and overall survival (OS), continued efforts in developing effective preparative regimens are needed. Busulfan is an alkylating agent that affects cells in an AUC-dependent manner. Recent data suggests that the combination of BU and MEL delivers better PFS compared to MEL 200 alone (Grande and Lahuerta; PETHEMA, 36th EBMT meeting. Vienna 2010). Moreover, the addition of bortezomib following MEL 200 appears to increase the VGPR rate when compared to historical cohort receiving MEL 200 alone (Lonial, et al; Blood. ASH Annual Meeting Abstracts, Nov 2008; 112: 3332). Furthermore, the recently published IFM trial of MEL 200 plus BTZ also demonstrated superior response rates and PFS compared to historical controls (Roussel et al Blood. 2010;115:32-7). Rationale:The combination of intravenous BU and MEL followed by BTZ (BuMelVel) will be an effective preparative regimen with acceptable toxicity for patients with MM. Methods:Patients received intravenous BU 130 mg/kg over 3 hours daily × 4 days from D-6 to D-3. Based on the pharmacokinetics of the first two doses, the subsequent 2 doses were adjusted to achieve an AUC of 20,000 mMol-min (5,000 mMol-min/day). MEL was administered at 140 mg/ m2 IV over 15–30 minutes on day -2. Bortezomib was administered IV push over 3–5 seconds on day -1. Bortezomib administration followed a phase I dose escalation design starting at 1.0 mg/m2 for the first cohort; then, 1.3 mg/m2 for the second cohort; then, 1.6 mg/m2/kg for the 3rd cohort and subsequent subjects at the 3rd dose level if no limiting toxicity was observed. Autologous stem cell infusion occurred on day 0. Results:20 patients have been enrolled to date, with 19 evaluable for toxicity and 13 for response assessment at D +100. The median age is 61 (47 - 69). The median time for engraftment for ANC ≥ 500 and plts ≥ 20, was 10 days. The median length of stay (LOS) was 18 days (16 – 21 days). 12 patients required a median of 2 units of PRBC and 16 patients required a median of 1 platelet transfusion. PRBC and PLT transfusions as well as LOS are not significantly different to what has been observed at our institution with MEL 200 (2 PRBC, 2 RD PLT transfusions, and 15 days LOS, respectively). All patients responded including: 77% ≥ VGPR and 54% nCR, CR, or sCR. The most common grade ≥ 3 toxicities were neutropenic fever (n = 11), mucositis (n = 9), and hypophosphatemia (n = 7). Three patients developed reversible transaminitis. One patient developed Clostridium difficile colitis and Klebsiella pneumonia UTI. Another patient developed E. coli UTI. No cases of VOD or interstitial pneumonitis were observed. There were no treatment related deaths and no re-admissions post discharge. Conclusion:BuMelVel proved to be an effective preparative regimen with ≥ VGPR and nCR/CR/sCR of 77% and 54%, respectively, as compared to responses reported with MEL/BTZ (70% and 32%, respectively); and to MEL 200 alone (43% and 11%, respectively) by Roussel et al. Furthermore, BuMelVel had an acceptable toxicity profile without any cases of VOD or interstitial pneumonitis, and mucositis/infections incidence and severity are comparable to our institutional experience with MEL 200. Therefore, the regimen of BuMelVel may lead to improvements in PFS and OS, critical criteria to improve the outcomes of patients with MM. These promising results will be further evaluated in a planned Phase III clinical trial with MEL 200. Disclosures:Rodriguez:Otsuka: Consultancy, Research Funding, Speakers Bureau; Millennium: Consultancy, Speakers Bureau; Celgene: Speakers Bureau. Kaufman:Celgene, Millenium: Consultancy; Celgene, Merck: Research Funding. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Speakers Bureau.